EP1660153A2 - Nanocomposites d'hydrogel pour applications ophtalmiques - Google Patents

Nanocomposites d'hydrogel pour applications ophtalmiques

Info

Publication number
EP1660153A2
EP1660153A2 EP04783018A EP04783018A EP1660153A2 EP 1660153 A2 EP1660153 A2 EP 1660153A2 EP 04783018 A EP04783018 A EP 04783018A EP 04783018 A EP04783018 A EP 04783018A EP 1660153 A2 EP1660153 A2 EP 1660153A2
Authority
EP
European Patent Office
Prior art keywords
hydrogel
nanoparticles
copolymer
solution
reversible
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04783018A
Other languages
German (de)
English (en)
Inventor
Nathan Ravi
Aliyar H. Department of Ophthalmology ALI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
US Department of Veterans Affairs VA
Original Assignee
US Department of Veterans Affairs VA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/706,081 external-priority patent/US8192485B2/en
Application filed by US Department of Veterans Affairs VA filed Critical US Department of Veterans Affairs VA
Publication of EP1660153A2 publication Critical patent/EP1660153A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids

Definitions

  • the present invention relates to hydrogel systems that contain nanoparticles or nanophases.
  • the hydrogel of the present invention is made up of copolymers solution containing nanoparticles that can form a hydrogel triggered by changes in oxidation state, or light frequency and intensity, or mechanical stress.
  • a solution of the copolymer can be oxidized to form a hydrogel; and the hydrogel can be reduced to form a solution of the copolymer.
  • One may also achieve reversibility using photo- addition chemistry, or using polymers that are sensitive to mechanical stress (physical gels that shear thin).
  • the priniciples of the above technique may also be used to form reversible nanogels from a dilute solution of the copolymer.
  • the hydrogel is formed with nanoparticles embedded therein to form a nanocomposite whose refractive index and modulus can be controlled by varying the amounts of nanoparticles and the polymer concentration of the hydrogel, respectively.
  • a cataract is a cloudy or opaque area in the normally transparent crystalline lens of the eye. As the opacity increases, it prevents light rays from passing through the lens and focusing on the retina, the light sensitive tissue lining the back of the eye. Early lens changes or opacities may not disturb vision, but as the lens continues to change, several specific symptoms may develop including blurred vision, sensitivity to light and glare, increased nearsightedness, and/or distorted images in either eye. There are no medications, eye drops, exercises, or glasses that will cause cataracts to disappear once they have formed. When a person is unable to see well enough to perform normal everyday activities, surgery is required to remove the cataract and restore normal vision.
  • cataract extraction surgery the cataract is removed from the lens through an opening in the lens capsule. Using an operating microscope, a small incision is made into the eye, and subsequently, the lens capsule. Microsurgical instruments are used to first fragment and then suction the cloudy lens from the eye. The back membrane of the lens (called the posterior capsule) is left in place. The focusing power of the optical system is then restored, usually only for distant vision, by replacement with a permanent pre-fabricated clear plastic intraocular lens (IOL) implant which became popular in the early 1980s.
  • IOL intraocular lens
  • Intraocular lenses can be divided into two main groups: non-foldable and foldable.
  • the original intraocular lenses were made from a hard plastic (non- foldable) material and could therefore be introduced into the eye only with an incision as large as the diameter of the lens.
  • Foldable lenses are made of acrylic or silicone and can be rolled up and placed inside a tiny tube. The tube is inserted through a very small incision, less than 3.2 mm in length. Once inside the eye, the IOL gently unfolds.
  • the corneal curvature and the axial length of the eye of the patient are measured to determine the proper focal power for the IOL that will be inserted.
  • the IOL uses sophisticated formulas to calculate the corrective prescription power of the lens, the IOL not only replaces the need for thick glasses, but it can also correct the existing refractive error of the eye.
  • standard IOLs are available in a variety of focal lengths, those lengths are fixed for any given lens.
  • a standard IOL is unable to change focus. Therefore, the patient who must rely upon a standard IOL loses accommodative capability after surgery. IOLs are usually chosen that provide adequate distance vision.
  • in situ forming gels have several potential uses in medicine, e.g., in intra-ocular lenses, as vitreous substitutes, and as drug delivery devices.
  • in situ forming gels have the advantage of being minimally invasive, easily deliverable, and able to fill native or potential cavities while conforming to different shapes, which may otherwise be difficult to prefabricate.
  • the mechanism of gelation may be physical (changes in temperature, hydrogen bonding, hydrophobic interactions) or chemical (ionic or covalent bond formation). Usually, physical crosslinks are less stable than chemical ones.
  • In situ gelation resulting in networks covalently crosslinked through free-radical polymerization, may be initiated by heat, chemical initiators, or absorption of photons.
  • Free-radical polymerization is seldom quantitative: the resulting gel usually contains significant amounts of unreacted monomers, initiator, and accelerators-some or all of which may be toxic, and the reaction itself may be very exothermic.
  • the requirements are stringent, and include a narrow range of reaction temperatures very close to ambient, optically clear material, very low chemical and photo-toxicity, and long-term stability in a wet, oxygenated, and photon-rich environment.
  • the aim of the present invention in forming in situ gels is to develop new vitreous substitutes and injectable intraocular lens materials.
  • Accommodation is a dynamic process by which the refractive power of the optical system, principally the lens, is automatically adjusted to focus light on the retina. This ability is significantly decreased, usually by the fourth decade of life, and lost almost completely by the seventh decade of life through a progressive change in the volume and the elasticity of the lens resulting in an inability to focus on objects closer than arms length, a condition called presbyopia.
  • Evacuating the capsular bag's contents and refilling it with an appropriate volume of a suitable material also offers a potential to restore accommodation to the presbyopic patient. Development of surgical procedures to evacuate the lens capsular bag through a small opening and identification of a suitable material to re-fill the capsular bag has been investigated.
  • Such materials preferably have several advantages, including restoration of accommodation, a smaller corneosoleral incision than now required for semirigid replacement lenses, improved physiological positioning of the intraocular lens, and reduced rate of secondary opacification.
  • Both physical and chemical crosslinks for forming gels within the capsular bag have been exploited.
  • Kessler Experiments in refilling the lens. Arch. Ophthalmol. 71:412-417, 1964
  • Carquille's immersion oil, silicone fluids, and damar gum to form physically crosslinked gels in rabbit eyes.
  • Parel et al. popularized formation of gels by chemical crosslinking (Phaco-Ersatz: Cataract surgery designed to preserve accommodation. Graefes Arch. Clin. Exp. Ophthalmol.
  • the present invention provides reversible hydrogel systems of that are reversibly converted between a sol-gel phases by oxidation/reduction or by irradiation with different wavelengths of light or by application of shear as in the case of physical gels.
  • the hydrogel can be reversed to form the solution; and the solution can be converted, by appropriate trigger, to form the hydrogel.
  • the system is reversibly converted between a hydrogel and a solution.
  • the chemically reversible redox hydrogel system of the present invention includes a copolymer that is formed by polymerization of a monomer with a crosslinker.
