U.S. patent application number 11/030421 was filed with the patent office on 2005-06-09 for method of producing an epithelial flap (ii).
Invention is credited to Perez, Edward.
Application Number | 20050124982 11/030421 |
Document ID | / |
Family ID | 24478269 |
Filed Date | 2005-06-09 |
United States Patent
Application |
20050124982 |
Kind Code |
A1 |
Perez, Edward |
June 9, 2005 |
Method of producing an epithelial flap (II)
Abstract
This relates to a lens made of donor corneal tissue suitable for
use as a contact lens or an implanted lens, to a method of
preparing that lens, and to a technique of placing the lens on the
eye. The lens is made of donor corneal tissue that is acellularized
by removing native epithelium and keratocytes. These cells
optionally are replaced with human epithelium and keratocytes to
form a lens that has a structural anatomy similar to human cornea.
The ocular lens may be used to correct conditions such as
astigmatism, myopia, aphakia, and presbyopia.
Inventors: |
Perez, Edward; (Redwood
City, CA) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Family ID: |
24478269 |
Appl. No.: |
11/030421 |
Filed: |
January 5, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11030421 |
Jan 5, 2005 |
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10243121 |
Sep 13, 2002 |
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6880558 |
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10243121 |
Sep 13, 2002 |
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PCT/US01/22633 |
Jul 18, 2001 |
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PCT/US01/22633 |
Jul 18, 2001 |
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09618580 |
Jul 18, 2000 |
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6544286 |
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Current U.S.
Class: |
606/4 ;
128/898 |
Current CPC
Class: |
A61L 27/3604 20130101;
A61F 2/145 20130101; A61L 27/3641 20130101; A61F 2/142 20130101;
A61L 2430/16 20130101; A61L 27/3839 20130101; A61L 27/3813
20130101; A61L 27/3683 20130101 |
Class at
Publication: |
606/004 ;
128/898 |
International
Class: |
A61B 018/20; A61B
019/00 |
Claims
1. A method for acting on an eye having an anterior corneal surface
and an epithelial tissue layer, the method comprising: a.) lifting
from the anterior corneal surface, a portion of the epithelial
tissue layer resulting in a lifted continuous epithelial layer
separated from a corneal stromal margin and having a portion of
that lifted continuous epithelial layer connected to the corneal
surface, b.) performing an action on the corneal stromal margin
from which a portion of the epithelial layer has been separated,
and c.) returning the lifted continuous epithelial layer to the eye
adjacent to the corneal stromal margin from which a portion of the
epithelial layer has been separated.
2. The method of claim 1 wherein the step of performing an action
on the corneal stromal margin comprises placing an ocular device
onto the corneal stromal margin from which a portion of the
epithelial layer has been separated.
3. The method of claim 1 wherein the step of performing an action
on the corneal stromal margin comprises placing a corrective ocular
device onto the corneal stromal margin from which a portion of the
epithelial layer has been separated.
4. The method of claim 1 wherein the step of performing an action
on the corneal stromal margin comprises performing a laser
corrective procedure on the corneal stromal margin from which a
portion of the epithelial layer has been separated.
5. The method of claim 1 wherein said lifting step comprises
employing vacuum to lift the epithelial layer from the anterior
surface.
6. A method for acting on an eye having an anterior corneal surface
and an epithelial tissue layer, the method comprising: a.) lifting
from the anterior corneal surface with a device, a portion of the
epithelial layer resulting in a living, lifted continuous
epithelial layer separated from a corneal stromal margin having a
portion connected to the corneal surface, and b.) removing the
device and leaving the separated epithelial layer connected to the
corneal surface.
7. The method of claim 6 further comprising the step of performing
an action on the corneal stromal margin from which a portion of the
epithelial layer has been separated.
8. The method of claim 6 further comprising the step of returning
the lifted continuous epithelial layer to the eye adjacent to the
corneal stromal margin from which a portion of the epithelial layer
has been separated.
9. The method of claim 7 wherein the step of performing an action
on the corneal stromal margin comprises placing an ocular device
onto the corneal stromal margin from which a portion of the
epithelial layer has been separated.
10. The method of claim 7 wherein the step of performing an action
on the corneal stromal margin comprises placing a corrective ocular
device onto the corneal stromal margin from which a portion of the
epithelial layer has been separated.
11. The method of claim 7 wherein the step of performing an action
on the corneal stromal margin comprises performing a laser
corrective procedure on the corneal stromal margin from which a
portion of the epithelial layer has been separated.
12. The method of claim 7 wherein said lifting step comprises
employing vacuum to lift the continuous epithelial layer separated
from the corneal stromal margin.
13. The method of claim 1 wherein the continuous epithelial layer
separated from a corneal stromal margin contains substantially no
corneal tissue.
14. A method for acting on an eye having a cornea and epithelial
tissue attached thereto, the method comprising: a) separating from
the cornea a tissue layer comprising epithelial tissue
substantially free of other corneal tissue resulting in an exposed
anterior corneal surface and a separated continuous epithelial
tissue layer separated from the exposed anterior corneal surface,
the separated layer having a portion connected to the eye, b)
placing a corrective ocular device entirely onto the exposed
anterior corneal surface, and c) placing at least a portion of the
separated layer onto the corrective ocular device.
15. The method of claim 14 wherein the separating step comprises
employing vacuum to lift the tissue layer comprising epithelial
tissue from the cornea.
16. The method of claim 14 wherein the corrective ocular device
further contains at least one of a therapeutic agent, an
immunosuppressive agent, and one or more growth factors.
17. The method of claim 14 wherein the corrective ocular device
comprises a lens.
18. The method of claim 14 wherein the separating step separates
from the cornea a tissue layer consisting essentially of epithelial
tissue.
19. The method of claim 14 wherein the separating step separates
from the cornea a tissue layer of substantially only epithelial
tissue.
