European Patent Office - EP 2490635 B1

Note: Within nine months of the publication of the mention of the grant of the European patent in the European PatentBulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with theImplementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has beenpaid. (Art. 99(1) European Patent Convention).

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(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention of the grant of the patent: 06.09.2017 Bulletin 2017/36

(21) Application number: 10825787.4

(22) Date of filing: 22.10.2010

(51) Int Cl.:A61F 9/007 (2006.01) A61B 18/02 (2006.01)

A61F 9/008 (2006.01) A61N 1/36 (2006.01)

A61N 1/40 (2006.01) A61N 7/02 (2006.01)

A61F 9/009 (2006.01)

(86) International application number: PCT/US2010/053854

(87) International publication number: WO 2011/050327 (28.04.2011 Gazette 2011/17)

(54) CORNEAL DENERVATION FOR TREATMENT OF OCULAR PAIN

HORNHAUT-DENERVATION ZUR BEHANDLUNG VON AUGENSCHMERZEN

INSENSIBILISATION DES NERFS DE LA CORNÉE EN VUE DE TRAITER LA DOULEUR OCULAIRE

(84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30) Priority: 23.10.2009 US 279612 P

(43) Date of publication of application: 29.08.2012 Bulletin 2012/35

(60) Divisional application: 17183160.5

(73) Proprietor: Nexisvision, Inc.Menlo Park, CA 94025 (US)

(72) Inventors: • ALSTER, Yair

Palo AltoCA 94306 (US)

• GIFFORD, Hanson, S.WoodsideCA 94062 (US)

• REICH, Cary, J.Los GatosCA 95032 (US)

• DE JUAN, Eugene, JR.San FranciscoCA 94117 (US)

• SCHOLL, John, A.San RamonCA 94583 (US)

• ALEJANDRO, Jose, D.SunnyvaleCA 94086 (US)

• SUTTON, DouglasPacificaCA 94044 (US)

• RAFAELI, OmerUdim 42905 (IL)

(74) Representative: Kazi, Ilya et alMathys & Squire LLPThe Shard32 London Bridge StreetLondon SE1 9SG (GB)

(56) References cited: WO-A1-01/68082 WO-A1-92/07617WO-A1-94/05225 WO-A1-95/15134WO-A1-2009/065061 WO-A1-2009/073213WO-A2-2007/011880 US-A- 4 381 007US-A- 5 649 922 US-A- 5 820 624US-A- 6 036 688 US-A1- 2002 095 199US-A1- 2007 014 760 US-A1- 2007 244 559US-A1- 2008 039 832 US-B2- 6 551 307

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• DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; 1982, SCHIMMELPFENNIG B ET AL: "A technique for controlled sensory denervation of the rabbit cornea.", XP002698298, Database accession no. NLM7129102 & GRAEFE’S ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY = ALBRECHT VON GRAEFES ARCHIV FÜR KLINISCHE UND EXPERIMENTELLE OPHTHALMOLOGIE 1982, vol. 218, no. 6, 1982, pages 287-293, ISSN: 0721-832X

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Description

BACKGROUND OF THE INVENTION

[0001] People like to see. The eye comprises severaltissues that allow a person to see, and these tissues in-clude the cornea, the lens and the retina. The cornea andlens focus light rays on to the retina so as to form animage on the retina. The cornea comprises an outer tis-sue of the eye that is coupled to air with a tear film, suchthat a majority of the focusing power of the eye isachieved based on the shape of the cornea. The retinacomprises photoreceptors that generate neural signalsin response to the light image formed on the retina, andthese neural signals are processed and transmitted tothe occipital cortex of the brain such that the person per-ceives the image.[0002] The cornea is a highly innervated tissue thatcomprises several layers including an epithelium dis-posed under the tear film and a stromal layer disposedunder the epithelium. In humans and at least some ani-mals a Bowman’s membrane is disposed between theepithelium and corneal stroma. The innervation of thecornea can be useful and help the person to blink so asto replenish the tear film for vision and to maintain ahealthy corneal epithelium. The innervation of the corneacan also help to protect the cornea and the persons sightwith the sensation of pain, such that in at least someinstances the person may be forced to protect the corneaand eye from further injury in response to a painful stim-ulus. However, this innervation of the cornea, may resultin substantial pain following surgery in at least some in-stances.[0003] Many surgeries and therapies of the eye aredirected to the treatment of the cornea, and in at leastsome instances significant pain can occur. Devices forcorneal surgery are described for example in documentUS 4,381,007. For example photorefractive keratectomy(hereinafter "PRK"), laser assisted in situ keratomileusis(hereinafter "LASIK"), and laser assisted epithelialkeratomileusis (hereinafter "LASEK"), each reshape thecornea of the eye so as to improve the focus of imageson the retina such that the patient can see better. Unfor-tunately, many of the corneal surgeries result in pain inat least some instances. For example, with PRK andLASEK, the epithelial layer of the cornea is removed soas to expose underlying tissue that is ablated, and in atleast some instances patients experience pain when theepithelium regenerates over the ablation. With LASIK, aflap of tissue comprising the epithelium and stroma is cutwith a laser or blade and opened with a hinge so as toexpose the underlying stromal bed where the ablation isperformed. As the LASIK flap can be positioned over theablated stromal bed with stroma to stroma contact, LASIKcan result in less pain for patients. However, in at leastsome instances LASIK can result in complications relatedto the cutting of the LASIK flap and the LASIK ablationof the exposed stromal bed that extends deeper into the

