U.S. patent application number 10/186295 was filed with the patent office on 2003-02-06 for methods for improving damaged retinal cell function using physical and/or mechanical stimulation.
Invention is credited to Chow, Alan Y., Chow, Vincent Y..
Application Number | 20030028225 10/186295 |
Document ID | / |
Family ID | 26735714 |
Filed Date | 2003-02-06 |
United States Patent
Application |
20030028225 |
Kind Code |
A1 |
Chow, Alan Y. ; et
al. |
February 6, 2003 |
Methods for improving damaged retinal cell function using physical
and/or mechanical stimulation
Abstract
Methods of using physical stimulation by itself or in
conjunction with growth factors to treat and prevent visual loss
due to choroidal, retinal pigment epithelial and/or neuroretinal
cell degeneration and dysfunction are presented.
Inventors: |
Chow, Alan Y.; (Wheaton,
IL) ; Chow, Vincent Y.; (Hanover Park, IL) |
Correspondence
Address: |
BRINKS HOFER GILSON & LIONE
P.O. BOX 10395
CHICAGO
IL
60611
US
|
Family ID: |
26735714 |
Appl. No.: |
10/186295 |
Filed: |
June 28, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10186295 |
Jun 28, 2002 |
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10056793 |
Jan 23, 2002 |
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60301877 |
Jun 29, 2001 |
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Current U.S.
Class: |
607/54 |
Current CPC
Class: |
A61N 1/36046 20130101;
A61F 9/0017 20130101; A61N 1/0543 20130101 |
Class at
Publication: |
607/54 |
International
Class: |
A61N 001/32 |
Claims
1. A method of improving visual function of a damaged and/or
degenerating retina in a human eye, the method comprising: applying
at least one of a chronic physical and mechanical stimulation to
the eye to improve or maintain visual function of the retina,
wherein applying the at least one of the chronic physical and
mechanical stimulation improves visual function of at least one
structure of the damaged retina.
2. The method of claim 1, wherein the improved visual function
comprises at least one of improved perception of light in the
presence of light, improved perception of darkness in the presence
of darkness, improved perception of contrast, color, shape,
resolution, movement and visual field size.
3. The method of claim 1, wherein the chronic physical stimulation
is applied by a source of physical stimulation comprising at least
one device in contact with any structure of the eye.
4. The method of claim 1, wherein the chronic physical stimulation
is provided to at least one of the damaged retina and a structure
of the eye.
5. The method of claim 3, wherein the at least one device comprises
a plurality of devices.
6. The method of claim 3, wherein the at least one device comprises
one of an electrically inert device, a chemical agent and a
biological agent.
7. The method of claim 1, wherein the source of physical
stimulation comprises a device having at least one photoactive
surface electrically connected to at least one stimulating
electrode.
8. The method of claim 7, wherein the photoactive surface comprises
at least one photodiode, photovoltaic device or photoelectric
device.
9. The method of claim 8, wherein the at least one photodiode
comprises a plurality of photodiodes, photovoltaic devices or
photoelectric devices.
10. The method of claim 3, wherein the at least one device is
implanted surgically into a subretinal space at an angle between
about 5.degree. and 80.degree. off-axis from a macula, wherein the
angle is defined by an intersection of an axis line extending from
the macula to a central structure of a pupil and an off-axis line
extending from the device to the central structure of the
pupil.
11. The method of claim 3, wherein the at least one device is
surgically implanted in at least one area of the damaged retina,
excluding a macula.
12. The method of claim 3, wherein the at least one device
comprises at least one fenestration.
13. The method of claim 1, wherein the damaged retina is the result
of at least one condition selected from the group consisting of
age-related macular degeneration, retinitis pigmentosa, choroidal
disease, choroidaremia, long-term retinal detachment, diabetic
retinopathies, Stargardt's retinopathy, Leber's congenital
amaurosis, Best's Disease, choroidal rupture, and choroidal
disease.
14. A method of treating visual degradation resulting from a
damaged retina, wherein the visual degradation comprises primary or
secondary degradation, the method comprising: applying chronic
physical stimulation to an eye containing the damaged retina.
15. The method of claim 14, wherein the damaged retina comprises a
damaged cell comprising at least one of a photoreceptor cell,
choroidal vasculature cell, retinal pigment epithelial cell,
bipolar cell, horizontal cell, amacrine cells and ganglion cells;
and wherein at least one portion of the damaged cell is
treated.
16. The method of claim 15, wherein the at least one portion that
is treated comprises at least one portion of an undamaged cell.
17. The method of claim 15, wherein the at least one portion that
is treated comprises a portion not in physical contact with a
source of chronic physical stimulation.
18. The method of any of claims 14-17, wherein the physical
stimulation is provided to at least one of the damaged retina and a
structure of the eye.
19. The method of claim 14, wherein applying chronic physical
stimulation comprises placing a source of physical stimulation in
contact with the eye, the source of physical stimulation comprising
at least one device.
20. The method of claim 19, wherein the at least one device is in
contact with the retina, and the applying physical stimulation
treats at least one of a structure of the damaged retina peripheral
to the portion of the retina in contact with the at least one
device and a portion of the damaged retina in contact with the
device.
21. The method of claim 19, wherein the at least one device
comprises a plurality of devices.
22. The method of claim 19, wherein the at least one device
comprises one of an electrically inert object, a chemical agent and
a biological agent.
23. The method of claim 19, wherein the at least one device
comprises at least one photoactive surface electrically connected
to at least one stimulating electrode.