20. The method of claim 14 wherein the separating step comprises
separating the tissue layer from Bowman's Membrane.
21. A method for acting on an eye having a cornea and epithelial
tissue attached thereto, the method comprising: a) separating from
the cornea with a device, a tissue layer comprising epithelial
tissue substantially free of other corneal tissue to produce an
exposed anterior corneal surface, and a lifted, living, continuous
epithelial tissue layer separated from the exposed anterior corneal
surface and having a portion connected to the eye, b) removing the
device from the eye leaving the lifted epithelial tissue layer
having a portion connected to the eye, c.) introducing a corrective
ocular device entirely onto the exposed anterior corneal surface,
and c) placing at least a portion of the lifted layer onto the
corrective ocular device.
22. The method of claim 21 wherein the using step comprises
employing a vacuum to lift the tissue layer comprising epithelial
tissue from the cornea.
23. The method of claim 21 wherein the corrective ocular device
further contains at least one of a therapeutic agent, an
immunosuppressive agent, and one or more growth factors.
24. The method of claim 21 wherein the corrective ocular device
comprises a lens.
25. The method of claim 21 wherein the separating step separates
from the cornea a tissue layer consisting essentially of epithelial
tissue.
26. The method of claim 21 wherein the separating step separates
from the cornea a tissue layer of substantially only epithelial
tissue.
27. The method of claim 21 wherein the separating step comprises
separating the tissue layer from Bowman's Membrane.
28. A method for acting on an eye having a cornea and epithelial
tissue attached thereto, wherein a tissue layer comprising
epithelial tissue substantially free of other corneal tissue has
been separated from the cornea, resulting in an exposed anterior
corneal surface and a separated continuous epithelial tissue layer
separated from the cornea and the separated layer having a portion
connected to the eye, the method comprising: a) placing a
corrective ocular device entirely onto the exposed anterior corneal
surface, and b) placing at least a portion of the separated layer
onto the corrective ocular device.
29. The method of claim 28 wherein the corrective ocular device
further contains at least one of a therapeutic agent, an
immunosuppressive agent, and one or more growth factors.
30. The method of claim 28 wherein the corrective ocular device is
a lens.
31. The method of claim 28 wherein the separated layer consists
essentially of epithelial tissue.
32. The method of claim 28 wherein the separated layer is
substantially only epithelial tissue.
33. The method of claim 28 wherein the separated layer is free of
Bowman's Membrane.
34. A method for acting on an eye having a cornea and epithelial
tissue attached thereto, wherein a tissue layer comprising
epithelial tissue substantially free of other corneal tissue has
been separated from the cornea, resulting in an exposed anterior
corneal surface and a separated continuous epithelial tissue layer
separated from the cornea and the separated layer having a portion
connected to the eye, and a corrective ocular device has been
placed entirely onto the exposed anterior corneal surface, the
method comprising the step of: placing at least a portion of the
separated layer onto the corrective ocular device.
35. The method of claim 34 wherein the corrective ocular device
further contains at least one of a therapeutic agent, an
immunosuppressive agent, and one or more growth factors.
36. The method of claim 34 wherein the corrective ocular device
comprises a lens.
37. The method of claim 34 wherein the separated layer consists
essentially of epithelial tissue.
38. The method of claim 34 wherein the separated layer is
substantially only epithelial tissue.
39. The method of claim 34 wherein the separated layer is free of
Bowman's Membrane.
40. A method for acting on an eye having a cornea and epithelial
tissue attached thereto, the method comprising the step of
separating from the cornea a tissue layer comprising epithelial
tissue substantially free of other corneal tissue, the separating
step producing an exposed anterior corneal surface and a separated
continuous epithelial tissue layer separated from the exposed
anterior corneal surface, the separated layer having a portion
connected to the eye.
41. The method of claim 40 further comprising the step of
performing an action on the corneal stromal margin from which the
separated continuous epithelial tissue layer has been
separated.
42. The method of claim 41 wherein the step of performing an action
on the corneal stromal margin comprises placing an ocular device
onto the corneal stromal margin from which the separated continuous
epithelial tissue layer has been separated.
43. The method of claim 41 wherein the step of performing an action
on the corneal stromal margin comprises placing a corrective ocular
device onto the corneal stromal margin from which the separated
continuous epithelial tissue layer has been separated.
44. The method of claim 41 wherein the step of performing an action
on the corneal stromal margin comprises performing a laser
corrective procedure on the corneal stromal margin from which the
separated continuous epithelial tissue layer has been
separated.
45. The method of claim 41 further comprising the step of returning
the separated continuous epithelial tissue layer to the eye
adjacent to the corneal stromal margin from which a portion of the
epithelial layer has been separated.
46. The method of claim 42 further comprising the step of returning
the separated continuous epithelial tissue layer to the eye
adjacent to the corneal stromal margin from which a portion of the
epithelial layer has been separated.
47. The method of claim 43 further comprising the step of returning
the separated continuous epithelial tissue layer to the eye
adjacent to the corneal stromal margin from which a portion of the
epithelial layer has been separated.
48. The method of claim 44 further comprising the step of returning
the separated continuous epithelial tissue layer to the eye
adjacent to the corneal stromal margin from which a portion of the
epithelial layer has been separated.
49. The method of claim 40 wherein the separating step comprises
employing vacuum to lift the tissue layer comprising epithelial
tissue from the cornea.
50. The method of claim 43 wherein the corrective ocular device
further contains at least one of a therapeutic agent, an
immunosuppressive agent, and one or more growth factors.
51. The method of claim 43 wherein the corrective ocular device
comprises a lens.
52. The method of claim 40 wherein the separating step separates
from the cornea a tissue layer consisting essentially of epithelial
tissue.
53. The method of claim 40 wherein the separating step separates
from the cornea a tissue layer of substantially only epithelial
tissue.
