[go: up one dir, main page]

EP4637631A1 - Greffes cornéennes mises au point par des techniques biologiques - Google Patents

Greffes cornéennes mises au point par des techniques biologiques

Info

Publication number
EP4637631A1
EP4637631A1 EP23906270.6A EP23906270A EP4637631A1 EP 4637631 A1 EP4637631 A1 EP 4637631A1 EP 23906270 A EP23906270 A EP 23906270A EP 4637631 A1 EP4637631 A1 EP 4637631A1
Authority
EP
European Patent Office
Prior art keywords
lenticule
collagen
graft
comeal
collagen solution
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.)
Pending
Application number
EP23906270.6A
Other languages
German (de)
English (en)
Inventor
Ariel EISENBACH
Amos Eitan
Michal MARCUS
Maayan MALKI
Lior Rosenberg Belmaker
Shai GARTY
Rajesh Kumar
Lior SHAV
Aryeh Batt
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.)
Precise Bio 3D Ltd
Original Assignee
Precise Bio 3D Ltd
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
Application filed by Precise Bio 3D Ltd filed Critical Precise Bio 3D Ltd
Priority claimed from PCT/IL2023/051288 external-priority patent/WO2024134653A1/fr
Publication of EP4637631A1 publication Critical patent/EP4637631A1/fr
Pending 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3813—Epithelial cells, e.g. keratinocytes, urothelial cells
    • 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
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS 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
    • A61F2/00—Filters 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
    • A61F2/02—Prostheses implantable into the body
    • A61F2/14—Eye parts, e.g. lenses or corneal implants; Artificial eyes
    • A61F2/145—Corneal inlays, onlays, or lenses for refractive correction
    • A61F2/1451—Inlays or onlays
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking

Definitions

  • the present invention pertains to bioengineered corneal grafts; and more specifically, to corneal Onlays and Inlays.
  • the invention also relates with implantable and biocompatible corneal grafts compositions, to methods for their production and grafting into the cornea and to methods for treating a medical condition of a patient.
  • Current vision correction techniques include eyeglasses, contact lenses and surgical methodologies which involve cutting and/or removal of tissue, such as laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK).
  • LASIK laser-assisted in situ keratomileusis
  • PRK photorefractive keratectomy
  • surgical methodologies require partially removement of the corneal stroma, which is an irreversible process, might induce complications such as scarring and hazing of the cornea, infections and glary vision.
  • laser surgeries cannot address severe cases of hyperopia, as it requires the removal of a too thick layer from the corneal stroma.
  • a corneal Onlay is a transparent refraction-corrective lens placed near the surface of the eye, directly below the epithelium. Vision correction using Onlay lenses may be preferable to LASIK and/or PRK since it is reversible, repeatable, minimally invasive and easily modifiable. Onlay can serve as an alternative for people whose corneas are too thin for LASIK and/or PRK. Also, in severe cases, Onlay can be combined with LASIK and/or PRK.
  • the Onlay is a thin lenticule (50 to 150 microns thick), which is placed on top of the corneal Bowman’s layer, below the epithelium. To some extent, the Onlay is similar to a commercial contact lens, but should not generate an immune response and should promote the growth of a healthy epithelium on top.
  • Onlay technology see e.g., US9125735 which is incorporated herein as a reference, is focusing in the vision-correction market, but since it is less invasive than existing laser treatments, it may compete also with contact lenses and eyeglasses solutions.
  • An Onlay made of a biocompatible material that is highly permeable yet has sufficient surface characteristics to stimulate stable and confirm growth and attachment of the corneal epithelium over its outer surface is still a long-felt need. Also, a stable Onlay which does not to degrade over time, does not induce immune response or scarring of the cornea and administrated via a minimal surgical invasiveness is still required.
  • Keratoconus is an illness of the cornea, which usually causes a weakening and thinning of the corneal stroma and leads to vision disorders. It affects about 200,000 patients in the US alone.
  • treatments exist for Keratoconus including contact lenses for early stages of the disease, methods of stiffening of the cornea, and corneal transplantation for patients with progressive keratoconus.
  • Other treatments involve the grafting of a synthetic and rigid ringshaped graft into the corneal stroma.
  • Hyperopia is the refractive disorder of the human eye, leading to the inability to focus on close objects and therefore results in far-sightless. It affects about 50% of the population in the US above the age of 40, and about 8% of children at age 6.
  • the treatments of hyperopia include regular wearing of eyeglasses or contact lenses, or alternatively, vision-correction laser surgeries as PRK, LASIK, SMILE, and RLE, see e.g., Tran, Khai, and Andrea Ryce. "Laser Refractive Surgery for Vision Correction: A Review of Clinical Effectiveness and Costeffectiveness.” (2018).
  • the technology of present invention is generally directed to a corneal graft for treating either or both Keratoconus and visual impairment, and selected from (i) an Onlay comprises or coated by at least one member of Group A, consisting of biocompatible synthetic materials; at least one member of Group B, consisting of at least one type of biological polymer; and optionally, at least one member of Group C, consisting of at least one type of protein and (ii) an intrastromal corneal lenticule graft, configured to mimic native corneal stroma tissue by means of its optical properties, mechanical properties, permeability and interaction with corneal stromal cells; wherein at least one portion of the lenticule comprises or coated by at least one member of Group D, consisting of transparent crosslinked hydrogel; at least one member of Group E, consisting of collagen; collagen methacrylate, collagen derivatives/fraction, collagen-like peptide(s), recombinant mammal collagen, mammal- sourced collagen; and optionally, at least one member of Group F, consisting
  • Some embodiments of the invention disclose the corneal graft as defined above, wherein collagen of Group E is used to make hydrogels of Group D.
  • an Onlay comprises or coated by at least one member of Group A, consisting of biocompatible synthetic materials; at least one member of Group B, consisting of at least one type of biological polymer and optionally at least one member of Group C, consisting of at least one type of protein.
  • Group A consists at least one of the following: 2-(hydroxyethyl)methacrylate (HEMA), HEA, methyl methacrylate (MMA), methacrylic acid (MAA), 2-methacryloyl-oxy ethyl phosphorylcholine (MPC), polyethylene glycol (PEG), poly caprolactone (PCL), polyvinyl alcohol (PVA), polyethylene glycol diacrylate, polyethylene diacrylamide, polyethylene glycol dimethacrylate and any mixture or combination thereof
  • Some embodiments of the invention disclose an Onlay as defined in any of the above, wherein the Group B consists at least one of the following: collagen, recombinant mammals’ collagen, collagen methacrylate (ColMA), gelatin, gelatin methacrylate (GelMA), collagen derivatives/fraction, collagen-like peptide(s), Elastin, mixtures thereof, and combinations thereof.
  • Some embodiments of the invention disclose an Onlay as defined in any of the above, wherein the Onlay is coated by one or more of the followings: collagen, laminin, fibronectin or a combination thereof, e.g., thereby it is configured to allow epithelium growth.
