WO2010083173A2 - Hydrophobic pseudo-endothelial implants for treating corneal edema - Google Patents

Hydrophobic pseudo-endothelial implants for treating corneal edema Download PDF

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Publication number
WO2010083173A2
WO2010083173A2 PCT/US2010/020828 US2010020828W WO2010083173A2 WO 2010083173 A2 WO2010083173 A2 WO 2010083173A2 US 2010020828 W US2010020828 W US 2010020828W WO 2010083173 A2 WO2010083173 A2 WO 2010083173A2
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WO
WIPO (PCT)
Prior art keywords
implant
cornea
posterior portion
binding agent
bonding
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.)
Ceased
Application number
PCT/US2010/020828
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English (en)
French (fr)
Other versions
WO2010083173A3 (en
Inventor
Ofer Daphna
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.)
Mor Research Applications Ltd
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Mor Research Applications Ltd
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Application filed by Mor Research Applications Ltd filed Critical Mor Research Applications Ltd
Priority to JP2011546304A priority Critical patent/JP5909094B2/ja
Priority to CN2010800098160A priority patent/CN102368975A/zh
Priority to ES10707705.9T priority patent/ES2442768T3/es
Priority to EP10707705.9A priority patent/EP2389137B1/en
Publication of WO2010083173A2 publication Critical patent/WO2010083173A2/en
Publication of WO2010083173A3 publication Critical patent/WO2010083173A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/22Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24Collagen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/14Eye parts, e.g. lenses or corneal implants; Artificial eyes
    • A61F2/142Cornea, e.g. artificial corneae, keratoprostheses or corneal implants for repair of defective corneal tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/14Eye parts, e.g. lenses or corneal implants; Artificial eyes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/14Eye parts, e.g. lenses or corneal implants; Artificial eyes
    • A61F2/147Implants to be inserted in the stroma for refractive correction, e.g. ring-like implants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007Methods or devices for eye surgery
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/16Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/18Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/20Polysaccharides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52Hydrogels or hydrocolloids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005The prosthesis being constructed from a particular material
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005The prosthesis being constructed from a particular material
    • A61F2310/00365Proteins; Polypeptides; Degradation products thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/16Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S623/00Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
    • Y10S623/902Method of implanting
    • Y10S623/905Eye
    • Y10S623/906Corneal