54. The method of claim 41 wherein the separating step comprises
separating the tissue layer from Bowman's Membrane.
55. A method for acting on an eye having a cornea and epithelial
tissue attached thereto, wherein a tissue layer comprising
epithelial tissue substantially free of other corneal tissue has
been separated from the cornea, resulting in an exposed anterior
corneal surface and a separated continuous epithelial tissue layer
separated from the cornea and the separated layer having a portion
connected to the eye, the method comprising the step of performing
a vision corrective action upon the exposed anterior corneal
surface.
56. The method of claim 55 wherein the step of performing an action
on the corneal stromal margin comprises placing an ocular device
onto the corneal stromal margin from which the separated continuous
epithelial tissue layer has been separated.
57. The method of claim 55 wherein the step of performing an action
on the corneal stromal margin comprises placing a corrective ocular
device onto the corneal stromal margin from which the separated
continuous epithelial tissue layer has been separated.
58. The method of claim 55 wherein the step of performing an action
on the corneal stromal margin comprises performing a laser
corrective procedure on the corneal stromal margin from which the
separated continuous epithelial tissue layer has been
separated.
59. The method of claim 55 further comprising the step of returning
the separated continuous epithelial tissue layer to the eye
adjacent to the corneal stromal margin from which a portion of the
epithelial layer has been separated.
60. The method of claim 56 further comprising the step of returning
the separated continuous epithelial tissue layer to the eye
adjacent to the corneal stromal margin from which a portion of the
epithelial layer has been separated.
61. The method of claim 57 further comprising the step of returning
the separated continuous epithelial tissue layer to the eye
adjacent to the corneal stromal margin from which a portion of the
epithelial layer has been separated.
62. The method of claim 58 further comprising the step of returning
the separated continuous epithelial tissue layer to the eye
adjacent to the corneal stromal margin from which a portion of the
epithelial layer has been separated.
63. The method of claim 57 wherein the corrective ocular device
further contains at least one of a therapeutic agent, an
immunosuppressive agent, and one or more growth factors.
64. The method of claim 57 wherein the corrective ocular device
comprises a lens.
65. The method of claim 55 wherein the separated continuous
epithelial tissue layer consists essentially of epithelial
tissue.
66. The method of claim 55 wherein the separated continuous
epithelial tissue layer is substantially only epithelial
tissue.
67. The method of claim 55 wherein the separated continuous
epithelial tissue layer is free of Bowman's Membrane.
Description
RELATED APPLICATIONS
[0001] This is a continuation of pending U.S. patent application
Ser. No. 10/243,121, filed Sep. 13, 2002, that, in turn, is a
continuation of PCT Application No. PCT/US01/22633, having an
International Filing Date of Jul. 18, 2001, and in turn, is a
continuation-in-part of U.S. patent application Ser. No.
09/618,580, filed Jul. 18, 2000, now issued as U.S. Pat. No.
6,544,286, on Apr. 8, 2003.
[0002] All of the above disclosures are herein incorporated by
reference in their entirety.
FIELD
[0003] This disclosure is in the field of ophthalmology. More
particularly, it relates to a device for lifting an epithelial
layer from the anterior surface of the cornea. The disclosure
includes methods for placement of a lens beneath that epithelial
layer.
BACKGROUND
[0004] The visual system allows the eye to focus light rays into
meaningful images. The most common problem an ophthalmologist or
optometrist will encounter is that of spherical ammetropia, or the
formation of an image by the eye which is out of focus with
accommodation due to an improperly shaped globe. The
ophthalmologist or optometrist determines the refractive status of
the eye and corrects the optical error with contact lenses or
glasses.
[0005] Many procedures have been developed to correct spherical
ammetropia by modifying the shape of the cornea. Light entering the
eye is first focused by the cornea, which possesses approximately
75% of the eye's overall refractory power. The majority of
refractive operations involve either decreasing or increasing the
anterior curvature of the cornea.
[0006] The procedures in early corneal refractive surgery such as
keratophakia and keratomileusis were originally developed to
correct myopia and involved removing a corneal disc from the
patient with a microkeratome. The removed corneal disc was then
frozen prior to reshaping the posterior surface with a cryolathe.
After thawing, the disc was returned to the eye and secured with
sutures.
[0007] Epikeratophakia, as described in U.S. Pat. No. 4,662,881, is
a procedure that involves inserting a precut donor corneal tissue
lens with beveled edges into corresponding grooves in recipient
cornea. The lens is then sutured to the corneal bed. The donor lens
is lyophilized and requires rehydration before placement on
recipient cornea.
[0008] These techniques and their variations were generally
considered to be unsuccessful due to frequent complications
involving irregular astigmatism, delayed surgical healing, corneal
scarring, and instability of the refractive result. The problems
were attributed to the technical complexity of the procedures as
well as to the distortion in architecture of the corneal tissue
secondary to lens manipulation. For example, in epikeratophakia,
epithelial irregularity is induced by lyophilization of the donor
lens. Freezing of the lenticule in keratophakia and keratomileusis
also causes severe damage to epithelial and stromal cells and
disrupts the lamellar architecture of the cornea.
[0009] Described is a pre-fabricated lens made of donor corneal
tissue obtained from tissue sources such as human or animal cornea.
The lens is a corneal disc that is preferably shaped on the
posterior surface generally to conform in shape to the eye's
anterior surface. The lens may be shaped by an ablative laser,
e.g., by an excimer laser or other suitable laser. The corneal
lenticule is living tissue that has not been frozen, lyophilized,
or chemically modified, e.g., fixed with glutaraldehyde to
crosslink corneal tissue. Pre-existing keratocytes are removed and
then replaced with human keratocytes to decrease antigenicity.
After removal of epithelium in the central zone of the recipient's
cornea, the lens is placed on this zone in the same manner that a
contact lens is placed on the eye.