  • the crosslinker provides disulfide linkages within the copolymer molecule to form a hydrogel.
  • the hydrogel When the hydrogel is reduced, the disulfide linkages are broken to yield a soluble copolymer solution.
  • the copolymer solution can be oxidized (by oxygenation, disulphide interchange reaction, or photo- oxidation in presence of riboflavin and oxygen) to form disulfide linkages to reform the hydrogel.
  • the oxidation is achievable at physiological pH of about 7.0 to about 7.4.
  • the gels may also be formed by incorporating photosensitive groups that undergo 2+2 photoaddition or groups that photochemically react with thiols, such as thiol-acrylamides reactions.
  • Hydrophobic hydrogels or assosiative hydrogels also exhibit such reversibility to shear forces, that is they will behave like a solution when a sheared and as a gel when the shearing force is removed or below a certain yield stress.
  • the present invention provides a method of making nanogels (hydrogel nanoparticles) containing disulfide crosslinks.
  • the nanogels are made from reversible hydrogel systems that are reversibly converted between a hydrogel state and a solution by oxidation/reduction or by different wavelengths of light.
  • the hydrogel can be reduced to form the solution; and the solution can be oxidized to form the hydrogel.
  • the system is reversibly converted between a hydrogel and a solution.
  • the nanogels are made by copolymerizing a monomer with a crosslinker to form a crosslinked hydrogel; reducing the crosslinked hydrogel to form a copolymer solution; diluting the copolymer solution to form a diluted copolymer solution; and subsequently oxidizing the diluted copolymer solution to form the nanogels.
  • the thiol containing nanogels can also incorporate a metal particle, such as gold, therein. Additionally, all of the above concepts used in forming hydrogles can be potentially used to form nanogels by first diluting the copolymer solution to be its critical concentration.
  • the present invention combines a reversible hydrogel with nanoparticles to form a hydrogel nanocomposite for use as an accommodating injectable intra-ocular lens.
  • the inventive nanocomposite comprises nanoparticles dispersed in a polymer hydrogel formulation, and is advantageous in that the refractive index and modulus of the material can be controlled using two variables, namely the concentration of nanoparticles and the copolymer concentration in the hydrogel.
  • the refractive index is controlled by changing the amount of nanoparticles; and the modulus can be controlled by changing the polymer concentration in the hydrogel.
  • the nanoparticle preferably has a particle size less than about 150 nm, and most preferably about 3-20 nm, most importantly it has to be non-scattering.
  • the nanoparticles be of such dimensions that they do not disperse or scatter visible light.
  • the nature of the nanoparticle is less critical and could be a nanogel, protein, silica, gold, silver, TiO 2 , any transition metals, ceramic, or combinations thereof as long as it is dispersible in aqueous medium, does not scatter visible light, and remains stable with the polymer formulation.
  • FIGURE 1 shows the general process of the making the reversible hydrogel system.
  • Figure 2 shows the schematic of the preparation of the polyacrylamide/BAC reversible hydrogel system.
  • Figure 3 shows the HPLC-GPC triple detector chromatograms of ABSH2
  • Figure 4 shows the Raman spectra of a) 4% (w/v) aqueous solution of ABSH6 before gelation; b) 4% (w/v) aqueous solution of ABSH6 after gelation; and c) 5% (w/v) aqueous solution of polyacrylamide (prepared using the same experimental condition without BAC). Insert shows the expanded region of b) and c) after a) is subtracted.
  • Figure 5 shows oxidative regelation of thiol containing ABSH polymers via a) air oxidation at alkaline pH; and b) thiol disulfide exchange reaction.
  • Figure 6 shows a schematic of the surgical procedure for endocapsular hydrogel formation: a) perforation of the cornea and retraction of the iris, followed by the removal of the lens content; b) refilling the empty lens capsular bag with a solution of the reversible hydrogel material; and c) in situ regelation of the reversible hydrogel material.
  • Figure 7 shows re-gelled sample of 10 w/v % ABSH4 a) inside the porcine lens capsular bag; b) explanted from the lens capsular bag; and c) prepared in a mold-
  • Figure 8 shows a) vitreous substitute in human cadaver eyes seen after excision of the sclera, RPE, and retina; and b) eye dissected along the visual axis.
  • Figure 9 is a schematic representation of the formation of a nanoparticle from
  • FIG. 10 shows refractive index values of disulfide containing nanogels and porcine lens crystalline proteins.
  • Figure 11 shows viscoelastic characteristics of synthetic polymers and crystallins.
  • Figure 12 is a schematic representation for preparation of silica nanoparticles through a) addition and b) acidic condensation reactions.
  • the hydrogel systems of the present invention contains a copolymer that is a hydrogel in one state and is in a solution in another state.
  • the copolymer is preferably obtained by copolymerizing a monomer with a crosslinker.
  • the crosslinker provides intermolecular crosslinkages to form the hydrogel.
  • the monomer can be acrylamide, N-ornithine acrylamide, N-(2- hydroxypropyl)acrylamide, hydroxy-ethylacrylate, hydroxyethylmethacrylate, N- vinyl pyrolidone, N-phenylacrylamide, dimethylammopropyl methacrylamide, acrylic acid, benzylmethacrylamide, methylthioethylacrylamide, or combinations thereof.
  • Macro-monomers or polymers with functional groups for example, polyethyleneglycol acrylates, polyethyleneglycol methacrylates, polyvinyl alcohol etc, that can be modified or derivatized to incorporate disulfide groups or reversible crosslinks may also be appropriate for the present invention.
  • the preferred polymer system has a semiflexible or rigid water soluble polymer backbone, such as polyacrylic acids, polystyrene sulfonic acids, collagen, polysaccharides.
  • the polymer preferably includes crosslinkable groups which are capable of forming covalent bonds within the polymer or with other polymers while in aqueous solution, which permit crosslinking of the polymer to form a gel, either after, or independently from thermally or photochemically dependent gellation of the macromer. Chemically or ionically crosslinkable groups known in the art may be provided in the macromers.
  • the preferred crosslinkable groups are unsaturated groups including vinyl groups, allyl groups, cirmamates, acrylates, diacrylates, oligoacrylates, methacrylates, dimethacrylates, oligomethoacrylates, acrylamides, or other biologically acceptable photopolymerizable groups.
  • the crosslinker is preferably a disulfide linker, such as N, N'-bis(acryloyl)cystamine (BAG).
  • crosslinkers include, but are not limited to, methylenebisacrylamide, methylenebismethacrylamide, esters of unsaturated mono- or polycarboxylic acids with polyols, such as diacrylate or triacrylate, e.g., butanediol diacrylate, butanediol dimethacrylate, ethylene glycol diacrylate, ethylene glycol dimethacrylate, and also trimethylolpropane triacrylate, allyl compounds, such as allyl (meth)acrylate, triallyl cyanurate, diallyl maleate, polyallyl esters, tetraallyloxyethane, triallylamine, tetraallylethylenediamine, pentaerythritol triallyl esters or allyl esters of phosphoric acid, and also vinyl compounds such as vinyl acrylate, divinyl adipate, divinylbenzene and vinylphosphonic acid derivatives.
  • polyols such as diacrylate or
  • Non-reversible linkers can be included in the polymer to form branches.
  • Photochemically reversible linkers appropriate for the present invention can mclude, but are not limited to, stilbene, azo, and cinnamoyl derivatives.
  • gellation of the copolymer occurs at a particular wavelength, while liquefaction of the copolymer occurs at a different wave length.
  • the copolymer solution forms a hydrogel by exposure to a first wavelength; and the hydrogel reverts to a copolymer solution by exposure to a second wavelength.
  • Figure 1 shows a schematic of the formation of the hydrogel, solubilization of the copolymer, and reformation of the hydrogel.
  • the copolymerization of the monomer with the linker forms a crosslinked hydrogel.
  • the polymerization is initiated with water-soluble or monomer-soluble initiators or redox initiator combinations.
