U.S. patent application number 13/503841 was filed with the patent office on 2013-03-14 for corneal denervation for treatment of ocular pain.
This patent application is currently assigned to NexisVision, Inc.. The applicant listed for this patent is Jose D. Alejandro, Yair Alster, Eugene de Juan, JR., Hanson S. Gifford, Omer Rafaeli, Cary J. Reich, John A. Scholl, Douglas Sutton. Invention is credited to Jose D. Alejandro, Yair Alster, Eugene de Juan, JR., Hanson S. Gifford, Omer Rafaeli, Cary J. Reich, John A. Scholl, Douglas Sutton.
Application Number | 20130066283 13/503841 |
Document ID | / |
Family ID | 43900715 |
Filed Date | 2013-03-14 |
United States Patent
Application |
20130066283 |
Kind Code |
A1 |
Alster; Yair ; et
al. |
March 14, 2013 |
Corneal Denervation for Treatment of Ocular Pain
Abstract
Methods and apparatus for the treatment of the eye to reduce
pain can treat at least an outer region of the tissue so as to
denervate nerves extending into the inner region and reduce the
pain. For example, the cornea of the eye may comprise an inner
region having an epithelial defect, and an outer portion of the
cornea can be treated to reduce pain of the epithelial defect. The
outer portion of the cornea can be treated to denervate nerves
extending from the outer portion to the inner portion. The outer
portion can be treated in many ways to denervate the nerve, for
example with one or more of heat, cold or a denervating noxious
substance such as capsaicin. The denervation of the nerve can be
reversible, such that corneal innervation can return following
treatment.
Inventors: |
Alster; Yair; (Palo Alto,
CA) ; Gifford; Hanson S.; (Woodside, CA) ;
Reich; Cary J.; (Los Gatos, CA) ; de Juan, JR.;
Eugene; (San Francisco, CA) ; Scholl; John A.;
(San Ramon, CA) ; Alejandro; Jose D.; (Sunnyvale,
CA) ; Sutton; Douglas; (Pacifica, CA) ;
Rafaeli; Omer; (Tel Aviv, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alster; Yair
Gifford; Hanson S.
Reich; Cary J.
de Juan, JR.; Eugene
Scholl; John A.
Alejandro; Jose D.
Sutton; Douglas
Rafaeli; Omer |
Palo Alto
Woodside
Los Gatos
San Francisco
San Ramon
Sunnyvale
Pacifica
Tel Aviv |
CA
CA
CA
CA
CA
CA
CA |
US
US
US
US
US
US
US
IL |
|
|
Assignee: |
NexisVision, Inc.
Menlo Park
CA
|
Family ID: |
43900715 |
Appl. No.: |
13/503841 |
Filed: |
October 22, 2010 |
PCT Filed: |
October 22, 2010 |
PCT NO: |
PCT/US10/53854 |
371 Date: |
August 20, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61279612 |
Oct 23, 2009 |
|
|
|
Current U.S.
Class: |
604/294 ; 606/27;
606/4 |
Current CPC
Class: |
A61F 9/0079 20130101;
A61N 1/36046 20130101; A61F 9/009 20130101; A61F 2009/00893
20130101; A61B 18/02 20130101; A61N 1/36021 20130101; A61F 9/008
20130101; A61N 1/40 20130101; A61N 7/02 20130101; A61F 2009/00872
20130101; A61F 9/00804 20130101 |
Class at
Publication: |
604/294 ; 606/4;
606/27 |
International
Class: |
A61F 9/01 20060101
A61F009/01 |
Claims
1-148. (canceled)
149. An apparatus to treat a cornea of an eye, the cornea having an
epithelium, the apparatus comprising: an applicator shaped to
contact the cornea to denervate nerves of an outer portion of the
cornea to inhibit pain of an inner portion of the cornea.
150. The apparatus of claim 149, wherein the applicator is
configured to stun or sever the nerves to denervate the nerves of
the epithelium without substantial penetration to nerves below a
Bowman's membrane of the eye, or to stun nerves extending along
lamella of a stroma disposed between the epithelium and an
endothelium of the outer portion to denervate the inner
portion.
151. The apparatus of claim 149, wherein applicator is configured
to stun the nerves with one or more of mechanical force, heat,
cooling, light, photodynamic treatment, ultrasound, neurapraxia or
a substance.
152. The apparatus of claim 149, wherein the applicator is
configured to sever axons of the nerves to denervate the nerves,
and wherein the applicator is configured to sever the axons of
nerves extending along lamella of a stroma disposed between the
epithelium and an endothelium of the outer portion to denervate the
inner portion, and/or wherein the applicator is configured to sever
the axons disposed at a depth of no more than about 300 .mu.m below
the epithelium.
153. The apparatus of claim 149, wherein the structure shaped to
contact the epithelium comprises a structure shaped to contact a
tissue region, the tissue region comprising an inner portion and an
outer portion, wherein the shaped structure comprises a pain
inhibiting substance and a lower side to release the pain
inhibiting substance to the outer portion of the tissue region.
154. The apparatus of claim 153, wherein the pain inhibiting
substance comprises capsaicin.
155. The apparatus of claim 153, wherein the shaped structure
comprises an annulus configured to contact the tissue along an
annular tissue region.
156. The apparatus of claim 153, wherein the applicator comprises a
first applicator and the shaped structure comprises an outer first
pain inhibiting substance disposed on an outer portion of a lower
side of the first applicator to release the pain inhibiting
substance to the outer portion of the tissue region; and further
comprising a second applicator comprising a structure shaped to
contact at least the outer portion of the tissue region, wherein
the shaped structure comprises an inner second pain inhibiting
substance disposed on an inner portion of a lower side of the
second applicator to release the pain inhibiting substance to the
inner portion of the tissue region.
157. The apparatus of claim 149, wherein the cornea has a region
with an outer portion and an inner portion; and wherein the shaped
structure is configured to conduct heat from at least the outer
portion to inhibit pain.
158. The apparatus of claim 157, wherein the shaped structure
comprises a cool material configured to conduct the heat, wherein
the cool material comprises an annular surface, and wherein the
cool material comprises a metal.
159. The apparatus of claim 149, wherein the shaped structure is
configured for one or more of cutting, trephination, and pulsed
laser cutting of the cornea.
160. The apparatus of claim 149, wherein applicator comprises a
light delivery surface and the nerves are denervated with
photodynamic treatment, wherein the photodynamic treatment
comprises one or more of photodynamic injury, dye uptake of the
nerve, irradiation of the dye with light, or excitation of the dye
with a predetermined wavelength.
161. The apparatus of claim 149, wherein the applicator comprises a
substance and the applicator is configured to apply the substance
to the cornea so that the nerves are denervated with the substance,
and wherein the substance comprises a calcium channel agonist, the
agonist comprising one or more of capsaicin, a capsaicin analog, a
capsaicinoid, dihydrocapsaicin, nordihydrocapsaicin,
homodihydrocapsaicin, homocapsaicin, resinferatoxin, an agent to
bind to TRPV1 protein, capsazepine, a neuropeptide depletory, or a
neurostimulating agent.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] The present application claims the benefit under 35 USC
119(e) of U.S. Provisional Application No. 61/279,612 filed Oct.
23, 2009; the full disclosure of which is incorporated herein by
reference in its entirety.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH AND DEVELOPMENT
[0002] NOT APPLICABLE
BACKGROUND OF THE INVENTION
[0003] People like to see. The eye comprises several tissues that
allow a person to see, and these tissues include the cornea, the
lens and the retina. The cornea and lens focus light rays on to the
retina so as to form an image on the retina. The cornea comprises
an outer tissue of the eye that is coupled to air with a tear film,
such that a majority of the focusing power of the eye is achieved
based on the shape of the cornea. The retina comprises
photoreceptors that generate neural signals in response to the
light image formed on the retina, and these neural signals are
processed and transmitted to the occipital cortex of the brain such
that the person perceives the image.
[0004] The cornea is a highly innervated tissue that comprises
several layers including an epithelium disposed under the tear film
and a stromal layer disposed under the epithelium. In humans and at
least some animals a Bowman's membrane is disposed between the
epithelium and corneal stroma. The innervation of the cornea can be
useful and help the person to blink so as to replenish the tear
film for vision and to maintain a healthy corneal epithelium. The
innervation of the cornea can also help to protect the cornea and
the persons sight with the sensation of pain, such that in at least
some instances the person may be forced to protect the cornea and
eye from further injury in response to a painful stimulus. However,
this innervation of the cornea, may result in substantial pain
following surgery in at least some instances.