[0010] Ocular lenses found in the prior art do not use native
cornea, but are formulated using soluble collagen such as collagen
hydrogels, e.g., polyhydroxyethylmethacrylate, or other
biocompatible materials. For example, in U.S. Pat. No. 5,213,720,
to Civerchia, soluble collagen is gelled and crosslinked to produce
an artificial lens. In addition to hydrogels, U.S. Pat. No.
4,715,858, to Lindstrom, discloses lenses made from various
polymers, silicone, and cellulose acetate butyrate.
[0011] In the cases where ocular lenses use corneal tissue, the
lenses are either corneal implants or require a separate agent to
adhere the lens to the corneal bed. U.S. Pat. Nos. 5,171,318, to
Gibson et al., and 5,919,185, to Peyman, relate to a disc of
corneal tissue that is partially or entirely embedded in stroma.
The ocular lens device disclosed in U.S. Pat. Nos. 4,646,720, to
Peyman et al., and 5,192,316, to Ting, is attached to recipient
cornea with sutures. The corneal inlay described in U.S. Pat. No.
4,676,790, to Kern, is bonded to recipient cornea using sutures,
laser welding, or application of a liquid adhesive or crosslinking
solution.
[0012] The ocular lens device described here does not alter the
anatomical structure of corneal tissue. U.S. Pat. No. 4,346,482, to
Tennant et al., discloses a "living contact lens" consisting of
donor cornea that has been anteriorly curved for correction of
vision. However, this lens is frozen prior to reshaping on a lathe
which results in stromal keratocyte death. U.S. Pat. No. 4,793,344,
to Cumming et al., also describes a donor corneal tissue lens that
is modified by treatment with a glutaraldehyde fixative that
preserves the tissue and prevents lens swelling. This treatment
alters the basic structure of the corneal lenticule by crosslinking
the tissue.
[0013] Furthermore, the cited documents do not show any methods of
lens preparation that remove native corneal tissue cells and
replace them with cells cultivated from human cornea. My device is
devitalized of native epithelium and keratocytes to create an
acellular corneal tissue, and then revitalized with human
epithelium and keratocytes. An attempt to construct a so-called
"corneal tissue equivalent" was shown in U.S. Pat. No. 5,374,515,
to Parenteau et al. However, the collagen used in that "equivalent"
is obtained from bovine tendon instead of from cornea. The added
keratocytes and epithelium are also not from human sources. The
tissue using these cell culturing procedures is also quite
fragile.
[0014] An excimer laser is used to reform a cornea via the "laser
in situ keratomileusis" (LASIK) procedure. In this technique, an
excimer laser is used to perform stromal photoablation of a corneal
flap or in situ photoablation of the exposed stromal bed. Studies
have shown that the inaccuracy of correction by this procedure may
be as much as one diopter from the desired value. Lenses (contacts
and spectacles), in contrast, are able to correct within 0.25
diopters of the desired value.
[0015] U.S. Pat. No. 6,036,683, to Jean et al., shows the use of a
laser to reshape the cornea. However, the laser changes the native
structure of the cornea by irreversibly coagulating collagen.
Post-laser relaxation of collagen is not possible with this
treatment.
[0016] My described lens, however, in some variations relates to a
pre-fabricated donor contact lens that adheres to recipient cornea
without sutures. The lens preserves the anatomy of normal corneal
tissue. The donor lens may be obtained from human and animal
sources, is devitalized of native keratocytes and epithelium to
create an acellular tissue, and then optionally revitalized with at
least one of human keratocytes and epithelial cells to maintain
lens viability and decrease antigenicity. The inventive corneal
overlay technique may be completed under local anesthesia as well
as general anesthesia, and the availability of a precut lens will
greatly decrease procedure time, patient cost, and risk of
operative complications. The duration of healing will also be
reduced due to the implementation of a lens already repopulated
with keratocytes.
[0017] None of the cited documents shows or suggest the lens and
procedures described herein.
SUMMARY
[0018] Described is a pre-fabricated ocular lens device having a
lens core made of donor corneal tissue from tissue sources such as
human or animal cornea. The device may be used as a contact lens or
as an implanted lens and may have a generally convex anterior
surface and, optionally, a concave posterior surface. The stroma
portion of the lens core may be repopulated with replaced
keratocytes and the anterior surface is preferably covered with a
replaced epithelium. The lens core adheres to recipient cornea
without sutures or other adhering materials.
[0019] The lens core may be variously used to correct astigmatism,
myopia, aphakia, and presbyopia. The lens core may be made of
transgenic or xenogenic corneal tissue. Properly treated, the
inventive lens may have a clarity at least 85% of that of human
corneal tissue of a corresponding thickness. The lens core is not
frozen, lyophilized, or chemically treated with a fixative.
However, variations of the device may contain therapeutic agents,
growth factors, or immunosuppressive agents.
[0020] Another component is a method for preparing the lens device.
After sharp dissection of a lenticule from donor corneal tissue,
the posterior surface is shaped using an ablative laser, such as an
excimer laser or other suitable shaping lasers. Native epithelium
and keratocytes are removed and then replaced, as desired, with
human epithelium and keratocytes.
[0021] Also described is a method of corneal overlay that involves
de-epithelialization of a portion of the anterior surface of the
recipient cornea and placement of the inventive ocular lens device
upon that anterior surface. Another method involves the temporary
separation of the epithelial tissue by suction or other procedures
and placement of a lens beneath that epithelial tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a superior, cross-sectional view of the eye.
[0023] FIG. 2A is a side view of the focusing point in myopia.
[0024] FIG. 2B is a side view of a focusing point corrected by
flattening the anterior curvature of the cornea.
[0025] FIG. 3A is a side, cross-sectional view of a pre-fabricated
donor lens.
[0026] FIG. 3B is a side, cross-sectional view of a pre-fabricated
donor lens suitable for correcting myopia.