  • water-soluble initiators are the sodium, potassium and ammonium salts of peroxodisulfuric acid, hydrogen peroxide, tert-butyl peroxide, tert- butyl hydroperoxide, potassium peroxodiphosphate, tert-butyl peroxypivalate, cumyl hydro eroxide, isopropylbenzyl monohydroperoxide and azobisisobutyronitrile.
  • monomer-soluble initiators are diacetyl peroxydicarbonate, dicyclohexyl peroxydicarbonate and dibenzoyl peroxide.
  • the initiators are generally used in an amount of 0.01 to 0.5% by weight, based on the total weight of the monomers.
  • Combinations of said initiators in combination with reducing agent(s) may be used as redox initiators.
  • Suitable reducing agents can be, but are not limited to, the sulfites and bisulfites of alkali metals and of ammonium, for example, sodium sulfite, derivatives of sulfoxylic acid such as zinc or alkali metal formaldehyde sulfoxylates, for example sodium hydroxymethanesulfonate, and ascorbic acid.
  • the amount of reducing agent is preferably 0.01 to 0.5% by weight, based on the total weight of the monomers.
  • acrylamide is a known carcinogen and neurotoxin; however, its polymer, polyacrylamide, is harmless.
  • the copolymer can be further swollen by a liquid, preferably water, to obtain the desired water content.
  • the hydrogel can be liquefied to form a solution of the copolymer by disruption of the crosslinkages. In the case of disulfide linkages, liquefaction can be accomplished by chemically reducing the hydrogel so that the disulfide linkages are reduced to thiols.
  • Reduction preferably takes place in the presence of a reducing agent, such as dithiolthreitol (DTT).
  • DTT dithiolthreitol
  • Other reducing agents can be, but are not limited to, of 2-mercaptoethanol, dithioerythritol, cystein, butanethiol, sodium borohydride, cyanoborohydride, mercaptoethylamine, ethylmaleimide, and tri(2- carboxyethyl)phosphine hydrochloride (TCEP ⁇ C1).
  • the reducing agent is selected based on the nature of the crosslinkage. For disulfide linkages, DTT is the preferred reducing agent.
  • copolymers having disulfide bonds reduction results in the thiols containing copolymers that are water soluble.
  • the copolymer solution can be diluted, concentrated and/or dried as desired.
  • the copolymer is preferably precipitated from solution, for example by methanol, filtered, and dried. Other methods, including freeze drying, are also appropriate.
  • the stored copolymer solids can subsequently be dissolved in a solution to desired concentrations for use.
  • the hydrogel can be reformed from the copolymer solution by reforming the crosslinkages within the copolymer molecule.
  • regelation can be accomplished by oxidization of the copolymer solution, preferably in the presence of an oxidizing agent, preferably atmospheric oxygen.
  • an oxidizing agent preferably atmospheric oxygen.
  • other oxidizing agent such as dithiodipropionic acid (DTDP), cystamine, 2-hydroxyethyldisulfide hydrogen peroxide, organic peracids, peroxy carbonates, ammonium sulfate peroxide, benzoyl peroxide, perborates, and the like, can also be used.
  • DTDP dithiodipropionic acid
  • cystamine 2-hydroxyethyldisulfide hydrogen peroxide
  • organic peracids organic peracids
  • peroxy carbonates such as ammonium sulfate peroxide, benzoyl peroxide, perborates, and the like
  • the preferred oxidizing agents should have no significant toxicity to human and/or animals.
  • photochemically dependent linkers such as stilbene, azo, cinnamoyl derivatives
  • regelation is accomplished by exposing the copolymer solution to light at an appropriate wavelength. Liquefaction of reversible groups can thus be accomplished by exposing the gel to light at an appropriate wavelength, usually one that is different from the gelation wavelength.
  • photochemically dependent linkers and oxidation dependent linkers are not exclusive. Both types of linkers can be used in the same polymer to achieve desired results. For example a polymer containing both types of linkers can be prepared and washed using oxidation/reduction; however, once a lens is formed, the photochemically dependent linker can also be activated to form a more permanent and stable hydrogel.
  • reversible linkers can be used along with non-reversible linkers.
  • the polymer can use a reversible oxidation/reduction reversible linker and a non-reversible photochemical dependent linker, such as thiol-acrylamide and/or thiol-acrylates.
  • Nanogels The hydrogels above can also be used to make nanogels whose particle size depends on the molecular weight of the copolymer.
  • the method of the present mvention teaches the art of making nanogels having diameters of less than 150 nm, preferably about 3-20 nm, which exhibit refractive indexes similar to that of the natural lens.
  • the chemistry involved in preparing reversible hydrogels in section I above are appropriate for making nanogels.
  • the nanogels are made by copolymerizing a monomer with a crosslinker to form a crosslinked hydrogel; reducing or irradiating the crosslinked hydrogel to form a copolymer solution; diluting the copolymer solution to form a diluted copolymer solution; and oxidizing the diluted copolymer solution to form the nanogels.
  • the process of making the nanogels is virtually identical to that of the reversible hydrogel, except that the nanogel is formed from a dilute copolymer solution.
  • dilute it is meant that the concentration of the copolymer solution is less than 1 percent (w/v), preferably less than 0.5 percent (w/v), and most preferably less than 0.01 percent (w/v).
  • the copolymer concentration when the copolymer concentration is dilute, nanogels forms by the oxidation and/or irradiation of the copolymer solution; and when the copolymer concentration is concentrated, a hydrogel form by the oxidation and/or irradiation of the copolymer solution.
  • the dilute copolymer solution minimizes intermolecular interaction, and thus, the crosslinkages are formed intramolecularly, which results in the formation of nanogels.
  • the copolymer solution when the copolymer solution is more concentrated, intermolecular crosslinkages dominate to form hydrogels.
  • the thiol containing nanogel particle can also encapsulate a metal particle, such as gold.
  • metal particles due to their propensity for thiol groups, react spontaneously.
  • the solution is oxidized or irradiated to form intramolecular crosslinkages resulting in nanogels.
  • metal particles are trapped within the nanogels. If the concentration of metal particles is low enough, it is possible to achieve association of a single metal particle with a nanogel particle.
  • crosslinkage can also occur between the metal particle and the nanogel.
  • gold can crosslink with -SH groups of the copolymer upon oxidation.
  • hydrogel Nanocomposite These hydrogel materials exhibit moduli similar to that of the natural lens; however, the refractive indexes of the hydrogel are usually less than that of natural lens material. Usually the refractive index scales linearly with polymer concentration while the modulus scales exponentially. Thus in an ideal hydrogel, it is almost impossible to have a material with high refractive index and low modulus. Applicant has discovered that a nanocomposite of the hydrogel and nanoparticles can achieve both high refractive index (RI) and low modulus, similar to those of the natural lens.
  • the nanocomposite system also exhibits similar accommodation characteristics of the natural lens, preferably within about 1 second, more preferably within about 50-250 milliseconds.
  • the hydrogel nanocomposite of the present invention contains nanoparticles dispersed in a reversible hydrogel matrix, and is advantageous in that the refractive index and modulus of the material can be controlled by varying two variables, namely nanoparticle concentration in the hydrogel and copolymer concentration in the hydrogel.
  • the RI is controlled by changing the nanoparticle concentration in the hydrogel; and the modulus can be controlled by changing the polymer concentration in the hydrogel. This is particularly true in the case of non-interacting nanoparticles. However, if the nanoparticles interact with the copolymer backbone then, depending on the crosslink density and particle size one may have a system in which the modulus increases with nanoparticles (or RI).