24. The method of claim 23, wherein the at least one photoactive
surface comprises at least one photodiode, photovoltaic device or
photoelectric device.
25. The method of claim 24, wherein the at least one photoactive
surface comprises a plurality of photodiodes, photovoltaic devices,
or photoelectric devices.
26. The method of claim 19, wherein the at least one device is
implanted surgically into a subretinal space at an angle between
about 5.degree. and 80.degree. off-axis from a macula, wherein the
angle is defined by an intersection of an axis line extending from
the macula to a central structure of a pupil, and an off-axis line
extending from the device to the central structure of the
pupil.
27. The method of claim 19, wherein the at least one device is
surgically implanted in at least one area of the retina, excluding
a macula.
28. The method of claim 14, wherein the physical stimulation is
intermittent.
29. The method of claim 14, wherein said damaged retina is the
result of at least one condition selected from the group consisting
of age-related macular degeneration, retinitis pigmentosa,
choroidal disease, choroidaremia, long-term retinal detachment,
diabetic retinopathies, Stargardt's retinopathy, Leber's congenital
amaurosis, Best's Disease and choroidal rupture.
30. A method of improving visual function in a damaged macula of a
human eye, the method comprising: selecting at least one
electrically inert device; implanting the at least one electrically
inert device in a subretinal space in the eye; and wherein the
device is positioned peripheral to the macula of the eye and in the
subretinal space.
31. The method of claim 30, wherein implanting the at least one
electrically inert device comprises implanting the device at a
position in the subretinal space at an angle between about
5.degree. and 80.degree. off-axis from the macula, wherein the
angle is defined by an intersection of an axis line extending from
the macula to a central structure of the pupil and an off-axis line
extending from the device to the central structure of the
pupil.
32. The method of claim 30, wherein implanting the device further
comprises implanting the device in a temporal half retina region of
the eye.
33. The method of claim 30, wherein implanting the device further
comprises implanting the device in a nasal half retina region of
the eye.
34. The method of claim 30, wherein selecting at least one
electrically inert device comprises selecting a plurality of
electrically inert devices, and wherein implanting the at least one
device comprises implanting the plurality of electrically inert
devices.
35. The method of claim 34, wherein implanting each of the
plurality of electrically inert devices comprises implanting each
of the plurality of electrically inert devices at a respective
position in the subretinal space at an angle between about 50 and
800 off-axis from the macula, wherein the angle is defined by an
intersection of an axis line extending from the macula to a central
structure of the pupil and an off-axis line extending from the
device to the central structure of the pupil.
36. The method of claim 34, wherein implanting the plurality of
electrically inert devices further comprises implanting the
plurality of electrically inert devices in a temporal region of the
eye.
37. The method of claim 34, wherein implanting the plurality of
electrically inert devices further comprises implanting the
plurality of electrically inert devices in a nasal region of the
eye.
38. The method of claim 34, wherein the plurality of electrically
inert devices are implanted symmetrically around a region centered
by the macula.
39. A method of implanting an physically stimulating device in an
eye of a patient having least one condition selected from the group
consisting of outer neuroretina disease, choroidal disease and
retinal epithelial disease, the method comprising: implanting in a
subretinal space in the eye of the patient at least one
electrically inert device configured to contact a plurality of
cells in the eye.
40. The method of claim 39, wherein the device is positioned in one
of a peripheral or mid-peripheral region in the subretinal space
outside of a macula of the eye.
41. The method of claim 39, wherein implanting the device comprises
implanting the device at a position in the subretinal space at an
angle between about 50 and 800 off-axis from the macula, wherein
the angle is defined by an intersection of an axis line extending
from the macula to a central structure of the pupil and an off-axis
line extending from the device to the central structure of the
pupil.
42. The method of claim 39, wherein implanting the device further
comprises implanting the device in a temporal half retina region of
the eye.
43. The method of claim 39, wherein implanting the device further
comprises implanting the device in a nasal half retina region of
the eye.
44. The method of claim 39, wherein the condition is selected from
the group consisting of age-related macular degeneration, retinitis
pigmentosa, choroidal disease, choroidaremia, long-term retinal
detachment, diabetic retinopathies, Stargardt's retinopathy,
Leber's congenital amaurosis, Best's Disease and choroidal
rupture.
45. The method of claim 39, wherein implanting the at least one
electrically inert device comprises implanting the plurality of
devices.
46. Use of a source of physical stimulation for producing an
implant for improving the visual function of a damaged retina in a
human eye by applying chronic physical stimulation to the eye,
47. The use of claim 46, wherein applying chronic physical
stimulation improves visual function of at least one structure
which is not in contact with the source of physical
stimulation.
48. The use of claim 46, wherein the improved visual function
comprises at least one of improved perception of light in the
presence of light, and improved perception of darkness in the
presence of darkness, improved perception of contrast, color,
shape, resolution, movement and visual field size.
49. The use of claim 46, wherein the source of physical stimulation
comprises at least one device in contact with any structure of the
eye.
50. The use of claim 46, wherein the physical stimulation is
provided to at least one of the damaged retina and a structure of
the eye.
51. The use of claim 46, wherein the at least one device is adapted
to be in contact with the damaged retina, and the applying chronic
physical stimulation improves the visual function of at least a
structure of the damaged retina peripheral to a portion of the
retina in contact with the at least one device.
52. The use of claim 49, wherein the at least one device comprises
a plurality of devices.
