WO2023142471A1 - 一种大直径人工角膜内皮片及其应用 - Google Patents

一种大直径人工角膜内皮片及其应用 Download PDF

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WO2023142471A1
WO2023142471A1 PCT/CN2022/114691 CN2022114691W WO2023142471A1 WO 2023142471 A1 WO2023142471 A1 WO 2023142471A1 CN 2022114691 W CN2022114691 W CN 2022114691W WO 2023142471 A1 WO2023142471 A1 WO 2023142471A1
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Prior art keywords
artificial
endothelial sheet
corneal
corneal endothelial
diameter
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PCT/CN2022/114691
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English (en)
French (fr)
Inventor
史伟云
王婷
周庆军
张晓玉
王红卫
Original Assignee
山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院)
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Application filed by 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) filed Critical 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院)
Priority to PCT/CN2022/114691 priority Critical patent/WO2023142471A1/zh
Priority to CN202280006351.6A priority patent/CN116322812B/zh
Publication of WO2023142471A1 publication Critical patent/WO2023142471A1/zh

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    • 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, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
    • 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
    • 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

Definitions

  • the invention relates to a large-diameter intraocular corneal implant, in particular to an artificial corneal endothelial sheet with a suction cup (circular, circular) and holes (full hole, half hole, plus loop), which belongs to medical equipment field.
  • a suction cup circular, circular
  • holes full hole, half hole, plus loop
  • the corneal endothelial cell layer is the innermost layer of the cornea, and its structural integrity and sound function are important factors for maintaining the normal physiological metabolism of the cornea. Decreased endothelial cell density and endothelial pump dysfunction will lead to corneal endothelial decompensation, manifested as corneal edema and turbidity, seriously affecting vision, patients with obvious eye pain, and decreased quality of life. It is one of the more common complications after cataract surgery and other internal eye surgery. First, it is also the end-stage manifestation of primary diseases such as corneal endothelial dystrophy. Initially, the only treatment for corneal endothelial decompensation is penetrating keratoplasty (PKP).
  • PGP penetrating keratoplasty
  • endothelial keratoplasty EK
  • EK endothelial keratoplasty
  • DSEK Descemet stripping endothelial keratoplasty
  • DMEK Descemet's membrane endothelial keratoplasty
  • some Patients may experience corneal graft endothelial decompensation due to excessive loss of corneal endothelial cells during the operation, and 35% of patients have corneal graft detachment after surgery and need one or more anterior chamber gas injections.
  • the EndoArt product of Aiyong Medical Co., Ltd. is an artificial endothelial patch with a diameter of 6.0mm and a thickness of 50 ⁇ m. Unlike the DMEK donor endothelial patch, it provides an impermeable barrier and is attached to the surface of the patient's posterior corneal stroma , prevent the inflow of aqueous humor, thereby preventing corneal stromal edema.
  • the diameter of the endothelial sheet described in PCT patent WO 2020/115605 A1 of Daphna of Aiyong Medical Co., Ltd. is 4.2-7.0mm.
  • the purpose of the present invention is to provide a large-diameter artificial corneal endothelial sheet; a further purpose is to make it function as an isolation room through the design of oxygen-permeable holes (full holes, lace, and loops). Eliminate corneal edema at the same time as the water barrier; the further purpose is to use the suction cup (round, oval, ring) to make it have the advantages of high adhesion and high oxygen permeability, reduce postoperative corneal graft displacement, Complications such as shedding.
  • the present invention is based on the foldable transparent optical material, which is made into a large-diameter artificial corneal endothelial sheet with curvature and with suckers and/or oxygen-permeable holes around the periphery.
  • the artificial corneal endothelial sheet provided by the invention has a total diameter of 7.0-9.0 mm, a thickness of 25.0-70.0 ⁇ m, a radius of curvature of 6.0-9.0 mm, and oxygen-permeable holes; the design of the oxygen-permeable holes includes punching (all hole), lace-like (half-hole), and one of peripheral loops, or two or more of punching (full holes), lace-like (half-hole) and peripheral loops.
  • the artificial corneal endothelial sheet includes a central optical zone 1 and a peripheral zone 2, the diameter of the central optical zone 1 is 5.0-7.0 mm, the peripheral zone 2 is located outside the central optical zone 1, and the oxygen-permeable hole 3 Located in the peripheral zone 2, the number of oxygen permeable holes is 2-8, and the total area is 0.5-5.3mm 2 .
  • the shape of the oxygen permeable holes 3 includes circular, elliptical, semicircular, and lace-shaped, and is evenly or unevenly distributed in the peripheral area 2 .
  • the oxygen permeable holes 3 are perforated in a circular or oval shape, and the diameter of the oxygen permeable holes 3 is 0.2-0.6 mm.
  • the oxygen permeable holes 3 adopt a lace-like design, the number is 4-8, and the shape is lace-shaped, semicircular or semi-elliptical.
  • the height of the oxygen permeable holes 3 is 0.5-0.75mm, and the side arc diameter is 1.0- 1.5mm.
  • the oxygen permeable hole 3 adopts a loop design, and the edge of the artificial corneal endothelial sheet is provided with a loop 5 , and the loop 5 and the central optical zone 1 or the peripheral zone 2 form the oxygen permeable hole 3 .
  • the edge of the artificial corneal endothelial sheet is provided with a loop 5, and the loop 5 forms an oxygen permeable hole 3 with the central optical zone 1 or the peripheral zone 2, and the height of the oxygen permeable hole 3 is 0.5-0.75mm ,
  • the side arc radius is 1.0-1.5mm.
  • the oxygen permeable hole 3 is a hole or gap formed on the outer edge of the central optical zone 1 or the peripheral zone 2 between the haptic 5 and its two ends, and its shape is crescent, ellipse, semicircle or semiellipse, etc.
  • the oxygen permeable holes 3 formed in the peripheral region 2 and the oxygen permeable holes 3 formed by the haptics coexist.
  • the artificial corneal endothelial sheet is provided with an oxygen permeable hole 3 and a suction cup 4, the suction cup 4 is located on the front side of the artificial corneal endothelial sheet, the depth is 5.0-10.0 ⁇ m, and the diameter or width is 0.2-0.5 mm.