[0005] Many surgeries and therapies of the eye are directed to the
treatment of the cornea, and in at least some instances significant
pain can occur. For example photorefractive keratectomy
(hereinafter "PRK"), laser assisted in situ keratomileusis
(hereinafter "LASIK"), and laser assisted epithelial keratomileusis
(hereinafter "LASEK"), each reshape the cornea of the eye so as to
improve the focus of images on the retina such that the patient can
see better. Unfortunately, many of the corneal surgeries result in
pain in at least some instances. For example, with PRK and LASEK,
the epithelial layer of the cornea is removed so as to expose
underlying tissue that is ablated, and in at least some instances
patients experience pain when the epithelium regenerates over the
ablation. With LASIK, a flap of tissue comprising the epithelium
and stroma is cut with a laser or blade and opened with a hinge so
as to expose the underlying stromal bed where the ablation is
performed. As the LASIK flap can be positioned over the ablated
stromal bed with stroma to stroma contact, LASIK can result in less
pain for patients. However, in at least some instances LASIK can
result in complications related to the cutting of the LASIK flap
and the LASIK ablation of the exposed stromal bed that extends
deeper into the cornea than PRK and LASEK ablations. Also, work in
relation to embodiments of the present invention suggests that the
cutting of corneal nerve fibers with the LASIK flap can result in
decreased corneal sensitivity for an extended time in at least some
instances. Although LASIK can result in complications in at least
some instances, many patients prefer the risks of LASIK to the pain
of PRK.
[0006] Although the control of pain with PRK and LASEK has been
proposed and implemented, many patients who undergo PRK report pain
and photophobia in at least some instances during the two to four
day period when the epithelium regenerates over the ablation. For
example, although the use of anesthetics such as lidocaine and
proparacaine have been proposed, use of these anesthetics in
amounts that significantly reduce pain may delay
reepithelialization, such that the safely prescribed dosage does
not sufficiently reduce pain in at least some instances. Even with
the use of safe amounts of analgesics with PRK and LASEK, patients
can still report undesirable pain in at least some instances.
Although the systemic use of opioids such as morphine can reduce
pain, the patient may be subjected to side effects of the systemic
opioid medication. Therefore, there is a significant unmet clinical
need to reduce pain associated with removal of the corneal
epithelium, for example following PRK, such that the patient is not
subjected to significant side effects.
[0007] In light of the above, it would be desirable to provide
improved methods and apparatus for pain control of the eye. Ideally
such methods and apparatus would be compatible with refractive
surgery, such that patients can receive a safe treatment to correct
vision with full recovery of corneal tissue and neural function,
and decreased pain.
BRIEF SUMMARY OF THE INVENTION
[0008] Although specific reference is made to treatment of the eye
with PRK, embodiments of the present invention will have
application to many patient treatments where the tissue such as
epithelium regenerates, for example regenerates subsequent to
removal after injury or treatment of an underlying tissue.
[0009] Embodiments of the present invention provide systems,
methods and apparatus for the treatment of the eye to reduce pain.
The pain may originate from an inner region of a tissue such as the
cornea, and the treatment can be applied to an outer region of the
tissue to denervate nerves extending into the inner region so as to
reduce the pain. For example, the cornea of the eye may comprise an
inner region having an epithelial defect, for example a central
region of the cornea having the epithelial defect. An outer portion
of the cornea can be treated so as to reduce pain of the epithelial
defect, for example with treatment of an outer region of the cornea
peripheral to the central region comprising the defect. The outer
portion of the cornea can be treated to denervate nerves extending
from the outer portion to the inner portion, and the denervation of
the cornea can inhibit pain for a plurality of days such that
epithelial healing is substantial and not inhibited. For example,
pain can be inhibited for a plurality of days when the epithelium
regenerates over a debridement, such that the regeneration of the
epithelium over the debridement is substantially uninhibited. The
debridement may comprise a debridement of a PRK and regeneration of
the epithelium may occur over the PRK ablation without substantial
inhibition when the cornea is denervated for a plurality of days.
The outer portion can be treated in many ways to denervate the
nerve, for example with one or more of heat, cold or a denervating
substance such as capsaicin. The outer portion can be treated with
a tissue treatment profile, so as to allow the use of an increased
amount of treatment to achieve the desired denervation with
decreased side effects. The denervation of the nerve can be
reversible, such that corneal innervation can return following
treatment. For example, the neurons of the nerves may be stunned or
desensitized to inhibit pain, or axons of the neurons of the nerves
can be cleaved to inhibit pain such that the neurons can regenerate
along the nerve sheathes into the inner portion. The outer portion
may extend around a perimeter of the inner portion, for example so
as to enclose the inner portion with the outer portion, and the
outer portion may comprise many shapes such as annular shape, an
oval shape or a disc.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1A shows an eye and layers of the cornea suitable for
treatment in accordance with embodiments of the present
invention;
[0011] FIG. 1B shows a side view nerves of the cornea as in FIG. 1A
suitable for treatment in accordance with embodiments of the
present invention;
[0012] FIG. 1C shows a top view of view nerves of the cornea as in
FIG. 1B suitable for treatment in accordance with embodiments of
the present invention;
[0013] FIG. 1D shows a schematic illustration of nerves of the
cornea as in FIG. 1C extending from the stroma through Bowman's
layer into the epithelium and suitable for treatment in accordance
with embodiments of the present invention;
[0014] FIGS. 2A and 2B show treatment of an portion of a region of
the cornea so as to denervate the cornea, in accordance with
embodiments of the present invention;
[0015] FIGS. 2A1 and 2B1 show denervation as in FIGS. 2A and 2B,
with the a treatment profile substantially applied and localized to
the epithelial layer of tissue, in accordance with embodiments of
the present invention;
[0016] FIGS. 2A2 and 2B2 show denervation as in FIGS. 2A and 2B,
with the a treatment profile substantially comprising the
epithelial layer and extending substantially into the stroma so as
to encompass nerve bundles, in accordance with embodiments of the
present invention;
[0017] FIGS. 2A3 and 2B3 shows denervation as in FIGS. 2A and 2B,
with the a treatment profile localized substantially to the stroma
so as to encompass nerve bundles, in accordance with embodiments of
the present invention;
[0018] FIGS. 2A4 and 2B4 shows denervation as in FIGS. 2A and 2B,
in which the an inner region is denervated with the outer region,
in accordance with embodiments of the present invention;
[0019] FIGS. 2A5 and 2B5 shows denervation as in FIGS. 2A and 2B,
in which the an inner region is denervated with the outer region
comprising a first outer region and a second outer region, in
accordance with embodiments of the present invention;
[0020] FIG. 2C shows an ablated cornea having an epithelial defect,
in which the cornea has been denervated in accordance with
embodiments of the present invention;
[0021] FIG. 2C1 shows denervation as in FIG. 2C with the
denervation treatment profile comprising the epithelium extending
to the debridement.
[0022] FIG. 2C2 shows denervation as in FIG. 2C with the
denervation treatment profile extending to nerve bundles disposed
within the stroma and peripheral to the ablation.
[0023] FIG. 2C3 shows denervation as in FIG. 2C with the
denervation treatment profile extending across the ablation.
[0024] FIGS. 3A and 3B show the severing of axons disposed within a
nerve such that sheath remains intact, in accordance with
embodiments of the present invention;
[0025] FIGS. 3C and 3D show regeneration of the axons along the
sheaths subsequent to cleavage of the axons as in FIGS. 3A and
3B;
[0026] FIGS. 4A and 4B show the severing of the nerve into an inner
portion of the nerve and an outer portion of the nerve, such that
the sheath of the inner portion remains substantially aligned with
the outer portion and axons regenerate from the outer portion along
the sheath of the inner portion, in accordance with embodiments of
the present invention;
[0027] FIGS. 4C and 4D show regeneration of the axons along the
inner sheaths subsequent to cleavage of the nerves as in FIGS. 4A
and 4B;
[0028] FIG. 5A shows an applicator coupled to the cornea to
denervate the nerves, in accordance with embodiments of the present
invention;
[0029] FIG. 5B shows an applicator as in FIG. 5A comprising a
channel to receive a liquid to denervate the nerves;
[0030] FIG. 5C shows an applicator as in FIG. 5A comprising a
trephine configured with the flange to denervate the nerves;
[0031] FIG. 5D shows an applicator as in FIG. 5A comprising an
optical component to deliver light to the cornea;
[0032] FIG. 5E shows an applicator as in FIG. 5A comprising at
least one electrode to deliver electrical energy to the cornea;
[0033] FIG. 5E1 shows an applicator as in FIG. 5A comprising at
least two electrodes to deliver electrical energy to the
cornea;
[0034] FIG. 5E2 shows an applicator as in FIG. 5A comprising at
least two electrodes to deliver electrical energy to the cornea
with a first nasal portion of the applicator and a second temporal
portion of the applicator.