  • the nanoparticle preferably has a particle size less than about 150 nm, and most preferably about 3-20 nm. It is critical that the nanoparticles be of such dimensions that they do not disperse or scatter visible light.
  • the nanoparticles can be, but is not limited to, polymeric nanogels (see section II above), proteins, silica, metals, such as gold, silver, and any transition metals, TiO 2 , ceramics, or combinations thereof as long as it is dispersible in aqueous medium and remains stable with the polymer formulation, and preferably does not interact with the polymer backbone.
  • the reversible hydrogel previously described in section I makes the preferred matrix for the nanocomposite; however, other hydrogels are also appropriate for the present invention.
  • the nanoparticles are added to the liquefied copolymer solution and stirred to form a uniform dispersion. The dispersion is then oxidized and/or irradiated to form the nanocomposite of the present invention.
  • the nanogels and the reversible hydrogel contain different crosslinkable groups.
  • the nanogels preferably use photochemical dependent linkers, and vice versa. More preferably, the nanogels contain both oxidation/reduction and photochemical dependent crosslinking groups to achieve greater stability and permanence.
  • the nanoparticle should be chosen so that crosslinking between the hydrogel matrix and the nanoparticles are minimized.
  • the RI and modulus of the nanocomposite can be controlled substantially independently.
  • the RI can be controlled by adjusting the concentration of nanoparticles in the hydrogel; and the modulus can be controlled by adjusting the copolymer concentration in the hydrogel. The higher the level of interaction and/or crosslinking between the hydrogel matrix and the nanoparticles, the lower the ability to independently control the RI and modulus of the nanocomposite.
  • the nanocomposite should achieve a RI of about 1.40 to 1.41 and a modulus of about 1,000 to 1,500 Pascals.
  • the resulting gels were removed from the beaker, swelled in 500 mL of water for two days, crashed into small pieces, and washed with distilled water.
  • the gels from the above copolymer compositions were labeled as ABSS2, ABSS4, and ABSS6, indicating that they contained disulfide (-SS-) bonds by incorporating 2, 4, and 6 acrylic mole % of BAC, respectively.
  • the above soluble polymers from ABSS2, ABSS4, and ABSS6 were labeled as ABSH2, ABSH4, and ABSH6 respectively, indicating that they now contained -SH groups instead of disulfide bonds. Characterization of the soluble copolymers
  • the thiol (-SH) content of each copolymer was determined using Ellman's reagent. Briefly, 50 ⁇ L of 0.5% (w/v) copolymer solution (pH 4, nitrogen bubbled) was added to a mixture of 50 ⁇ L of 0.01 M Ellman's reagent (in 0.1M phosphate buffer, pH 8.0), 500 ⁇ L of 0.1 M phosphate buffer (pH 8), and 450 ⁇ L of distilled water. Absorbance (using Beckman DU54 spectrophotometer) of the resulting solution at 412 nm was determined five minutes after mixing. The concentration of the -SH in each ABSH polymer was calculated using the molar absorptivity of 13,600
  • Polymer solutions (1 mL each) were placed in test tubes and the pH of the solutions were adjusted to approximately 7.4 using calculated amounts of 10 M NaOH, followed by the addition of the required amounts of DTDP (0.5M, pH 7) and vigorous stirring. An equimolar amount of DTDP, based on the -SH content of each ABSH polymer solution, was added. Gelation was observed visually by tilting the tube. To evaluate the ease of injection and uniformity of the gel within a capsular bag, a special mold, mimicking the natural pig lens, was used. Preparation of cylindrical-shape gels was carried out using a Teflon mold.
  • Endocapsular gelation Copolymer solutions (% w/v) of 10.0 and 12.5% from ABSH2; of 5.0 and 7.5% from ABSH4; and of 2.0% from ABSH6, respectively, were evaluated for endocapsular gelation.
  • Freshly enucleated pig eyes were purchased from a local abattoir shortly after slaughter. Typically, each eye was stabilized on a Styrofoam
  • a capsulotomy of from 1.0 to 1.2 mm
  • Figure 3 shows the GPC traces of ABSH copolymers observed by the three detectors of the HPLC-GPC. Increasing the BAC content in the copolymerization increases the molecular weight and leads to broader molecular weight distribution, as shown in Figure 3, trace a.
  • Mw weight-average molecular weight
  • the thioldisulfide exchange reaction resulted in gelation within a few minutes at pH between 7.0 and 7.5, which is closer to physiological pH. Since the gelation times were so short (all less than five minutes), we were able to carry out regelation experiments for several different concentrations of ABSH polymers.
  • concentrations of ABSH polymers and the static moduli of the re-gelled specimens are tabulated in Table 2. The modulus of gels formed at the same concentration increases with increasing molecular weight and -SH content. All of the reformed gels were transparent.
  • Endocapsular gelation was performed using 10.0 and 12.5% solutions of freshly prepared ABSH2, 5.0 and 7.5% solutions of ABSH4, and 2.0% solution of ABSH6. In all these cases, regelation occurred within five minutes. Thanks to the high initial viscosity, which progressively, increased upon addition of DTDP, leakage during refilling did not occur.
  • the surgical procedure of in- vitro refilling for endocapsular gelation is schematically represented in Figure 6. Here, the cornea was perforated and the content of the lens was removed by phagofragmentation resulting in an empty capsular bag. The empty capsular bag was then refilled with the appropriate ABSH solution and regelled in situ.
  • Figure 7a shows a representative porcine eye sample where endocapsular gelation was carried out with a 10% (w/v) solution ABSH4. Objects viewed through the lens appeared clear and undistorted.
  • Figure 7b shows the re-gel lens explanted from the porcine lens capsular bag. Formation of uniformly transparent gels was also verified in molds shaped in the form of a lens ( Figure 7c).
  • the primary aim of this work is to demonstrate the feasibility of using thiol containing copolymers as injectable precursors for in vivo chemical crosslinking under physiological conditions (ambient temperature, in the presence of oxygen, and at near-neutral pH).
  • the gelling chemistry uses the facile oxidation of pendant thiols to disulfide by slow air oxidation or the rapid exchange reaction mediated by suitable, non-toxic disulfide reagents.
  • Such system is free of toxic monomers, does not involve exothermic reactions close to the living tissues, is leak-free, and has a rate of gelling that can be modulated by appropriate biocompatible accelerators and photons.
  • polyacrylamide is used as a model scaffold or backbone structure and may be replaced by any polymer chain.
  • Incorporating hydrophobic moieties can significantly enhance the solution property of the copolymer, i.e., viscosity and/or thixotropy.
  • thiols could be either pendant or at chain ends in a multi- armed polymer.
  • the chemistry is also applicable to thiol-containing silicones, which have unusually high oxygen permeability. Because hydrophilic, water- swellable acrylates are usually biodegradable and not suitable for long-term use as vitreous substitutes or intraocular lens material, acrylamide derivatives are chosen for their generally greater hydrolytic stability.
  • Another distinct advantage of this system is that the initial formation of a network outside the body facilitates the removal of heat as well as monomers and other toxic chemicals, problems that otherwise severely limit in vivo polymerization.
  • the reduction of disulfide bonds in the hydrogel using DTT to obtain water-soluble ABSH copolymers is an important step that is influenced not only by the redox potential of the reducing agent, but also by concentration, time, pH, and nitrogen atmosphere. After considering these factors, it is found that using 10 molar excess of DTT and stirring under nitrogen to be most suitable approach for obtaining copolymers for endocapsular regelation.
  • Use of acidified methanol (pH 3) during precipitation of the polymer was critical to maintaining the thiols in the reduced state during subsequent processing.