  • Some embodiments of the invention disclose an Onlay as defined in any of the above, wherein the Onlay is made in a method consisting of (a pre-maturating one or more of the followings: seeding stem cells; Limbal stem cells; Epithelial cells on its anterior surface, and then (b) removing the cells prior to grafting.
  • Some embodiments of the invention disclose an Onlay as defined in any of the above, wherein the Onlay is made in a method consisting of incorporating one or more of the followings: limbal stem cells and epithelial cells, on its anterior surface.
  • Some embodiments of the invention disclose an Onlay as defined in any of the above, wherein the Onlay is made by one or more techniques selected from a group consisting of molding, 3D-printing, laser-ablating and a combination thereof; e.g., thereby providing for optimal and/or patient-specific vision-correction.
  • Some embodiments of the invention disclose an Onlay as defined in any of the above, wherein the Onlay is made by 3D-printing to shape for optimal and/or patient-specific visioncorrection.
  • Some embodiments of the invention disclose an Onlay as defined in any of the above, wherein the Onlay is made in a method consisting of laser-ablating to the required shape for optimal and/or patient-specific vision-correction.
  • Some embodiments of the invention disclose an Onlay as defined in any of the above, wherein Onlay comprises sub-micron sized pores, [configured to allow permeability of oxygen, glucose and nutrients].
  • Some embodiments of the invention disclose an Onlay as defined in any of the above, wherein the Onlay is at least partially made of recombinant mammals, e.g., human collagen.
  • Some embodiments of the invention disclose an Onlay as defined in any of the above, wherein the Onlay is characterized by that one or more of the following is held true: (a) the Onlay has an optical refractive index which is similar to the native corneal stroma, to avoid light scattering and/or reflections; (b) the Onlay is at least partially blocks UV light; (c) the Onlay is coated by recombinant human collagen; and (d) the Onlay is marked for the correct orientation by a laser engraving, mechanical pressure, pigmented ink, or a combination thereof.
  • refractive index depends on the specific gravity of the hydrogel.
  • the hereto provided refractive index is very close to water (i.e., 1.34) whereas refractive index of the cornea is ranging from 1.34 to 1.38.
  • Some embodiments of the invention disclose a method for treating visual impairment, comprising a step of grafting an Onlay as defined in any of the above.
  • Some embodiments of the invention disclose a method for grafting an Onlay as defined in any of the above.
  • Some embodiments of the invention disclose a method for grafting an Onlay as defined in any of the above, wherein at least one of the following is held true: (a) the method further comprising a step of shaping the Onlay using a laser after grafting; (b) the method further comprising a step of shaping the Onlay using a laser after grafting and a maturation period; e.g., useful in the case of relapsed visual acuity disorder; and (c) the method further comprising a step of utilizing an insertion tool; e.g., to avoid damage of the lenticule and/or the cornea, and to eliminate corneal epithelial cells present inside the cornea after grafting.
  • an insertion tool e.g., to avoid damage of the lenticule and/or the cornea, and to eliminate corneal epithelial cells present inside the cornea after grafting.
  • Some embodiments of the invention disclose a corneal device for treating visual impairment, comprising an Onlay as defined in any of the above.
  • Some embodiments of the invention disclose an intrastromal corneal lenticule graft for either or both Keratoconus treatment and vision-correction, configured to mimic native corneal stroma tissue by means of its optical properties, mechanical properties, permeability and interaction with corneal stromal cells; wherein at least one portion of the lenticule comprises or coated by at least one member of Group D, consisting of transparent crosslinked hydrogel; at least one member of Group E, consisting of collagen; collagen methacrylate, recombinant mammal collagen, collagen derivatives/fraction, collagen-like peptide(s), mammal- sourced collagen; and optionally, at least one member of Group F, consisting of Keratocytes and/or stem cells and any combination thereof.
  • Group D consisting of transparent crosslinked hydrogel
  • Group E consisting of collagen
  • at least one member of Group F consisting
  • Some embodiments of the invention disclose an intrastromal corneal lenticule graft as defined above, configured to at least partially mimic the native tissue. [0033] Some embodiments of the invention disclose an intrastromal corneal lenticule graft as defined in any of the above, wherein the lenticule is configured to integrate with surrounding corneal stroma tissue.
  • Some embodiments of the invention disclose an intrastromal corneal lenticule graft as defined in any of the above, wherein the lenticule is configured to be at least partially remodeled in the eye and replaced by native tissue in a way that the remodeling is not affecting the lenticule geometry and/or optical functionality.
  • Some embodiments of the invention disclose an intrastromal corneal lenticule graft as defined in any of the above, wherein the lenticule is at least partially made of recombinant mammal, e.g., human collagen.
  • Some embodiments of the invention disclose an intrastromal corneal lenticule graft as defined in any of the above, wherein the lenticule is coated by recombinant human collagen.
  • Some embodiments of the invention disclose an intrastromal corneal lenticule graft as defined in any of the above, wherein the lenticule is at least partially made of mammal, e.g., human sourced collagen.
  • Some embodiments of the invention disclose an intrastromal corneal lenticule graft as defined in any of the above, wherein the lenticule comprises either or both Keratocytes and/or stem cells.