cornea than PRK and LASEK ablations. Also, work inrelation to embodiments of the present invention sug-gests that the cutting of corneal nerve fibers with theLASIK flap can result in decreased corneal sensitivity foran extended time in at least some instances. AlthoughLASIK can result in complications in at least some in-stances, many patients prefer the risks of LASIK to thepain of PRK.[0004] Although the control of pain with PRK andLASEK has been proposed and implemented, many pa-tients who undergo PRK report pain and photophobia inat least some instances during the two to four day periodwhen the epithelium regenerates over the ablation. Forexample, although the use of anesthetics such as lido-caine and proparacaine have been proposed, use ofthese anesthetics in amounts that significantly reducepain may delay reepithelialization, such that the safelyprescribed dosage does not sufficiently reduce pain in atleast some instances. Even with the use of safe amountsof analgesics with PRK and LASEK, patients can stillreport undesirable pain in at least some instances. Al-though the systemic use of opioids such as morphinecan reduce pain, the patient may be subjected to sideeffects of the systemic opioid medication. Therefore,there is a significant unmet clinical need to reduce painassociated with removal of the corneal epithelium, forexample following PRK, such that the patient is not sub-jected to significant side effects.[0005] In light of the above, it would be desirable toprovide improved methods and apparatus for pain controlof the eye. Ideally such methods and apparatus wouldbe compatible with refractive surgery, such that patientscan receive a safe treatment to correct vision with fullrecovery of corneal tissue and neural function, and de-creased pain. WO 92/07617 discloses a method of treat-ing a patient by providing a signal that is exponential incharacter to the patient. The signal includes a relativelylow-frequency, constant amplitude, periodic-exponentialfirst component and a relatively high-frequency, periodic-exponential second component. The signal is providedto a structure associated with the eye by positioning adevice for conducting the electrical signal at a point onthe exterior of the patient that is substantially interior tothe bone structure defining the eye socket.

BRIEF SUMMARY OF THE INVENTION

[0006] Although specific reference is made to treat-ment of the eye with PRK, embodiments of the presentinvention will have application to many patient treatmentswhere the tissue such as epithelium regenerates, for ex-ample regenerates subsequent to removal after injury ortreatment of an underlying tissue.[0007] Embodiments of the present invention provideapparatus for the treatment of the eye to reduce pain.The pain may originate from an inner region of a tissuesuch as the cornea, and the treatment can be applied toan outer region of the tissue to denervate nerves extend-

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ing into the inner region so as to reduce the pain. Forexample, the cornea of the eye may comprise an innerregion having an epithelial defect, for example a centralregion of the cornea having the epithelial defect. An outerportion of the cornea can be treated so as to reduce painof the epithelial defect, for example with treatment of anouter region of the cornea peripheral to the central regioncomprising the defect. The outer portion of the corneacan be treated to denervate nerves extending from theouter portion to the inner portion, and the denervation ofthe cornea can inhibit pain for a plurality of days suchthat epithelial healing is substantial and not inhibited. Forexample, pain can be inhibited for a plurality of days whenthe epithelium regenerates over a debridement, such thatthe regeneration of the epithelium over the debridementis substantially uninhibited. The debridement may com-prise a debridement of a PRK and regeneration of theepithelium may occur over the PRK ablation without sub-stantial inhibition when the cornea is denervated for aplurality of days. The denervation of the nerve can bereversible, such that corneal innervation can return fol-lowing treatment. For example, the neurons of the nervesmay be stunned or desensitized to inhibit pain, or axonsof the neurons of the nerves can be cleaved to inhibitpain such that the neurons can regenerate along thenerve sheathes into the inner portion. The outer portionmay extend around a perimeter of the inner portion, forexample so as to enclose the inner portion with the outerportion, and the outer portion may comprise manyshapes such as annular shape, an oval shape or a disc.[0008] The invention is defined in the claims, other em-bodiments being merely exemplary.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009]

Figure 1A shows an eye and layers of the cornea;

Figure 1B shows a side view nerves of the corneaas in Fig. 1A;

Figure 1C shows a top view of view nerves of thecornea as in Fig. 1B;

Figure 1D shows a schematic illustration of nervesof the cornea as in Fig. 1C extending from the stromathrough Bowman’s layer into the epithelium;

Figures 2A and 2B show treatment of an portion ofa region of the cornea so as to denervate the cornea;

Figures 2A1 and 3B show denervation as in Figs. 2Aand 2B, with the a treatment profile substantially ap-plied and localized to the epithelial layer of tissue;