[0027] FIG. 3C is a side, cross-sectional view of a pre-fabricated
donor lens suitable for correcting aphakia.
[0028] FIG. 3D is a front view of a pre-fabricated donor lens
suitable for bifocal use.
[0029] FIG. 3E is a side, cross-sectional view of the FIG. 3C lens
positioned away from the cornea of an eye.
[0030] FIG. 3F is a front view of an inventive lens having an
overlapping epithelial layer.
[0031] FIG. 3G shows a side cross sectional view of the FIG. 3F
lens.
[0032] FIG. 3H shows a side cross sectional view of an inventive
lens in a carrier.
[0033] FIG. 3I is a front view of an annular inventive lens.
[0034] FIG. 3J shows a side cross sectional view of the FIG. 3I
lens.
[0035] FIG. 4A is a side, cross-sectional view of an area of
de-epithelialized recipient cornea prepared to receive the optical
lens of the present invention.
[0036] FIG. 4B is a side, cross-sectional view of the donor lens
after placement on recipient cornea.
[0037] FIG. 5 show a series of steps for introducing an inventive
lens subepithelially.
DETAILED DESCRIPTION
[0038] The eye is designed to focus light onto specialized
receptors in the retina that turn quanta of light energy into nerve
action potentials. As shown in FIG. 1, light rays are first
transmitted through the cornea (100) of the eye. The cornea is
transparent due to the highly organized structure of its collagen
fibrils. The margins of the cornea merge with a tough
fibrocollagenous sclera (102) and is referred to as the
corneo-scleral layer.
[0039] The cornea (100) is the portion of the corneo-scleral layer
enclosing the anterior one-sixth of the eye. The smooth curvature
of the cornea is the major focusing power of images on the retina
(104) and it provides much of the eye's 60 diopters of converging
power. The cornea is an avascular structure and is sustained by
diffusion of nutrients and oxygen from the aqueous humor (106).
Some oxygen is also derived from the external environment. The
avascular nature of the cornea decreases the immunogenicity of the
tissue, increasing the success rate of corneal transplants.
[0040] The cornea consists of five layers. The outer surface is
lined by stratified squamous epithelium which is about five cells
thick. Failure of epithelialization results in necrosis of the
stromal cap and potential scarring of recipient cornea. The
epithelium is supported by a specialized basement membrane known as
Bowman's membrane, which gives the cornea a smooth optical surface.
The bulk of the cornea, the substantia propria (stroma), consists
of a highly regular form of dense collagenous connective tissue
forming thin lamellae. Between the lamellae are spindle-shaped
keratocytes which can be stimulated to synthesize components of the
connective tissue. The inner surface of the cornea is lined by a
layer of flattened endothelial cells which are supported by
Descemet's membrane, a very thick elastic basement membrane.
[0041] As previously mentioned, the focusing power of the cornea is
primarily dependent on the radius of curvature of its external
surface. In myopia, as seen in FIG. 2A, increased curvature of the
cornea (200) causes the focusing point of light rays (202) to fall
short of the retina (204). In FIG. 2B, flattening the anterior
curvature of the cornea (206) corrects the focal point (208).
[0042] Lens Structures
[0043] In a first variation of the described lens, the physical
shape generally is of a size and configuration that upon
installation on the cornea, supplements the curvature of the cornea
to correct abnormal conditions such as astigmatism, myopia,
hyperopia, presbyopia, and aphakia. Other variations of the lens
may be shaped to be placed beneath the anterior surface of the host
cornea or to serve as a source of medication.
[0044] Typically, the lens core may comprise or consist essentially
of acellular donor corneal tissue that has been devitalized, e.g.,
treated to remove native keratocytes and epithelium, to lessen the
chances of tissue rejection and then at least partially
revitalized, e.g., treated to introduce at least one of human
keratocytes and an epithelial layer, to allow and to support
continued use of the inventive lens in place on the eye. The
epithelial cells may (often in the form of a discrete layer) be
placed on at least a portion of the anterior surface of a lens. In
some variations, all of the anterior surface will be so-covered. In
one variation discussed below, an epithelial layer will extend
beyond the periphery of the lens core and optionally the lens be
carried in a biodegradable carrier that is used during placement in
the eye and later disappears.
[0045] The described lens may be placed on a host eye from which at
least a major portion of the native epithelium on that cornea, has
been removed. Preferably in this variation, substantially all of
the epithelium has been removed from the region upon which the
inventive lens will be sited. The lens may also be placed beneath a
layer of epithelium lifted from the eye surface during the
procedure of introducing the lens onto the anterior surface of the
host cornea or in other instances beneath the surface of the host
cornea. The described lens may be used variously to correct
refraction (because of its shape) or it may be used simply to
provide a source of infused medication to the eye.
[0046] The donor lenticule or lens core may be obtained from other
human (allogeneic) or foreign tissue (xenogenic) sources.
Appropriate xenogenic sources include rabbit, bovine, porcine, or
guinea pig corneal tissue. The ocular lens cores may also come from
transgenic corneal tissue or corneal tissue grown in vitro. In many
instances, it is desired that the architecture of the corneal
layers in the donated tissue, the normal corneal tissue matrix,
e.g., the connective tissue or the stroma, be substantially
preserved. The "corneal tissue matrix" is made up of thin layers of
collagen fibrils. The term "donor corneal tissue", as used here, is
meant to include donor or harvested corneas or corneal tissue
containing the "corneal tissue matrix". Additionally, in most
variations, it is highly desirable to preserve the anterior surface
of the donated corneal tissue as found beneath the native
epithelium. The donor corneal tissue is not to undergo harsh
treatments such as lyophilization, freezing, or other chemical
fixation. Nevertheless, it is sometimes desirable to utilize only a
portion of the anterior surface of the donor lens, e.g., in those
instances where the inventive lens structure is annular in
shape.