  • Some embodiments of the invention disclose an intrastromal corneal lenticule graft as defined in any of the above, wherein the lenticule is configured to be tailored made for a specific patient.
  • Some embodiments of the invention disclose an intrastromal corneal lenticule graft as defined in any of the above, wherein at least one of the following is held true: (a) the lenticule is configured for a spherical refractive correction in the range between about -10 diopters to about 15 diopters; (b) the lenticule is characterized by a non-spherical shape for astigmatism vision correction; (c) the lenticule is characterized by shape for patient-tailored vision correction; (d) the lenticule has an optical refractive index which is similar to the native corneal stroma, to avoid light scattering and/or reflections; (e) the lenticule has elastic modulus between about 50kPA and about 13MPa; (f) the lenticule has permeability to glucose, oxygen, and proteins which is comparable to native corneal stroma tissue, i.e., having a permeability which is in the range of about 50% to about 200% of an healthy cornea;
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft for either or both Keratoconus treatment and visioncorrection, configured to mimic native corneal stroma tissue by means of its optical properties, mechanical properties, permeability and interaction with corneal stromal cells; wherein the method comprising steps of (a) providing at least one portion of the lenticule to comprise or to be coated by at least one member of Group D consisting of transparent crosslinked hydrogel; at least one member of Group E, consisting of collagen; collagen solution, collagen methacrylate, recombinant mammal collagen, collagen derivatives/fraction, collagen-like peptide(s), mammal- sourced collagen; and optionally, at least one member of Group F, consisting of Keratocytes and/or stem cells and any combination thereof; and (b) processing the same by a method selected from 3D printing, laser ablating, molding, and any combinations thereof.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined above.
  • the method further characterized by step of 3D printing and/or molding a collagen solution, and crosslinking the same to form a transparent hydrogel.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above.
  • the method further characterized by step of concentrating collagen solution to a predefined value in the rage of about 1 to about 15% w/v.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above. The method further characterized by step of centrifuging collagen solution.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above.
  • the method further characterized by step of 3D printing the collagen solution to a predefined shape.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above. The method further characterized by step of molding of the collagen solution. [0047] Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above; wherein the crosslinking is provided by admixing photo -initiator to the collagen solution and applying light on it.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above; wherein the crosslinking is provided by admixing N-(3 -dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) and/or N- hydroxysuccin-imide (NHS) to the collagen solution.
  • EDC N-(3 -dimethylaminopropyl) -N'-ethylcarbodiimide
  • NHS N- hydroxysuccin-imide
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above; wherein the crosslinking is provided in a controlled temperature and humidity.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above; wherein the is provided in a controlled gas mixture environment, other than air.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above; wherein the molding is provided by designated tool, having the predefined geometry and surface roughness.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above; wherein the tool is made of a material selected from a group consisting of composite material, glass, PP, PE, PET, PDMS, PTFE, FEP, and any combination thereof.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above; wherein the solution is provided to form hydrogel with an optical refractive index which is similar to the native corneal stroma, thereby configured to avoid light scattering and/or reflections.
  • Some embodiments of the invention disclose a method for the production of an intrastromal corneal lenticule graft as defined in any of the above; wherein the at least one of the following is held true: (a) the solution is configured to form a hydrogel characterized by elastic modulus ranging between about 50kPA to about 13MPa; (b) the solution is configured to form a hydrogel characterized with permeability to glucose, oxygen and proteins which is at least about 50% of the permeability of native corneal stroma tissue; (c) the solution is configured to form a hydrogel which at least partially blocks UV light. [0055] Some embodiments of the invention disclose a method of implementing an intrastromal corneal lenticule graft as defined in any of the above.
  • Some embodiments of the invention disclose a method of implementing an intrastromal corneal lenticule graft as defined in any of the above; wherein prior to grafting, a step of marking the transparent crosslinked hydrogel for the correct orientation is provided by one or more members of a group consisting of a laser engraver, mechanical press, pigmented ink, or a combination thereof.
  • Some embodiments of the invention disclose methods of grafting the intrastromal lenticule comprising a step of using a laser system, including an excimer laser, e.g., Dippel, Eric J., et al. "Randomized controlled study of excimer laser atherectomy for treatment of femoropopliteal in-stent restenosis: initial results from the EXCITE ISR trial (EXCImer Laser Randomized Controlled Study for Treatment of Femoropopliteal In-Stent Restenosis)" JACC: Cardiovascular Interventions 8.1 Part A (2015): 92-101; and/or femtosecond laser, e.g., Soong H. K. and Malta J.B “Femtosecond lasers in ophthalmology” Am J Ophthalmol 2009; 147: 189- 197.