[0035] FIGS. 5E3A and 5E3B show an applicator as in FIG. 5E2
positioned on a cornea so as to define treatment profile 120 with
the electrode fields from the spacing of the electrodes and the
profile of RF pulses.
[0036] FIG. 5E4 shows circuitry coupled to applicator so as to
generate the profiled RF pulses and treatment profile.
[0037] FIG. 5E5 shows RF pulses of the circuitry;
[0038] FIG. 5F shows an applicator as in FIG. 5A comprising at
least one transducer to deliver energy to the cornea;
[0039] FIGS. 6A to 6C show an applicator as in FIG. 5A comprising a
metal to conduct heat from the cornea;
[0040] FIG. 6D shows an insulator disposed around an applicator as
in FIGS. 6A to 6C;
[0041] FIG. 7A shows an applicator as in FIG. 5A to deliver a
substance to an outer portion of the cornea;
[0042] FIGS. 7A1 and 7A2 shows an applicator as in FIG. 5A
comprising an annular ring with the substance disposed thereon to
deliver the substance to the outer portion of the cornea;
[0043] FIG. 7A3 shows a substance coated on a support along an
outer portion of the support to deliver the substance to the outer
portion of the cornea;
[0044] FIG. 7A4 shows an applicator with a channel to deliver the
substance to the outer portion of the cornea and a wall structure
to inhibit release of the substance;
[0045] FIGS. 7A5 and 7A6 show top and side and views, respectively,
of an applicator as in FIG. 7A in which the applicator comprises
micro-needles to deliver the substance to outer portion of the
cornea;
[0046] FIG. 7A7 shows an applicator as in FIG. 7A comprising a
compartment with the substance disposed therein so as to deliver
the substance to the outer portion of the cornea;
[0047] FIG. 7B shows an applicator as in FIG. 5A to deliver a
substance to an inner portion of the cornea;
[0048] FIG. 7C shows an apparatus comprising applicators as in
FIGS. 7A and 7B to deliver a first substance to the inner portion
and a second substance to the outer portion of the region of the
cornea to denervate the cornea, in accordance with embodiments of
the present invention;
[0049] FIG. 7D shows an apparatus to deliver a first substance to
the inner portion and the outer portion of the region of the cornea
to denervate the cornea, in accordance with embodiments of the
present invention;
[0050] FIG. 7E shows a side view of an applicator as in FIG.
7A;
[0051] FIG. 8A shows the chemical structure of Capsaicin, in
accordance with embodiments of the present invention;
[0052] FIG. 8B shows Vanilloid Receptor 1 (VR1) receptor, which
comprises a Capsaicin receptor suitable for use with a denervating
substance, in accordance with embodiments of the present
invention;
[0053] FIG. 8C desensitization with Capsaicin, in accordance with
embodiments of the present invention;
[0054] FIG. 8D shows neural channels sensitive to Capsaicin and
afferent transmission of acute pain to the central nervous system
and efferent transmission neurogenic inflammation to the cornea, in
accordance with embodiments of the present invention;
[0055] FIG. 9 shows a covering positioned on the eye over an
epithelial defect so as to inhibit delivery of an anesthetic to the
epithelial defect when the covering conforms to a boundary of the
epithelium and the defect and seals the cornea, in accordance with
embodiments of the present invention;
[0056] FIG. 10 shows a method of treating an eye of a patient in
accordance with embodiments of the present invention; and
[0057] FIG. 11 shows experimental cooling data and profiles of
corneal temperature at depths, in accordance with embodiments.
DETAILED DESCRIPTION OF THE INVENTION
[0058] Embodiments of the present invention can treat may types of
pain of the eye, for example pain of the cornea, and can be used
for treatment of pain corresponding to refractive surgery of the
cornea. The embodiments described herein can be used to treat the
eye following trauma of the eye, such as corneal abrasions, and can
also be used to treat pain originating from pathology of the eye
such as pseudophakic bullous keratopathy (hereinafter "PBK") or
aphakic bullous keratopathy (hereinafter "ABK"). In many
embodiments, the pain of the cornea corresponds to pain associated
with an epithelial debridement of the cornea used in conjunction
with refractive surgery. For example, with PRK, an inner portion of
the cornea is defined for treatment over the pupil, and the
epithelium removed from the region and the cornea ablated with a
pulsed laser such as an excimer laser. The epithelium may take at
least one day to heal, for example three days, and the embodiments
described herein can be used to treat nerves of the cornea so as to
inhibit pain experienced by the patient when the epithelium
regenerates over the ablation.
[0059] Many embodiments described herein provide denervation that
inhibits pain but does not significantly impact or inhibit
epithelial healing.
[0060] Although previous studies on mammals and humans has
indicated that corneal nerves that are injured or destroyed can
regenerate, the destruction of corneal nerves such as stromal
nerves may be linked to post-PRK haze, such that there may be a
correlation between the development of post-PRK haze and the lack
of stromal nerve regeneration. The treatment of pain control as
described herein can be used to treat nerves such that the nerves
can regenerate so as to restore substantially the neural function
and decrease haze following PRK.
[0061] As used herein denervation of tissue encompasses deprivation
of nerve activity of the tissue, for example with cutting of the
nerve or blocking signals of the nerve.
[0062] FIG. 1A shows an eye, the cornea 20 and layers of the cornea
suitable for treatment in accordance with embodiments. The eye
comprises a cornea 22, an iris, a lens and a retina. The cornea and
lens focus light on the retina. The iris defines a pupil that
passes light rays, and the iris can open and close so as to adjust
the pupil size in response to light so as to light to keep the
amount of light striking the eye within tolerable amounts. The
cornea comprises a transparent, dome-shaped structure covering the
iris and pupil. The cornea refracts light that enters the eye, and
can provide approximately two-thirds of the eye's refractive
power.
[0063] The cornea 20 may comprise up to five layers, depending on
the species. Starting on the first tissue surface of the cornea,
the epithelium 22 comprises the surface layer of cells which
provide a barrier function and a smooth surface for the tear film.
The epithelium 22 comprises basal columnar cells 22B, wing cells
22W disposed over the basal cells and an outer squamous protective
layer 22S. Disposed under the epithelium, the second layer
comprising Bowman's membrane 24 comprises a tough substantially
collagenous layer disposed under the epithelium. The Bowman's
membrane 24 is present in many species of primates, humans and at
least some birds. The Bowman's membrane may push swelling of the
cornea posteriorly towards the retina. The third layer comprising
the stroma 26 comprises a substantially collagenous tissue layer
composed of highly arranged collagen fibers. The stroma supports
keratocytes, and forms the majority of the cornea. The fourth layer
comprising Descemet's membrane 29 is an inner layer of basement
membrane and plays an important role in the health of endothelial
cells. The fifth layer comprises the endothelium 28, and the
endothelium acts as a pump so as to regulate the liquid content of
the cornea. The drying of the cornea provided by the epithelium can
preserve clarity of the cornea, for example the clarity of the
stroma. The endothelial pumping of water from the cornea to
maintain the proper hydration and thickness of the eye is often
referred to as deturgescence. A figure similar to FIG. 1A is a
available on the world wide web at (http://www.aafp.org) Structure
of the Cornea
[0064] Corneal Innervation
[0065] FIG. 1B shows a side view nerves 30 of the cornea as in FIG.
1A, and FIG. 1C shows a top view of view nerves of the cornea as in
FIG. 1B. The cornea comprises a width across W of about 12 mm in
the human, and a thickness T of about 550 um. The cornea is densely
innervated, although the cornea is generally not vascularized. The
nerves of the cornea can be located at a depth D within the cornea,
for example a depth of about 265 um, although the depth can vary.
The nerves 30 of the cornea bifurcate at bifurcations 32. The
nerves of the stroma and Bowman's membrane comprise sheath 32S on
each side of the bifurcation, and each of the nerves 30 comprises
sheath 32S that extends along the nerve on each side of the
bifurcation. The sheath 32S of each nerve can extend along the
nerves throughout the stroma and Bowman's membrane, such that the
sheath 32S can extend upward into the epithelium. Radially-oriented
nerve bundles originating from the trigeminal nerve enter the
cornea through the sclera. The cornea comprises nerve bundles. The
nerve bundles are located substantially in the stroma and run
parallel to the collagen bundles; the nerve bundles include nuclei
of Schwann cells. The nerve bundles can be suitable for treatment
so as to denervate the cornea and inhibit pain. As can be seen with
reference to FIG. 1C, the large nerve fibers entering the cornea
run substantial in the 9-3 hours direction. After the first
bifurcation, they nerve fibers run in the 12-6 hours direction, and
after the second bifurcation the nerves can run in the 9-3 hours
direction again. A figure similar to FIG. 1C can be found in
Muller-Architecture of Human Cornea p. 991 (Muller L T, Vrensen G F
J M, et al. Architecture of human corneal nerves. (1997). Invest
Ophthalmol Vis Sci. 38:985-994, 991.)