53. The use of claim 49, wherein the at least one device comprises
an electrically inert device.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of
non-provisional application serial No.10/056,793, filed Jan. 23,
2002, which claims the benefit of provisional application serial
no. 60/301,877, filed Jun. 29, 2001, and both of the aforementioned
applications are hereby incorporated by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to generally to improving
biological cell function and more specifically to improving retinal
cell visual function in damaged and/or degenerated retinas and also
to protecting retinal cells from degeneration.
BACKGROUND
[0003] Certain biological chemical compounds such as nerve growth
factors (NGF), neurotropins, brain-derived neurotrophic factors
(BNDF), fibroblastic growth factor (FGF), glial cell line-derived
neurotrophic factors (BDNF), and numerous other similar biological
chemical compounds, all collectively known as survival-type factors
can slow down the process of cellular degeneration in a number of
biological degenerative diseases, specifically in retinal
degenerative diseases and also promote cellular growth in other
situations.
[0004] In studies, the application of survival-type factors was
found to promote and maintain certain retinal cellular functions.
For example, brain-derived neurotrophic factor (BDNF),
neurotrophin-4 (NT-4), neurotrophin-5 (NT-5), fibroblastic growth
factor (FGF) and glial cell line-derived neurotrophic factor (GDNF)
have been shown to enhanced neurite outgrowth of retinal ganglion
cells and to increase their survival in cell culture. GDNF has been
shown to preserve rod photoreceptors in the rd/rd mouse, an animal
model of retinal degeneration. Nerve growth factor (NGF) injected
into the intra-ocular area of the C3H mouse, also a model of
retinal degeneration, results in a significant increase of
surviving photoreceptor cells compared to controls (Bosco and
Linden, 1999; Caleo et al., 1999; Carmignoto et al., 1989; Cui et
al., 1998; Frasson et al., 1999; Lambiase and Aloe, 1996; Reh et
al., 1996).
[0005] However, while many prostheses are known that attempt to
restore vision by using photoactive properties of semiconductors
designed to mimic the electric charge that damaged retinal cells
would otherwise generate, few devices or treatments are available
that can slow, stop or reverse retinal degeneration.
SUMMARY
[0006] According to a first aspect of the invention, a method of
improving visual function of a damaged retina in a human eye is
disclosed. The method includes applying a chronic physical
stimulation to the eye to improve or maintain visual function of
the damaged retina, wherein applying chronic physical stimulation
improves visual function of at least one structure of the damaged
retina. In one embodiment the chronic physical stimulation is
applied by a source of physical stimulation comprising at least one
device in contact with any structure of the eye. The physical
stimulation may be provided to at least one of the damaged retina
and a structure of the eye. Also, the physical stimulation may be
provided by one or more devices. The device or devices may be
constructed of electrically inert, chemical or biological
materials.
[0007] According to another aspect of the invention, a method of
implanting a physically stimulating device in an eye of a patient
having least one condition selected from the group consisting of
outer neuroretina disease, choroidal disease and retinal epithelial
disease is disclosed. The method includes implanting in a
subretinal space in the eye of the patient at least one
electrically inert device configured to contact a plurality of
cells in the eye. The electrically inert device could also be
implanted in other spaces of the eye of the patient, such as an
epiretinal space, a subconjunctival space, a subscleral space,
and/or in a subchoroidal space of the eye. In one embodiment, the
device may be positioned in one of a peripheral or mid-peripheral
region in the subretinal space, outside of a macula of the eye. In
another embodiment, the electrically inert device may be implanted
at a position in the subretinal space between an angle of about 50
to 800 off-axis from the macula, where the angle is defined by an
intersection of an axis line extending from the macula to a central
structure of the pupil and an off-axis line extending from the
device to the central structure of the pupil.
[0008] In another aspect, the invention provides a use of a source
of electrical stimulation for producing an implant for improving
visual function that includes the perception of brightness in the
presence of light, the perception of darkness in the absence of
light, the perceptions of contrast, color, resolution, shape,
motion, and visual field size of a damaged retina in a human eye by
applying electrical stimulation to the damaged retina, eye or to
both, wherein this electrical stimulation improves visual function
of at least a portion of the damaged retina not in contact with the
source of electrical stimulation.
[0009] In another aspect, the invention provides a use of a source
of chronic or prolonged physical stimulation for producing an
implant for treating primary and secondary visual degradation
resulting from a damaged retina by applying physical stimulation to
the eye with the damaged retina, wherein a portion of the damaged
retina not in contact with the source of physical stimulation is
treated. The damaged retina, for example, may comprise damaged
photoreceptor cells, and such cells peripheral to the source of
physical stimulation exhibit improved visual function as a result
of the physical stimulation.
[0010] Both of these aspects of the invention may have the
following characteristics. Conditions that result in damaged
retinas that may be treated with the various embodiments of uses of
the sources of physical stimulation of the invention include
age-related macular degeneration, retinitis pigmentosa, long-term
retinal detachment, diabetic retinopathies, Stargardt's
retinopathy, Leber's congenital amaurosis, Best's Disease, and
choroidal disease or damage. Physical stimulation may be, for
example, provided to the retina or eye. Suitable devices that
provide chronic physical stimulation may be constructed of a
material that is electrically inert. The implant may also be
fenestrated. Suitable locations of the eye for stimulation include,
but are not limited to, the subretinal space, the epiretinal space,
the subscleral space, the subconjunctival space, the vitreous
cavity and the anterior chamber.
[0011] In all aspects of the invention, the devices used for
producing an implant for improving visual function of a damaged
retina may be adapted to be surgically implanted into the
subretinal space at an angle between about 5.degree. and 80.degree.
off-axis from a macula, wherein the angle is defined by an
intersection of an axis line extending from the macula to a central
portion of a pupil, and an off-axis line extending from the device
to the central portion of the pupil. The device (with or without at
least one fenestration) may be adapted to be surgically implanted
in at least one sector of a retina, excluding the macula. The
device or devices may be adapted to be implanted in the temporal or
nasal (or both) half retina region of the eye, or symmetrically
around a region centered by the macula.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1A presents top cross-section of a human eye.
[0013] FIG. 1B presents a cross-section through the human eye that
include the layers of the outer and inner anatomical retina, as
indicated by the inset of FIG. 1A.
[0014] FIG. 2 illustrates one preferred shape of an implantable
device.
[0015] FIG. 3 illustrates a first alternative shape of the
implantable device of FIG. 2.
[0016] FIG. 4 illustrates a second alternative shape of the
implantable device of FIG. 2.
[0017] FIG. 5 is a two dimensional array of implantable
devices.
[0018] FIG. 6 is a three dimensional array of implantable
devices
[0019] FIG. 7 is a cross-sectional view of an embodiment showing an
array of retina stimulation devices positioned in an eye in the
periphery and/or mid-periphery outside the macula.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
[0020] Many human retinal diseases cause vision loss by partial to
complete destruction of the vascular layers of the eye that include
the choroid and choriocapillaris, both of which nourish the outer
anatomical retina and a portion of the inner anatomical retina of
the eye. A number of other retinal diseases cause vision loss due
to partial to complete degeneration of one or both of the two
anatomical retinal layers directly, due to inherent abnormalities
of these layers. The components of the retinal layers include
Bruch's membrane and retinal pigment epithelium which comprise the
"outer anatomical retinal layer", and the photoreceptor, outer
nuclear, outer plexiform, inner nuclear, inner plexiform, amacrine
cell, ganglion cell and nerve fiber layers which comprise the
"inner anatomical retinal layer", also known as the "neuroretina".
The outer portion of the neuroretina is comprised of the
photoreceptor and bipolar cell layers and is also known as the
"outer retina" which is to be distinguished from the "outer
anatomical retinal layer" as defined above.
[0021] Loss of function of the outer retina is commonly the result
of dysfunction of the outer anatomical retinal layer that provides
nourishment to the outer retina and/or to direct defects of the
outer retina itself. The final common result, however, is
dysfunction of the outer retina that contains the light sensing
cells, the photoreceptors. Some of these "outer retina" diseases
include age-related macula degeneration, retinitis pigmentosa,
choroidal disease, long-term retinal detachment, diabetic
retinopathies, Stargardt's disease, choroideremia, Best's disease,
and rupture of the choroid. The inner portion of the neuroretina,
however, often remains functionally and anatomically quite intact
and may be activated by the appropriate stimuli.
[0022] Although prosthetic electrical devices designed to replace
damaged or missing retinal cells have been used to treat vision
loss caused by outer retinal degeneration, physical stimulation to
improve large areas of retinal cell visual function is novel. As a
non-limiting explanation, the promotion of improved retinal cell
visual function by physical stimulation may be explained by the
stimulation of production and release of growth factors (GFs); more
specifically, neurotrophic-type growth factors (NTGFs), by the
stimulated retinas in response to the wounding or trauma inflicted
by the physical stimulation. The synthesis and/or secretion of
neurotrophic factors would then improve retinal cell function and
survival in conditions where these activities would be lost.
[0023] Animal and human studies have be used to show that
electrical stimulation may be used to improve the general inherent
visual function of damaged retinal cells in direct contact with and
surrounding an implanted electrical artificial silicon retina
prosthesis (Chow et al., 2002). The mechanism of action may be
related to the upregulation and production of endogenous
survival-type factors by the retina due to an electrical effect on
cellular membranes which may include a direct irritant effect of
the electric current.
[0024] An irritant effect is also produced by the physical effect
that includes a mechanical foreign-body effect, of an implant
placed into or in contact with the retina. Such an irritant effect
is akin to a mild damage effect on the retina which is known to
upregulate the production of survival-type factors. For example, an
incision into the retina, called a retinotomy, is known to
upregulate, albeit temporarily, certain survival-type factors that
also temporarily slow down retina degeneration in a rat model of
retinal degeneration (Peng et al., 1997). A non-electrical foreign
body that is inert or almost inert is therefore capable of
producing a chronic irritant effect that chronically upregulates
endogenous survival factors in the retina and to produce a
long-term slow down or prevention of a retinal degenerative
process.
[0025] A system and method are disclosed of placing a
non-electrical physical and/or mechanical foreign body into or in
contact with the retina to irritate and therefore chronically
stimulate the upregulation of survival-type factors to slow down
and/or prevent retinal degeneration. The subject matter of this
application also includes the devices used to produce the said
chronic irritation of the retina. Such non-electrical chronic
irritant devices theoretically may have the ability to slow down
the degeneration in other organ systems such as the central nervous
system.
[0026] The present invention discloses both devices and novel
methods to non-electrically irritate and/or stimulate the retina by
physical and/or mechanical stimulation/irritation to improve large
areas of retinal visual function and to protect the retina from
degeneration.
[0027] Definitions
[0028] Subject/patient
[0029] A subject (patient) may be a human being or a non-human
animal, but is preferably a human. Usually the individual has
suffered some type of retinal damage and/or degeneration that
results in some degree of visual loss and/or has a condition that
will result in retinal damage and/or degeneration. A normal
(healthy) subject does not have a condition that will result in
retinal damage and/or degeneration and/or has not suffered retinal
damage and/or degeneration.
[0030] Improving Visual Function
[0031] Improving visual function refers to improving a targeted
function of the eye, selected by the artisan, and includes
improving any to all of the following capabilities of the eye,
retina and visual system: perception of brightness in the presence
of light, perception of darkness in the absence of light,
perceptions of contrast, color, shape, resolution, movement and
visual field size.
[0032] Primary visual degradation means loss of visual function due
to malfunctioning, damaged or degeneration of structures found in
the eye. Secondary visual degradation means loss of visual function
due to secondary damage, typically from lack of use of the
vision-associated portions of the brain. Improving visual function
means to improve the visual function of primary visual degradation,
secondary visual degradation or both.
[0033] Eye/eyeball
[0034] The eye (or eyeball) has the usual definition in the art.
Eye includes all interior and exterior surfaces, components,
contents and cavities of the eye. The eye does not include the
eyelid.
[0035] The retina of the eye can be divided into sectors as is
commonly accepted in the art. Such sectors are described by the use
of the terms temporal, nasal, superior, inferior, by clock hour
designation, and by the number of degrees away from the macula. For
example, the temporal sector of the retina is the retina temporal
to a perpendicular plane cutting through retina from the 12 o'clock
to the 6 o'clock positions and through the macula. In another
example, the superior sector is the retina superior to a
perpendicular plane cutting through the 9 o'clock to 3 o'clock
positions and through the macula. In a further example, the
superior-temporal sector is the intersection of these two sectors,
a pie-shaped area delineated from the 9 o'clock position of the
peripheral retina to the macula and then clockwise to the 12
o'clock position. More specific locations of the retina can be
designated by degrees away from the macula and clock hour location:
for example, 20 degrees away from the macula at the 3 o'clock
(nasal) position. The number of degrees away from the macula is in
visual axes degrees. These axes all intersect through the lens of
the eye.
[0036] The visual field sectors correspond oppositely to the
retinal sectors as is commonly understood in the art. For example,
the superior-temporal sector of the retina corresponds to the
inferior-nasal portion of the visual field.
[0037] Peripheral
[0038] To be peripheral to an object, device or other landmark
includes all surrounding parts, but not the object, device or
landmark, i.e., the object, device or landmark, together with the
peripheral portion, constitutes the whole.
[0039] Light
[0040] Light refers not only to the electromagnetic spectrum that
humans can readily perceive visually (approximately 400 nm to 750
nm), but also includes ultraviolet light (<400 nm in wavelength)
as well as infrared light (>750 nm in wavelength).
[0041] Indications
[0042] The invention can be used to improve visual function in
subjects in which the retina is damaged by disease, degeneration,
condition, or trauma and/or to slow down or stop the progression of
damage by disease, degeneration, condition or trauma. Common
diseases, conditions, degeneration or trauma that are particularly
amenable to this treatment include age-related macula degeneration,
retinitis pigmentosa, Leber's congenital amaurosis, Stargardt's
disease, Best's disease, diabetic retinopathy, long-term retinal
detachment, and choroidal damage.
[0043] Eye Structure
[0044] Referring to the drawings, FIG. 1A illustrates a section
through the eyeball. The neuroretina 150 comprises multiple layers
of cells and structures (see FIG. 1B). The photoreceptor components
of the retina are situated within the neuroretina which covers the
internal posterior cavity of the eye, terminating anteriorly at the
ora serrata 167. The ciliary body 168 and the iris 162 are covered
by extensions of the retina, lacking photoreceptor components. The
outermost layers of the eye consist of the sclera 164 and cornea
158. The sclera is pierced by the emerging optic nerve 166. The
lens 160 and vitreous cavity 154 are also indicated. The macula 169
of the retina is typically a 3 mm by 5 mm oval region, at the
center of which is the fovea 170.
[0045] The layers of the eye at the posterior pole from inside to
outside are shown in FIG. 1B: internal limiting membrane 40, nerve
fiber layer 42, ganglion and amacrine cell layer 44, inner
plexiform 46, inner nuclear layer 48, outer plexiform 50, outer
nuclear and bipolar cell layer 52, and photoreceptor layer 54, all
of which constitute the anatomical inner retinal layer, also known
as the neuroretina 56. The retinal pigment epithelium 58, and
Bruch's membrane 60 constitute the outer retinal layer 62. The
choriocapillaris 64, and choroid 66 comprise the choroidal
vasculature 68. The outer coat of the eye is the sclera 70. Light
156 enters the retina as shown.
[0046] Devices and Methods to Provide Physical Stimulation
[0047] Any object that can provide a chronic or prolonged physical
stimulation or irritation to the eye can be used as a source of
physical stimulation. These devices may include, but are not
limited to, electrically inert objects, mechanically or
electrically activated objects, and chemical or biological agents.
Several electrically activated devices, including retina
stimulation devices (RSDs), have been used to provide electrical
stimulation to an eye or the retina. For example, electrical
devices previously described (Chow, U.S. Pat. No. 5,024,223, 1991;
Chow and Chow, U.S. Pat. No. 5,397,350, 1995; Chow and Chow, U.S.
Pat. No. 5,556,423, 1996; Chow and Chow, 1997; Chow et al., 2001;
Chow and Peachey, 1999; Chow and Chow, U.S. Pat. No. 5,895,415,
1999; Chow and Chow, U.S. Pat. No. 6,230,057 B1, 2001), may be
used. The entirety of the disclosure of each of these patents is
incorporated herein by reference.