  • an excimer laser e.g., Dippel, Eric J., et al.
  • femtosecond laser e.g., Soong H. K
  • Some embodiments of the invention disclose a method of implementing an intrastromal corneal lenticule graft as defined in any of the above, comprising step ablating the lenticule by laser to shape and size.
  • Some embodiments of the invention disclose a method of implementing an intrastromal corneal lenticule graft as defined in any of the above, comprising scanning the lenticule by an OCT, simultaneously to the step of ablating, hence forming a closed-loop feedback mechanism.
  • Some embodiments of the invention disclose a method of implementing an intrastromal corneal lenticule graft as defined in any of the above; wherein the laser system comprises excimer and/or a femtosecond laser.
  • Some embodiments of the invention disclose a method of grafting an intrastromal corneal lenticule graft as defined in any of the above, comprising a step of using a laser system, including an excimer laser and/or a femtosecond laser.
  • Some embodiments of the invention disclose a method of grafting an intrastromal corneal lenticule graft as defined in any of the above, wherein the laser system is used to create a corneal pocket.
  • Some embodiments of the invention disclose a method of grafting an intrastromal corneal lenticule graft as defined in any of the above, comprising a step of shaping the intrastromal lenticule, by means of laser within patient’s cornea, after grafting the same.
  • Some embodiments of the invention disclose a method of grafting an intrastromal corneal lenticule graft as defined in any of the above, comprising step of optimizing depth and position within the cornea, which was optimized based on OCT scans and mechanical properties measurement of the cornea.
  • Some embodiments of the invention disclose a method of grafting an intrastromal corneal lenticule graft as defined in any of the above, comprising step of utilizing an insertion tool to avoid damage of the lenticule and/or the cornea, and to eliminate corneal epithelial cells present inside the cornea after grafting.
  • Some embodiments of the invention disclose a method of grafting an intrastromal corneal lenticule graft as defined in any of the above, wherein the grafting of the lenticule is provided before or after a corneal crosslinking.
  • FIG. 1 schematically illustrates a corneal Onlay according one embodiment of the present invention
  • FIG. 2 schematically illustrates a corneal intrastromal lenticule graft according to one embodiment of the present invention, reference is made to currently available link https://commons.wikimedia.Org/wiki/File:Hypermetropia.svg which is incorporated herein; and
  • FIG. 3 shows OCT scans of an intrastromal lenticule graft before and after laser processing, in accordance with a few embodiments of the present invention.
  • the hereto disclosed technology provides novel corneal grafts; and more specifically, bioengineered corneal Onlays and Inlays.
  • the invention also discloses novel corneal grafts’ compositions, methods for their production and inserting, transplanting and/or grafting into the cornea, and methods for treating a medical condition of a patient.
  • corneal graft and “corneal implant” interchangeably refer hereinafter to a bioengineered construct that is designed to be implantable in a mammalian (e.g., human) eye and to have properties of at least part of a cornea. The terms further refer to either and both corneal Inlays and Onlays.
  • Cornea transplant is a surgical procedure to modify properties of part of the cornea with corneal tissue from a donor or a “synthetic” cornea or portions thereof.
  • Intrastromal corneal lenticule graft interchangeably refer to an intracorneal Inlay, e.g., an alloplastic lenticule placed at the interface of the free corneal cap and the stromal bed or in a corneal pocket.
  • Onlay refers to corneal graft, namely an implantable lens or portion thereof, that is placed between Bowman's membrane of the cornea of an eye and the corneal epithelium of the eye.
  • grafting and “implanting” interchangeably refers, when relevant, to medical procedures of inserting, grafting, and transplanting of corneal Inlay or corneal Onlay onto or into the cornea.
  • a first aspect of the invention is to disclose affordable, stable, biocompatible, easily- implantable and patient-tailored corneal Onlay:
  • the Onlay comprises or coated by at least one member of Group A, consisting of biocompatible synthetic materials; at least one member of Group B, consisting of at least one type of biological polymer and optionally at least one member of Group C, consisting of at least one type of protein.
  • the thickness of the grafted member is ranging between about 30 to about 200 microns. Diameter of about 6-8 mm. Refractive correction is ranging from about -15D to about +20D, spherical or with astigmatism correction. Possibly having thinner periphery. Possibly incorporating marks for astigmatism axis alignment.
  • the Onlay is made of natural occurring compositions, including polymers.
  • polymers are selected from a group consisting, inter alia, collagen and/or collagen methacrylate, human, animal or recombinant source, e.g., about 1 to about 15% w/v; fibronectin; elastin, laminin and any combination thereof.
  • biocompatible synthetic polymers including polymers that are selected from a group consisting, inter alia, 2-hydroxyl methacrylate (HEMA); 2 -hydroxy ethylacrylate (HEA); Methyl methacrylate (MM A); Methacrylic acid (MAA); Methacryloyloxy ethyl phosphorylcholine (MPC); Poly(ethylene glycol) (PEG) and/or Poly(ethylene glycol) diacrylate (PEGDA) and/or poly(ethylene glycol) dimethacrylate (PEGDMA), Multi-arm Poly(ethylene glycol) diacrylate; Poly(e-caprolactone) (PCL); Poly(vinyl alcohol) (PVA); Photo -initiator LAP; Irgacure 2959; APS-TEMED and any combination thereof.