[0066] The cornea comprises regions that can be useful for
treatment in accordance embodiments as described herein. For
example the cornea may comprise a region 40 suitable for treatment,
and the region 40 may comprise an inner portion 42 and an outer
portion 44. A region outside region 40 may comprise an outer region
46 of the cornea that can extend to the limbus. Treatment of an
outer region or portion can result in denervation of the
corresponding inner region or portion of the cornea.
[0067] FIG. 1D shows a schematic illustration of nerves 30 of the
cornea as in FIG. 1C extending from the stroma through Bowman's
layer into the epithelium. This 3D illustration shows penetration
and the distribution of stromal bundles into the basal plexus. The
nerves 30 comprise unmylenated nerve fibers 32UM, which can have
bifurcations substantially at right angles. The unmylenated nerve
fibers can comprise several straight 32UMS and beaded fibers 32UMB.
The beaded fibers can bifurcate obliquely and turn upward between
basal cells 22B to reach wing cells 22W of the epithelium 22. Upon
passing through Bowman's layer and into basal lamina, the nerve
bundles make a 90.degree. turn and separate into smaller bundles
separate and single nerve fibers with nerve endings in the
epithelium. The nerve endings originate from myelinated A-.delta.
and unmyelinated C-nerve fibers. The A-.delta. nerve fibers that
reach the Bowman's layer spread out below the basal epithelial
cells. The C-nerve fibers actually penetrate the epithelium layer.
Due to their size, the majority of the nerve fibers in the cornea
are classified as C-nerve fibers. Further, some of the nerve fibers
are beaded, while others are not. The beaded nerve fibers can turn
upward, for example make the 90.degree. turn, so as to penetrate to
the level of the wing cells. A figure similar to FIG. 1D is shown
in Muller L T, Vrensen G F J M, et al. Architecture of human
corneal nerves. (1997). Invest Ophthalmol Vis Sci. 38:985-994,
992.
[0068] Treatment of Corneal Pain
[0069] FIGS. 2A and 2B show treatment 100 of at least an outer
portion 44 of a region 40 of the cornea so as to denervate the
cornea. An applicator 110 can be coupled to the cornea, for example
placed against the cornea or positioned so as to transmit to or
receive energy from the cornea. The applicator 110 is configured to
treat the cornea so as to denervate the cornea in accordance with a
denervation treatment profile 120. The denervation treatment
profile 120 may comprise an annular portion of the epithelium,
Bowman's membrane and the underlying stroma to a depth of about 100
um. The profile 120 of denervated tissue can be determine in many
ways, for example with at least one of an amount of treatment, an
intensity of treatment or a duration of treatment. The denervation
treatment profile 120 can decrease sensitivity of a receptor field
of the nerves. The receptor field with decreased sensitivity
comprises nerves of the treatment profile can extend inward from
the treatment profile, for example extend centrally of the
treatment profile 120.
[0070] The ability of a patient to determine the source of pain
within a receptor field, for example pain from nocioceptors, may
not be sufficiently resolved so as to localize the pain spatially
on the cornea, and the denervation of the pain receptor field
sensed by the patient can extend beyond the portions of the nerves
treated with treatment profile 120. For example, the treatment
profile 120 can also denervate the pain receptor field sensed by
the patient outward from the treatment profile, for example
peripheral to the treatment profile 120.
[0071] FIGS. 2A1 and 2B1 shows denervation as in FIGS. 2A and 2B,
with treatment 100 such substantially applied and localized to the
epithelial layer of tissue, such that the denervation treatment
profile 120 is localized substantially to the epithelial layer 22.
As the nerves of the epithelium, as shown above, can extend inward,
treatment of the outer portion 44 of region 40 can denervate at the
inner portion 42 of the region 40.
[0072] FIGS. 2A2 and 2B2 shows treatment 100 as in FIGS. 2A and 2B,
with the denervation treatment profile 120 substantially comprising
the epithelial layer and extending substantially into the stroma so
as to encompass nerve bundles extending along the layers of the
stroma. The nerve bundles may comprise deep nerve bundles such that
treatment of the outer portion 42 denervates the inner portion 44
of the region.
[0073] FIGS. 2A3 and 2B3 shows denervation as in FIGS. 2A and 2B,
with the denervation treatment profile 120 localized substantially
to the stroma so as to encompass nerve bundles. The denervation
profile 120 can be obtained in many ways, for example with focused
energy, such that the inner portion 42 of region 40 can be
denervate with treatment to the outer portion 44 of region 40.
[0074] FIGS. 2A4 and 2B4 shows denervation as in FIGS. 2A and 2B,
in which the an inner region is denervated with the outer region.
The treatment 100 may comprise a disc shaped applicator 110, such
that the denervation treatment profile 120 comprises a
substantially circular portion of tissue that extends to along a
cylindrical axis to maximum depth of the tissue near the center of
the treatment;
[0075] FIGS. 2A5 and 2B5 shows denervation as in FIGS. 2A and 2B,
in which the an inner region is denervated with the outer region
comprising a first outer region and a second outer region. The
treatment 100 may comprise an applicator 110 a first portion 110A
and a second portion 110B, such that the denervation treatment
profile 120 comprises a first outer portion of tissue and as second
outer portion of tissue. Many of the nerves extending into the
cornea extend substantially nasal to temporal and temporal to
nasal, such that a first outer portion 110A located on a first
nasally disposed portion of the cornea and a second outer portion
110B disposed on a temporally disposed portion of the cornea can
treat the inner portion, for example the central portion.
[0076] FIG. 2C and shows an ablation 200 of cornea 20 having an
epithelial defect 220. The ablation 200 comprises an ablation
profile 210 that is shaped to correction vision of the patient. The
cornea is denervated in accordance with a denervation treatment
profile 120. The denervation treatment profile 120 may comprise an
annular denervation treatment profile. Work in relation to
embodiments as described herein related to PRK suggests that the
periphery of the debrided area corresponds to pain of PRK patients,
and treatment of the epithelium and cornea near the edge of the
debrided area can attenuate pain in PRK patients. This suggests
that perhaps little or no pain may emanates from the center of
ablation profile 210 the debrided area, such that treatment of the
outer portion 44 of region 40 can be sufficient to inhibit pain
from the inner portion 42.
[0077] The temporary depravation of nerve supply in accordance with
denervation profile 120 can be used to mitigate post-PRK and
corneal pain, and may comprise the temporary deprivation of a nerve
supply. The corneal denervation may last for a for a few days, and
can include one or more of stunning the corneal nerves, increasing
the threshold the corneal nerves, inhibiting the corneal nerve
signals, or completely blocking the corneal nerve signals, so as to
allow reduced pain when the epithelium regenerates and until the
epithelium heals.
[0078] Work in relation to embodiments related to corneal pain
suggests that it may be advantageous to cause a temporary
denervation of nerves at the edge and/or the whole portion of the
debrided area so as to reduce post-PRK pain. Similar denervation
can be used with pain originating from other traumatic, surgical or
other causes of corneal surface disruption. The pain may originate
from nerve endings at the wound edge or from the area along the
periphery of the debrided area.
[0079] In many embodiments as described herein, at least the sheath
32S of each nerve remains substantially intact along the portions
of the nerve extending through the stroma and Bowman's membrane,
such that the nerves can regenerate along the sheath so as to
restore enervation.
[0080] FIG. 2C1 shows denervation as in FIG. 2C with the
denervation treatment profile 120 comprising the epithelium
extending to the debridement and wherein the denervation treatment
profile is localized substantially to the epithelium 22. As noted
above, the treatment of the outer portion 44 can inhibit pain of
the inner portion 42.
[0081] FIG. 2C2 shows denervation as in FIG. 2C with the
denervation treatment profile 120 extending to nerve bundles
disposed within the stroma and peripheral to the ablation. The
denervation treatment profile 120 may be localized to the stroma 26
in many ways, for example with focused energy, such that the inner
portion 42 is denervated with treatment of the outer portion
44.
[0082] FIG. 2C3 shows denervation as in FIG. 2C with the
denervation treatment profile 120 extending across the ablation
200.
[0083] The denervation treatment profile 120 can be used for
denervation for mitigating pain after PRK, and the denervation
profile 120 may comprise one or more of increasing nerve stimuli
threshold, desensitizing the nerve with a desensitizing agent,
stunning the nerve, substantially inhibiting the corneal nerve
signals, completely blocking the corneal nerve signals, pruning the
nerve or pruning the axons of the nerve without substantially
pruning the sheath of the nerves.