  • the suction cup 4 is located on the front side or the convex surface of the artificial corneal endothelial sheet, that is, the side close to the posterior corneal stroma when the artificial corneal endothelial sheet is implanted into the anterior chamber of the human eye.
  • the suction cup 4 can be completely in the peripheral area 2, or It can be partly in the central optical zone 1.
  • the material of the artificial corneal endothelial sheet is an acrylic material selected from hydroxyethyl methacrylate/methyl methacrylate copolymer, polymethyl methacrylate, polyhydroxyethyl methacrylate, acrylic hydrogel glue, methacrylic hydrogel, etc.
  • the large-diameter artificial corneal endothelial sheet provided by the present invention is a transparent, non-degradable optical material, the design of the suction cup (circular, annular), and oxygen-permeable holes (including punching, lace-like, and peripheral loops), It can play a barrier role in isolating aqueous humor and eliminate corneal edema.
  • the suction cup and the oxygen-permeable hole increases the adhesion between the artificial endothelial sheet and the posterior corneal stroma from a physical point of view, and the large diameter can increase the stability of the endothelial sheet and reduce the risk of postoperative corneal graft loss.
  • the artificial endothelial sheet is extremely soft and easy to fold, and can be implanted in the anterior chamber with a small incision, without loading cells, and there is no need to consider the problem of cell destruction during the operation, which greatly reduces the difficulty of the operation, thereby reducing postoperative corneal endothelial damage. Complications such as excessive cell loss, corneal graft displacement or detachment.
  • the large-diameter corneal implant provided by the invention is expected to replace the traditional donor corneal endothelial graft and reduce the number of corneal transplants.
  • Fig. 1 is a three-dimensional schematic diagram of an artificial corneal endothelial sheet provided by the present invention.
  • Fig. 2 is a physical diagram of the artificial corneal endothelial sheet provided by the present invention.
  • Fig. 3 is a schematic plan view and a section view of artificial endothelial sheets perforated around the periphery of Examples 2, 3, and 4.
  • Fig. 4 is a schematic plan view and a section view of the lace-shaped artificial endothelial sheet in Example 6.
  • Fig. 5 is a schematic plan view of the loop-added artificial endothelial sheet in Example 7.
  • Fig. 6 is a slit lamp and OCT observation diagram of rabbit cornea in an animal experiment.
  • the "large-diameter artificial corneal endothelial sheet” refers to an artificial endothelial sheet with a diameter of 7.0-9.0 mm, and the large diameter is that the diameter of the artificial corneal endothelial sheet and corneal implants disclosed in the prior art is generally below 7 mm. Relatively speaking, the artificial corneal endothelial sheet provided by the present invention has a larger diameter.
  • the “suction cup” refers to the depression located on the front side or convex surface of the artificial corneal endothelial sheet, all or part of it in the peripheral area, and toward the rear side or concave surface of the artificial corneal endothelial sheet.
  • the cross-section of the sucker is circular or ring-shaped, and the bottom of the depression is hemispherical.
  • the suction cup diameter is the diameter of the largest cross-section of a circular suction cup.
  • the suction cup width is the width of the largest cross-section of the annular suction cup.
  • the suction cup depth is the depression depth of the circular or annular suction cup to the front side of the artificial corneal endothelial sheet.
  • the "haptics” refer to the semi-circular or semi-elliptical support portions of the peripheral region.
  • the arc radius of the oxygen permeable hole is the diameter of the circle where the oxygen permeable holes such as lace-shaped, semicircular, and semi-elliptical are located.
  • Oxygen permeable hole height the maximum diameter between the circle where the oxygen permeable holes such as lace-shaped, semi-circular, and semi-elliptical shapes are located and the circle where the inner skin sheet is located.
  • the posterior side or concave surface of the artificial corneal endothelium refers to the side close to the aqueous humor when the artificial corneal endothelium is implanted in the anterior chamber of the human eye.
  • the front side or convex side of the artificial corneal endothelium refers to the side close to the posterior corneal stroma when the artificial corneal endothelium is implanted into the anterior chamber of the human eye.
  • the present invention has no special limitation on the source of the artificial corneal endothelial sheet, and the source of the artificial corneal endothelial sheet known in the art can be used.
  • the large-diameter artificial corneal endothelial sheet is made by the Institute of Ophthalmology, Shandong First Medical University.
  • the material of the artificial endothelial sheet is acrylic ester, which can be selected from hydroxyethyl methacrylate/methyl methacrylate copolymer, polymethyl methacrylate, polyhydroxyethyl methacrylate, acrylic hydrogel, methyl methacrylate One or more of the base acrylic hydrogels.
  • the light transmittance of the artificial endothelial sheet increases gradually with the increase of the light wavelength in the wavelength range of 300-800nm, and can reach 79%-85% in the wavelength range above 400nm.
  • the artificial corneal endothelial sheet provided by the present invention includes a central optical zone 1 and a peripheral zone 2, and there is no obvious boundary between the central optical zone 1 and the peripheral zone 2, and the corneal endothelial sheet
  • the total diameter is 7.0-9.0mm
  • the thickness is 25.0-70.0 ⁇ m
  • the radius of curvature is 6.0-9.0mm
  • the diameter of the central optical zone 1 is 5.0-7.0mm
  • the peripheral zone 2 is located in the extension of the central optical zone 1, and contains at least 2 transparent
  • the oxygen hole 3 and the oxygen permeable hole 3 have a diameter of 0.2-0.6 mm and a total area of 0.5-5.3 mm 2 .
  • the oxygen-permeable hole 3 runs through the artificial corneal endothelium, is located in the peripheral area 2 in whole or in part, and forms a complete circle, semicircle, ellipse or other shape on the front and rear sides of the artificial endothelium shape (Fig. 1A, B, D, E).
  • the oxygen permeable hole 3 is located at the edge of the artificial corneal endothelial sheet peripheral area 2, forming incomplete shapes on the front and rear sides of the artificial endothelial sheet, such as semicircle, semiellipse, lace shape etc. ( Figure 1C).
  • the edge of the artificial corneal endothelial sheet is provided with at least two haptics 5, and the haptics 5 are connected to the peripheral area 2, and the cavity between the two (the outer side of the peripheral area between the haptics and its two ends)
  • the hole formed on the edge) is the oxygen permeable hole 3, the height of the oxygen permeable hole 3 is 0.5-0.75mm, and the edge arc diameter is 1.0-1.5mm (Fig. 1B).
  • the area of the peripheral zone 2 is 0.0 mm
  • the edge of the artificial corneal endothelial sheet is provided with at least two haptics 5, and the haptics 5 are connected with the central optical zone 1, and the cavity between the two ( The hole formed on the outer edge of the central optical zone between the haptic and its two ends) is the oxygen permeable hole 3, the height of the oxygen permeable hole 3 is 0.5-0.75mm, and the side arc radius is 1.0-1.5mm ( Figure 1B).
  • the artificial corneal endothelial sheet provided by the present invention is also provided with a suction cup 4 (Fig. 1D, E).
  • the anterior chamber of the anterior chamber is close to one side of the posterior corneal stroma, and is sunken toward the other side of the artificial corneal endothelium, but does not go through the artificial corneal endothelium, and the depression is the sucker 4 .
  • the aqueous humor and air in the suction cup are discharged during the operation, so that a negative pressure is generated inside the suction cup, thereby improving the attachment of the artificial endothelial sheet to the posterior corneal stroma.
  • the suction cup 4 is located entirely within the peripheral zone 2 (FIG. 1D); in other embodiments, the suction cup 4 is partially within the peripheral zone 2 and partially within the central optical zone 1 (FIG. 1E); 4 has a depth of 5.0-10.0 ⁇ m and a width of 0.2-0.5 mm.
  • the suction cup 4 forms a ring with a width of 0.2-0.5 mm in the peripheral area 2 of the front side of the artificial corneal endothelium, and forms a depression with a depth of 5.0-10.0 ⁇ m toward the rear side of the artificial corneal endothelium.
  • Adopt the hydroxyethyl methacrylate/methyl methacrylate copolymer to make the artificial endothelial sheet obtain the artificial endothelial sheet provided by the present invention after drilling with a microdissection instrument, and the light transmittance in the wavelength range above 400nm is 79%- 83%.
  • Figure 2A shows the actual picture of the artificial endothelial sheet.
  • the diameter of the artificial endothelial sheet is 8.0 mm
  • the thickness is 50.0 ⁇ m
  • the radius of curvature is 7.32 mm
  • the central optical zone 1 is 6.5 mm
  • Oxygen pores 3 (uniform or non-uniform distribution) have a diameter of 0.5 mm and a total area of the pores of 0.785 mm 2 .
  • Embodiment 2 Preparation of large-diameter artificial endothelial sheet (full hole)
  • the artificial endothelial sheet is prepared by using the acrylic acid hydrogel, and the artificial endothelial sheet provided by the invention is obtained after drilling with a microdissection instrument, and the light transmittance is 80%-85% in the wavelength range above 400nm.
  • Figure 3A is a schematic plan view of the artificial endothelial sheet.
  • the diameter of the endothelial sheet is 8.0 mm, the thickness is 25.0 ⁇ m, the radius of curvature is 9.0 mm, the central optical zone is 5.0 mm, and there are 8 circular oxygen permeable holes (evenly distributed) around it.
  • the diameter is 0.4 mm and the total area of the holes is 1.0 mm 2 .
  • Embodiment 3 the preparation of large-diameter artificial endothelial sheet (full hole, sucker)
  • the artificial endothelial sheet is prepared by using polymethyl methacrylate, and the artificial endothelial sheet provided by the invention is obtained after drilling with a microdissection instrument, and the light transmittance is 79%-84% in the wavelength range above 400nm.
  • Figure 3B is a schematic plan view of the artificial endothelial sheet.
  • the diameter of the endothelial sheet is 8.0 mm, the thickness is 25.0 ⁇ m, the radius of curvature is 9.0 mm, the central optical zone is 7.0 mm, and there are 8 circular oxygen permeable holes in the peripheral area.
  • Embodiment 4 the preparation of large-diameter artificial endothelial sheet (full hole, sucker)
  • the artificial endothelial sheet is prepared by using the methacrylic acid hydrogel, and the artificial endothelial sheet provided by the invention is obtained after drilling with a microdissection instrument, and the light transmittance is 81%-83% in the wavelength range above 400nm.
  • Figure 3C is a schematic plan view of the artificial endothelial sheet.
  • the diameter of the endothelial sheet is 8.0 mm, the thickness is 70.0 ⁇ m, the radius of curvature is 9.0 mm, the central optical zone is 6.5 mm, and there are 8 circular oxygen-permeable holes in the peripheral area.
  • On the front side of the endothelial sheet there is a ring-shaped suction cup at the edge of the central optical zone.
  • the diameter of the oxygen permeable hole is 0.4 mm, the total area of the hole is 1.0 mm 2 , the width of the suction cup is 0.2 mm, and the depth is 5.0 ⁇ m.
  • Embodiment 5 the preparation of large-diameter artificial endothelial sheet (lace)
  • Figure 2B shows the actual picture prepared by the inventor.
  • the total diameter of the corneal endothelial sheet is 8.0 mm, the thickness is 50.0 ⁇ m, the radius of curvature is 7.32 mm, the central optical zone is 6.5 mm, and there are 6 oxygen permeable holes around it.
  • the hole height is 0.75mm, the side arc diameter is 1.5mm, and the total area of the hole is 5.3mm 2 .
  • Embodiment 6 the preparation of large-diameter artificial endothelial sheet (lace, sucker)
  • the artificial endothelial sheet is prepared by using the acrylic hydrogel, and the artificial endothelial sheet provided by the invention is obtained after trephine drilling, and the light transmittance is 80%-85% in the wavelength range above 400nm.
  • Figure 4 is a schematic plan view of the artificial endothelial sheet.
  • the total diameter of the artificial corneal endothelial sheet is 9.0 mm, the thickness is 70.0 ⁇ m, the radius of curvature is 6.0 mm, the diameter of the central optical zone is 6.5 mm, and the periphery contains 6 oxygen-permeable holes.
  • the height of the oxygen hole is 0.5mm, the side arc diameter is 1.0mm, the depth of the suction cup is 5.0 ⁇ m, and the diameter of the suction cup is 0.5mm.
  • the artificial endothelial sheet is prepared by adopting polyhydroxyethyl methacrylate, and the light transmittance is 79%-85% in the wavelength range above 400nm.
  • the total diameter of the artificial corneal endothelium is 8.0 mm
  • the thickness is 50.0 ⁇ m
  • the radius of curvature is 9.0 mm
  • the diameter of the central optical zone is 7.0 mm
  • the height of the oxygen holes is 0.75 mm
  • the side arc diameter is 1.5 mm
  • the total area of the holes is 3.5 mm 2 .
  • Embodiment 8 Preparation of large-diameter artificial endothelial sheet (suction cup)
  • the artificial endothelial sheet is prepared by adopting hydroxyethyl methacrylate/methyl methacrylate copolymer, and the light transmittance is 79%-83% in the wavelength range above 400nm.
  • the artificial corneal endothelium has a diameter of 8.0mm, a thickness of 50.0 ⁇ m, a radius of curvature of 9.0mm, a central optical zone of 5.0mm, and a ring-shaped suction cup in the peripheral area.
  • the width of the suction cup is 0.3mm and the depth is 5.0 ⁇ m.
  • Embodiment 9 Preparation of large-diameter artificial endothelial sheet (full hole, plus loop)
  • the artificial endothelial sheet is prepared by using polymethyl methacrylate, and the artificial endothelial sheet provided by the invention is obtained after drilling with a microdissection instrument, and the light transmittance is 79%-84% in the wavelength range above 400nm.
  • the diameter of the artificial corneal endothelium is 8.0mm, the thickness is 25.0 ⁇ m, the radius of curvature is 9.0mm, the central optical zone is 5.0mm, and there are 8 circular oxygen permeable holes in the peripheral zone, and the diameter of the oxygen permeable holes is 0.6mm. There are also 4 evenly distributed loops in the peripheral area, the height of the oxygen permeable hole is 0.75mm, and the side arc diameter is 1.5mm.
  • Embodiment 10 Preparation of large-diameter artificial endothelial sheet (full hole, sucker, loop)
  • the artificial endothelial sheet is prepared by using the methacrylic acid hydrogel, and the artificial endothelial sheet provided by the invention is obtained after drilling with a microdissection instrument, and the light transmittance is 81%-83% in the wavelength range above 400nm.
  • the diameter of the artificial corneal endothelium is 8.0mm, the thickness is 70.0 ⁇ m, the radius of curvature is 9.0mm, the central optical zone is 5.0mm, and there are 8 circular oxygen permeable holes in the peripheral area, on the front side of the artificial endothelium, on the edge of the central optical zone
  • There is an annular suction cup at the center the diameter of the oxygen permeable hole is 0.4mm, the width of the suction cup is 0.2mm, and the depth is 8.0 ⁇ m.
  • Unperforated group the endothelium in the central area of the rabbit cornea was stripped, and an unperforated large-diameter artificial corneal endothelial sheet was implanted (the artificial corneal endothelial sheet prepared in Example 1 was not subjected to perforation).
  • Lace-shaped group the endothelium of the central area of the rabbit cornea was peeled off, and the lacy-shaped large-diameter artificial corneal endothelium prepared in Example 5 was implanted.
  • Loop-adding group the endothelium in the central area of the rabbit cornea was stripped, and the large-diameter artificial corneal endothelium sheet with adding loops prepared in Example 7 was implanted.
  • Suction cup group the endothelium in the central area of the rabbit cornea was stripped, and the large-diameter artificial corneal endothelium sheet prepared in Example 8 without perforation and with a ring-shaped suction cup in the peripheral area was implanted.
  • New Zealand white rabbits were anesthetized by injecting 25.0mg/kg sodium pentobarbital into the ear vein.
  • Corneal OCT showed that on the first day after operation, the artificial endothelial sheet fell off in all rabbits in the non-perforated group (100%), and the endothelial sheet was usually located in the lower anterior chamber after the endothelial sheet fell off.
  • the lace-shaped group and the loop group still had corneal edema at 1 week after operation, but the corneas in the seven groups all recovered within 2 weeks after operation.
  • the average corneal thickness of the non-perforated group was (211 ⁇ 33) ⁇ m
  • the average corneal thickness of the perforated group was (293 ⁇ 11) ⁇ m
  • the average corneal thickness of the lace-shaped group was (290 ⁇ 17) ⁇ m
  • the average corneal thickness of the loop group was (290 ⁇ 17) ⁇ m.
  • the average corneal thickness was (286 ⁇ 12) ⁇ m
  • the thickness of the cornea in the sucker group was thinner
  • the average was (207 ⁇ 28) ⁇ m
  • the average thickness of the cornea in the whole hole/add loop group was (294 ⁇ 21) ⁇ m
  • the whole hole/suction cup/add The average corneal thickness of the haptic group was (306 ⁇ 15) ⁇ m.
  • the corneal stroma can remain transparent without obvious thinning, and the artificial corneal endothelium after perforation is better attached to the corneal stroma, and the rate of graft loss after surgery is reduced .

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Abstract

一种大直径角膜植入物作为人工角膜内皮层，用于植入角膜内皮细胞失代偿的患者眼内，通过吸盘（4）、全孔、花边、加襻的透氧孔（3）设计，使其在起到隔离房水的屏障作用，消除角膜水肿的同时，兼具高粘附、高透氧的优势，能够满足角膜基质正常代谢所需要的养分，维持正常的角膜厚度，并减少术后角膜移植片脱落等并发症。

Description

一种大直径人工角膜内皮片及其应用 技术领域
本发明涉及一种大直径的眼内角膜植入物，特别涉及到一种有吸盘(圆形、环形)和有孔(全孔、半孔、加襻)的人工角膜内皮片，属于医疗器械领域。
背景技术
角膜内皮细胞层是角膜的最内层，其结构完整和功能健全是维持角膜正常生理代谢的重要因素。内皮细胞密度降低和内皮泵功能失调会导致角膜内皮失代偿，表现为角膜水肿混浊，严重影响视力，患者眼疼明显，生活质量下降，是白内障手术等内眼手术后较常见的并发症之一，也是角膜内皮营养不良等原发疾病的终末期表现。最初对于角膜内皮失代偿的治疗，只能采取穿透性角膜移植术(Penetrating keratoplasty，PKP)手术治疗。随着手术技术的发展，内皮移植术(Endothelial keratoplasty,EK)的占比逐渐上升，即保留患者自身的基质部分，而仅移植病变的内皮细胞层，术式为角膜后弹力层剥除内皮移植术(Descemet stripping endothelial keratoplasty，DSEK)或角膜后弹力层内皮移植术(Descemet’s membrane endothelial keratoplasty，DMEK)，但不仅需要新鲜角膜供体，并且手术操作难度高、对供体质量要求也较高，部分患者可能会因术中角膜内皮细胞丢失过多而再次发生角膜植片内皮失代偿，有35％患者术后发生角膜植片脱落而需要进行一次或多次前房注气术。
爱拥医疗有限公司的EndoArt产品是直径为6.0mm、厚度为50μm的人工内皮片，与DMEK供体内皮片不同的是，它提供了一种不透水的屏障，贴附于患者角膜后基质表面，阻止房水的流入，从而防止角膜基质水肿。爱拥医疗有限公司Daphna的PCT专利WO 2020/115605 A1所述内皮片直径为4.2-7.0mm。然而，临床上的角膜内皮失代偿的患者通常为全角膜水肿，临床需常规剥除约8mm范围的内皮，小直径的人工内皮片面临周边角膜水肿的问题，而大直径人工内皮片在防水的同时，会阻挡角膜组织的营养来源，从而导致中央角膜厚度变薄，且该人工内皮片存在术后角膜植片脱落的风险。Auffarth等在“cornea”杂志上报道了2例临床病例使用EndoArt产品的临床效果，2例患者均存在术后角膜植片脱落。
发明内容
基于大量的临床研究，本发明的目的是提供一种大直径的人工角膜内皮片；更进一步的目的是通过透氧孔(全孔、花边、加襻)的设计，使其在起到隔离房水的屏障作用的同时消除角膜水肿；更进一步的目的是通过吸盘(圆形、椭圆形、环形)，使其兼具高粘附、高透氧的优势，减少术后角膜移植片移位、脱落等并发症。
本发明是在可折叠的透明的光学材料的基础上，将其制作成具有曲率的、周边含有吸盘和/或透氧孔的大直径人工角膜内皮片。
本发明提供的人工角膜内皮片，总直径为7.0-9.0mm，厚度为25.0-70.0μm，曲率半径为6.0-9.0mm，设有透氧孔；所述透氧孔的设计包括打孔(全孔)、花边状(半孔)、以及周边加襻之一的方法构成，或者打孔(全孔)、花边状(半孔)和周边加襻之中的两种及以上共同组成。
优选地，人工角膜内皮片包括中央光学区1和周边区2，所述中央光学区1直径为5.0-7.0mm，所述周边区2位于所述中央光学区1外侧，所述透氧孔3位于周边区2，透氧孔数量为2-8个，总面积为0.5-5.3mm 2。
优选地，透氧孔3的形状包括圆形、椭圆形、半圆形、花边形，均匀或不均匀分布于周边区2。
优选地，透氧孔3采用打孔设计的形状为圆形或椭圆形，透氧孔3直径为0.2-0.6mm。
优选地，透氧孔3采用花边状设计，数量为4-8个，形状为花边形、半圆形或半椭圆形，透氧孔3孔高为0.5-0.75mm，边弧径为1.0-1.5mm。
优选地，透氧孔3采用加襻的设计，人工角膜内皮片的边缘设有襻5，所述襻5与所述中央光学区1或所述周边区2形成透氧孔3。
优选地，人工角膜内皮片的边缘设有襻5，所述襻5与所述中央光学区1或所述周边区2形成透氧孔3，所述透氧孔3孔高为0.5-0.75mm，边弧径为1.0-1.5mm。
优选地，透氧孔3是襻5与其两端之间的中央光学区1或周边区2外侧边缘形成的孔或空隙，其形状为月牙形、椭圆形、半圆形或半椭圆形等。
优选地，在周边区2形成的透氧孔3和由襻形成的透氧孔3共同存在。
更优选地，人工角膜内皮片设有透氧孔3和吸盘4，所述吸盘4位于人工角膜内皮片前侧面，深度为5.0-10.0μm，直径或宽度为0.2-0.5mm。
所述吸盘4位于人工角膜内皮片前侧面或凸面，即在将人工角膜内皮片植入人眼的前房时靠近角膜后基质的一侧，所述吸盘4可以完全在周边区2内，还可以部分在中央光学区1内，当所述人工角膜内皮片被置于眼部时，术中将吸盘内的房水和空气排出，使吸盘内部产生负压，从而提高人工内皮片与角膜后基质的贴附。
优选地，人工角膜内皮片的材质为丙烯酸酯类材料，选自甲基丙烯酸羟乙酯/甲基丙烯酸甲酯共聚物、聚甲基丙烯酸甲酯、聚甲基丙烯酸羟乙酯、丙烯酸水凝胶、甲基丙烯酸水凝胶等。
有益效果
本发明提供的大直径人工角膜内皮片，是一种透明的、不降解的光学材料，吸盘(圆形、环形)、透氧孔的设计(包括打孔、花边状、以及周边加襻)，使其在起到隔离房水的屏障作用，消除角膜水肿的同时，兼具高粘附、高透氧的优势，能够满足角膜基质正常代谢所需要的养分，维持正常的角膜厚度；在未经任何修饰的情况下，吸盘、透氧孔的设计从物理角度增加人工内皮片与角膜后基质的粘附性，加之大直径可以增加内皮片的稳定性，降低术后角膜植片脱落的风险。该人工内皮片极软且易折叠，可在小切口的情况下植入前房，且无需负载细胞，在手术过程中无需考虑细胞破坏的问题，大大降低了手术难度，从而减少术后角膜内皮细胞丢失过多、角膜植片移位或脱落等并发症。
本发明提供的大直径角膜植入物有望替代传统的供体角膜内皮植片，减少角膜移植的数量。
附图说明
图1为本发明提供的人工角膜内皮片立体示意图。
图2为本发明提供的人工角膜内皮片的实物图。
图3为实施例2、3、4周边打孔的人工内皮片平面示意图及其切面图。
图4为实施例6花边状人工内皮片平面示意图及其切面图。
图5为实施例7加襻人工内皮片平面示意图。
图6为动物实验中兔角膜的裂隙灯及OCT观察图。
图中，
1：中央光学区
2：周边区
3：透氧孔
4：吸盘
5：襻
具体实施方式
本发明进一步由解释本发明的以下实施例进行示例性说明，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。除非另有说明，本文所使用的技术和科学术语为本发明所属领域的普通技术人员通常所理解的含义。
所述“大直径人工角膜内皮片”是指直径为7.0-9.0mm的人工内皮片,大直径是相对于现有技术公开的人工角膜内皮片、角膜植入物等普遍采用直径在7mm以下，相对而言本发明提供的人工角膜内皮片直径较大。
所述“吸盘”是指位于人工角膜内皮片前侧面或凸面，全部或部分在周边区内，并向所述人工角膜内皮片后侧面或凹面方向的凹陷。
吸盘的横截面为圆形或环形，凹陷的底部为半球形。吸盘直径为圆形吸盘的最大横截面的直径。吸盘宽度为环形吸盘的最大横截面的宽度。吸盘深度为圆形或环形吸盘向所述人工角膜内皮片前侧的凹陷深度。
所述“襻”指的是周边区的半圆形或半椭圆形的支撑部分。
透氧孔边弧径为花边形、半圆形、半椭圆形等透氧孔所在圆的直径。
透氧孔孔高：花边形、半圆形、半椭圆形等透氧孔所在圆与内皮片所在圆之间的最大径。
人工角膜内皮片后侧面或凹面是指人工角膜内皮片植入人眼的前房时靠近房水的一面。
人工角膜内皮片前侧面或凸面是指人工角膜内皮片植入人眼的前房时靠近角膜后基质的一面。
实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
本发明对人工角膜内皮片的来源没有特殊限制，采用本领域所熟知的人工角膜内皮片来源即可。在本发明实施例中，所述大直径人工角膜内皮片由山东第一医科大学眼科研究所自制。
人工内皮片的相关参数
1.人工内皮片材料为丙烯酸酯类，可以选自甲基丙烯酸羟乙酯/甲基丙烯酸甲酯共聚物、聚甲基丙烯酸甲酯、聚甲基丙烯酸羟乙酯、丙烯酸水凝胶、甲基丙烯酸水凝胶中的一种或多种。
2.透光率：人工内皮片透光率在300-800nm波长范围内均随着光波波长的增加而逐渐升高，在400nm以上波长范围内透光率可达到79％-85％。
在一些实施例中，本发明提供的人工角膜内皮片如图1所示，包括中央光学区1和周边区2，所述中央光学区1和周边区2之间无明显界限，角膜内皮片的总直径为7.0-9.0mm，厚度为25.0-70.0μm，曲率半径为6.0-9.0mm，中央光学区1直径为5.0-7.0mm，周边区2位于中央光学区1的外延，含有至少2个透氧孔3，透氧孔3直径为0.2-0.6mm，总面积为0.5-5.3mm 2。
在一些实施例中，所述透氧孔3贯穿人工角膜内皮片，全部或部分位于周边区2，在人工内皮片的前侧面和后侧面形成完整的圆形、半圆形、椭圆形或其他形状(图1A、B、D、E)。
在另一些实施例中，所述透氧孔3位于人工角膜内皮片周边区2的边缘，在人工 内皮片的前侧面和后侧面形成不完整的形状，如半圆形、半椭圆形、花边形等(图1C)。
在另一些实施例中，所述人工角膜内皮片的边缘设有至少2个襻5，所述襻5与周边区2相连，两者之间的空洞(襻与其两端之间的周边区外侧边缘形成的孔)即为透氧孔3，透氧孔3孔高为0.5-0.75mm，边弧径为1.0-1.5mm(图1B)。
在另一些实施例中，所述周边区2的面积为0.0mm，人工角膜内皮片的边缘设有至少2个襻5，所述襻5与中央光学区1相连，两者之间的空洞(襻与其两端之间的中央光学区外侧边缘形成的孔)即为透氧孔3,透氧孔3孔高为0.5-0.75mm，边弧径为1.0-1.5mm(图1B)。
在一些实施例中，本发明提供的人工角膜内皮片还设有吸盘4(图1D、E)，所述吸盘4的开口位于人工角膜内皮片凸面，即在将人工角膜内皮片植入眼部的前房时靠近角膜后基质的一侧，并向人工角膜内皮片的另一侧凹陷，但不贯穿人工角膜内皮片，所述凹陷即为吸盘4。当人工角膜内皮片施用于眼部前房时，术中将吸盘内的房水和空气排出，使吸盘内部产生负压，从而提高人工内皮片与角膜后基质的贴附。
在一些实施例中，吸盘4全部位于周边区2内(图1D)；在另一些实施例中，吸盘4部分在周边区2内，部分在中央光学区1内(图1E)；所述吸盘4的深度为5.0-10.0μm，宽度为0.2-0.5mm。
在另一些实施例中，吸盘4在人工角膜内皮片前侧面周边区2内形成宽度为0.2-0.5mm的环形，并向人工角膜内皮片的后侧面方向形成深度为5.0-10.0μm的凹陷。
实施例1：大直径人工内皮片的制备(全孔)
采用甲基丙烯酸羟乙酯/甲基丙烯酸甲酯共聚物制得人工内皮片，显微切割仪钻孔后获得本发明提供的人工内皮片，在400nm以上波长范围内透光率为79％-83％。
图2A所示为制得的人工内皮片实物图，人工内皮片直径为8.0mm，厚度为50.0μm，曲率半径为7.32mm，中央光学区1为6.5mm，周围4个圆形或椭圆形透氧孔3(均匀或不均匀分布)，直径为0.5mm，孔的总面积为0.785mm 2。
实施例2：大直径人工内皮片的制备(全孔)
采用丙烯酸水凝胶制得人工内皮片，显微切割仪钻孔后获得本发明提供的人工内皮片，在400nm以上波长范围内透光率为80％-85％。
图3A所示为人工内皮片的平面示意图，内皮片直径为8.0mm，厚度为25.0μm，曲率半径为9.0mm，中央光学区为5.0mm，周围8个圆形透氧孔(均匀分布)，直径为0.4mm，孔的总面积为1.0mm 2。
实施例3：大直径人工内皮片的制备(全孔、吸盘)
采用聚甲基丙烯酸甲酯制得人工内皮片，显微切割仪钻孔后获得本发明提供的人工内皮片，在400nm以上波长范围内透光率为79％-84％。
图3B所示为人工内皮片的平面示意图，内皮片直径为8.0mm，厚度为25.0μm，曲率半径为9.0mm，中央光学区为7.0mm，周边区有8个圆形透氧孔，8个圆形吸盘，透氧孔与吸盘交叠均匀分布，透氧孔的直径为0.6mm，吸盘的直径为0.25mm，深度为10.0μm。
实施例4：大直径人工内皮片的制备(全孔、吸盘)
采用甲基丙烯酸水凝胶制得人工内皮片，显微切割仪钻孔后获得本发明提供的人工内皮片，在400nm以上波长范围内透光率为81％-83％。
图3C所示为人工内皮片的平面示意图，内皮片直径为8.0mm，厚度为70.0μm，曲率半径为9.0mm，中央光学区为6.5mm，周边区有8个圆形透氧孔，在人工内皮片前侧，中央光学区的边缘处有环形吸盘，透氧孔的直径为0.4mm，孔的总面积为1.0mm 2，吸盘的宽度为0.2mm，深度为5.0μm。
实施例5：大直径人工内皮片的制备(花边)
采用甲基丙烯酸羟乙酯/甲基丙烯酸甲酯共聚物制得人工内皮片，环钻钻孔后获得本发明提供的人工内皮片，在400nm以上波长范围内透光率为79％-83％。
图2B所示为发明人制备的实物图，角膜内皮片的总直径为8.0mm，厚度为50.0μm，曲率半径为7.32mm，中央光学区为6.5mm，周边6个透氧孔，透氧孔孔高为0.75mm，边弧径为1.5mm，孔的总面积为5.3mm 2。
实施例6：大直径人工内皮片的制备(花边、吸盘)
采用丙烯酸水凝胶制得人工内皮片，环钻钻孔后获得本发明提供的人工内皮片，在400nm以上波长范围内透光率为80％-85％。
如图4所示为人工内皮片的平面示意图，人工角膜内皮片的总直径为9.0mm，厚度70.0μm，曲率半径6.0mm，中央光学区直径为6.5mm，周边含有6个透氧孔，透氧孔孔高为0.5mm，边弧径为1.0mm，吸盘深度为5.0μm，吸盘直径为0.5mm。
实施例7：大直径人工内皮片的制备(加襻)
采用聚甲基丙烯酸羟乙酯制得人工内皮片，在400nm以上波长范围内透光率为79％-85％。
如图5所示，人工角膜内皮片的总直径为8.0mm，厚度为50.0μm，曲率半径为9.0mm，中央光学区直径为7.0mm，周边区外侧有4个均匀分布的襻5构成，透氧孔孔高为0.75mm，边弧径为1.5mm，孔的总面积为3.5mm 2。
实施例8：大直径人工内皮片的制备(吸盘)
采用甲基丙烯酸羟乙酯/甲基丙烯酸甲酯共聚物制得人工内皮片，在400nm以上波长范围内透光率为79％-83％。
人工角膜内皮片直径为8.0mm，厚度为50.0μm，曲率半径为9.0mm，中央光学区为5.0mm，周边区有环形吸盘，吸盘的宽度为0.3mm，深度为5.0μm。
实施例9：大直径人工内皮片的制备(全孔、加襻)
采用聚甲基丙烯酸甲酯制得人工内皮片，显微切割仪钻孔后获得本发明提供的人工内皮片，在400nm以上波长范围内透光率为79％-84％。
人工角膜内皮片直径为8.0mm，厚度为25.0μm，曲率半径为9.0mm，中央光学区为5.0mm，周边区有8个圆形透氧孔，透氧孔的直径为0.6mm。周边区还设有4个均匀分布的襻，透氧孔孔高为0.75mm，边弧径为1.5mm。
实施例10：大直径人工内皮片的制备(全孔、吸盘、加襻)
采用甲基丙烯酸水凝胶制得人工内皮片，显微切割仪钻孔后获得本发明提供的人工内皮片，在400nm以上波长范围内透光率为81％-83％。
人工角膜内皮片直径为8.0mm，厚度为70.0μm，曲率半径为9.0mm，中央光学区为5.0mm，周边区有8个圆形透氧孔，在人工内皮片前侧，中央光学区的边缘处有环形吸盘，透氧孔的直径为0.4mm，吸盘的宽度为0.2mm，深度为8.0μm。周边区还设有4个均匀分布的襻，透氧孔孔高为0.5mm，边弧径为1.0mm。
动物实验
1.材料与方法
1.1实验动物
新西兰白兔35只，体重3.0-3.5Kg，雄兔。
1.2分组
将35只新西兰大白兔随机分为七组，每组5只。
(1)未打孔组：剥除兔角膜中央区内皮，植入未经打孔的大直径人工角膜内皮片(实施例1制备的人工角膜内皮片不经打孔处理)。
(2)全孔组：剥除兔角膜中央区内皮，植入实施例1制备的全孔的大直径人工角膜内皮片。
(3)花边形组：剥除兔角膜中央区内皮，植入实施例5制备的花边形的大直径人工角膜内皮片。
(4)加襻组：剥除兔角膜中央区内皮，植入实施例7制备的加襻的大直径人工角膜内皮片。
(5)吸盘组：剥除兔角膜中央区内皮，植入实施例8制备的未经打孔、周边区设有环形吸盘的大直径人工角膜内皮片。
(6)全孔/加襻组：剥除兔角膜中央区内皮，植入实施例9制备的全孔、加襻的大直径人工角膜内皮片。
(7)全孔/吸盘/加襻组：剥除兔角膜中央区内皮，植入实施例10制备的全孔、吸盘、加襻的大直径人工角膜内皮片。
1.3角膜内皮失代偿动物模型的建立
(1)25.0mg/kg戊巴比妥钠耳缘静脉注射麻醉新西兰白兔。
(2)将0.5％盐酸丙美卡因滴在兔角膜表面局部镇痛。
(3)使用0.9％氯化钠注射液冲洗结膜囊，使用棉签充分清洁眼表。
(4)使用相应大小的环钻于兔角膜上皮面中央做印记。
(5)使用15°穿刺刀于12点位角膜缘做穿刺口，注入0.02mg/mL卡米可林注射液缩瞳，注入粘弹剂形成前房。
(6)使用1ml注射器针头及晶体调位钩去除角膜中央标记的内皮。
(7)使用0.9％氯化钠注射液冲洗前房，置换粘弹剂。
(8)依次向前房内注入4.0mg/mL庆大霉素注射液及肝素钠注射液，减轻前房炎症反应。
(9)再次注入粘弹剂形成前房，未经打孔组植入未经打孔的人工角膜内皮片；打孔组植入实施例1制备的全孔的人工角膜内皮片；花边形组植入实施例5制备的花边形的人工角膜内皮片；加襻组植入实施例7制备的加襻的人工角膜内皮片；吸盘组植入实施例8未经打孔、周边区设有环形吸盘的大直径人工角膜内皮片；全孔/加襻组植入实施例9制备的全孔/加襻的大直径人工角膜内皮片。全孔/吸盘/加襻组植入实施例10制备的全孔、吸盘、加襻的大直径人工角膜内皮片。
(10)将人工角膜内皮片折叠，并使用无齿镊将其置入前房，使用调位钩将角膜植入物固定于中央刮除区内皮。
(11)使用0.9％氯化钠注射液再次冲洗前房，置换粘弹剂。
(12)使用10-0缝线缝合切口，并使用胰岛素针头进行前房注气。
2.结果
使用裂隙灯、眼前节OCT(见表1、图6)，在术后第1天、第7天、第14天进行角膜观察和中央厚度测量。角膜OCT显示，术后第1天，未打孔组兔子均发生人工内皮片脱落(100％)，内皮片通常脱落后位于下方前房，其余各组人工内皮片的脱落比例分别为：全孔组20％、花边形组40％，加襻组40％，吸盘组20％、全孔/加襻组20％，全孔/吸盘/加襻组20％。花边形组、加襻组在术后1周时仍有角膜水肿，但七组均在术后2周内角膜恢复透明。2周时，未打孔组角膜厚度平均为(211±33)μm，打孔组角膜厚度平均为(293±11)μm，花边形组角膜厚度平均为(290±17)μm，加襻组角膜厚度平均为(286±12)μm，吸盘组角膜厚度变薄，平均为(207±28)μm，全孔/加襻组角膜厚度平均为(294±21)μm，全孔/吸盘/加襻组角膜厚度平均为(306±15)μm。证明打孔(限定打孔面积)后，角膜基质既可以维持透明，角膜基质又无明显变薄，且打孔后的人工角膜内皮片与角膜基质贴附更好，术后植片脱落率降低。
表1 植入打孔与未打孔人工内皮片的处理及结果
Figure PCTCN2022114691-appb-000001
a为与未打孔组比较，P＜0.05
尽管本发明的具体实施方式己经得到详细的描述，本领域技术人员将会理解。根据己经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (10)

  1. 一种人工角膜内皮片，其特征在于，所述人工角膜内皮片的总直径为7.0-9.0mm，厚度为25.0-70.0μm，曲率半径为6.0-9.0mm，所述角膜内皮片上设有透氧孔(3)，所述透氧孔(3)的设计包括打孔、花边状、以及周边加襻之一的方法构成，或者打孔、花边状和周边加襻之中的两种及以上共同组成。
  2. 如权利要求1所述的人工角膜内皮片，其特征在于，包括中央光学区(1)和周边区(2)，所述周边区(2)位于所述中央光学区(1)外侧，所述中央光学区(1)直径为5.0-7.0mm；所述透氧孔(3)位于所述周边区(2)，透氧孔(3)数量为2-8个，所述透氧孔(3)的总面积为0.5-5.3mm 2。
  3. 如权利要求1-2所述的人工角膜内皮片，其特征在于，所述透氧孔(3)的形状包括圆形、椭圆形、半圆形、花边形、月牙形或半椭圆形，均匀或不均匀分布于周边区。
  4. 如权利要求1-2所述的人工角膜内皮片，其特征在于，所述透氧孔(3)的形状为圆形或椭圆形，直径为0.2-0.6mm。
  5. 如权利要求1-2所述的人工角膜内皮片，其特征在于，所述透氧孔采用花边状构成，所述透氧孔(3)数量为4-8个，形状为花边形、月牙形、半椭圆形或半圆形，孔高为0.5-0.75mm，边弧径为1.0-1.5mm。
  6. 如权利要求1-2所述的人工角膜内皮片，其特征在于，所述透氧孔采用加襻结构构成，所述人工角膜内皮片的边缘设有襻(5)，所述透氧孔(3)是所述襻(5)与其两端之间的人工角膜内皮片外侧边缘形成的空隙，其形状为椭圆形、半圆形或半椭圆形。
  7. 如权利要求6所述的人工角膜内皮片，其特征在于，所述透氧孔(3)孔高为0.5-0.75mm，边弧径为1.0-1.5mm。
  8. 如权利要求1-7任一所述的人工角膜内皮片，其特征在于，在周边区形成的透氧孔(3)和由襻形成的透氧孔(3)共同存在。
  9. 如权利要求1-8任一所述的人工角膜内皮片，其特征在于，在所述人工角膜内皮片凸面还设有吸盘(4)，所述吸盘(4)深度为5.0-10.0μm，直径或宽度为0.2-0.5mm。
  10. 如权利要求1-9任一所述的人工角膜内皮片，其特征在于，所述人工角膜内皮片的材质为丙烯酸酯类材料，选自甲基丙烯酸羟乙酯/甲基丙烯酸甲酯共聚物、聚甲基丙烯酸甲酯、聚甲基丙烯酸羟乙酯、丙烯酸水凝胶、甲基丙烯酸水凝胶。
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