  • the copolymers are only partly soluble. Upon drying, the samples were kept under reduced pressure until further use. As seen from the -SH content in Table 1, it is possible to reduce the disulfide bonds almost quantitatively. The gel can be reformed through either simple air oxidation or thiol-disulfide exchange reaction by adding DTDP. While the -SH content, concentration, and molecular weight of the copolymer influenced the regelation characteristics and moduli of the resultant gels, it is obvious from Table 2 that very high or low values of the above parameters render the material unsuitable for endocapsular gelation. In general, the modulus of the hydrogel increases with increasing -SH and copolymer concentration; and the hydrogel remains optically clear.
  • Cystamine and 2-hydroxyethyldisulfide can also been used for regelation, but DTDP is less toxic than either of them.
  • In situ endocapsular hydrogel formation using reversible disulfide chemistry is a promising technique, not only for developing injectable intraocular lenses but also for use as vitreous substitutes, and topical medicaments.
  • the reversible hydrogel system described here involves only in situ gelation, with no noticeable change in temperature. Because the copolymer is free of monomers and was injected at a concentration with a viscous consistency, toxicity from monomers and leakage is avoided.
  • the time of regelation can be easily manipulated using DTDP, oxygen, pH, and/or photons.
  • aqueous ethanol was used as the solvent.
  • the resulting gel was removed from the beaker, swelled in 500 mL of water for two days, crushed into small pieces and washed with distilled water.
  • the copolymeric gel was labeled AB4N2SS indicating that it contained disulfide (-SS-) bonds by incorporating 4 acrylic mole % of BAC and 2 acrylic mole % of NPA.
  • the liquefaction of crushed gels (AB4N2SS) was achieved by the addition of dithiothreitol (DTT) (10 mol mol of BAC used) to the crushed hydrogels. The reduction was carried out at pH 7.0 for 4 hours, while nitrogen was bubbled through the solution with stirring.
  • DTT dithiothreitol
  • the copolymer solution was acidified to pH 4 using 10% (v/v) HC1 and precipitated in methanol (pH 4) with vigorous stirring.
  • the precipitated -SH copolymer was filtered, dried under vacuum, and stored under reduced pressure at all times.
  • the above obtained thiol containing water-soluble copolymer, from AB4N2SS was labeled AB4N2SH.
  • the total volume of the composition was 3 ml.
  • 7%, 9%, and 11% (w/v) solutions of AB4N2SH were also prepared and used for the formation of hydrogels.
  • the hydrogels were analyzed for their modulus values.
  • the polymer solution (9, 11%) exhibited "honey-like" consistency, shear thinning when injected through the syringe, and almost instantaneously set within the pocine capsular bag as a physical gel without leaking. This physical gel was then transformed into a chemical gel.
  • Example 3 Hydrogels as Vitreous Substitute
  • the copolymer (AB4SH) was prepared from the hydrogel obtained by polymerizing acrylamide with 4 acrylic mole % of bisacryloylcystamine (BAC).
  • the detailed experimental procedure was similar to those described in Example 1.
  • the thiol (-SH) content present in the copolymers were determined using Ellman's analysis (Ellman, Arch. Biochem. Biophys., 1959, 82:70-77).
  • the molecular weight of the reduced polymer (ABSHs) was determined using a Viscotek HPLC- GPC system (Houston, Texas, USA) using dual column of G6000PWXL and G4000PWXL (Tosoh Biosep, Montgomery Ville, PA, USA), connected in series.
  • the mobile phase was 20mM Bis-Tris buffer (pH 6.0, 0.1% sodium azide). Samples were prepared in water (pH 4, N 2 saturated) at a concentration of 0.5% (w/v).
  • Polyethylene glycol standards (Viscotek, Houston, Texas, USA) of molecular weight (Mw) 1000 to 950,000 were used for calibration. Preparation of nanogels
  • a large volume of 0.1% w/v of thiol copolymer solution was prepared in water at pH 4.
  • the pH of the solutions was adjusted to 7 using a small amount of IM NaOH and bubbled with air for 3 days.
  • the solution was concentrated to 25% w/w.
  • Preparation of crystallin solution Porcine eye balls were obtained from the local abattoir and the lenses were dissected out. Decapsulated lenses were placed in buffer, (50mM Tris, 50mM NaCl, ImM EDTA, ImM DTT and 0.1% Na Azide) homogenized, and centrifuged at 12,000 RPM for 30 min.
  • refractive indexes of the all the nanoparticles as well as crystallin solutions at different concentration were measured using Abbe refractometer (ATAGO's Abbe refractometer 1T/4T, Kirkland, WA, USA) at 25°C.
  • Abbe refractometer ATAGO's Abbe refractometer 1T/4T, Kirkland, WA, USA
  • RESULTS AND DISCUSSION Preparation and characterization of thiol copolymers Copolymerization of AAm and BAC resulted in hydrogel.
  • the important step in obtaining the desired water-soluble copolymers (AB6SH) from the crosslinked gels (AB6SS) involves the complete reduction of all the disulfide bonds (-S-S-) in the gels into -SH groups as shown in Figure 2.
  • the weight average molecular weights (Mw) were 9.1, 3.0, 4.3 and 1.75xl0 5 Da for AB6SH, AB4N4SH, AB4N4AA2SH and AB4N4DA2SH respectively.
  • AB6SH pendent -SH groups
  • NP-AB6SS nanoparticles
  • very dilute concentrations favored the nanoparticle formation by intramolecular crosslinking only, the concentration studied (0.1%w/v) in this work still showed some intermolecularly formed nanoparticles.
  • AB6SH is the copolymeric thiol obtained from the hydrogel prepared by polymerizing acrylamide and BAC at 94/6 acrylic mole ratio.
  • RAB6SS is the re- gelled hydrogel sample from AB6SH polymer.
  • NP-AB6SS is the nanogel sample prepared from the same AB6SH polymer as mentioned in the experimental section. The viscoelastic characteristics of nanogel (NP-AB6SS) showed very close resemblance to that of crystalline as observed in Figure 11.
  • Thiol containing polyacrylamide copolymers were prepared from the hydrogels obtained by the polymerization of acrylamide and other monomers using disulfide containing crosslinking agent, bisacrylcystamine.
  • the thiol polymers were used to prepare the nanogels through intramolecular crosslinking between thiol groups. Refractive index and viscosity of these nanogels were comparable to that of
  • poly(AAm-co-BAC) hydrogel and its reduction Polyacrylamide/BAC hydrogel was prepared as above in Example 1.
  • the polymer obtained was labeled as AB4SH.
  • Characterization of the soluble copolymer The thiol (-SH) content present in the copolymer (AB4SH) was determined using Ellman's analysis.
  • the molecular weight of the reduced polymer (AB4SH) was determined using a Viscotek HPLC-GPC system (Houston, Texas, USA) using dual column of G6000PWXL and G4000PWXL (Tosoh Biosep, Montgomery Ville, PA, USA), connected in series.
  • the mobile phase was 20mM Bis-Tris buffer (pH 6.0, 0.1% sodium azide).
  • the key step in obtaining the desired water-soluble copolymers (AB4SH) from the crosslinked gels (AB4SS) involves the complete reduction of all the disulfide bonds (-S-S-) in the gels into -SH groups as shown in Figure 2. Reduction of the gels by DTT resulted in almost complete reduction of the disulfide bonds as evidenced by the -SH determination.
  • the Ellman's analysis showed -SH content to be 5.1xl0 "4 moles/g. The calculated value is 5.4x10 "4 moles/g.
  • the molecular weight distribution analysis of AB4SH showed a broad distribution with a polydispersity of 3.4 and weight average molecular weight (Mw) of 3.8x10 5 Da
  • the silica nanoparticles were prepared by the addition reaction between glycidol and aminopropyltriethoxysilane followed by the acidic condensation of the addition product through sol-gel technique as reported by Mori et al.
  • the particle size was reported as ⁇ 3nm diameter. Because of higher hydroxyl group functionality of each silicon atom and very small size, these particles are well dispersed and behave like a dissolved molecule in water.
  • a very high concentrated (65%w/w) solution was prepared and used in the nanocomposite hydrogel composition at different concentration. The preparation of the silica nanoparticles is shown in Figure 12.
  • BSA (30%w/w)
  • RI refractive index
  • moduli values are presented in the Table for all the nanocomposites.
  • RI refractive index
  • moduli values also increased.
  • NP-AB4SS was prepared from AB4SH and was stable unless it was subjected to any reducing environment.