[0047] The described ocular lens device desirably includes Bowman's
membrane, where the donor tissue includes it, to maintain the
native structure of human epithelium. Again, it is highly desirable
to harvest from donor sources in such a way that the native
anterior surface below the epithelium is preserved. I have found
that these native structures have a superior ability, particularly
after the revitalization steps discussed below, to support and to
maintain the replaced epithelium also discussed below. The clarity
of the inventive tissue lens core handled in such a way generally
will be at least 85%, preferably between 75%-100%, and most
preferably at least 90%, of that of human corneal tissue of
corresponding thickness.
[0048] The overall diameter of my lens is functionally appropriate
to perform the desired correction, and generally is less than about
25 mm and more preferably is between 10 and 15 mm. The thickness of
the resulting lens is, again, functionally appropriate to perform
the desired correction, e.g., generally less than 300 .mu.m, more
preferably between 5-100 .mu.m.
[0049] As shown in FIG. 3B, a lens core (316) for myopic patients
is formed, preferably using the procedures discussed below, in such
a way that a generally circular region (318) in the center is
flattened in its anterior curvature. In correction of aphakia, a
lens such as is shown in FIG. 3C is formed having a comparatively
thicker center (322) and a thinner perimeter (324). In general, the
shapes discussed here are similar to those found in the so-called
"soft" contact lenses and instruction may be had from that
technology relating to the overall form of the lenses selected for
correcting specific ocular maladies.
[0050] As shown in FIGS. 3D and 3E, the lens may also be used to
correct presbyopia. In particular, to treat presbyopia, the lens
(330) is also provided with an generally opaque annular region
(332) adjacent the center of the device. The open center (334)
preferably has plano-lens characteristics and an effective diameter
of less than about 1.5 mm, preferably between about 0.5-1.5 mm, and
most preferably between 0.75 mm and 1.75 mm. The diameter of that
open center (334) or central area or "pinhole" is generally formed
and selected to be less than the pupillary diameter of the host eye
in daylight. This creates a "pinhole" effect, thereby lengthening
the overall effective focal length of the eye and minimizing the
need for the eye to accommodate. Other bifocal lens designs can
also be incorporated, e.g., concentric rings, segmented or sectors
of the annular region or ring, or progressive diffractive.
[0051] FIG. 3E shows a side, cross-sectional view of my lens (330)
shown in FIG. 3D, adjacent the anterior surface of a cornea (344)
to illustrate certain features of this variation. The outer
diameter (336) of the opaque annular ring (332) is generally
selected so that it is smaller than the diameter (338) of the pupil
(340) in the iris (342) in low light conditions. In this way, the
eye's cornea and lens and the inventive lens cooperate in such a
way that incident light passes both though the center of the opaque
ring (334), but more importantly, around the periphery of the
opaque ring (332), to allow corrected sight during low light
conditions.
[0052] The annular ring (332) may be situated on the lens core
either by placement of a suitable dye, i.e., by "tattooing", or by
placement of a substantially opaque biocompatible member of, e.g.,
Dacron mesh or the like, on the posterior surface to filter light
rays. Other placements of the annular ring (332) may be envisioned,
e.g., on the anterior surface of the inventive lens. The annular
ring (332) itself preferably is quite opaque, e.g., passing less
than about 80% of incident visible light, but may be chosen in such
a way to be less opaque or to correct other maladies such as
colorblindness by shifting an incident color into a visible range
by color refraction or the like.
[0053] As is shown in FIGS. 3F (in front view) and 3G (in cross
section), another variation of the lens device (346) includes a
core lens (348) as discussed above but having an epithelial layer
(352) that extends beyond the periphery (350) of that lens core
(348). The method for producing the variation (346) with an
extra-periphery epithelial layer (352) is similar to the method
described elsewhere herein except that the lens core (348) is
desirably placed in a carrier (354 in FIG. 3H)) having a shape
generally conforming to the anterior surface of the donor core lens
(348).
[0054] The carrier (354), as shown in FIG. 3H, desirably serves
several functions. First, it provides a substrate for growth of the
epithelial layer (352) prior to the time that the core lens (348)
is placed on that epithelial layer (352). This extra surface beyond
the periphery of the core lens (348) provides support for the
otherwise fragile epithelial layer (352). The carrier (354) may be
placed in or formed in a properly shaped receptacle that, in turn,
provides support for the fragile carrier (354) during the steps of
growing an epithelial layer (352).
[0055] The combination (356) of carrier (354), epithelial layer
(352)--whether the epithelial layer (352) extends beyond the
periphery of the core lens (348) or not, e.g., the epithelial layer
(352) is situated only on some or all of the core lens (348)--and
core lens (348) placed on that epithelial layer (352), as shown in
FIG. 3H, is another variation of the invention. The construct (356)
shown in FIG. 3H may, upon proper choice of materials for the
carrier, be placed directly in the host eye thereby providing
support for the epithelial layer (352) and core lens (348), as well
as optionally, medication or other treatment materials for the eye
during initial placement.
[0056] When the carrier is used for placement in the eye, the
carrier (354) preferably comprises a material meeting two related
criteria. First, the material desirably is one that dissolves,
erodes, or otherwise shortly clears from the eye to be treated
after the combination (356) of the carrier (354) , epithelial layer
(352), and the donor lens (348) are introduced to that eye.
Preferably also, the carrier is of a material that serves as a
substrate for a pre-grown epithelial layer. Most desirably, the
carrier (354) satisfies both criteria. The carrier (354) may
comprise a material such as collagen, gelatin, starch, glucosamine
glucans, proteins, carbohydrates, polyanhydrides such as
polylactides and polyglycolides, their mixtures and copolymers,
polydiaxanone, etc.
[0057] The carrier (354) may also be infused with medication or
other treatment material, antiangiogenesis materials or the
like.