Figures 2A2 and 2B2 show denervation as in Figs.2A and 2B, with the a treatment profile substantially

comprising the epithelial layer and extending sub-stantially into the stroma so as to encompass nervebundles;

Figures 2A3 and 2B3 shows denervation as in Figs.2A and 2B, with the a treatment profile localized sub-stantially to the stroma so as to encompass nervebundles;

Figures 2A4 and 2B4 shows denervation as in Figs.2A and 2B, in which the an inner region is denervatedwith the outer region;

Figures 2A5 and 2B5 shows denervation as in Figs.2A and 2B, in which the an inner region is denervatedwith the outer region comprising a first outer regionand a second outer region;

Figures 2C shows an ablated cornea having an ep-ithelial defect, in which the cornea has been dener-vated;

Figures 2C1 shows denervation as in Fig. 2C withthe denervation treatment profile comprising the ep-ithelium extending to the debridement.

Figures 2C2 shows denervation as in Fig. 2C withthe denervation treatment profile extending to nervebundles disposed within the stroma and peripheralto the ablation.

Figures 2C3 shows denervation as in Fig. 2C withthe denervation treatment profile extending acrossthe ablation.

Figures 3A and 3B show the severing of axons dis-posed within a nerve such that sheath remains intact;

Figures 3C and 3D show regeneration of the axonsalong the sheaths subsequent to cleavage of the ax-ons as in Fig. 3A and 3B;

Figures 4A and 4B show the severing of the nerveinto an inner portion of the nerve and an outer portionof the nerve, such that the sheath of the inner portionremains substantially aligned with the outer portionand axons regenerate from the outer portion alongthe sheath of the inner portion;

Figures 4C and 4D show regeneration of the axonsalong the inner sheaths subsequent to cleavage ofthe nerves as in Fig. 4A and 4B;

Figure 5A shows an applicator coupled to the corneato denervate the nerves;

Figure 5B shows an applicator as in Fig. 5A com-prising a channel to receive a liquid to denervate the

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nerves;

Figure 5C shows an applicator as in Fig. 5A com-prising a trephine configured with the flange to den-ervate the nerves;

Figure 5D shows an applicator as in Fig. 5A com-prising an optical component to deliver light to thecornea;

Figure 5E shows an applicator as in Fig. 5A com-prising at least one electrode to deliver electrical en-ergy to the cornea;

Figure 5E1 shows an applicator as in Fig. 5A com-prising at least two electrodes to deliver electricalenergy to the cornea;

Figure 5E2 shows an applicator as in Fig. 5A com-prising at least two electrodes to deliver electricalenergy to the cornea with a first nasal portion of theapplicator and a second temporal portion of the ap-plicator.

Figures 5E3A and 5E3B show an applicator as inFig. 5E2 positioned on a cornea so as to define treat-ment profile 120 with the electrode fields from thespacing of the electrodes and the profile of RF puls-es.

Figures 5E4 shows circuitry coupled to applicator soas to generate the profiled RF pulses and treatmentprofile.

Figures 5E5 shows RF pulses of the circuitry;

Figure 5F shows an applicator as in Fig. 5A compris-ing at least one transducer to deliver energy to thecornea;

Figures 6A to 6C show an applicator as in Fig. 5Acomprising a metal to conduct heat from the cornea;

Figure 6D shows an insulator disposed around anapplicator as in Figs. 6A to 6C;

Figure 7A shows an applicator as in Fig. 5A to delivera substance to an outer portion of the cornea;

Figures 7A1 and 7A2 shows an applicator as in Fig.5A comprising an annular ring with the substancedisposed thereon to deliver the substance to the out-er portion of the cornea;

Figures 7A3 shows a substance coated on a supportalong an outer portion of the support to deliver thesubstance to the outer portion of the cornea;

Figures 7A4 shows an applicator with a channel todeliver the substance to the outer portion of the cor-nea and a wall structure to inhibit release of the sub-stance;

Figures 7A5 and 7A6 show top and side and views,respectively, of an applicator as in Fig. 7A in whichthe applicator comprises micro-needles to deliverthe substance to outer portion of the cornea;

Figure 7A7 shows an applicator as in Fig. 7A com-prising a compartment with the substance disposedtherein so as to deliver the substance to the outerportion of the cornea;

Figure 7B shows an applicator as in Fig. 5A to delivera substance to an inner portion of the cornea;

Figure 7C shows an apparatus comprising applica-tors as in Figs. 7A and 7B to deliver a first substanceto the inner portion and a second substance to theouter portion of the region of the cornea to denervatethe cornea;

Figure 7D shows an apparatus to deliver a first sub-stance to the inner portion and the outer portion ofthe region of the cornea to denervate the cornea;

Figure 7E shows a side view of an applicator as inFig. 7A;

Figure 8A shows the chemical structure of capsaicin;

Figure 8B shows Vanilloid Receptor 1 (VR1) recep-tor, which comprises a Capsaicin receptor suitablefor use with a denervating substance;

Figure 8C desensitization with capsaicin;

Figure 8D shows neural channels sensitive to Cap-saicin and afferent transmission of acute pain to thecentral nervous system and efferent transmissionneurogenic inflammation to the cornea;

Figure 9 shows a covering positioned on the eyeover an epithelial defect so as to inhibit delivery ofan anesthetic to the epithelial defect when the cov-ering conforms to a boundary of the epithelium andthe defect and seals the cornea;

Figure 10 shows a method of treating an eye of apatient; and

Figure 11 shows experimental cooling data and pro-files of corneal temperature at depths, in accordancewith embodiments.