Abstract

L'invention concerne des systèmes réversibles d'hydrogel. En particulier, ledit hydrogel comporte des copolymères pouvant être un hydrogel sous une forme oxydée et un solution sous une forme réduite. Une solution du copolymère peut être oxydée de façon à former un hydrogel et l'hydrogel peut être réduit de façon à former une solution du copolymère. Des nanogels réversibles peuvent être formés aussi à partir d'une solution diluée des copolymères. L'hydrogel est formé avec des nano-particules noyées dans celui-ci de façon à former un nanocomposite dont l'indice de réfraction et le module peuvent être contrôlés en modifiant les quantités de nano-particules et la concentration de polymère de l'hydrogel respectivement.
EP04783018A 2003-09-04 2004-09-03 Nanocomposites d'hydrogel pour applications ophtalmiques Withdrawn EP1660153A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US49988703P 2003-09-04 2003-09-04
US10/706,081 US8192485B2 (en) 2002-11-13 2003-11-13 Reversible hydrogel systems and methods therefor
US56459204P 2004-04-23 2004-04-23
PCT/US2004/028637 WO2005023331A2 (fr) 2003-09-04 2004-09-03 Nanocomposites d'hydrogel pour applications ophtalmiques

Publications (1)

Publication Number Publication Date
EP1660153A2 true EP1660153A2 (fr) 2006-05-31

Family

ID=34279817

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04783018A Withdrawn EP1660153A2 (fr) 2003-09-04 2004-09-03 Nanocomposites d'hydrogel pour applications ophtalmiques

Country Status (4)

Country Link
EP (1) EP1660153A2 (fr)
JP (2) JP4988345B2 (fr)
CA (1) CA2542512A1 (fr)
WO (1) WO2005023331A2 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9486311B2 (en) 2013-02-14 2016-11-08 Shifamed Holdings, Llc Hydrophilic AIOL with bonding
US10195018B2 (en) 2013-03-21 2019-02-05 Shifamed Holdings, Llc Accommodating intraocular lens
CN109351204A (zh) * 2018-09-12 2019-02-19 济南大学 一种含氟水凝胶膜的制备方法及应用
US10350056B2 (en) 2016-12-23 2019-07-16 Shifamed Holdings, Llc Multi-piece accommodating intraocular lenses and methods for making and using same
US10548718B2 (en) 2013-03-21 2020-02-04 Shifamed Holdings, Llc Accommodating intraocular lens
US10736734B2 (en) 2014-08-26 2020-08-11 Shifamed Holdings, Llc Accommodating intraocular lens
US10987214B2 (en) 2017-05-30 2021-04-27 Shifamed Holdings, Llc Surface treatments for accommodating intraocular lenses and associated methods and devices
US11141263B2 (en) 2015-11-18 2021-10-12 Shifamed Holdings, Llc Multi-piece accommodating intraocular lens
US11266496B2 (en) 2017-06-07 2022-03-08 Shifamed Holdings, Llc Adjustable optical power intraocular lenses

Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7473738B2 (en) * 2004-09-30 2009-01-06 Johnson & Johnson Vision Care, Inc. Lactam polymer derivatives
JP4879554B2 (ja) * 2005-10-21 2012-02-22 株式会社メニコン ポストインプリント可能なヒドロゲル材料の製造方法
JP4974533B2 (ja) * 2006-01-30 2012-07-11 富士フイルム株式会社 ジスルフィド架橋したタンパク質ナノ粒子
JP5204097B2 (ja) 2006-05-03 2013-06-05 ビジョン シーアールシー リミティド 眼の治療
CN101721349B (zh) * 2008-10-16 2011-07-20 常州百瑞吉生物医药有限公司 可注射原位交联水凝胶及其制备方法和用途
AU2012249759A1 (en) 2011-04-25 2013-11-07 Bio-Rad Laboratories, Inc. Methods and compositions for nucleic acid analysis
US10584381B2 (en) 2012-08-14 2020-03-10 10X Genomics, Inc. Methods and systems for processing polynucleotides
US10752949B2 (en) 2012-08-14 2020-08-25 10X Genomics, Inc. Methods and systems for processing polynucleotides
US10221442B2 (en) 2012-08-14 2019-03-05 10X Genomics, Inc. Compositions and methods for sample processing
US9701998B2 (en) 2012-12-14 2017-07-11 10X Genomics, Inc. Methods and systems for processing polynucleotides
US9388465B2 (en) 2013-02-08 2016-07-12 10X Genomics, Inc. Polynucleotide barcode generation
US11591637B2 (en) * 2012-08-14 2023-02-28 10X Genomics, Inc. Compositions and methods for sample processing
US9951386B2 (en) 2014-06-26 2018-04-24 10X Genomics, Inc. Methods and systems for processing polynucleotides
US10273541B2 (en) 2012-08-14 2019-04-30 10X Genomics, Inc. Methods and systems for processing polynucleotides
US10323279B2 (en) 2012-08-14 2019-06-18 10X Genomics, Inc. Methods and systems for processing polynucleotides
CN114891871A (zh) 2012-08-14 2022-08-12 10X基因组学有限公司 微胶囊组合物及方法
US10533221B2 (en) 2012-12-14 2020-01-14 10X Genomics, Inc. Methods and systems for processing polynucleotides
EP3567116A1 (fr) 2012-12-14 2019-11-13 10X Genomics, Inc. Procédés et systèmes de traitement de polynucléotides
US10395758B2 (en) 2013-08-30 2019-08-27 10X Genomics, Inc. Sequencing methods
US9824068B2 (en) 2013-12-16 2017-11-21 10X Genomics, Inc. Methods and apparatus for sorting data
US10178950B2 (en) * 2013-12-20 2019-01-15 Novartis Ag Imaging probes and associated devices, systems, and methods utilizing an elastomeric optical element
JP6427811B2 (ja) * 2014-03-20 2018-11-28 国立大学法人愛媛大学 タンパク質の保存方法
US9694361B2 (en) 2014-04-10 2017-07-04 10X Genomics, Inc. Fluidic devices, systems, and methods for encapsulating and partitioning reagents, and applications of same
WO2015200891A1 (fr) 2014-06-26 2015-12-30 10X Technologies, Inc. Procédés et systèmes pour l'assemblage de séquences d'acide nucléique
CN113249435A (zh) 2014-06-26 2021-08-13 10X基因组学有限公司 分析来自单个细胞或细胞群体的核酸的方法
BR112017008877A2 (pt) 2014-10-29 2018-07-03 10X Genomics Inc métodos e composições para sequenciamento de ácido nucleico-alvo
US9975122B2 (en) 2014-11-05 2018-05-22 10X Genomics, Inc. Instrument systems for integrated sample processing
AU2016207023B2 (en) 2015-01-12 2019-12-05 10X Genomics, Inc. Processes and systems for preparing nucleic acid sequencing libraries and libraries prepared using same
CN107209814B (zh) 2015-01-13 2021-10-15 10X基因组学有限公司 用于使结构变异和相位信息可视化的系统和方法
MX2017010142A (es) 2015-02-09 2017-12-11 10X Genomics Inc Sistemas y metodos para determinar variacion estructural y ajuste de fases con datos de recuperacion de variantes.
WO2016137973A1 (fr) 2015-02-24 2016-09-01 10X Genomics Inc Procédés et systèmes de traitement de cloisonnement
CN115651972A (zh) 2015-02-24 2023-01-31 10X 基因组学有限公司 用于靶向核酸序列覆盖的方法
EP3384048B1 (fr) 2015-12-04 2021-03-24 10X Genomics, Inc. Procédés et compositions pour l'analyse d'acide nucléique
JP6735348B2 (ja) 2016-02-11 2020-08-05 １０エックス ジェノミクス， インコーポレイテッド 全ゲノム配列データのデノボアセンブリのためのシステム、方法及び媒体
WO2017197338A1 (fr) 2016-05-13 2017-11-16 10X Genomics, Inc. Systèmes microfluidiques et procédés d'utilisation
WO2018000242A1 (fr) * 2016-06-29 2018-01-04 南京大学 Application d'un matériau autoréparateur pour une utilisation en impression 3d
US10815525B2 (en) 2016-12-22 2020-10-27 10X Genomics, Inc. Methods and systems for processing polynucleotides
US10550429B2 (en) 2016-12-22 2020-02-04 10X Genomics, Inc. Methods and systems for processing polynucleotides
US10011872B1 (en) 2016-12-22 2018-07-03 10X Genomics, Inc. Methods and systems for processing polynucleotides
CN117512066A (zh) 2017-01-30 2024-02-06 10X基因组学有限公司 用于基于微滴的单细胞条形编码的方法和系统
CN110870018A (zh) 2017-05-19 2020-03-06 10X基因组学有限公司 用于分析数据集的系统和方法
CN109526228B (zh) 2017-05-26 2022-11-25 10X基因组学有限公司 转座酶可接近性染色质的单细胞分析
US10400235B2 (en) 2017-05-26 2019-09-03 10X Genomics, Inc. Single cell analysis of transposase accessible chromatin
SG11201913654QA (en) 2017-11-15 2020-01-30 10X Genomics Inc Functionalized gel beads
US10829815B2 (en) 2017-11-17 2020-11-10 10X Genomics, Inc. Methods and systems for associating physical and genetic properties of biological particles
CN108276593B (zh) * 2018-01-31 2020-06-05 合肥工业大学 一种集紫外-可见-近红外光诱导的自修复纳米复合水凝胶的制备方法
EP3775271A1 (fr) 2018-04-06 2021-02-17 10X Genomics, Inc. Systèmes et procédés de contrôle de qualité dans un traitement de cellules uniques
CN110403920B (zh) * 2019-08-26 2022-12-02 江苏远恒药业有限公司 一次性医用水凝胶眼贴
CN112646069B (zh) * 2020-12-15 2022-10-21 内蒙古民族大学 一种氮化碳复合水凝胶及其制备方法和应用