[0084] FIGS. 3A and 3B show the severing 300 of axons 32A disposed
within a nerve such that sheath 32S remains intact. The denervation
treatment profile 120 can be configured such that the nerve sheath
remains intact when the axons are severed, as the threshold for
severing the axons of the nerve can be lower than the threshold for
severing the sheath. The severing 300 of axons 32A results in dead
portions 32D of the axons that are replaced with regeneration of
the axons 32A. The regeneration occurs along a path 310 defined by
the nerve sheath. The severing of axons 32A may occur at many
locations of the cornea, for example location 350.
[0085] FIGS. 3C and 3D show regeneration of the axons along the
sheaths subsequent to cleavage of the axons as in FIGS. 3A and 3B.
The regeneration can occur along the nerve sheath upwards through
the stroma to one or more of Bowman's membrane, the ablated
surface, or the epithelium. As the regeneration can occur along the
path of the nerve sheath, the regenerated nerve can correspond
substantially to the nerve conduction path prior to severance of
the axons.
[0086] FIGS. 4A and 4B show the severing 400 of the nerve into an
inner portion of the nerve 321 and an outer portion of the nerve
320, such that the sheath of the inner portion 321 remains
substantially aligned with the outer portion 320 so that axons
regenerate from the outer portion along the sheath of the inner
portion. When the nerve 30 is severed with sheath 32S, the axons
32A grow toward the outer portion of the sheath 320. The dead
portions 32D of the severed axons are replaced with regeneration of
the axons 32A along the sheath 32S of the outer portion 320.
[0087] FIGS. 4C and 4D show regeneration of the axons along the
inner sheaths subsequent to cleavage of the nerves as in FIGS. 4A
and 4B. The axons 32A comprise a regenerated portion 32R that
extends along the sheath. Work in relation to embodiments suggests
that the sheath 32S may also regenerate.
[0088] FIG. 5A shows an applicator 110 coupled to the cornea to
treat the cornea with a denervation treatment profile 110. The
applicator 110 can be used to threat the cornea before, during or
after PRK, or combinations thereof. Denervation for mitigating pain
after PRK may be achieved in many ways, and the denervation
treatment profile 120 as described herein may encompass one or more
of one or more of increasing nerve stimuli threshold, desensitizing
the nerve with a desensitizing agent, stunning the nerve,
destroying the nerve, pruning the nerve or pruning the axons of the
nerve without substantially pruning the sheath of the nerves. The
applicator 110 can be configured for interaction 500 with the
cornea, so as to transmit energy to the cornea, receive energy from
the cornea, or deliver at least one substance to the cornea, or
combinations thereof. For example, applicator 110 can be configured
to receive thermal energy from the cornea so as to cool the cornea
to achieve denervation treatment profile 120. Applicator 110 can be
configured to heat the cornea, for example with light or electrical
current or heat conduction, so as to achieve derivation treatment
profile 120. Applicator 110 can be configured to apply a substance
to the cornea, for example a noxious substance such as
capsaicin.
[0089] Stunning the Nerves:
[0090] Applicator 110 can be configured to stun the nerves in many
ways. For example applicator 110 can be configured to stun the
cornea with cooling. Applicator 110 may comprise an annular ring
configuration which contacts the cornea at the outer portion 44 so
as to cool the cornea to a desired temperature profile. For example
an application for a given time can achieve a desired effect at
desired depth within the cornea, so that nerves at different depths
can be numbed selectively (depth wise). Alternatively, the
applicator may comprise a disc shaped flat surface such as the end
of a cylindrical rod or a cooled contact lens, such that a disc
shaped portion of the cornea comprising the outer portion 44 and
the inner portion 42 of the region 40 is treated.
[0091] Applicator 110 can be configured to treat the cornea with
photodynamic treatment. For example, the nerves can be stained with
nerve specific stains or dyes such as horseradish peroxidase. Such
molecules can attach to a molecule of the nerve for photodynamic
activation. The nerve and dye can be exposed to light so as to stun
the nerve. The irradiation may comprise selective local, for
example ring shaped, photo therapy which will stimulate the
molecule to cause local damage to nerves with minimal effect on
surrounding tissue. For example the ring may comprise outer region
44 stained and treated with light so as to denervate inner region
42 with minimal effect on inner region 42. The applicator 110 may
comprise one or more optical elements, such as lenses, prisms,
mirrors so as to form a ring of light on the cornea.
[0092] The nerves may be stunned with cooling, and applicator 110
can be configured to cool the cornea. For example, at least the
peripheral portion of the region can be treated with a coolant, for
example chilled BSS at 8.degree. C. used for 3 minutes before
ablation, and the cornea may be cooled a ring during the ablation.
The cornea was also cooled post-PRK, to lessen pain. Work in
relation to embodiments suggests that -4.degree. C. is threshold
temperature where damage to mammalian cells occurs, and cooling
within a range from about -8 to about 5-6.degree. C. for a duration
can provide a transient interruption of nerve conduction, with full
return of function within about 12 days. The cooling with treatment
profile 120 can denervate the nerves without substantial damage to
the endothelial layer of cells.
[0093] The nerves may be stunned so as to provide transient local
desensitization. The stunning may comprise nerve damage in which
there is no disruption of the nerve or its sheath. In this case
there is an interruption in conduction of the impulse down the
nerve fiber, and recovery takes place without true regeneration of
the nerve fiber. This modified neurapraxia may comprise a mild foam
of nerve injury, for example a biochemical lesion caused by
concussion or shock-like injuries to the fiber. The applicator 110
can be configured so as to provide compression or relatively mild,
blunt blows, including some low-velocity missile injuries close to
the nerve. The modified neurapraxia stunning may provide be a
temporary loss of function which is reversible within hours to
months of the injury (the average is 6-8 weeks).
[0094] Destroying of Portions of Nerves
[0095] The nerves may be pruned, such that the end portions of the
nerves are destroyed, for example by pruning of the nerve at an
intermediate location such that the distal portion of the nerve is
killed. The killing of the distal portion of the nerve may comprise
severing axons of the nerve, and the sheath may remain intact where
the axons are cut or may also be severed, both of which are shown
above.
[0096] The nerves may be pruned mechanically. For example, the
nerve may be cut. The nerve may be cut in many ways. For example,
applicator 110 may comprise a trephine to cut the cornea at the
outer portion 44 to the desired depth. The trephination may
comprise a peripheral cut to specific depth. The cut can be done as
superficial as reaching Bowman's layer, or can be farther into the
cornea. The mechanical pruning may comprise laser cutting of the
cornea, for example with pulsed laser cutting such as a known
commercially available femto second pulsed laser. The denervation
treatment profile 120 may comprise laser cutting at with an
interior cut at a specific depth, for example in the epithelium or
the stroma or both, as described above.
[0097] The nerves may be pruned thermally, for example with thermal
heating treatment. Applicator 110 can be configured to prune the
nerves thermally. The thermal treatment may comprise heating the
cornea to obtain the denervation treatment profile 120. The heating
may comprise radiofrequency (hereinafter "RF") heating. The
radiofrequency heating may comprise one or more of low voltage,
high current, desiccation of corneal nerve tissue, denaturing of
corneal nerve tissue, or destroying corneal nerve tissue. The RF
heating may comprise one or more frequencies within a range from
about 1 kHz to about 1 GHz, for example within a range from about
10 kHz to about 100 MHz. The heating may comprise high voltage with
low current, for example so as to produce sparks. The nerves may
also be pruned with plasma, for example plasma from sparks.
[0098] The nerves may be pruned with cooling. For example,
applicator 110 may comprise a ring configuration which is cooled to
a desired temperature. The ring at an intended temperature can be
applied for a predetermined amount of time so as to achieve an
effect at a specific depth with denervation treatment profile 120,
so that nerves at different depths can be numbed selectively (depth
wise). The applicator 110 may comprise a whole plate or a contact
lens configuration.
[0099] The applicator 110 can be configured with cryogenic
processing, for example -10.degree. C. or below. The cooling
induced degeneration can preserve nerve sheath when axons are
severed, as described above, and thus allow restoration of nerve
activity within days so to allow painless period during epithelium
healing period. For example, the nerve can be frozen to a
temperature which causes internal nerve damage while preserving the
nerve sheath. This freezing can be done locally, for example ring
shaped to the outer portion of the region 44, and the duration and
the temperature of applicator can be determined prior to treatment
with the applicator 110 so as to obtain the desired effect at
specific areas and depths and to specific nerve layers with the
denervation treatment profile 110.
[0100] The nerves may be pruned with photodynamic treatment, and
applicator 110 can be configured to deliver a combination of
photosensitizing dye and light energy to generate denervation
treatment profile 110, and the profile can be selective to nerves
when the dye is selectively attached to the axons, for example
receptors of channels. Selective photodynamic injury, for example
the uptake of specific dye by nerves and excitation at specific
wavelength can severe at least the axons, and may sever the sheath,
depending on the amount of dye and intensity of light
treatment.
[0101] The nerves may be pruned with ultrasound, and applicator 110
can be configured to deliver the ultrasound energy so as to
generate the denervation treatment profile 120. The ultrasound may
comprise shock waves to the target tissue and applicator 110 may
comprise lithotripsy circuitry and transducers modified for
treatment of the cornea.
[0102] Based on the teachings described herein, a person of
ordinary skill in the art can conduct experiments to determine
empirically parameters of applicator 110, so as to denervate the
cornea with treatment profile 120. Such as person will also
recognize, applicator 110 and the use thereof can be adjusted so as
to stun the nerves similar to the above configurations that can be
used to prune the nerves. Similarly applicator 110 can be
configured such that denervation treatment profile 120 comprises
regions of stunned nerves and regions of pruned nerves, and a
person of ordinary skill in the art will recognize such variations
and combinations based on the teachings described herein.
[0103] FIG. 5B shows an applicator 110 as in FIG. 5A comprising a
channel 520 to receive a liquid to denervate the nerves. The liquid
may comprise a warm liquid to heat the cornea or a cool liquid to
cool the cornea.
[0104] FIG. 5C shows an applicator as in FIG. 5A comprising a
trephine 530 configured with the flange 532 to denervate the nerves
within a predetermined depth 534. The nerves may be stunned, the
axons severed and the sheath intact, or the axons and sheath
severed, as described above based on the target nerves and depth
534.
[0105] FIG. 5D shows an applicator 110 as in FIG. 5A comprising an
optical component 540 to deliver light 542 to the cornea. The light
542 can be focused to a desired treatment location and can be
scanned to produce the denervation treatment profile 120.
[0106] FIG. 5E shows an applicator 110 as in FIG. 5A comprising an
insulator 552 and at least one electrode 550 to deliver electrical
energy to the cornea outer portion of the cornea disposed
peripheral to the inner portion, for example central portion.
[0107] FIG. 5E1 shows an applicator as in FIG. 5A comprising at
least two electrodes 556 to deliver electrical energy to the
cornea. The applicator may comprise an electrode structure with the
at least two electrodes shaped to define the treatment profile. For
example, the electrode may comprise an arcuate shape with the
electrodes spaced apart by a distance so as to define the treatment
profile. The at least two electrodes can be arranged in many ways
to deliver RF electrical energy in accordance with the treatment
profile 120. The at least two electrodes may comprise bipolar
electrodes, for example. The insulator 552, for example a
dielectric material, can extend between the electrodes to define
the treatment profile 120 with the spacing of the electrodes. The
electrode spacing and energy to the electrodes can be configured
such that there is no substantial damage to endothelial cells with
treatment profile 120 to denervate the nerves.
[0108] FIG. 5E2 shows an applicator as in FIG. 5A comprising at
least two electrodes 556 to deliver electrical energy to the cornea
with a first nasal portion 550A of the applicator and a second
temporal portion 550B of the applicator. When the first portion and
second portion are substantially symmetrical, the applicator can be
used on either eye, such that the nasal portion 550A can be used on
the temporal portion of the opposite eye and the temporal portion
550B can be used on the nasal portion of the eye.
[0109] FIGS. 5E3A and 5E3B show an applicator as in FIG. 5E2
positioned on a cornea so as to define treatment profile 120 with
the electrode fields 556E from the spacing of the at least two
electrodes 556 and the profile of RF pulses. The electrodes can be
spaced in many ways to achieve the desired depth penetration into
tissue.
[0110] FIG. 5E4 shows circuitry 557 coupled to at least two
electrodes 556 of applicator 110 so as to generate the profiled RF
pulses and treatment profile. The electrodes can be coupled to the
circuitry in many ways, for example with a flexible cable 558.
[0111] FIG. 5E5 shows RF pulses of the circuitry. The circuitry and
RF pulses can be configured in many ways to denervate the nerve.
For example, the RF energy can comprise continuous energy delivered
for a period of seconds so as to heat the tissue. Alternatively or
in combination, the circuitry can be configured to deliver short
pulses of RF energy with a low duty cycle so as to inhibit heating
of tissue. The RF energy may comprise many known frequencies and
can be within a range from about 1 kHz to about 1 GHz, for example
from about 10 kHz to about 100 MHz. Each pulse comprises a duration
.tau., and the pulses can be separated by a delay .DELTA., such the
waveform comprises a period T. The frequency of the RF energy
corresponds to many oscillations of the electric field per pulse.
For example, the duration of the pulse can be from about 0.2 ms to
about 200 ms, and the frequency can be from about 50 kHz to about 5
MHz. The duty cycle may be no more than about 10%, for example no
more than about 5%, even 2% so as to inhibit heating of the tissue.
For example, the pulse duration can be about 20 ms, and the delay
between pulses about 48 ms, such that the pulses are delivered at
about 2 Hz.
[0112] Work in relation to embodiments suggests that the electric
field can produce sustained denervation without substantially
heating of the nerve. A person of ordinary skill in the art can
conduct experiments appropriate electrode spacing, pulse duration,
frequency and duty cycle based on the teachings describe herein so
as to denervate the nerve without substantial heating of the nerve
with treatment profile 120. Alternatively, the nerve may be heated
with the electric field and current so as to form a lesion, and a
person of ordinary skill in the art can conduct similar experiments
to determine appropriate parameters.
[0113] FIG. 5F shows an applicator as in FIG. 5A comprising at
least one transducer to deliver energy to the cornea.
[0114] FIG. 5F shows an applicator 110 as in FIG. 5A comprising a
housing 560 and at least one transducer 562 to deliver energy 564
to the cornea, for example ultrasound energy. For example, the
transducer 562 may comprise ultrasound energy for sonoporation of
one or more of the corneal nerves or the corneal epithelium so as
to deliver the substance as described herein.
[0115] FIGS. 6A to 6C show an applicator 110 as in FIG. 5A
comprising a heat conduction apparatus 600 to conduct heat to or
from the cornea. For example, apparatus 600 can be heated prior to
application so as to heat the cornea. Alternatively, apparatus 600
can be cooled prior to application so as to cool the cornea.
Apparatus 600 comprises a handle 620 and an annular portion 620 to
contact the cornea along an annular region of the cornea, such as
outer portion 44. Apparatus 600 may comprise a metal with high heat
capacity and conduction to cool the cornea. Apparatus 600 can be
cooled to an intended temperature prior to placement, and can be
placed on the cornea for an intended duration, such that the cornea
is cooled with a targeted denervation treatment profile 120. The
inner portion of the distal portion of the applicator can be shaped
to inhibit contact with the cornea centrally when the end contacts
the cornea at outer portion 42.
[0116] The applicator 600 may be placed against a sphere having a
radius of curvature corresponding to the cornea, for example a 7.94
mm radius of curvature.
[0117] FIG. 6D shows an insulator disposed around an applicator as
in FIGS. 6A to 6C, with an insulator 650, for example silicone,
disposed around an outer portion.
[0118] FIG. 7A shows an applicator 110 as in FIG. 5A comprising an
apparatus 700 configured to deliver a substance 700S as described
herein to an outer portion of the cornea. The apparatus 700 may
comprise an outer portion 710 having the substance 700S disposed
thereon and an inner portion 720, which inner portion may comprise
an opening or a portion of a substrate substantially without the
substance.
[0119] FIGS. 7A1 and 7A2 shows an applicator 110 as in FIG. 5A
comprising apparatus 700 with outer portion 710 comprising an
annular ring with the substance 700S disposed thereon to deliver
the substance to the outer portion of the cornea. The outer portion
710 may define an inner aperture 710A, and a handle may extend from
the outer portion.
[0120] FIG. 7A3 shows the substance coated on a support 702 along
outer portion 710 so as to deliver the substance to the outer
portion of the cornea.
[0121] FIG. 7A4 shows an applicator 110 with a channel 720 to
deliver the substance 700S to the outer portion of the region
cornea and a wall structure 722 to inhibit release of the
substance. The applicator may comprise a foam portion 724 disposed
therein to retain the liquid in the channel. Alternatively or in
combination, a thin porous membrane can be disposed on the lower
portion to the applicator to release the substance to the cornea.
The apparatus may comprise a luer connector to connect the
applicator to an injection apparatus 728.
[0122] FIGS. 7A5 and 7A6 show top and side and views, respectively,
of applicator 700 in which the applicator comprises micro-needles
716 to deliver the substance 700S to outer portion of the cornea.
The substance can be coated on the micro-needles, for example.
Alternatively or in combination, the substance can be injected with
the micro-needles. The micro-needles may comprise a length
extending from a base located at the support to a tip, and the
length can be sized to deliver the substance to a target location.
For example, the length of the micro-needles may comprise no more
than about 50 um to deliver the substance to the epithelium.
Alternatively, the micro-needles may comprise a greater length to
extend into the stroma.
[0123] FIG. 7A7 shows applicator 700 comprising a compartment 718
with the substance 700S disposed therein to deliver the substance
to the outer portion of the cornea. The substance 700S can be
contained in the compartment as a liquid, for example a liquid
having a concentration of the substance. A porous membrane 719 can
extend on toward the outer region of the cornea to deliver the
substance. The compartment 718 may comprise an annular compartment.
A wall can extend substantially around an inner perimeter of the
compartment and an outer perimeter of the compartment. For example,
the wall can extend around outer perimeter of an annulus and the
inner perimeter of the with an annular portion extending
therebetween along an upper surface, with the porous membrane 719
disposed along the lower surface.
[0124] FIG. 7B shows an applicator as in FIG. 5A to deliver a
substance to an inner portion of the cornea. The applicator 740
comprises an inner portion 742 having the substance disposed
thereon. The applicator comprises an outer portion 744
substantially without the substance. The applicator 740 can be
applied to the epithelium before PRK over the intended ablation
zone. Alternatively, the applicator 740 can be applied to the
ablated stroma after ablation with direct applicator to ablated
nerve contact, for example with direct contact of a noxious
substance such as comprising capsaicin to nerve comprising a cation
channel which mediates stimuli.
[0125] FIG. 7C shows an apparatus 750 comprising applicators as in
FIGS. 7A and 7B to deliver an inner substance to the inner portion
and an outer substance to the outer portion of the region of the
cornea to denervate the cornea. The apparatus 750 comprises an
inner applicator 752 to apply an inner substance to the inner
region and an outer applicator 754 to apply an outer substance to
the outer region. Work in relation to embodiments suggests that
such combination of substances can be beneficial to obtain the
denervation treatment profile as described herein. For example, the
substance of the inner portion may comprise a noxious substance
such as capsaicin or a capsaicin analog, and the outer portion may
comprise an anesthetic such as a calcium channel blocker.
Alternatively, the substance of the outer portion may comprise the
noxious substance such as capsaicin or a capsaicin analog, and the
inner portion may comprise the anesthetic such as a calcium channel
blocker. This separation of the calcium channel agonist from the
calcium channel blocker can allow the agonist to effect the nerves
substantially without inhibition from the calcium channel
blocker.
[0126] The inner applicator 752 may be applied to the cornea before
the outer applicator 754. Alternatively, the outer applicator can
be applied to the cornea before the inner applicator. For example
the outer applicator 754 can be applied to cornea with an
anesthetic comprising a calcium channel blocker before the inner
applicator 752 is applied. The outer applicator 754 comprising the
calcium channel blocker can be removed when a sufficient amount of
calcium channel blocker has been delivered to the cornea. The inner
applicator 752 comprising the noxious substance, for example a
calcium channel agonist such as capsaicin, can be applied to cornea
to release the agonist to the inner portion without substantial
inhibition from the blocker that has been previously applied to the
outer region. The inner applicator 752 can then be removed. The eye
may then be ablated with PRK.
[0127] FIG. 7D shows an apparatus 760 to deliver a first substance
to the inner portion 42 and the outer portion 44 of the region of
the cornea to denervate the cornea. FIG. 7E shows a side view of an
applicator as in FIG. 7A. Apparatus 760 comprise an inner portion
762 with a first substance disposed thereon and an outer portion
764 with second substance disposed thereon. The first substance of
inner portion 762 may comprise a noxious substances such as a
calcium channel agonist such as a capsaicin and the second
substance of the outer portion 764 may comprise a calcium channel
blocker anesthetic. Alternatively, the first substance of inner
portion 762 may comprise may comprise a calcium channel blocker
anesthetic and the second substance of the outer portion 764 may
comprise a noxious substances such as a calcium channel agonist
such as a capsaicin.
[0128] A person of ordinary skill in the art can conduct
experiments to determine empirically the inner or outer location of
the noxious substance comprising the calcium channel agonist such
as capsaicin and the inner or outer location of the anesthetic
comprising the calcium channel blocker, and also the concentration
of the first and second substances and duration of application.
[0129] The first and second substances may be coated on the inner
and outer portions of the substrate with an amount per unit
area.
[0130] Desensitizing Agents
[0131] The desensitizing agent as described herein can be delivered
in accordance with treatment profile 120 so as to denervate the
target tissue, for example the cornea, for a plurality of days. As
the substance is delivered in accordance with the treatment profile
120, the amount of desensitizing agent delivered to the target
tissue can be increased substantially to achieve the desired amount
of desensitization. The desensitizing agent may comprise one or
more of a noxious substance, a chemical, or a neurotoxin. The
desensitizing agent may comprise Botulinum A toxin. The Botulinum A
toxin may comprise one or more serotypes of Botulinum toxin such as
Botulinum type A, Botulinum type B. For example, the substance may
comprise Botulinum Toxin Type, commercially available as
Botox.RTM., delivered in accordance with the treatment profile 120
so as to treat the target tissue safely. The Botulinum toxin may
comprise one or more of a heavy chain or a light chain of the
toxin. The substance may act upon a receptor of the corneal nerves,
such as one or more of a sodium channel blocking compound, or a
potassium channel blocking compound. For example the substance may
bind to and activate the transient potentially vanilloid
receptor.
[0132] The substance may comprise a neurotoxin, such as a
pharmaceutically acceptable composition of a long-acting sodium
channel blocking compound, in which said compound binds to the
extracellular mouth of the sodium channel, occluding the channel by
a mechanism separate from that of local anesthetics, such as
proparacaine. The substance may comprise a toxins or analogs
thereof that specifically bind to a site formed in part by an
extracellular region of the alpha subunit of a sodium channel. For
example, the substance may comprise the class of toxins and analogs
that specifically bind to a site formed by the SS1 and SS2
extracellular regions of the alpha subunit of a sodium channel. The
substance may comprise on or more of tetrodotoxin, saxitoxin and
analogs thereof.
[0133] The transient receptor potential vanilloid-1 (TRPV1) is a
capsaicin-responsive ligand-gated cation channel selectively
expressed on small, unmyelinated peripheral nerve fibers (cutaneous
nociceptors). When TRPV1 is activated by agonists such as capsaicin
and other factors such as heat and acidosis, calcium enters the
cell and pain signals are initiated. After disease or injury,
cutaneous nociceptors may become persistently hyperactive,
spontaneously transmitting excessive pain signals to the spinal
cord in the absence of painful stimuli, resulting in various types
of pain. When TRPV1 is continuously activated through prolonged
exposure to an agonist (e.g., capsaicin), excessive calcium enters
the nerve fiber, initiating processes that result in long-term yet
reversible impairment of nociceptor function. The application of
capsaicin can provide relief from pain with this mechanism.
[0134] FIG. 8A shows the chemical structure of Capsaicin.
[0135] The substance comprising desensitization agent may comprise
a substantially hydrophobic and lipophilic substance such as
Capsaicin. When delivered to the surface of the epithelium as
described above, the hydrophobic Capsaicin can be substantially
localized to the epithelium, with treatment profile 120 as
described above. For example, the elevated concentration of
Capsaicin may be localized to the epithelium near the edge of a
debridement of the epithelium.
[0136] Capsaicin may comprise a purified extract from chili peppers
(Genus Capsicum). Capsaicin comprises an odorless, flavorless,
lipophilic substance. Capsaicin is a capsaicinoid, a family of
chemicals found in these peppers which can induce the feeling of
heat upon ingestion.
[0137] FIG. 8B shows Vanilloid Receptor 1 (VR1) receptor, which
comprises a Capsaicin receptor suitable for use with a denervating
substance. VR1 receptors are found in the peripheral neurons in the
skin and cornea, for example A8 and C fibers. The primary receptors
have somata in the dorsal root ganglion and the trigeminal
ganglion. The VR1 receptor comprises a non selective cation channel
which mediates stimuli from both chemical and physical triggers,
including heat, low pH, capsaicin and some chemical biproducts from
inflammation. As capsaicin is lipophilic, the binding site for
capsaicin can be inside or outside of the cell membrane.