Definitions

  • the present invention relates generally to endothelial implants for treating an over-hydrated, edematous cornea.
  • the quality of the eye's sensory function greatly depends on the qualities of light conduction through the cornea and through the lens, and also the optical qualities of these organs and the transparency of the cornea and the eye lens, as well as other factors.
  • corneal transparency generally depends on the ability of the cornea to remain in a dehydrated state.
  • the cornea dehydrated state is affected by several interdependent factors, the most important of which is an active pump present in the deepest cell layer of the cornea, the endothelium. Any disruption of the endothelial function beyond a certain level as a result of surgery, trauma, infection, or congenital predisposition results in influx of water to all layers of the cornea thus distorting its transparency.
  • the morbidity of this situation is not only a significant decrease in vision, but also at an advanced state may result in significant pain and scars, a situation known as bullous keratopathy.
  • Another important physiological mechanism for dehydrating the cornea is the evaporation of water from the tear film while the eye is open during wakefulness. Dehydration works by water evaporating from the tear film, which leaves behind a more concentrated solution at the surface of the eye, causing the tear film to be more hypertonic. The hypertonic tear film draws more water by osmosis from the cornea itself; the opposite is true during the night. There are some hypertonic solution eye drops available in the market to augment this mechanism but unfortunately their action is short lived due to the blinking of the eyelids.
  • DLEK deep lamellar striping keratoplasty
  • DSEK Descemets striping endothelial keratoplasty
  • the present invention relates to implantation of an artificial hydrophobic pseudo- endothelial implant to the posterior surface of the cornea for the treatment of edematous eyes, as is described more in detail hereinbelow.
  • an ocular implant including a hydrophobic pseudo-endothelial implant and a binding agent applied thereto, the binding agent capable of bonding the implant to a posterior portion of a cornea such that the implant serves as a water barrier enabling dehydration of the cornea.
  • a method for treating corneal edema including bonding a hydrophobic pseudo-endothelial implant to a posterior portion of a cornea with a binding agent, such that the implant serves as a water barrier enabling dehydration of the cornea.
  • the implant is constructed of a clear, transparent, biologically compatible material, and may be rigid, semi-rigid or foldable.
  • the binding agent can be placed between the implant and the posterior surface of the cornea only at the periphery of the implant cornea interface or on the entire interface surface or any other combination.
  • a portion of the posterior portion of the cornea may be removed (although does not have to be removed) prior to bonding the implant to the posterior portion of the cornea, such as for example, a thin posterior portion of stromal tissue along with Descemet's membrane and endothelial cells attached thereto, or just a thin posterior portion of Descemet's membrane and endothelial cells attached thereto.
  • the refractive state of the patient may be taken into account in the design of the implant thus enabling refractive correction including astigmatic correction along with alleviating the edematous state.
  • the implant can be designed in several sizes, such as from a radius of 1-2 mm up to 6 mm or more covering the whole surface of the posterior cornea or any size in between.
  • the thickness of the implant may be from a few microns up to more than 100 microns.
  • the thickness may be equal through the entire implant diameter or may be different at different portions thereof in order to have refractive power, for example, being thinner at the periphery compared to the center or the opposite.
  • the curvature of the posterior surface of the cornea may be taken into account especially in the case of a rigid implant to provide better adhesion.
  • Figs. 1 and 2 are front view and side view simplified illustrations of a hydrophobic pseudo-endothelial implant, constructed and operative in accordance with an embodiment of the present invention.
  • Fig. 3 is a simplified flow chart of a method for bonding the implant of Figs. 1 and 2 to the posterior portion of the cornea, in accordance with an embodiment of the present invention.
  • sutures are detrimental to the success of the hydrophobic implant.
  • the present invention does not use sutures; rather different adhesive materials are used to bond the implant to the posterior portion of the cornea, as is now explained.
  • Figs. 1 and 2 illustrate a hydrophobic pseudo- endothelial implant 10, constructed and operative in accordance with an embodiment of the present invention.
  • the hydrophobic pseudo-endothelial implant 10 can be used instead of an implant from a donor in a DSEK surgery.
  • Implant 10 serves as a water barrier enabling the dehydration of the cornea.