  • HEMA 2-hydroxyl methacrylate
  • HEMA 2-hydroxyl methacrylate
  • HEMA 2-hydroxyl methacrylate
  • HEMA 2-hydroxy ethylacrylate
  • MM A Me
  • the Onlay is characterized by the following parameters: it is transparent (e.g., more than 85% visible light transmission, less than 5% haze); stiffness similar to natural cornea (about 50kPa to about 13MPa), to enable healthy epithelial cells growth; it is permeable to glucose and proteins, similarly to native corneal stroma and not less than about 10 A -6 cm A 2 per sec for glucose; it enables epithelium cells growth on anterior surface and the formation of healthy epithelial layers; it comprises high water content, it is non-degradable or has long term stability; it is biocompatible with low immune response, not induce fibrosis, and it can be shaped with laser processing and/or 3D printing or molding.
  • the Onlay is substantially mainly synthetic, as the enzymatic activity in the epithelium is relatively high, and natural hydrogel would be degraded significantly after grafting. It is possible that Onlay based on natural compounds would be remodeled by the body and form native tissue.
  • a transparent, permeable hydrogel can be grafted into the cornea, below the epithelium layer, to fix the curvature of the cornea.
  • Onlays can be referred to as permanent bio-compatible contact lenses.
  • the development of an Onlay graft has two main challenges: (1) the surface of the Onlay should be protein -based in order to enable normal epithelium growth above it. Yet, the Onlay needs to be non-degradable in order achieve stable vision correction; and, (2) the Onlay must be permeable to glucose and nutrients in order to nourish the epithelium layer.
  • a healthy epithelium is essential as it acts as a protective barrier to keep bacteria, dust and other foreign substances from penetrating the eye.
  • the Onlay comprises a hydrogel layer and a coating layer.
  • the hydrogel layer is made of biocompatible synthetic polymer, with additional bio-mimicking substances, and the coating is made of biological proteins which present binding sites and other nutrients and indicators for the epithelial cells.
  • the Onlay lens graft can be molded, 3D printed, or laser ablated to the required curvature and geometry.
  • the grafted lenticules are designed specifically to the patient, allowing better correction of the refractive disorder.
  • the preparation methods consists, inter alia, the following steps: (a) mixing materials; (b) injecting into mold and/or 3D printing; (c) photo and/or thermal polymerization; (d) washing out residues; (e) possibly laser processing; (f) possibly applying an additional coating layer to allow cells growth; (g) possibly seeding epithelial and/or limbal and/or stem cells on top of the Onlay for a maturation period (see below); (h) testing (refraction, transparency, homogeneity etc.); and (i) applying thrombin and/or fibrinogen on the posterior side
  • the maturation-period is provided herein useful for seed cells in vitro on top of the Onlay, after or instead the coating process, and let them mature the Onlay and produce binding sites and/or ECM and/or collagen for better and faster epithelization after grafting. After the maturation period the cells are removed to minimize any immune response, and the Onlay is tested and grafted.
  • graft of the Onlay is provided useful by the following method: (a) removing the epithelium and exposing the Bowman’s layer; (b) applying fibrinogen and/or thrombin on the Bowman’s layer; (c) aligning and attaching the Onlay to the cornea for about 10 to about 60 seconds, possibly with a designated tool; (d) Possibly applying protective contact lens to prevent dry eyes and infections; and (e) possibly post-treating with nutrients, steroids, antibiotics and lubricants for up to four weeks.
  • shaping is provided by one of the following techniques: Laser processing of the lenticule before grafting, according to patient’s OCT scan; Laser processing of the lenticule immediately after grafting; and/or laser processing of the lenticule after a maturation period (about 1 day to about 12 weeks), during which the cornea heals and possibly changes its geometry.
  • a second aspect of the invention is to disclose affordable, stable, biocompatible, easily - implantable and patient-tailored corneal Inlay, also termed as intrastromal corneal lenticule graft:
  • intrastromal corneal lenticule graft is provided useful for either or both Keratoconus treatment and vision-correction (e.g., hyperopia).
  • the intrastromal corneal lenticule graft is configured to mimic native corneal stroma tissue by means of its optical properties, mechanical properties, permeability and noninteraction with corneal stromal cells.
  • At least one portion of the lenticule comprises or coated by at least one member of Group D, consisting of transparent crosslinked hydrogel; at least one member of Group E, consisting of collagen; collagen methacrylate, collagen derivatives/fraction, collagen-like peptide(s), recombinant mammal collagen, mammal- sourced collagen; and optionally, at least one member of Group F, consisting of Keratocytes and/or stem cells and any combination thereof.
  • a collagen-based hydrogel of the present invention can be grafted into the corneal stroma, mimicking the functionality and characteristics of the natural tissue.
  • the grafted lenticules are designed specifically for the patient, allowing better correction of the refractive disorder.
  • the graft is made of recombinant human collagen with additional proteins and polymers, allowing the graft to integrate and fuse with surrounding tissue over time.
  • stem cells or keratocytes cells are incorporated into or on the surface of the graft.
  • the graft can be grafted into a corneal flap made by a laser.
  • the graft is molded, 3D printed, or laser ablated to the required curvature and geometry.
  • FIG 2 schematically illustrates an intrastromal corneal lenticule graft according to a few embodiments of the present invention.