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6222754A (ja) * 1985-07-23 1987-01-30 Nippon Shokubai Kagaku Kogyo Co Ltd Ｎ，ｎ′−ジメタクリロイルシスタミン
US6132765A (en) * 1996-04-12 2000-10-17 Uroteq Inc. Drug delivery via therapeutic hydrogels
JP4219485B2 (ja) * 1999-05-21 2009-02-04 株式会社メニコン 光学性含水ゲルからなる眼科用材料
US6514535B2 (en) * 1999-05-21 2003-02-04 Noveon Ip Holdings Corp. Bioadhesive hydrogels with functionalized degradable crosslinks
JP4975919B2 (ja) * 1999-07-16 2012-07-11 ウィリアム・マーシュ・ライス・ユニバーシティ 光熱的に調節される薬剤投与のための感熱性ポリマ／ナノシェル複合体
WO2001005578A1 (fr) * 1999-07-16 2001-01-25 Wesley-Jessen Corporation Lentille ophthalmique thermoformable
IL133196A0 (en) * 1999-11-29 2001-03-19 Yissum Res Dev Co Gastroretentive controlled release pharmaceutical dosage forms
AUPR569501A0 (en) * 2001-06-14 2001-07-12 Proteome Systems Ltd Dissolvable gels

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005023331A3 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10709549B2 (en) 2013-02-14 2020-07-14 Shifamed Holdings, Llc Hydrophilic AIOL with bonding
US11540916B2 (en) 2013-02-14 2023-01-03 Shifamed Holdings, Llc Accommodating intraocular lens
US10350057B2 (en) 2013-02-14 2019-07-16 Shifamed Holdings, Llc Hydrophilic AIOL with bonding
US9486311B2 (en) 2013-02-14 2016-11-08 Shifamed Holdings, Llc Hydrophilic AIOL with bonding
US10548718B2 (en) 2013-03-21 2020-02-04 Shifamed Holdings, Llc Accommodating intraocular lens
US10195018B2 (en) 2013-03-21 2019-02-05 Shifamed Holdings, Llc Accommodating intraocular lens
US11583390B2 (en) 2014-08-26 2023-02-21 Shifamed Holdings, Llc Accommodating intraocular lens
US10736734B2 (en) 2014-08-26 2020-08-11 Shifamed Holdings, Llc Accommodating intraocular lens
US11141263B2 (en) 2015-11-18 2021-10-12 Shifamed Holdings, Llc Multi-piece accommodating intraocular lens
US10350056B2 (en) 2016-12-23 2019-07-16 Shifamed Holdings, Llc Multi-piece accommodating intraocular lenses and methods for making and using same
US11065109B2 (en) 2016-12-23 2021-07-20 Shifamed Holdings, Llc Multi-piece accommodating intraocular lenses and methods for making and using same
US10987214B2 (en) 2017-05-30 2021-04-27 Shifamed Holdings, Llc Surface treatments for accommodating intraocular lenses and associated methods and devices
US11266496B2 (en) 2017-06-07 2022-03-08 Shifamed Holdings, Llc Adjustable optical power intraocular lenses
CN109351204A (zh) * 2018-09-12 2019-02-19 济南大学 一种含氟水凝胶膜的制备方法及应用

Also Published As

Publication number Publication date
JP4988345B2 (ja) 2012-08-01
WO2005023331A3 (fr) 2007-05-03
WO2005023331A2 (fr) 2005-03-17
CA2542512A1 (fr) 2005-03-17
JP2011063816A (ja) 2011-03-31
JP2007517077A (ja) 2007-06-28

Similar Documents

Publication Publication Date Title
US8877227B2 (en) Hydrogel nanocomposites for intraocular lens applicatons
WO2005023331A2 (fr) Nanocomposites d'hydrogel pour applications ophtalmiques
US8192485B2 (en) Reversible hydrogel systems and methods therefor
Aliyar et al. Refilling of ocular lens capsule with copolymeric hydrogel containing reversible disulfide
Lin et al. Polymeric hydrogels as a vitreous replacement strategy in the eye
Swindle et al. In situ formation of hydrogels as vitreous substitutes: viscoelastic comparison to porcine vitreous
JP3681393B2 (ja) 角膜に移植される架橋ポリエチレンオキシドゲルを製造する方法、及び該方法で製造された角膜に移植される架橋ポリエチレンオキシドゲル
US8025696B2 (en) Artificial meniscus and process of making thereof
NZ506347A (en) Methods of producing intraocular lenses and materials suitable for their production
Chirila et al. Synthetic polymers as materials for artificial vitreous body: review and recent advances
TW201026752A (en) Ionic silicone hydrogels having improved hydrolytic stability
US20100210752A1 (en) Pva hydrogels having improved creep resistance, lubricity, and toughness
KR20010013074A (ko) 콜라겐을 주성분으로 하는 생체적합성, 광학 투명성 및자외선 흡수성이 있는 중합체 물질 및 그 제조 방법
US20110054622A1 (en) Creep resistant, highly lubricious, tough, and ionic hydrogels including pva-paamps hydrogels
Karayilan et al. Polymeric materials for eye surface and intraocular applications
EP1410074B1 (fr) Compositions pouvant former des hydrogels dans l'oeil
JP2007130386A (ja) 眼用装置
Annaka et al. Organic–inorganic nanocomposite gels as an in situ gelation biomaterial for injectable accommodative intraocular lens
AU2002328901A1 (en) Compositions capable of forming hydrogels in the eye
Ravi et al. Hydrogel nanocomposite as a synthetic intra‐ocular lens capable of accommodation
Wang et al. Polymeric hydrogel as a vitreous substitute: current research, challenges, and future directions
Foster et al. Internal osmotic pressure as a mechanism of retinal attachment in a vitreous substitute
Aliyar et al. Towards the development of an artificial human vitreous
JP3561740B2 (ja) 生体適合性の、光学的に透明なコラーゲン基ポリマー材料およびその製造方法
Swindle-Reilly et al. Designing hydrogels as vitreous substitutes in ophthalmic surgery

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060310

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL HR LT LV MK

DAX Request for extension of the european patent (deleted)
PUAK Availability of information related to the publication of the international search report

Free format text: ORIGINAL CODE: 0009015

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 47/30 20060101ALI20070529BHEP

Ipc: A61K 9/50 20060101AFI20070529BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20090212