  • Implant 10 may be constructed of a clear, transparent, biologically compatible material, such as but not limited to, polymethylmethacrylate (PMMA), silicone, silicone rubber, collagen, hyaluronic acid (including the sodium, potassium and other salts thereof), hydrogel, such as acrylic or methacrylic hydrogels, e.g., hydroxyethyl methacrylate or methacrylic acid copolymer/partially hydrolyzed poly(2-hydroxyethyl methacrylate) (known as PoIyHEMA), polysulfones, thermolabile materials and other relatively hard or relatively soft and flexible biologically inert optical materials, or any combination of such materials, such as a gel encapsulated in a polymer. Implant 10 may thus be rigid, semi-rigid or foldable, for example.
  • PMMA polymethylmethacrylate
  • silicone silicone
  • silicone rubber collagen
  • hyaluronic acid including the sodium, potassium and other salts thereof
  • hydrogel such as acrylic or methacrylic hydrogels,
  • a thin posterior or lenticule of stromal tissue (along with Descemet's membrane and endothelial cells attached) is removed from the cornea of the patient's eye.
  • Descemets strip endokeratoplasty only the Descemet's membrane and endothelial cells are removed.
  • the implant may be attached to the endothelium of the cornea without any posterior surface striping.
  • Implant 10 is bonded to the posterior portion of the cornea 12 with a binding agent 14 (Fig. 1 shows the posterior side of the cornea 12).
  • Binding agent 14 can be placed between the implant 10 and the posterior surface of the cornea 12 only at the periphery of the implant cornea interface or on the entire interface surface or any other combination (Fig. 3).
  • Suitable binding agents for use in accordance with the present invention include for example, but are not limited to, poly-L-lysine and poly-D-lysine. For purposes of simplicity, each poly-L-lysine and poly-D- lysine is hereinafter referred to indiscriminately as "polylysine".
  • binding agents include, but are not limited to, fibronectin, laminin, type I, II, III and IV collagen, thrombospondin, polystyrene, vitronectin, polyarginine and platelet factor IV.
  • the binding agent may include one of the above or any combination thereof.
  • one or more of the binding agents may be conjugated with one or more cytotoxic agents which can be applied on the inner surface of the implant or its outer surface at the center or both or not at all, in order to prevent opacities that might occur by new tissue growth over the implant.
  • Suitable cytotoxic agents include, but are not limited to, ribosomal inhibitory proteins, such as but not limited to, saporin and ricin.
  • antimitotic drugs such as methotrexate, 5-fluorouracil, daunomycin, doxorubicin, mitoxanthrone, vinca alkaloids, vinblastine, colchicine, and cytochasins
  • ionophores such as monensin and ouabain.
  • implant 10 may be formed with one or more through holes 16 to control a small flow of fluid to and from the cornea, which will be sufficient for nutritional support but will not cause corneal edema.
  • the outer surface of the implant 10 (facing the cornea) may have hydrophilic properties in order to further enhance adhesion to the cornea, thus creating a hydrophobic -hydrophilic implant.
  • the refractive state of the patient may be taken into account in the design of the implant thus enabling refractive correction along with alleviating the edematous state.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Transplantation (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Surgery (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)
PCT/US2010/020828 2009-01-18 2010-01-13 Hydrophobic pseudo-endothelial implants for treating corneal edema Ceased WO2010083173A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2011546304A JP5909094B2 (ja) 2009-01-18 2010-01-13 角膜浮腫を治療するための疎水性疑似内皮インプラント
CN2010800098160A CN102368975A (zh) 2009-01-18 2010-01-13 用于治疗角膜水肿的疏水性假内皮植入物
ES10707705.9T ES2442768T3 (es) 2009-01-18 2010-01-13 Implantes pseudoendoteliales hidrófobos para tratar un edema corneal
EP10707705.9A EP2389137B1 (en) 2009-01-18 2010-01-13 Hydrophobic pseudo-endothelial implants for treating corneal edema

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12/355,781 2009-01-18
US12/355,781 US8109997B2 (en) 2009-01-18 2009-01-18 Hydrophobic pseudo-endothelial implants for treating corneal edema

Publications (2)

Publication Number Publication Date
WO2010083173A2 true WO2010083173A2 (en) 2010-07-22
WO2010083173A3 WO2010083173A3 (en) 2010-10-07

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ID=42272516

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Application Number Title Priority Date Filing Date
PCT/US2010/020828 Ceased WO2010083173A2 (en) 2009-01-18 2010-01-13 Hydrophobic pseudo-endothelial implants for treating corneal edema

Country Status (6)

Country Link
US (2) US8109997B2 (https=)
EP (1) EP2389137B1 (https=)
JP (1) JP5909094B2 (https=)
CN (2) CN102368975A (https=)
ES (1) ES2442768T3 (https=)
WO (1) WO2010083173A2 (https=)

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US8109997B2 (en) 2012-02-07
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EP2389137A2 (en) 2011-11-30
JP5909094B2 (ja) 2016-04-26
WO2010083173A3 (en) 2010-10-07
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US8500803B2 (en) 2013-08-06
US20100185281A1 (en) 2010-07-22

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