  • the intrastromal lenticule graft is characterized by thickness ranging between about 30 to about 400 microns.
  • the diameter is ranging from about 4 to about 9 mm.
  • Refractive correction varies from about -10D to about +15D, spherical or with astigmatism correction, or customized for a specific patient’s corneal condition.
  • the lenticule is characterized by a possible thinner periphery and/or a possible mark for astigmatism axis alignment.
  • intrastromal lenticule is made by compositions comprising collagen.
  • the collagen is selected from a group consisting of collagen and/or Collagen methacrylate; collagen of human, animal, or recombinant source, e.g., from about 1% to about 15% w/v., preferably between about 6 and about 13% w/v, where native corneal stroma has about 13% collagen.
  • intrastromal lenticule is made by compositions comprising additional natural polymers. Including those selected from a group consisting of gelatin and/or gelatin methacrylate, hyaluronic acid (HA) and/or N-(2-hydroxypropyl) methacrylamide (HAMA), elastin, fibronectin, or a mixture thereof.
  • additional natural polymers Including those selected from a group consisting of gelatin and/or gelatin methacrylate, hyaluronic acid (HA) and/or N-(2-hydroxypropyl) methacrylamide (HAMA), elastin, fibronectin, or a mixture thereof.
  • intrastromal lenticule is made by compositions comprising biocompatible synthetic polymers, including those selected from a group consisting of PEG and its derivatives (PEGDA, PEGDMA, multi-arm PEG); 2-Hydroxy ethyl methacrylate HEMA; HEA; PCL; poly(lactic-co-glycolic acid) (PLGA); MPC; and/or additional proteins, such as Laminin, as defined in Aumailley, Monique, et al. "A simplified laminin nomenclature.” Matrix biology 24.5 (2005): 326-332.
  • biocompatible synthetic polymers including those selected from a group consisting of PEG and its derivatives (PEGDA, PEGDMA, multi-arm PEG); 2-Hydroxy ethyl methacrylate HEMA; HEA; PCL; poly(lactic-co-glycolic acid) (PLGA); MPC; and/or additional proteins, such as Laminin, as defined in Aumailley, Monique, et al
  • intrastromal lenticule is made by utilizing photo-initiator(s) crosslinker, such as LAP, and commercially available Irgacure 2959 product by Sigma-Aldrich, USA. It possibly may comprise biocompatible dye for easy handling.
  • the lenticule is made utilizing other crosslinkers, such as EDC and/or NHS molecules.
  • the intrastromal lenticule graft of the present invention is characterized by the following parameters: it is transparent ( ⁇ 85% visible light transmission, >3% haze); its stiffness is similar to central corneal stroma (from about 50kPa to about 13MPa, e.g., about 150kPa); it is stiff enough to allow the grafting procedure; it is permeable to glucose, oxygen, and proteins; it has high water content; it is non- degradable or slow degradable and can be slowly remodeled by the body and replaced with native tissue without affecting its geometry and optical properties; it is not stimulating an immune response and can be shaped with laser processing and/or 3D printing or molding.
  • the intrastromal lenticule of the present invention is prepared by various methods, including those selected from a group consisting of the following steps: mixing materials; injecting into mold and/or pressing in mold and/or 3D printing; UV and/or thermal and/or chemical casting; washing out residues; possibly additional step(s) of laser processing; coating with soaking in collagen and/or proteins and/or nutrients
  • the intrastromal lenticule of the present invention is grafted by various other methods, including those selected from a group consisting steps of providing a corneal flap using a mechanical tool or PRK and/or LASIK excimer laser; providing a corneal pocket using a mechanical tool or femtosecond laser (e.g., SMILE procedure); possibly to use a designated tool and/or viscoelastic material for the insertion and alignment in the pocket.
  • a mechanical tool or femtosecond laser e.g., SMILE procedure
  • an Inlay is made by lyophilized human collagen type I, mixed in 20mM hydrochloric acid to get 6-9% (w/v) collagen solution. Additional 1 to 10% v/v HE A solution is mixed with the collagen, and l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide (EDC) is admixed to form 0.5% (w/v) solution. The yield is thoroughly mixed and centrifuged, and poured into poly propylene (PP) contact lens molds. The molds are inserted into nitrogen chambers at 10 degrees C for 12 to 24 hours.
  • PP poly propylene
  • lenticules are washed in saline for 24 to 72 hours. Washed hydrogel is then placed in an Excimer Laser system and ablated to form a lenticule with optical power according to an OCT scan of the patient’s eyes. The resulting Inlay lenticule is further scanned by an OCT system to assure its optical properties, and possibly, lenticules are marked using Gentian Violet surgical marker by an arrow shaped and an “S” shaped marks, for easier grafting orientation.
  • FIG. 3 shows OCT scans of an intrastromal lenticule graft before and after laser processing, in accordance with a few embodiments of the present invention.
  • EDC-NHS crosslinking a. Mix the collagen with EDC/NHS . b. Place the collagen at the center of a mold. c. incubate the mold in at least 50% humidity for at least 12 hours.
  • EDC-NHS crosslinking a. Mix the collagen with EDC/NHS. b. Place the collagen at the center of a mold. c. incubate the mold in at least 50% humidity for at least 12 hours.
  • UV crosslinking by exposing the films to UV light at the light crosslinker surface for the required time.
  • compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Cell Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Zoology (AREA)
  • Urology & Nephrology (AREA)
  • Botany (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials Engineering (AREA)
  • Developmental Biology & Embryology (AREA)
  • Hematology (AREA)
  • Manufacturing & Machinery (AREA)
  • Dispersion Chemistry (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)