[0058] FIGS. 3I and 3J show, respectively, a front view and a side
cross sectional view of a lens (360) having a central opening (362)
passing through the lens body. Although this lens variation (360)
is shown without an epithelial layer, it is within the scope of the
invention to so include the layer.
[0059] Process for Shaping the Lens
[0060] Returning to FIG. 3A, the donor core lens (300) desirably is
obtained after slicing corneal tissue from the donor with a
microkeratome to form that lens core (300). The donor lens (300)
has a structural surface, the anterior surface of the lens core,
which serves as the structural surface of the donor corneal tissue.
The lens core anterior surface is harvested preferably to retain
the Bowman's membrane (where the donor lens contains one) and
epithelium (302). The posterior surface (304) of the resulting lens
is generally concave in shape, although it need not be so. The
anterior surface of the lens may be shaped via a shaping step which
preferably involves the use of an ablative laser, such as an
excimer laser, to obtain the necessary power of the lens. Another
suitable forming step is high pressure water jet cutting.
[0061] Sterilization, Devitalization, and Revitalization Steps
[0062] Although the order of the process steps outlined below is
typical, it should be understood that such steps may be varied as
needed to produce the desired result.
[0063] Generally, the lens will first be shaped to an appropriate
shape as discussed above. The lens core may then be subjected to
processes of sterilization, devitalization, and revitalization.
Removal of epithelium (de-epithelialization) and keratocytes
(acellularization) from the donor lens will be referred to as
"devitalization". The addition of human epithelium and keratocytes
will be referred to as "revitalization". One desirable method for
accomplishing those steps is found just below. Other equivalent
methods are known.
[0064] Phosphate buffered saline (PBS) with antibiotics, epithelial
cell media, and keratocyte media are solutions used during these
processes. The "PBS with antibiotics" solution may contain:
[0065] PBS With Antibiotics
[0066] 1. Amphotericin B (ICN Biomedicals) 0.625 .mu.g/ml
[0067] 2. Penicillin (Gibco BRL) 100 IU/ml
[0068] 3. Streptomycin (Gibco BRL) 100 .mu.g/ml
[0069] 4. Phosphate buffered saline (Gibco BRL)
[0070] The composition of the epithelial cell media may
include:
[0071] Epithelial Cell Media
[0072] 1. Dulbecco's Modified Eagle Media/Ham's F12 media (Gibco
BRL) 3:1
[0073] 2. 10% fetal calf serum (Gibco BRL)
[0074] 3. Epidermal growth factor (ICN Biomedicals) 10 ng/ml
[0075] 4. Hydrocortisone (Sigma-Aldrich) 0.4 .mu.g/ml
[0076] 5. Cholera toxin (ICN Biomedicals) 10.sup.-10 M
[0077] 6. Adenine (Sigma-Aldrich) 1.8.times.10.sup.-4 M
[0078] 7. Insulin (ICN Biomedicals) 5 .mu.g/ml
[0079] 8. Transferrin (ICN Biomedicals) 5 .mu.g/ml
[0080] 9. Glutamine (Sigma-Aldrich) 2.times.10.sup.-3 M
[0081] 10. Triiodothyronine (ICN Biomedicals) 2.times.10.sup.-7
M
[0082] 11. Amphotericin B (ICN Biomedicals) 0.625 .mu.g/ml
[0083] 12. Penicillin (Gibco BRL) 100 IU/ml
[0084] 13. Streptomycin (Gibco BRL) 100 .mu.g/ml
[0085] The composition of the keratocyte media may include:
[0086] Kerat
[0087] 1. DMEM
[0088] 2. 10% neonatal calf serum (Gibco BRL)
[0089] 3. Glutamine (Sigma-Aldrich) 2.times.10.sup.-3 M
[0090] 4. Amphotericin B (ICN Biomedicals) 0.625 .mu.g/ml
[0091] Sterilization Step
[0092] After harvesting the lens core from donor corneal tissue and
following the shaping step, the lens may be sterilized, for
instance, by immersion into 98% glycerol at room temperature. Three
weeks of glycerol treatment inactivates intracellular viruses and
any bacteria or fungi. Ethylene oxide gas sterilization may also be
used, but tends to induce variable damage to stromal tissue.
[0093] Devitalization Step
[0094] De-epithelialization
[0095] I prefer to de-epithelialize the donor lens by placing it in
a one molar solution of salt (preferably sodium chloride) at a
temperature from 4 to 25.degree. C. After four to eight hours of
incubation, the entire epithelial layer generally will split from
the corneal stroma and may be easily removed. Thereafter the lens
may be washed in a PBS solution with antibiotics to remove salt and
cellular material.
[0096] Another method of removing the epithelium is via the use of
vacuum. The epithelium may be split from the stroma by means of
suction (-100 mm Hg to -450 mm Hg). After fifteen minute to 1 hour,
the epithelium typically will separate from the stroma at the
basement membrane layer. Thereafter the lens may be washed in a PBS
solution with antibiotics to remove salt and cellular material.
[0097] Finally, the donor lens may be de-epithelialized by placing
it in sterile PBS with antibiotics for four hours and changing the
solution many times. The lens core may then be kept submerged in
the PBS solution at 37.degree. C. for one week to produce a split
between the epithelium and the stroma. The epithelium may then be
removed, e.g., by physically scraping or washing with a liquid
stream. Small numbers of lenses may be stripped of epithelium by
gentle scraping with forceps.
[0098] Acellularization
[0099] The de-epithelialized lens may be then immersed in a
solution of detergent (for example 0.025% to 15% sodium dodecyl
sulfate) to wash out the keratocyte cellular material. A detergent
will solubilize and wash out the keratinocytic material. This can
take place from 1 to 8 hours. Afterward the cellular material can
be washed in a buffered solution with antibiotics to remove
detergent and cellular material.
