WO2020223211A1 - Système de réticulation cornéenne in vitro pour la préparation d'échantillons de tissu transplantable - Google Patents

Système de réticulation cornéenne in vitro pour la préparation d'échantillons de tissu transplantable Download PDF

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Publication number
WO2020223211A1
WO2020223211A1 PCT/US2020/030227 US2020030227W WO2020223211A1 WO 2020223211 A1 WO2020223211 A1 WO 2020223211A1 US 2020030227 W US2020030227 W US 2020030227W WO 2020223211 A1 WO2020223211 A1 WO 2020223211A1
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WIPO (PCT)
Prior art keywords
cornea
light
catalyst
crosslinking
riboflavin
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PCT/US2020/030227
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English (en)
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WO2020223211A9 (fr
Inventor
Patrick David Lopath
Edward Paul Harhen
Najwa Haleh Simone TAYLOR
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TECLens, LLC
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Publication of WO2020223211A1 publication Critical patent/WO2020223211A1/fr
Publication of WO2020223211A9 publication Critical patent/WO2020223211A9/fr

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Classifications

    • 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
    • A61F9/00—Methods 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
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/0079—Methods or devices for eye surgery using non-laser electromagnetic radiation, e.g. non-coherent light or microwaves
    • 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
    • A61F9/00—Methods 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
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
    • 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
    • A61F9/00—Methods 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
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A61F2009/00861—Methods or devices for eye surgery using laser adapted for treatment at a particular location
    • A61F2009/00872—Cornea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0661—Radiation therapy using light characterised by the wavelength of light used ultraviolet

Definitions

  • the cornea of the human eye includes a layer of cells referred to as the epithelium at the anterior surface; a thin layer referred to as“Bowman’s layer” immediately posterior of the epithelium, the collagenous comeal stroma constituting the major portion of the thickness of the cornea, a thin layer referred to as Descemet’s membrane posterior to the stroma, and a further layer of cells referred to as the endothelium forming the posterior surface of the cornea.
  • Corneal crosslinking is a common procedure used to strengthen the comeal tissue in vivo for patients with progressive keratoconus.
  • the stiffening provided by crosslinking can also be applied in vitro to harvested graft tissue to improve the handling properties.
  • In vitro crosslinking procedures face a different set of challenges than in vivo crosslinking.
  • the depth of crosslinking depends on many factors: the wavelength and intensity of the applied light, the total dose of light energy applied, the thickness off the stroma and the concentration profile of the riboflavin within it, and the stromal oxygen content. Many of these variables are either hard to control or hard to know accurately or both.
  • the endothelial cells are very sensitive to the applied crosslinking light energy in the presence of riboflavin.
  • the established UV dose limit for the endothelium is 0.65J/cm 2 .
  • standard in vivo CXL procedures err on the side of caution and intentionally do not attempt full thickness crosslinking. This conservative approach, combined with the unknown variables, means that crosslinking to a precise depth in vivo is very difficult.
  • the value of the stromal riboflavin diffusion coefficient D is known from literature (6.5xl0 5 mm 2 /s). To assess the dose of UV deposited in the endothelium by light applied from the front of the cornea, the intensity of the light as a function of depth in the cornea must be calculated. Ignoring scattering in the eye (which may or may not be valid for 375nm UV) Lambert-Beer law gives:
  • m is the linear attenuation coefficient, which is the sum of the attenuation in the corneal tissue and the absorption in the riboflavin.
  • the attenuation coefficient of the riboflavin is concentration dependent, with the axial and temporal distribution given above as c(z,t).
  • riboflavin when exposed to UV, undergoes photobleaching, where some fraction of the riboflavin molecules break down into non-photoreactive species.
  • the photobleaching rate is a function of the UV intensity and the concentration of the riboflavin, thus also dependent on time and axial position.
  • a method according to this aspect of the invention desirably includes contacting the posterior surface of the cornea with a liquid containing a crosslinking catalyst so as to instill the crosslinking catalyst into the cornea from the posterior surface.
  • the method desirably further includes applying light to the cornea through the anterior surface of the cornea to cause crosslinking of the stroma.
  • the light- applying step desirably commences after commencement of the contacting step.
  • the contacting step may be continued during the light-applying step, or may be terminated before the light- applying step.
  • the cornea treated in the process desirably includes an intact endothelium, and the catalyst is instilled into the stroma of the cornea through the endothelium and through Descemet’s membrane.
  • the crosslinking catalyst is riboflavin, and the light applied is ultraviolet (“UV”) light.
  • a further aspect of the present invention provides apparatus for corneal crosslinking.
  • Apparatus according to this aspect of the invention desirably includes means for contacting the posterior surface of the cornea with a liquid containing a crosslinking catalyst.
  • the apparatus desirably also includes means for applying light to the cornea through the anterior surface of the cornea.
  • Figure 1 is a diagrammatic sectional view depicting apparatus according to one embodiment of the invention in conjunction with a cornea.
  • Figure 2 is a fragmentary, diagrammatic sectional view on an enlarged scale of the cornea depicted in Figure 1.
  • Figure 3 is a graph schematically depicting catalyst distributions at different times during a method according to an embodiment of the invention.
  • Apparatus according to one embodiment of the invention includes a sample holder 10.
  • the sample holder includes a ring-shaped carrier 12 having an opening 13.
  • Carrier 12 has a set of ring-shaped corrugations or teeth 14 on an upper surface.
  • a handle 16 partially depicted in Fig. 1, projects from carrier 12.
  • Sample holder 10 further includes a ring- shaped upper element 18 having an opening 20.
  • the carrier 12 and upper element 18 are adapted to grip a tissue sample between them, with the weight of upper element 18 bearing on the tissue sample and holding the sample in engagement with the upper element and with the ring, and with the openings 13 and 20 aligned with one another.
  • the tissue sample extends across the opening 20 in the upper element and engages the lower surface of upper element 20.
  • the tissue sample includes an intact cornea 30 surrounded by a ring 32 of scleral tissue which is used for handling the sample but which will not form a part of the transplant.
  • the scleral tissue ring 32 is engaged between the elements of the sample holder, whereas the cornea 30 is aligned with the openings so that the cornea projects downwardly through opening 13 of carrier 12.
  • the elements of the sample holder do not touch the cornea.
  • the posterior surface 34 of the cornea faces upwardly towards upper element 18, and is aligned with opening 20 in upper element 18.
  • the apparatus further includes a source 36 of a liquid containing a cross-linking catalyst such as riboflavin.
  • Source 36 is arranged to introduce the liquid into the opening 20 of the upper element, so that the liquid contacts the tissue sample. This liquid contacts the posterior surface 32 of the cornea, but desirably does not contact the opposite, anterior surface of the cornea.
  • the scleral tissue may form a reasonably liquid-tight seal with the upper element 20.
  • the upper element may include a soft gasket (not shown) on its lower surface so as to improve the seal.
  • the apparatus further includes a light- applying device 40.
  • the light-applying device includes a light source 42.
  • the source may include a lamp or laser adapted to emit light such as UV light at a wavelength which will interact with the catalyst to cause cross-linking of comeal stroma.
  • the light-applying device includes a fiber optic 44 connected to the light source and a collimating lens 46 aligned with the fiber optic, as well as a light scattering element 48 commonly referred to as a diffuser.
  • the diffuser 48, lens 46 and the end of the fiber optic 44 adjacent the lens are aligned with the opening 13 of carrier 12.
  • the handle 16 of carrier 12 may be connected to a frame (not shown) which is also connected to the diffuser, lens and fiber optic.
  • the apparatus in this embodiment further includes a reservoir 50 having an open top and having a bottom wall 52 formed from a material which is transparent or translucent to the light from source 42.
  • the bottom wall 52 may be formed from borosilicate glass which is transparent to UV light at about 375 nm wavelength.
  • Reservoir 50 may be mounted to the same frame (not shown) as the other elements. The reservoir, sample holder 10 or both may be slidably mounted on the frame (not shown) so the positions of these elements may be adjusted during use.
  • a sample including an intact whole cornea 30 and scleral ring 32 is engaged in sample holder 10 as discussed above.
  • a liquid 38 including a catalyst such as riboflavin at the desired concentration is added to the concave posterior well formed by the cornea 30. Care must be taken to not touch the endothelium at the posterior surface 34 of the cornea. Thus, liquid 38 is contacted with the posterior surface of the cornea, without contacting the anterior surface 35.
  • Another fluid 56 such as balanced saline, cornea preservation medium, or perfluorocarbon is placed into reservoir 50. Fluid 56 typically contains dissolved oxygen, but desirably does not contain the catalyst so that fluid 56 is transparent to the UV light which will be applied by source 42.
  • Sample holder 10 may be lowered or reservoir 50 may be raised to bring the anterior surface 52 of the cornea into contact with the fluid 56. During this process, some of the fluid 56 may be displaced from the reservoir.
  • the top edge of the reservoir may be provided with channels (not shown) to allow fluid 56 to spill even if carrier ring 12 contacts the top edge.
  • a catch basin (not shown) may be provided around reservoir 50 to catch spilled fluid.
  • FIG. 2 schematically depicts the distribution of catalyst in the cornea at different times after the beginning of contact with the catalyst-bearing liquid.
  • the vertical axis denotes position within the cornea, with the various layers of the cornea labelled with the same reference numerals shown in Figure 2.
  • the catalyst concentration at a time shortly after the beginning of contact is shown by solid line 66.
  • the catalyst concentration in Descemet’s layer 63 and in the adjacent portion of the corneal stroma 64 is approximately equal to the catalyst concentration in liquid 38.
  • the catalyst concentration at a later time is schematically shown by curve 68, and the catalyst distribution at a still later time is shown by curve 70.
  • the catalyst concentration at and immediately adjacent the posterior surface 34 remains at or near the catalyst concentration in liquid 38, and declines to nearly zero at a location within the stroma. However, this location moves in the anterior direction as time passes.
  • a catalyst field is diffusing from the posterior surface toward the anterior surface.
  • the catalyst-bearing liquid 38 remains in contact with the posterior surface of the cornea for a time referred to as the“soak time” before the light-applying device 40 (Fig. 1) is actuated to apply light to the cornea, and the catalyst bearing liquid remains in contact with the posterior surface during light application.
  • the soak time is selected to that by the time light application begins, the catalyst field in the stroma and Descemet’s layer contains sufficient catalyst to substantially absorb the light, and thus protect the endothelium 62 from the light.
  • the depth of penetration of the catalyst from the posterior toward the anterior can be calculated by Fick’s second law.
  • the light- applying device 40 directs light from the source 42 into the anterior surface 35 of the cornea. Because the crosslinking light energy is applied through the anterior side of the cornea, no crosslinking occurs until the light reaches the front of the catalyst field. Only the constant stromal UV attenuation coefficient affects the incident intensity on the catalyst front within the tissue. This can be easily accounted for. By instilling the riboflavin from the posterior side of the epithelium, the thickness of the cornea, which can vary from graft to graft as much as 100 microns or more, is not a factor in the depth of the crosslinked section of the tissue.
  • Maintaining the riboflavin-bearing liquid in contact with the endothelium during the crosslinking procedure can assure the Descemet’s layer and the deepest layers of the stroma remain at a riboflavin concentration at or near the concentration in the riboflavin-bearing liquid during UV application, despite diffusion of riboflavin during the crosslinking procedure.
  • the procedures and structures discussed above can be varied.
  • the details of the sample holder and the device used to apply ultraviolet light can be modified.
  • the apparatus depicted in Figure 1 directs light from a single light source onto a single cornea.
  • light from a single source could also be scattered and diffused over a larger area, to impinge on multiple corneas.
  • the weight of the upper element 18 serves to clamp the scleral ring of the sample against carrier 12.
  • the sample holder may include other force-applying elements such as springs for urging the upper element and carrier ring together.
  • the epithelium may be removed or the epithelial barrier to riboflavin diffusion may be disabled by application of a drug.
  • the fluid 56 (Fig. 1) in contact with the anterior surface of the cornea will tend to extract riboflavin from the anterior surface.
  • extraction of riboflavin through the anterior surface helps to reduce riboflavin concentration in the anterior layers of the cornea.
  • the fluid in contact with the anterior surface may be continually replaced by fresh fluid to keep the concentration of catalyst in this fluid at or near zero, and thus minimize attenuation of the light by the fluid.
  • the container 50 and the fluid 56 may be omitted, and the anterior surface of the cornea may be exposed to the atmosphere or to another gas containing oxygen so as to maintain oxygenation of the cornea during light application.
  • Riboflavin is the most commonly used crosslinking catalyst. Where riboflavin is used as the crosslinking catalyst, the light applied typically is UV at about 375nm wavelength.
  • the term“riboflavin” as used herein should be understood as including riboflavin 5’ phosphate sodium salt and another pharmaceutically acceptable forms of riboflavin.
  • the present invention may be employed with crosslinking catalysts other than riboflavin. Also, light other than UV light can be used.
  • antioxidants such as those commonly used in corneal preservation fluid can be applied to the epithelium to provide additional protection for the endothelium from oxidative damage. This raises the endothelial cells’ ability to survive exposure to UV light.
  • the antioxidant can be incorporated in the catalyst-bearing liquid 38 (Fig.l) which is applied to the posterior surface of the cornea.
  • the catalyst-bearing liquid can be removed and replaced by corneal preservation fluid after instillation of the catalyst, such as after the“soak time” discussed above, but before or during application of the crosslinking light.
  • the replacement fluid may also contain the catalyst, at the same concentration used for instillation, or at a different concentration.
  • the apparatus and methods discussed above can be used to prepare corneas for use in procedures such as Descemet’s stripping automated keratoplasty (DSAEK) or Descemet’s and endothelial keratoplasty (DMEK), where the epithelium, Descemet’s layer or both will be separated from the stroma of the sample and transplanted into the patient’s eye.
  • the apparatus and methods discussed above also can be used to prepare corneas for other procedures in which part or all of the stroma from the sample will be implanted.

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  • Health & Medical Sciences (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une cornée qui est traitée in vitro pour la préparer à une transplantation par mise en contact de la surface postérieure (34) de la cornée (30) avec un liquide (38) contenant un catalyseur de réticulation cornéenne et dirigeant la lumière dans la cornée à travers la surface antérieure (35) pour provoquer la réticulation du stroma cornéen. La cornée comprend de préférence un endothélium intact, et le catalyseur se diffuse dans la cornée à travers l'endothélium. Le procédé facilite la réticulation du stroma à proximité de la surface postérieure.
PCT/US2020/030227 2019-04-30 2020-04-28 Système de réticulation cornéenne in vitro pour la préparation d'échantillons de tissu transplantable WO2020223211A1 (fr)

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US201962840677P 2019-04-30 2019-04-30
US62/840,677 2019-04-30

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WO2020223211A1 true WO2020223211A1 (fr) 2020-11-05
WO2020223211A9 WO2020223211A9 (fr) 2021-03-25

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5789240A (en) * 1995-09-21 1998-08-04 Abdulrazik; Mohammad Diffusion cell for ex-vivo pressure-controlled transcorneal drug penetration studies
US20160029618A1 (en) * 2013-03-14 2016-02-04 Universite Jean Monnet Medical device intended for the long-term storage of a cornea, or for ex vivo experimentation on a human or animal cornea
US10195081B1 (en) * 2014-05-12 2019-02-05 Gholam A. Peyman Method of prevention of capsular opacification and fibrosis after cataract extraction and/or prevention of fibrosis around a shunt or stent after glaucoma surgery

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5789240A (en) * 1995-09-21 1998-08-04 Abdulrazik; Mohammad Diffusion cell for ex-vivo pressure-controlled transcorneal drug penetration studies
US20160029618A1 (en) * 2013-03-14 2016-02-04 Universite Jean Monnet Medical device intended for the long-term storage of a cornea, or for ex vivo experimentation on a human or animal cornea
US10195081B1 (en) * 2014-05-12 2019-02-05 Gholam A. Peyman Method of prevention of capsular opacification and fibrosis after cataract extraction and/or prevention of fibrosis around a shunt or stent after glaucoma surgery

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WOLLENSAK G ET AL: "Corneal endothelial cytotoxicity of riboflavin/uva treatment in vitro", OPHTHALMIC RESEARCH, S. KARSER AG. BASEL, CH, no. 35, 30 June 2003 (2003-06-30), pages 324 - 328, XP002285679, ISSN: 0030-3747, DOI: 10.1159/000074071 *

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