Abstract

La présente invention concerne des greffes cornéennes mises au point par des techniques biologiques, destinées au traitement d'un kératocône et d'une déficience visuelle, sélectionnées parmi (i) une greffe cornéenne apposée comprenant ou étant revêtue par au moins un élément du groupe A, constitué de matériaux synthétiques biocompatibles; au moins un élément du groupe B, constitué d'au moins un type de polymère biologique et éventuellement d'au moins un élément du groupe C, constitué d'au moins un type de protéine et (ii) une greffe de lenticule cornéen intrastromal, conçue pour imiter un tissu de stroma cornéen natif au moyen de ses propriétés optiques, de ses propriétés mécaniques, de sa perméabilité et de son interaction avec des cellules stromales cornéennes; au moins une partie dudit lenticule comprenant ou étant revêtue par au moins un élément du groupe D, constitué d'un hydrogel réticulé transparent; au moins un élément du groupe E, constitué de collagène; un méthacrylate de collagène, un collagène de mammifère recombinant, un collagène d'origine mammifère; et éventuellement, au moins un élément du groupe F, constitué de kératocytes et/ou de cellules souches et toute combinaison de ces derniers. La présente invention concerne en outre des compositions, des procédés de production, de mise en œuvre et de traitement d'indications médicales par la greffe cornéenne susmentionnée.
EP23906270.6A 2022-12-20 2023-12-20 Greffes cornéennes mises au point par des techniques biologiques Pending EP4637631A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263433932P 2022-12-20 2022-12-20
PCT/IL2023/051288 WO2024134653A1 (fr) 2022-12-20 2023-12-20 Greffes cornéennes mises au point par des techniques biologiques

Publications (1)

Publication Number Publication Date
EP4637631A1 true EP4637631A1 (fr) 2025-10-29

Family

ID=97228702

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23906270.6A Pending EP4637631A1 (fr) 2022-12-20 2023-12-20 Greffes cornéennes mises au point par des techniques biologiques

Country Status (1)

Country Link
EP (1) EP4637631A1 (fr)

Similar Documents

Publication Publication Date Title
Ahearne et al. Designing scaffolds for corneal regeneration
Mahdavi et al. Bioengineering approaches for corneal regenerative medicine
US20230172704A1 (en) Bioengineered corneal grafts
CN101018513B (zh) 视力增强眼科器件及相关方法和组合物
US5114627A (en) Method for producing a collagen hydrogel
US4983181A (en) Collagen hydrogel for promoting epithelial cell growth and artificial lens using the same
CN1243573C (zh) 预制的角膜组织镜片及其制备方法(ii)
US20070182920A1 (en) Corneal Onlays and Related Methods
US9937033B1 (en) Corneal lenslet implantation with a cross-linked cornea
MXPA05002669A (es) Dispositivos y metodos para mejorar la vision.
WO2024134653A1 (fr) Greffes cornéennes mises au point par des techniques biologiques
US10314690B1 (en) Method of corneal transplantation or corneal inlay implantation with cross-linking
CN101522133A (zh) 可植入的光学系统，其开发和应用的方法
US10709546B2 (en) Intracorneal lens implantation with a cross-linked cornea
WO1988002622A1 (fr) Lentille de collagene-hydrogel pour promouvoir la croissance des cellules epitheliales
US11259914B2 (en) Molding or 3-D printing of a synthetic refractive corneal lenslet
US20240122697A1 (en) Bioengineered corneal grafts
RU2084468C1 (ru) Способ получения биосовместимого полимерного материала
EP4637631A1 (fr) Greffes cornéennes mises au point par des techniques biologiques
CN120129542A (zh) 一种低溶胀脱细胞角膜及其制备方法和应用
US12383393B2 (en) Ablatable corneal inlay for correction of refractive errors and/or presbyopia
US9744029B1 (en) Method of preventing capsular opacification and fibrosis utilizing an accommodative intraocular lens implant
RU2124331C1 (ru) Кератопротез
US20240216123A1 (en) Scleral Lens For Correction Of Keratoconus And/Or Presbyopia
US20250177119A1 (en) Ablatable Corneal Inlay For Simultaneous Correction Of Refractive Errors And Presbyopia

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

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

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

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20250718

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR