Corneal Denervation for Treatment of Ocular Pain
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.
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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 DEVELOPMENTNOT APPLICABLE
BACKGROUND OF THE INVENTIONPeople 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.
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.
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.
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.
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 INVENTIONAlthough 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.
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.
FIGS. 2A1 and 2B1 show denervation as in
FIGS. 2A2 and 2B2 show denervation as in
FIGS. 2A3 and 2B3 shows denervation as in
FIGS. 2A4 and 2B4 shows denervation as in
FIGS. 2A5 and 2B5 shows denervation as in
FIG. 2C1 shows denervation as in
FIG. 2C2 shows denervation as in
FIG. 2C3 shows denervation as in
FIG. 5E1 shows an applicator as in
FIG. 5E2 shows an applicator as in
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.
FIG. 5E4 shows circuitry coupled to applicator so as to generate the profiled RF pulses and treatment profile.
FIG. 5E5 shows RF pulses of the circuitry;
FIGS. 7A1 and 7A2 shows an applicator as in
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;
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;
FIGS. 7A5 and 7A6 show top and side and views, respectively, of an applicator as in
FIG. 7A7 shows an applicator as in
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.
Many embodiments described herein provide denervation that inhibits pain but does not significantly impact or inhibit epithelial healing.
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.
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.
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
Corneal Innervation
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.
Treatment of Corneal Pain
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.
FIGS. 2A1 and 2B1 shows denervation as in
FIGS. 2A2 and 2B2 shows treatment 100 as in
FIGS. 2A3 and 2B3 shows denervation as in
FIGS. 2A4 and 2B4 shows denervation as in
FIGS. 2A5 and 2B5 shows denervation as in
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.
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.
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.
FIG. 2C1 shows denervation as in
FIG. 2C2 shows denervation as in
FIG. 2C3 shows denervation as in
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.
Stunning the Nerves:
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.
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.
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° 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° C. is threshold temperature where damage to mammalian cells occurs, and cooling within a range from about −8 to about 5-6° 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.
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).
Destroying of Portions of Nerves
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.
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.
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.
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.
The applicator 110 can be configured with cryogenic processing, for example −10° 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.
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.
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.
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.
FIG. 5E1 shows an applicator as in
FIG. 5E2 shows an applicator as in
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.
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.
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 τ, and the pulses can be separated by a delay Δ, 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.
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.
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.
FIGS. 7A1 and 7A2 shows an applicator 110 as in
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.
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.
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.
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.
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.
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.
The first and second substances may be coated on the inner and outer portions of the substrate with an amount per unit area.
Desensitizing Agents
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®, 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.
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.
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.
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.
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.
Capsaicin can induce a feeling of pain. Capsaicin binds to nociceptors, which stimulate afferent thinly-myelinated Aδ 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.
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.
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.
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.
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.
Capsaicin comprises a high safety profile suitable for use with refractive surgery such as PRK.
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.
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.
Inhibition of Pain with Post-Op Anesthetic
Experimental
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.
Similar studies can be conducted with heat, substances, ultrasound, light, photodynamic therapy and cutting as described herein.
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.
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 μm 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.
Type: Application
Filed: Oct 22, 2010
Publication Date: Mar 14, 2013
Applicant: NexisVision, Inc. (Menlo Park, CA)
Inventors: Yair Alster (Palo Alto, CA), Hanson S. Gifford (Woodside, CA), Cary J. Reich (Los Gatos, CA), Eugene de Juan, JR. (San Francisco, CA), John A. Scholl (San Ramon, CA), Jose D. Alejandro (Sunnyvale, CA), Douglas Sutton (Pacifica, CA), Omer Rafaeli (Tel Aviv)
Application Number: 13/503,841
International Classification: A61F 9/01 (20060101);