1TABLE A Device References Artificial Silicon Retina (ASR .TM.)
(Chow, U.S. Pat. No. 5,016,633, 1991; Chow, U.S. Pat. No.
5,024,223, 1991) Independent Surface Electrode (Chow and Chow, U.S.
Pat. No. Microphotodiodes (ISEMCP) 5,397,350, 1995; Chow and Chow,
U.S. Pat. No. 5,556,423, 1996) Independent Surface Electrode (Chow
and Chow, U.S. Pat. No. Microphotodiodes with an electrical
5,397,350, 1995; Chow and Chow, capacitor (ISEMCP-Cs) U.S. Pat. No.
5,556,423, 1996) Multi-phasic Photodiode Retinal (Chow and Chow,
U.S. Pat. No. Implants (MMRIs, such as MMRI-4) 5,895,415, 1999;
Chow and Chow, U.S. Pat. No. 6,230,057 B1, 2001) Variable Gain
Multi-phasic (Chow and Chow, U.S. application Photodiode Retinal
Implants No. 09/539,399, 2000) (VGMMRIs)
[0048] As stated above, the physical stimulation may be provided by
any object that can remain in physical contact with and/or irritate
cells, such as retinal cells of an eye, for an extended period of
time. The extended period of time may be years, such as would be
the case with a device that would be implanted in the eye and
persist indefinitely in the eye unless it was purposefully
extracted. Alternatively, the extended period of time may be a
limited time, for example one year, after which the implanted
device or agent would biodegrade or otherwise be absorbed.
[0049] In one preferred embodiment, the source of physical
stimulation is one or more devices or objects that is electrically
inactive such that it is neither photoactive, a source of
electrical stimulation, nor in electrical communication with a
source of electrical stimulation. The device may be constructed
from silicon, metal, plastic, ceramic, glass, wood, sand or any of
a number of materials. For example, an object of any shape or depth
may be used. These shapes may include, but not be limited to, to
geometric shapes, such as straight lines, circles, squares,
rectangles, and triangles as well as three-dimensional shapes, such
as balls, cubes, cylinders, or cones.
[0050] Referring to FIGS. 2-4, several suitable shapes of
implantable devices are shown. The device may be a disk-shaped
object 174 with or without fenestrations 176, as shown in FIG. 2.
In order to increase the surface area available to physically
contact cells in the eye, the object 174 may be constructed to
include various shape protrusions 178. The object 180 shown in FIG.
2 illustrates a spherical shape. Again, fenestrations 182 may be
incorporated in the object to allow nutrients to pass through.
Irregularly-shaped objects 184, such as illustrated in FIG. 4, may
be also be used. While the devices may be of various different
dimensions, one preferred size range is greater than approximately
1 micron and less than approximately 20 mm in linear dimensions,
and more preferrably greater than approximately 0.5 mm and less
than approximately 5 mm in linear dimensions. Substrates for such
objects include, without limitation, bio-absorbable polymers,
silicon and other metals, and biomaterials. These devices can be
implanted in the same region or regions of an eye as discussed for
the RSDs. Many materials, shapes, sizes and devices may be used as
long as they interact with cells in the eye to physically stimulate
these cells. Also, in yet other embodiments, one or more
electrically inert devices may be implanted in the eye in
combination with one or more devices intended to supply electrical
stimulation to the eye.
[0051] In yet other embodiments, the device may be an
interconnected array of implantable elements. For example, FIG. 5
shows a two dimensional array 190 of implantable objects 186
interconnected by a flexible biocompatible mesh 188. Each of the
objects 186 may be of the same or different shape and maintains its
physical connection with one or more of the other objects while in
the eye via the mesh 188. Alternatively, as shown in FIG. 6, the
array may be a three dimensional array 192 of implantable objects
186 interconnected by a flexible mesh 188.
[0052] Other means to provide physical stimulation includes
implanting devices that deliver an irritant. For example, oils,
detergents, bile salts, etc. may be applied in small quantities
that are yet sufficient to physically stimulate the cells.
Preferably, the irritant is packaged, such as in a capsule, so that
the irritant is slowly released over time, and so that the
"packaging" is ultimately absorbed by the body. Examples of
biodegradable substances include biodegradable polymers.
Biodegradable polymers decompose when placed inside an organism and
thus eliminate the need to remove the implant after the bioactive
agent has been released, since the polymer will gradually break
down and may be metabolized or excreted from the body. The
decomposition of a biodegradable polymer can be observed as a
decline in the molecular weight of the polymer over time. Polymer
molecular weights can be determined by a variety of methods
including size exclusion chromatography (SEC), and are generally
expressed as weight averages or number averages. A polymer is
biodegradable if, when in phosphate buffered saline (PBS) of pH 7.4
and a temperature of 37.degree. C., its weight-average molecular
weight is reduced by at least 25% over a period of 6 months as
measured by SEC.
[0053] Polymers which could be useful as "packaging" capsules
include, but are not limited to, polyesters, such as
poly(caprolactone), poly(glycolic acid), poly(lactic acid),
poly(hydroxybutryate); copolymers of caprolactone, glycolic acid,
lactic acid, and hydroxybutryate; polyanhydrides, such as
poly(adipic anhydride); poly(para-dioxanone); poly(malic acid);
polyamines; polyurethanes; polyesteramides; polyorthoesters;
polyacetals; polyketals; polycarbonates; polyorthocarbonates;
polyphosphazenes; poly(amino acids); chitin; chitosan; and
copolymers and mixtures thereof.
[0054] Chemical or biological agents, including growth factors, can
also be introduced into the eye to provide a prolonged stimulation
to enhance rescue and retina functional improvement. This
additional step is attractive because some factors, especially
neurotrophictype growth factors, may improve retinal function and
provide limited neuronal rescue in eyes with retinal degeneration
and dysfunction. These growth factors include, but are not limited
to, glial cell line-derived neurotrophic factor (GDNF), nerve
growth factor (NGF), brain derived neurotrophic growth factor
(BDNGF), neurotropin-3 (NT-3), neurotropin-4 (NT-4), neurotropin-5
(NT-5), ciliary neurotropic factor (CNTF) and fibroblastic growth
factor (FGF). These growth factors can be delivered to the eye by
coating the RSD with growth factor(s) before implantation, by
injection of the growth factor(s) into the locations of the
subretinal space, vitreous cavity, subconjunctival space,
subscleral space, and/or the anterior chamber either singly or in
combination with each other, as a single dose or as multiple repeat
doses before, during and/or after implantation of the RSD(s) or
other electrical stimulating device.
[0055] Location of Stimuli
[0056] The chronic physical stimulation provided by at least one
device may be provided subretinally, epiretinally, subsclerally
(between the sclera and choroid), on the scleral surface, on the
conjuctival surface and/or from or within any structure of the eye.
Other means of providing physical simulation to the retina and eye
may include devices that deliver chronic stimulation from the
underside of the eyelid(s). Preferably, physical stimulation is
from the subretinal space which is an area that is in a close
proximity to the damaged retinal cells.
[0057] Therefore, in one embodiment, the chronically
irritating/stimulating agent can be inserted in a way that it is
placed in direct contact with the damaged retinal cells. In another
embodiment, the chronically irritating/stimulating agent can be
placed adjacent to, but not in direct contact with, the damaged
retinal cells. In response to the prolonged trauma inflicted by the
irritant, healthy retinal cells may be chronically stimulated to
produce and release growth factors, such as neurotrophic growth
factors, to help enhance retinal cell function.
[0058] Implantation Sites and Surgical Methods
[0059] In one embodiment, the physical stimulation is preferably in
the subretinal space in the periphery and/or mid-periphery of the
eye, outside of the macula. For devices that are implanted, more
than one device may be implanted, if needed, in an eye to stimulate
a larger area of the retina, and multiple devices can be implanted
in paracentral locations such as one in each of the four
paracentral quadrants, approximately, but not limited to, 5 to 80
degrees peripheral to the macula. In other embodiments, one or more
devices may be implanted in the macular region of the eye. In one
embodiment the implants may be placed in the subretinal space in
the mid-periphery approximately 20 degrees away from the macula,
using one device or up to approximately four devices evenly spaced
on a perimeter in the midperiphery. Cells to stimulate include the
remaining cells of the inner retina.
[0060] FIG. 7 is a cross-sectional view of an eye 6 showing an
array 200 of RSDs 10 in the subretinal space. Although RSDs 10 are
discussed below with respect to FIG. 7, the implantation locations
and techniques discussed apply equally to the other types of
implantable objects and agents mentioned above. One or more RSDs
may be spaced symmetrically around the macula in the peripheral or
mid-peripheral regions of the eye in one embodiment. Alternatively,
the RSDs may be spaced asymmetrically around the macula. In one
embodiment, the RSDs are implanted at a position in the subretinal
space between about a 5 degrees and an 80 degrees angle off-axis
from the macula, where the angle is defined by an intersection of
an axis line extending from the macula to a central portion of the
pupil and an off-axis line extending from the retina stimulation
device to the central portion of the pupil. The RSDs may also be
implanted in the temporal half retina region and/or nasal half
retina region, within the subretinal space. Any of a number of
techniques and instruments may be used to perform the implantation
into the subretinal space (Chow, U.S. Pat. No. 5,024,223, 1991;
Chow and Chow, U.S. Pat. No. 5,397,350, 1995).
[0061] In yet another embodiment, an implantable device is designed
to be implanted onto the epiretinal surface (i.e. on the nerve
fiber layer side) of the retina. It is retained in position by
retinal tacks, biocompatible glues, or other means. In the case of
electrical implantable devices, subconjunctival/scleral placement
of the device results in less efficient electrical stimulation of
the retina compared to a subretinally or epiretinally placed
device, but the extraocular location of the device decreases the
surgical risk to a patient since intraocular surgery would not be
required for its implantation. The subconjunctival/scleral
placement of a device also allows a stable device position to be
achieved without fixating devices or glues (i.e., the device is
held in place between the conjunctiva and sclera).
[0062] Surgical methods are well known in the art (Peyman et al.,
2000). Descriptions of specific surgeries for RSD implantation,
which are also applicable to other physical stimulating devices,
have been extensively described (Chow, U.S. Pat. No. 5,024,223,
1991; Chow and Chow, U.S. Pat. No. 5,397,350, 1995; Chow and Chow,
U.S. Pat. No. 5,556,423, 1996; Chow and Chow, 1997; Chow et al.,
2001; Chow and Peachey, 1999; Chow and Chow, U.S. Pat. No.
5,895,415,1999; Chow and Chow, U.S. Pat. No. 6,230,057 B1,
2001).
[0063] For example, direct insertion may be accomplished as
follows: the device or plurality of devices is inserted into the
vitreous cavity of the eye through a pars plana incision. A
horizontal incision is then made through the retina from the
vitreous side in the temporal portion of the posterior pole into
the potential space between the photoreceptor layer and the retinal
pigment epithelium. A horizontal incision made at this location
avoids cutting inner retinal vasculature and is parallel to
coursing nerve fiber layers, therefore also avoiding their injury.