[0100] Alternatively, the de-epithelialized lens may be immersed in
sterile PBS with antibiotics for an appropriate period, e.g.,
several weeks, perhaps six weeks to remove native keratocytes. The
solution may be changed twice weekly. In some instances, it may not
be necessary to remove keratocytes from the donor lens, e.g., when
the donor tissue is obtained from a transgenic source and has
minimal antigenicity.
[0101] Revitalization Step
[0102] Preparation of Cells
[0103] Human epithelial cells and keratocytes are used in the
revitalization process. Epithelial cells may be obtained from a
tissue bank, but are preferably obtained from fetal or neonatal
tissue. Fetal cells are most preferable, since the properties of
fetal tissue minimize scarring during any wound healing
process.
[0104] In any event, freshly isolated epithelial cells, obtained by
trypsinization of corneal tissue, may be seeded onto a precoated
feeder layer of lethally irradiated 3T3 fibroblasts (i.3T3) in
epithelial cell media. Cells are cultured and media changed every
three days until the cells are 80% confluent, about 7-9 days.
Residual i.3T3 are removed with 0.02% EDTA (Sigma-Aldrich) before
the epithelial cells are detached using trypsin (ICN Biomedicals).
Another method of regenerating epithelium involves culturing
autologous epithelial cells on human amniotic membrane as described
in Tsai et al. (2000). "Reconstruction of Damaged Corneas by
Transplantation of Autologous Limbal Epithelial Cells," New England
Journal of Medicine 343:86-93.
[0105] Keratocytes may be extracted from the remaining stromal
tissue. The stroma is washed in PBS, finely minced, and placed in
0.5% collagenase A (ICN Biomedicals) at 37.degree. C. for 16 hours.
Keratocytes obtained from this enzyme digest are then serially
cultured in keratocyte media. The epithelial cells and keratocytes
generated in the. revitalization step will be referred to as
"replaced" epithelial cells and keratocytes.
[0106] Production of the Donor Lens
[0107] The acellular donor lens core may then be placed on a
hydrophilic, polyelectrolyte gel for completion of the
re-vitalization. The preferred polyelectrolytes are chondroitin
sulfate, hyaluronic acid, and polyacrylamide. Most preferred is
polyacrylic acid. The lens is immersed in keratocyte media and
incubated with approximately 3.times.10.sup.-5 keratocytes for 48
hours 37.degree. C. Approximately the same amount of epithelial
cells are then added to the anterior stromal surface. Tissue
culture incubation continues for another 48 hours. Keratocyte media
is changed every two to three days. Once the epithelium is
regenerated, the polyelectrolyte gel draws water out of the lens at
a pressure of about 20-30 mm Hg until the original lens dimensions
are obtained.
[0108] Replaced epithelium covers at least a portion of the
anterior surface of this variation of the inventive lens and
replaced keratocytes repopulate the stroma of the lens core after
revitalization.
[0109] As noted above, another variation of the lens includes an
epithelial layer (352 in FIG. 3G) that extends from the periphery
of the lens core (348). The same procedure as just outlined may be
used to prepare the epithelial cell layer in the carrier (354)
prior to placement of the lens core (348) onto the pre-prepared
epithelial cell layer.
[0110] It may be beneficial in some instances also to incorporate
therapeutic agents, growth factors, or immunosuppressive agents
into the lens core further to decrease the risk of rejection or
remedy disease states.
[0111] Placement of the Lens on the Eve
[0112] One procedure for applying the lens of this invention is
depicted in FIGS. 4A and 4B. During the procedure, the donor lens
(300), as shown in FIG. 3A, is placed on a portion of recipient
cornea that has been de-epithelialized (308). The result is the
placement and construct (312) shown in FIG. 4B. The lens' replaced
epithelium and the host epithelium eventually grow to form a
continuous, water-tight layer (310). I have found that the
inventive lens bonds or adheres to the recipient cornea without
sutures or adhesives, but can also be removed without substantial
difficulty.
[0113] Another placement procedure variation is shown in FIG. 5. In
this variation, it is preferable to use a core lens that has been
only partially revitalized in that the keratocytes have been
replaced but the epithelial layer has not. Of course, a core lens
that has been partially covered with a seed layer of epithelial
cells is also acceptable. In any event, step a. of FIG. 5 shows a
native eye (600) having an epithelial layer (602) and a corneal
stroma (604). Step b. of FIG. 5 shows the placement of a suction
device (606) on the anterior surface of the eye (600). The suction
device (606) applies a modest vacuum to the epithelial layer (602),
e.g., between about -100 mmHg and -450 mmHg, to raise a section of
the epithelial layer (602) as shown in step c. This blister (608)
typically is filled with a physiologic fluid. Obviously, the
suction device (606) has a footprint on the surface of the cornea
similar to the size of the lens to be placed on that cornea. Step
d. shows the opened epithelial flap (608) and the placement of the
lens towards the corneal stromal margin (612) beneath that
epithelial flap (608). Step c. of FIG. 5 shows the finished
placement of the lens (610) on the cornea beneath the native
epithelial membrane. This procedure has a number of benefits
including that of being less traumatic to the surface of the eye
than simple removal of the epithelium.
[0114] It is also within the scope of the description to use the
preparation procedure for the LASEK procedure for the step of
exposing the corneal surface for application of the lens. The LASEK
procedure is known and, unlike the LASIK procedure, does not
involve temporary removal of an anterior flap of corneal tissue
with a surgical tool but rather only utilizes an ethanol wash and a
temporary withdrawal of the epithelial layer for a laser treatment.
Such a preliminary step, the washing with ethanol to perturb the
junction between the corneal stroma and the epithelium is adequate
to provide a layer of epithelium for temporary movement and
insertion of the inventive lens on the corneal surface.
[0115] I have described the structural and physiologic properties
and benefits of this donor ocular lens. This manner of description
should not, however, be taken as limiting the scope of the
disclosure in any way.
* * * * *