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DETAILED DESCRIPTION OF THE INVENTION

[0010] Embodiments of the present invention can treatmay types of pain of the eye, for example pain of thecornea, and can be used for treatment of pain corre-sponding to refractive surgery of the cornea. The embod-iments described herein can be used to treat the eyefollowing trauma of the eye, such as corneal abrasions,and can also be used to treat pain originating from pa-thology of the eye such as pseudophakic bullous kerat-opathy (hereinafter "PBK") or aphakic bullous keratopa-thy (hereinafter "ABK"). In many embodiments, the painof the cornea corresponds to pain associated with anepithelial debridement of the cornea used in conjunctionwith refractive surgery. For example, with PRK, an innerportion of the cornea is defined for treatment over thepupil, and the epithelium removed from the region andthe cornea ablated with a pulsed laser such as an excimerlaser. The epithelium may take at least one day to heal,for example three days, and the embodiments describedherein can be used to treat nerves of the cornea so asto inhibit pain experienced by the patient when the epi-thelium regenerates over the ablation.[0011] Many embodiments described herein providedennervation that inhibits pain but does not significantlyimpact or inhibit epithelial healing.[0012] Although previous studies on mammals and hu-mans has indicated that corneal nerves that are injuredor destroyed can regenerate, the destruction of cornealnerves such as stromal nerves may be linked to post-PRK haze, such that there may be a correlation betweenthe development of post-PRK haze and the lack of stro-mal nerve regeneration. The treatment of pain control asdescribed herein can be used to treat nerves such thatthe nerves can regenerate so as to restore substantiallythe neural function and decrease haze following PRK.[0013] As used herein denervation of tissue encom-passes deprivation of nerve activity of the tissue, for ex-ample with cutting of the nerve or blocking signals of thenerve.[0014] Figure 1A shows an eye, the cornea 20 andlayers of the cornea suitable for treatment in accordancewith embodiments. The eye comprises a cornea 22, aniris, a lens and a retina. The cornea and lens focus lighton the retina. The iris defines a pupil that passes lightrays, and the iris can open and close so as to adjust thepupil size in response to light so as to light to keep theamount of light striking the eye within tolerable amounts.The cornea comprises a transparent, dome-shapedstructure covering the iris and pupil. The cornea refractslight that enters the eye, and can provide approximatelytwo-thirds of the eye’s refractive power.[0015] The cornea 20 may comprise up to five layers,depending on the species. Starting on the first tissue sur-face of the cornea, the epithelium 22 comprises the sur-face layer of cells which provide a barrier function and asmooth surface for the tear film. The epithelium 22 com-prises basal columnar cells 22B, wing cells 22W dis-

posed over the basal cells and an outer squamous pro-tective layer 22S. Disposed under the epithelium, thesecond layer comprising Bowman’s membrane 24 com-prises a tough substantially collagenous layer disposedunder the epithelium. The Bowman’s membrane 24 ispresent in many species of primates, humans and at leastsome birds. The Bowman’s membrane may push swell-ing of the cornea posteriorly towards the retina. The thirdlayer comprising the stroma 26 comprises a substantiallycollagenous tissue layer composed of highly arrangedcollagen fibers. The stroma supports keratocytes, andforms the majority of the cornea. The fourth layer com-prising Descemet’s membrane 29 is an inner layer ofbasement membrane and plays an important role in thehealth of endothelial cells. The fifth layer comprises theendothelium 28, and the endothelium acts as a pump soas to regulate the liquid content of the cornea. The dryingof the cornea provided by the epithelium can preserveclarity of the cornea, for example the clarity of the stroma.The endothelial pumping of water from the cornea tomaintain the proper hydration and thickness of the eyeis often referred to as deturgescence. A figure similar toFigure 1A is a available on the world wide web at (ht-tp://www.aafp.org) Structure of the Cornea

Corneal Innervation

[0016] Figure 1B shows a side view nerves 30 of thecornea as in Fig. 1A, and Figure 1C shows a top view ofview nerves of the cornea as in Fig. 1B. The cornea com-prises a width across W of about 12 mm in the human,and a thickness T of about 550 um. The cornea is denselyinnervated, although the cornea is generally not vascu-larized. The nerves of the cornea can be located at adepth D within the cornea, for example a depth of about265 um, although the depth can vary. The nerves 30 ofthe cornea bifurcate at bifurcations 32. The nerves of thestroma and Bowman’s membrane comprise sheath 32Son each side of the bifurcation, and each of the nerves30 comprises sheath 32S that extends along the nerveon each side of the bifurcation. The sheath 32S of eachnerve can extend along the nerves throughout the stromaand Bowman’s membrane, such that the sheath 32S canextend upward into the epithelium. Radially-orientednerve bundles originating from the trigeminal nerve enterthe cornea through the sclera. The cornea comprisesnerve bundles. The nerve bundles are located substan-tially in the stroma and run parallel to the collagen bun-dles; the nerve bundles include nuclei of Schwann cells.The nerve bundles can be suitable for treatment so asto denervate the cornea and inhibit pain. As can be seenwith reference to Fig. 1C, the large nerve fibers enteringthe cornea run substantial in the 9-3 hours direction. Afterthe first bifurcation, they nerve fibers run in the 12-6 hoursdirection, and after the second bifurcation the nerves canrun in the 9-3 hours direction again. A figure similar toFigure 1C can be found in Muller-Architecture of HumanCornea p. 991 (Müller LJ, Vrensen GFJM, et al. Archi-

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tecture of human corneal nerves. (1997). Invest Ophthal-mol Vis Sci. 38:985-994, 991.)[0017] The cornea comprises regions that can be use-ful for treatment in accordance embodiments as de-scribed herein. For example the cornea may comprise aregion 40 suitable for treatment, and the region 40 maycomprise an inner portion 42 and an outer portion 44. Aregion outside region 40 may comprise an outer region46 of the cornea that can extend to the limbus. Treatmentof an outer region or portion can result in denervation ofthe corresponding inner region or portion of the cornea.[0018] Figure 1D shows a schematic illustration ofnerves 30 of the cornea as in Fig. 1C extending from thestroma through Bowman’s layer into the epithelium. This3D illustration shows penetration and the distribution ofstromal bundles into the basal plexus. The nerves 30comprise unmylenated nerve fibers 32UM, which canhave bifurcations substantially at right angles. The un-mylenated nerve fibers can comprise several straight32UMS and beaded fibers 32UMB. The beaded fiberscan bifurcate obliquely and turn upward between basalcells 22B to reach wing cells 22W of the epithelium 22.Upon passing through Bowman’s layer and into basallamina, the nerve bundles make a 90° turn and separateinto smaller bundles separate and single nerve fibers withnerve endings in the epithelium. The nerve endings orig-inate from myelinated A-δ and unmyelinated C-nerve fib-ers. The A-δ nerve fibers that reach the Bowman’s layerspread out below the basal epithelial cells. The C-nervefibers actually penetrate the epithelium layer. Due to theirsize, the majority of the nerve fibers in the cornea areclassified as C-nerve fibers. Further, some of the nervefibers are beaded, while others are not. The beadednerve fibers can turn upward, for example make the 90°turn, so as to penetrate to the level of the wing cells. Afigure similar to Figure 1 D is shown in Müller LJ, VrensenGFJM, et al. Architecture of human corneal nerves.(1997). Invest Ophthalmol Vis Sci. 38:985-994, 992.

Treatment of Corneal Pain

[0019] Figure 2A and 2B show treatment 100 of at leastan outer portion 44 of a region 40 of the cornea so as todenervate the cornea. An applicator 110 can be coupledto the cornea, for example placed against the cornea orpositioned so as to transmit to or receive energy from thecornea. The applicator 110 is configured to treat the cor-nea so as to denervate the cornea in accordance with adenervation treatment profile 120. The denervation treat-ment profile 120 may comprise an annular portion of theepithelium, Bowman’s membrane and the underlyingstroma to a depth of about 100 um. The profile 120 ofdenervated tissue can be determine in many ways, forexample with at least one of an amount of treatment, anintensity of treatment or a duration of treatment. The den-ervation treatment profile 120 can decrease sensitivityof a receptor field of the nerves. The receptor field withdecreased sensitivity comprises nerves of the treatment

profile can extend inward from the treatment profile, forexample extend centrally of the treatment profile 120.[0020] The ability of a patient to determine the sourceof pain within a receptor field, for example pain from no-cioceptors, may not be sufficiently resolved so as to lo-calize the pain spatially on the cornea, and the denerva-tion of the pain receptor field sensed by the patient canextend beyond the portions of the nerves treated withtreatment profile 120. For example, the treatment profile120 can also denervate the pain receptor field sensedby the patient outward from the treatment profile, for ex-ample peripheral to the treatment profile 120.[0021] Figures 2A1 and 2B1 shows denervation as inFigs. 2A and 2B, with treatment 100 such substantiallyapplied and localized to the epithelial layer of tissue, suchthat the denervation treatment profile 120 is localizedsubstantially to the epithelial layer 22. As the nerves ofthe epithelium, as shown above, can extend inward,treatment of the outer portion 44 of region 40 can den-ervate at the inner portion 42 of the region 40.[0022] Figures 2A2 and 2B2 shows treatment 100 asin Figs. 2A and 2B, with the denervation treatment profile120 substantially comprising the epithelial layer and ex-tending substantially into the stroma so as to encompassnerve bundles extending along the layers of the stroma.The nerve bundles may comprise deep nerve bundlessuch that treatment of the outer portion 42 denervatesthe inner portion 44 of the region.[0023] Figures 2A3 and 2B3 shows denervation as inFigs. 2A and 2B, with the denervation treatment profile120 localized substantially to the stroma so as to encom-pass nerve bundles. The denervation profile 120 can beobtained in many ways, for example with focused energy,such that the inner portion 42 of region 40 can be den-ervate with treatment to the outer portion 44 of region 40.[0024] Figures 2A4 and 2B4 shows denervation as inFigs. 2A and 2B, in which the an inner region is dener-vated with the outer region. The treatment 100 may com-prise a disc shaped applicator 110, such that the dener-vation treatment profile 120 comprises a substantially cir-cular portion of tissue that extends to along a cylindricalaxis to maximum depth of the tissue near the center ofthe treatment;[0025] Figures 2A5 and 2B5 shows denervation as inFigs. 2A and 2B, in which the an inner region is dener-vated with the outer region comprising a first outer regionand a second outer region. The treatment 100 may com-prise an applicator 110 a first portion 110A and a secondportion 110B, such that the denervation treatment profile120 comprises a first outer portion of tissue and as sec-ond outer portion of tissue. Many of the nerves extendinginto the cornea extend substantially nasal to temporaland temporal to nasal, such that a first outer portion 110Alocated on a first nasally disposed portion of the corneaand a second outer portion 110B disposed on a tempo-rally disposed portion of the cornea can treat the innerportion, for example the central portion.[0026] Figures 2C and shows an ablation 200 of cornea

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20 having an epithelial defect 220. The ablation 200 com-prises an ablation profile 210 that is shaped to correctionvision of the patient. The cornea is denervated in accord-ance with a denervation treatment profile 120. The den-ervation treatment profile 120 may comprise an annulardenervation treatment profile. Work in relation to embod-iments as described herein related to PRK suggests thatthe periphery of the debrided area corresponds to painof PRK patients, and treatment of the epithelium and cor-nea near the edge of the debrided area can attenuatepain in PRK patients. This suggests that perhaps little orno pain may emanates from the center of ablation profile210 the debrided area, such that treatment of the outerportion 44 of region 40 can be sufficient to inhibit painfrom the inner portion 42.[0027] The temporary depravation of nerve supply inaccordance with denervation profile 120 can be used tomitigate post-PRK and corneal pain, and may comprisethe temporary deprivation of a nerve supply. The cornealdenervation may last for a for a few days, and can includeone or more of stunning the corneal nerves, increasingthe threshold the corneal nerves, inhibiting the cornealnerve signals, or completely blocking the corneal nervesignals , so as to allow reduced pain when the epitheliumregenerates and until the epithelium heals.[0028] Work in relation to embodiments related to cor-neal pain suggests that it may be advantageous to causea temporary denervation of nerves at the edge and/orthe whole portion of the debrided area so as to reducepost-PRK pain. Similar denervation can be used with painoriginating from other traumatic, surgical or other causesof corneal surface disruption. The pain may originatefrom nerve endings at the wound edge or from the areaalong the periphery of the debrided area.[0029] In many embodiments as described herein, atleast the sheath 32S of each nerve remains substantiallyintact along the portions of the nerve extending throughthe stroma and Bowman’s membrane, such that thenerves can regenerate along the sheath so as to restoreenervation.[0030] Figures 2C1 shows denervation as in Fig. 2Cwith the denervation treatment profile 120 comprising theepithelium extending to the debridement and wherein thedenervation treatment profile is localized substantially tothe epithelium 22. As noted above, the treatment of theouter portion 44 can inhibit pain of the inner portion 42.[0031] Figures 2C2 shows denervation as in Fig. 2Cwith the denervation treatment profile 120 extending tonerve bundles disposed within the stroma and peripheralto the ablation. The denervation treatment profile 120may be localized to the stroma 26 in many ways, for ex-ample with focused energy, such that the inner portion42 is denervated with treatment of the outer portion 44.[0032] Figures 2C3 shows denervation as in Fig. 2Cwith the denervation treatment profile 120 extendingacross the ablation 200.[0033] The denervation treatment profile 120 can beused for denervation for mitigating pain after PRK, and