Illumination for surgery is provided by an optical fiber light
pipe. The potential space is then be opened by cannula irrigation
of a balanced salt solution into the subretinal space.
[0064] The device is then placed into the subretinal cavity at the
posterior pole under the macula area. Specifically, the device is
placed between the retinal pigment epithelium and photoreceptor
layer, or if the photoreceptor layer is atrophied or lost, then
between the retinal pigment epithelium and the bipolar and
horizontal cell layer. The device is positioned such that the
electrical ground(s) is overlaying the retinal pigment epithelium,
and the active electrode(s) faces incident light.
[0065] After insertion, a series of endolaserphotocoagulation or
endocautery burns may be made around the periphery of the device to
secure the device, although these burns may not be necessary in
many cases. The scar tissue so formed around the periphery of the
device by these burns may prevent the device from moving out of
position in some patients. Endolaserphotocoagulation or
endoelectrocautery may also be used to seal the retinal incision.
Air or other medically approved gaseous compounds may also be
injected into the vitreous cavity to tamponade the retinal opening
during healing. The pars plana incision is then closed in the usual
surgical manner.
[0066] An alternate method for implantation of a device involves
making an incision through the sclera just posterior to the ora
serata. Dissection proceeds through the choroid, choriocapillaris,
Bruch's membrane and retinal pigment epithelium under stereo
operating microscope control into the potential space between the
inner and outer anatomical retinal layers. The artificial retinal
implant is then inserted into this space and directed posteriorly
towards the macula by a pushing action imparted by a formed curved
iris spatula or by use of an insertion guide. The RSD or other
implantable device rests in the retinal periphery of the eye
between the inner and outer anatomical retinal layers.
[0067] In another approach, some devices can be implanted by simple
injection into the subretinal space through cannulas. Preferably,
the devices are placed in a vehicle such as a biocompatible liquid
and injected into the subretinal space via a retinotomy incision
using a cannula. Such a liquid vehicle may be a balanced salt
solution or a more viscous material like methylcellulose.
[0068] The retina is preferably illuminated by a light pipe to
facilitate the injection of the devices. The cannula is introduced
into the vitreous cavity of the eye via a pars plana incision.
Dissection of the posterior vitreous is performed to separate the
posterior hyaloid face from the retinal surface along with a
vitrectomy. A small retinotomy incision is made through the retina
following the direction of the nerve fiber layer using a stiletto
type MVR blade. Dissection of the inner retina from the outer
retinal layers is accomplished hydrostatically with the cannula
using a fluid such as saline.
[0069] When the retinal areas to be implanted have been prepared
with cannula hydro-dissection, the liquid vehicle with suspended
devices is injected. An attempt should be made to distribute the
suspended devices in a uniform monolayer. The cannula is then
withdrawn, and a heavier-than-water non-miscible material
(preferably, a perfluorocarbon) is placed over the posterior pole
of the vitreous cavity to aid settling the retina. The non-miscible
material is preferably removed after an appropriate time, usually
15 to 20 minutes, leaving a reattached retina. Alternatively, air
may also be used to settle the retina. With settling and
reattachment of the retina, the implanted devices tend to
distribute into the desired monolayer.
[0070] Other surgical procedures and related materials will be
evident to one of skill in the art and depend in part on the design
of the device and the subject to be implanted.
[0071] In another embodiment, electrically inert objects, chemical,
and/or biological agents can be inserted into an eye in several
ways. Chemical and biological agents, such as growth factors, can
be delivered to the eye by coating a substrate with these factor(s)
before implantation and/or by injecting these factor(s) into the
locations of the subretinal space, vitreous cavity, subconjunctival
space, subscleral space, and/or the anterior chamber either singly
or in combination with each other, as a single dose or as multiple
repeat doses independent of, before, during and/or after
implantation of the coated substrate or other electrical
stimulating device. Electrically inert object(s) can be delivered
to the eye by placing it directly into the subretinal space,
vitreous cavity, subconjunctival space, subscleral space, and/or
the anterior chamber through implantation or injection performed as
previously described for the retinal implantable devices.
[0072] Demonstration of Efficacy
[0073] The demonstration of safety and efficacy of a preferred
embodiment of this invention has been shown in multiple persons
with retinal dysfunction that have been implanted with RSDs in the
subretinal space as part of a clinical study to evaluate the
feasibility of and effectiveness of these devices to act as
prostheses. All persons so implanted have reported no complications
and have reported improved levels of visual function subsequent to
the placement of the RSDs. Such improvements have included improved
perception of light, darkness, contrast, shape, resolution, color,
motion, and visual field size. It will be appreciated by those of
skill in the art that the improved levels of visual function
reported represent results of RSDs and methods discovered by the
inventors to function well in the practice of the invention.
However, those skilled in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments that are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention. For example, a variety of mechanically and/or physically
inert to partially inert materials can be used. Moreover, a variety
of sizes and shapes of the RSD can be used. The RSD can also be
inserted into various structures of the eye.
EQUIVALENTS
[0074] Although particular embodiments have been disclosed herein
in detail, this has been done for purposes of illustration only and
is not intended to be limiting with respect to the scope of the
appended claims that follow. In particular, it is contemplated by
the inventors that various substitutions, alterations, and
modifications may be made to the invention without departing from
the spirit and scope of the invention as defined by the claims.
Other aspects, advantages, and modifications are considered to be
within the scope of the following claims.
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