[0138] Capsaicin can induce a feeling of pain. Capsaicin binds to
nociceptors, which stimulate afferent thinly-myelinated A.delta.
and un-myelinated C fibers. When the VR1 receptor is not activated,
the VR1 receptor remains closed. Upon activation, for example with
capsaicin binding, the VR1 channel opens. Since the VR1 receptor is
a non-selective cation channel, when capsaicin binds, positive
ions, for example calcium, can flow into the axons and dendrites of
the neurons. The substantial effect of the opening of the channel
of the VR1 receptor is an influx of calcium ions, resulting in a
depolarization. This depolarization can eventually induce an action
potential. When the neurons containing these receptors are
stimulated, the neurons release a neurotransmitter, substance P.
Substance P can communicate a message eventually perceived as an
itch, burning sensation, or pain, for example with release of
substance P (SP) into the cornea.
[0139] FIG. 8C desensitization with Capsaicin and mechanisms of
desensitization. Desensitization with Capsaicin may comprise
functional desensitization or pharmacological desensitization or
both. Functional desensitization comprises the eventual reduction
or loss of responsiveness of the neuron to other stimuli.
Pharmacological desensitization comprises the progressive decline
in the size of subsequent responses to capsaicin after prolonged or
repeated exposures.
[0140] Capsaicin can cause desensitization via multiple mechanisms.
At least one mechanism involves the calcium dependent activation of
a protein phosphatase called calcineurin, which is mainly
associated with activating the T cell immune response. Capsaicin
activation of the VR1 receptor can induce an increase in the
intracellular calcium concentration. This increase in calcium ions
stimulates calcineurin, causing the calcium-dependent
dephosphorylation of various proteins, ion channels, and enzymes.
The dephosphorylation of one of calcineurin's protein targets can
result in a functional desensitizing effect.
[0141] Capsaicin comprises a TRPV1 agonist, that can be
administered locally to the site of pain, for example to the
cornea. Two substantial types of pain sensing nerves are C-fiber
neurons and A-delta neurons, for example of the cornea as described
above. Long-lasting "noxious pain" can be transmitted in the body
by C-fiber neurons and is associated with longer-term, dull,
aching, throbbing pain. In contrast, A-fiber neurons can transmit
immediate "adaptive pain," such as that experienced milliseconds
after the slamming fingers in a door or after touching a hot
surface. Capsaicin acts on TRPV-1 receptors expressed most densely
in C-fiber neurons. These C-fiber neurons transmit long-term pain
signal to the brain, and Capsaicin acts as a TRPV-1 agonist so as
to bind these pain receptors and open the calcium ion channels as
described above.
[0142] After initial stimulation with Capsaicin, desensitization of
the TRPV-1 receptors blocks noxious pain. This desensitization
leads to a prolonged, reversible and localized desensitization of
the pain fibers.
[0143] The Capsaicin drug generally has a short half-life of 1 to 2
hours when absorbed into the blood stream, and is undetectable in
the blood after 24 hours.
[0144] Capsaicin comprises a high safety profile suitable for use
with refractive surgery such as PRK.
[0145] Because Capsaicin acts primarily on C-fiber neurons,
Capsaicin may not to have an adverse effect on normal sensation
such as temperature or touch, depending upon the dose based on the
teachings as described herein.
[0146] FIG. 8D shows neural channels sensitive to Capsaicin and
afferent transmission of acute pain to the central nervous system
(hereinafter "CNS") and efferent transmission neurogenic
inflammation to the cornea. The Capsaicin can trigger the release
from the neuron of one or more of substance P (SP), adenosine
triphosphate (ATP) or calcitonin gene-related peptide (CGRP). In at
least some embodiments, the Capsaicin can be applied to the
epithelium to trigger the release of one or more neuropeptides such
as SP or CGRP and the epithelium removed, for example scraped away,
so as to remove the neuropeptide with the epithelium.
[0147] Capsaicin can be used for PRK. For example, the release of
Capsaicin can be controlled with an applicator as described above.
The controlled release may comprise one or more of a quantity of
release, a rate of release, region of release such as to an inner
portion of the cornea or an outer portion of the cornea, or both
the inner portion and the outer portion. The quantity of capsaicin
may be determined with concentration of Capsaicin applied to the
cornea for an amount of time. For example, the covering, or shield,
as described herein can be provided with Capsaicin coated thereon
for accelerated release and delivery of fixed amount of Capsaicin
to a target location on the eye with the covering.
[0148] Inhibition of Pain with Post-Op Anesthetic
[0149] FIG. 9 shows a method of treatment 900 with a covering 910
positioned on the eye over an epithelial defect so as to inhibit
delivery of an anesthetic to the epithelial defect when the
covering conforms to a boundary of the epithelium and the defect
and seals the cornea. The cornea 20 may ablated with PRK and the
covering 910 positioned over the ablation. The covering may
comprise a soft portion that conforms to the epithelium so as to
seal the cornea. For example, the covering 910 may comprise a
conformable covering as described in U.S. app. No. 12/384,659 filed
Apr. 6, 2009, entitled "Therapeutic Device for Pain Management and
Vision," the entire disclosure of which is incorporated herein by
reference and suitable for combination in accordance with some
embodiments described herein. An anesthetic, for example that
alters function of calcium release channels, can be applied 922 to
the cornea with a drop 920. The drop of anesthetic spreads over the
tear film of the eye. A the shield 920 conforms to the edge of the
epithelium that defines the epithelial defect, the cornea is
substantially sealed to inhibit swelling. The drop of anesthetic is
absorbed preferentially by the epithelium away from the covering at
location 924, as the covering 910 can inhibit penetration of the
anesthetic to the cornea. The anesthetic can treat the nerves of
the cornea peripheral to the epithelial defect to inhibit pain and
so as to inhibit effect of the anesthetic on the regenerating
epithelium near the defect, such that re-epithelialization is not
delayed substantially with application of the anesthetic.
[0150] FIG. 10 shows a method 1000 of treating an eye of a patient
in accordance with embodiments of the present invention. A step
1005 provides an eye, for example as described above. A step 1010
defines a region of the eye comprising an inner portion and an
outer portion, for example as described above. A step 1015 applies
a topical anesthetic, for example as described above. A step 1020
denervates one or of the outer portion of the inner portion with a
delivery profile, for example as described above. A step 1025
removes the epithelium from the inner portion, for example as
described above. A step 1030 ablates the inner portion with a laser
beam, for example an excimer laser PRK as described above. A step
1035 provides a covering for the eye, for example a silicone shield
with a wettable upper coating as described above. A step 1040
places the covering on the eye, for example when the eye is dry,
such that the covering conforms to the epithelium so as to seal the
cornea. A step 1045 regenerates the epithelium under the covering.
A step 1050 applies a topical anesthetic to the eye, for example
with drops, when the covering is sealed to the epithelium so as to
inhibit delivery of the anesthetic to the epithelial defect and the
regenerating epithelium near the defect. A step 1055 inhibits the
deliver of anesthetic over the defect, for example with the
covering and the seal, such that the anesthetic penetrates the
epithelium near the limbus and so as to denervate the nerve bundle
disposed in the stroma and denervate the inner portion of the
ablated region of the cornea. A step 1060 regenerates the
epithelium under the covering to cover the ablated stromal tissue
and close the epithelial defect. A step 1065 removes the
covering.
[0151] Experimental
[0152] Based on the teachings described herein, a person of
ordinary skill in the art can conduct experiments to determine
empirically the parameters to denervate the cornea to decrease
pain, for example pain following PRK.
[0153] FIG. 11 shows experimental cooling data and profiles of
corneal temperature at depths. For example, the cooling apparatus
as described above can be chilled to a temperature such as 0
degrees C., or -70 degrees C. The apparatus can be contacted to the
cornea to determine the temperature of the cornea as a function of
time and depth. For example, a 0 degree C. probe can be placed on
the cornea and the temperature of the eye determined over time at
depths of 200, 400 and 600 microns. A -20 degree C. probe can be
placed on the cornea and the temperature of the eye determined over
time at depths of 200, 400 and 600 microns. A -70 degree C. probe
can be placed on the cornea and the temperature of the eye
determined over time at depths of 200, 400 and 600 microns. The
temperature can be determined experimentally, or can be modeled
with finite element analysis and non corneal heat transfer
parameters, or a combination thereof. The denervation treatment
profile can be determined, and the parameters adjusted such that
pain is inhibited and also such that corneal innervation is
restored after reepithelialization.
[0154] Similar studies can be conducted with heat, substances,
ultrasound, light, photodynamic therapy and cutting as described
herein.
[0155] While the exemplary embodiments have been described in some
detail, by way of example and for clarity of understanding, those
of skill in the art will recognize that a variety of modifications,
adaptations, and changes may be employed. Hence, the scope of the
present invention should be limited solely by the appended
claims.
* * * * *
References