the denervation profile 120 may comprise one or moreof increasing nerve stimuli threshold, desensitizing thenerve with a desensitizing agent, stunning the nerve, sub-stantially inhibiting the corneal nerve signals, completelyblocking the corneal nerve signals, pruning the nerve orpruning the axons of the nerve without substantially prun-ing the sheath of the nerves.[0034] Figures 3A and 3B show the severing 300 ofaxons 32A disposed within a nerve such that sheath 32Sremains intact. The denervation treatment profile 120 canbe configured such that the nerve sheath remains intactwhen the axons are severed, as the threshold for sever-ing the axons of the nerve can be lower than the thresholdfor severing the sheath. The severing 300 of axons 32Aresults in dead portions 32D of the axons that are re-placed with regeneration of the axons 32A. The regen-eration occurs along a path 310 defined by the nervesheath. The severing of axons 32A may occur at manylocations of the cornea, for example location 350.[0035] Figures 3C and 3D show regeneration of theaxons along the sheaths subsequent to cleavage of theaxons as in Fig. 3A and 3B. The regeneration can occuralong the nerve sheath upwards through the stroma toone or more of Bowman’s membrane, the ablated sur-face, or the epithelium. As the regeneration can occuralong the path of the nerve sheath, the regenerated nervecan correspond substantially to the nerve conductionpath prior to severance of the axons.[0036] Figures 4A and 4B show the severing 400 ofthe nerve into an inner portion of the nerve 32I and anouter portion of the nerve 32O, such that the sheath ofthe inner portion 32I remains substantially aligned withthe outer portion 32O so that axons regenerate from theouter portion along the sheath of the inner portion. Whenthe nerve 30 is severed with sheath 32S, the axons 32Agrow toward the outer portion of the sheath 32O. Thedead portions 32D of the severed axons are replacedwith regeneration of the axons 32A along the sheath 32Sof the outer portion 32O.[0037] Figures 4C and 4D show regeneration of theaxons along the inner sheaths subsequent to cleavageof the nerves as in Fig. 4A and 4B. The axons 32A com-prise a regenerated portion 32R that extends along thesheath. Work in relation to embodiments suggests thatthe sheath 32S may also regenerate.[0038] Figures 5A shows an applicator 110 coupled tothe cornea to treat the cornea with a denervation treat-ment profile 110. The applicator 110 can be used to threatthe cornea before, during or after PRK, or combinationsthereof. Denervation for mitigating pain after PRK maybe achieved in many ways, and the denervation treat-ment profile 120 as described herein may encompassone or more of one or more of increasing nerve stimulithreshold, desensitizing the nerve with a desensitizingagent, stunning the nerve, destroying the nerve, pruningthe nerve or pruning the axons of the nerve without sub-stantially pruning the sheath of the nerves. The applicator110 can be configured for interaction 500 with the cornea,

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so as to transmit energy to the cornea, receive energyfrom the cornea, or deliver at least one substance to thecornea, or combinations thereof. For example, applicator110 can be configured to receive thermal energy fromthe cornea so as to cool the cornea to achieve denerva-tion treatment profile 120. Applicator 110 can be config-ured to heat the cornea, for example with light or electricalcurrent or heat conduction, so as to achieve derivationtreatment profile 120. Applicator 110 can be configuredto apply a substance to the cornea, for example a noxioussubstance such as capsaicin.

Stunning the Nerves:

[0039] Applicator 110 can be configured to stun thenerves in many ways. For example applicator 110 canbe configured to stun the cornea with cooling. Applicator110 may comprise an annular ring configuration whichcontacts the cornea at the outer portion 44 so as to coolthe cornea to a desired temperature profile. For examplean application for a given time can achieve a desiredeffect at desired depth within the cornea, so that nervesat different depths can be numbed selectively (depthwise). Alternatively, the applicator may comprise a discshaped flat surface such as the end of a cylindrical rodor a cooled contact lens, such that a disc shaped portionof the cornea comprising the outer portion 44 and theinner portion 42 of the region 40 is treated.[0040] Applicator 110 can be configured to treat thecornea with photodynamic treatment. For example, thenerves can be stained with nerve specific stains or dyessuch as horseradish peroxidase. Such molecules canattach to a molecule of the nerve for photodynamic acti-vation. The nerve and dye can be exposed to light so asto stun the nerve. The irradiation may comprise selectivelocal, for example ring shaped, photo therapy which willstimulate the molecule to cause local damage to nerveswith minimal effect on surrounding tissue. For examplethe ring may comprise outer region 44 stained and treatedwith light so as to denervate inner region 42 with minimaleffect on inner region 42. The applicator 110 may com-prise one or more optical elements, such as lenses,prisms, mirrors so as to form a ring of light on the cornea.[0041] The nerves may be stunned with cooling, andapplicator 110 can be configured to cool the cornea. Forexample, at least the peripheral portion of the region canbe treated with a coolant, for example chilled BSS at 8°Cused for 3 minutes before ablation, and the cornea maybe cooled a ring during the ablation. The cornea was alsocooled post-PRK, to lessen pain. Work in relation to em-bodiments suggests that -4°C is threshold temperaturewhere damage to mammalian cells occurs, and coolingwithin a range from about -8 to about 5-6°C for a durationcan provide a transient interruption of nerve conduction,with full return of function within about 12 days. The cool-ing with treatment profile 120 can denervate the nerveswithout substantial damage to the endothelial layer ofcells.

[0042] The nerves may be stunned so as to providetransient local desensitization. The stunning may com-prise nerve damage in which there is no disruption of thenerve or its sheath. In this case there is an interruptionin conduction of the impulse down the nerve fiber, andrecovery takes place without true regeneration of thenerve fiber. This modified neurapraxia may comprise amild form of nerve injury, for example a biochemical le-sion caused by concussion or shock-like injuries to thefiber. The applicator 110 can be configured so as to pro-vide compression or relatively mild, blunt blows, includingsome low-velocity missile injuries close to the nerve. Themodified neurapraxia stunning may provide be a tempo-rary loss of function which is reversible within hours tomonths of the injury (the average is 6-8 weeks).

Destroying of Portions of Nerves

[0043] The nerves may be pruned, such that the endportions of the nerves are destroyed, for example bypruning of the nerve at an intermediate location such thatthe distal portion of the nerve is killed. The killing of thedistal portion of the nerve may comprise severing axonsof the nerve, and the sheath may remain intact wherethe axons are cut or may also be severed, both of whichare shown above.[0044] The nerves may be pruned mechanically. Forexample, the nerve may be cut. The nerve may be cut inmany ways. For example, applicator 110 may comprisea trephine to cut the cornea at the outer portion 44 to thedesired depth. The trephination may comprise a periph-eral cut to specific depth. The cut can be done as super-ficial as reaching Bowman’s layer, or can be farther intothe cornea. The mechanical pruning may comprise lasercutting of the cornea, for example with pulsed laser cut-ting such as a known commercially available femto sec-ond pulsed laser. The denervation treatment profile 120may comprise laser cutting at with an interior cut at aspecific depth, for example in the epithelium or the stromaor both, as described above.[0045] The nerves may be pruned thermally, for exam-ple with thermal heating treatment. Applicator 110 canbe configured to prune the nerves thermally. The thermaltreatment may comprise heating the cornea to obtain thedenervation treatment profile 120. The heating may com-prise radiofrequency (hereinafter "RF") heating. The ra-diofrequency heating may comprise one or more of lowvoltage, high current, desiccation of corneal nerve tissue,denaturing of corneal nerve tissue, or destroying cornealnerve tissue. The RF heating may comprise one or morefrequencies within a range from about 1 kHz to about 1GHz, for example within a range from about 10 kHz toabout 100 MHz. The heating may comprise high voltagewith low current, for example so as to produce sparks.The nerves may also be pruned with plasma, for exampleplasma from sparks.[0046] The nerves may be pruned with cooling. Forexample, applicator 110 may comprise a ring configura-

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tion which is cooled to a desired temperature. The ringat an intended temperature can be applied for a prede-termined amount of time so as to achieve an effect at aspecific depth with denervation treatment profile 120, sothat nerves at different depths can be numbed selectively(depth wise). The applicator 110 may comprise a wholeplate or a contact lens configuration.[0047] The applicator 110 can be configured with cry-ogenic processing, for example -10°C or below. The cool-ing induced degeneration can preserve nerve sheathwhen axons are severed, as described above, and thusallow restoration of nerve activity within days so to allowpainless period during epithelium healing period. For ex-ample, the nerve can be frozen to a temperature whichcauses internal nerve damage while preserving the nervesheath. This freezing can be done locally, for examplering shaped to the outer portion of the region 44, and theduration and the temperature of applicator can be deter-mined prior to treatment with the applicator 110 so as toobtain the desired effect at specific areas and depths andto specific nerve layers with the denervation treatmentprofile 110.[0048] The nerves may be pruned with photodynamictreatment, and applicator 110 can be configured to de-liver a combination of photosensitizing dye and light en-ergy to generate denervation treatment profile 110, andthe profile can be selective to nerves when the dye isselectively attached to the axons, for example receptorsof channels. Selective photodynamic injury, for examplethe uptake of specific dye by nerves and excitation atspecific wavelength can severe at least the axons, andmay sever the sheath, depending on the amount of dyeand intensity of light treatment.[0049] The nerves may be pruned with ultrasound, andapplicator 110 can be configured to deliver the ultrasoundenergy so as to generate the denervation treatment pro-file 120. The ultrasound may comprise shock waves tothe target tissue and applicator 110 may comprise lithot-ripsy circuitry and transducers modified for treatment ofthe cornea.[0050] Based on the teachings described herein, a per-son of ordinary skill in the art can conduct experimentsto determine empirically parameters of applicator 110,so as to denervate the cornea with treatment profile 120.Such as person will also recognize, applicator 110 andthe use thereof can be adjusted so as to stun the nervessimilar to the above configurations that can be used toprune the nerves. Similarly applicator 110 can be config-ured such that denervation treatment profile 120 com-prises regions of stunned nerves and regions of prunednerves, and a person of ordinary skill in the art will rec-ognize such variations and combinations based on theteachings described herein.[0051] Figures 5B shows an applicator 110 as in Fig.5A comprising a channel 520 to receive a liquid to den-ervate the nerves. The liquid may comprise a warm liquidto heat the cornea or a cool liquid to cool the cornea.[0052] Figures 5C shows an applicator as in Fig. 5A

comprising a trephine 530 configured with the flange 532to denervate the nerves within a predetermined depth534. The nerves may be stunned, the axons severed andthe sheath intact, or the axons and sheath severed, asdescribed above based on the target nerves and depth534.[0053] Figures 5D shows an applicator 110 as in Fig.5A comprising an optical component 540 to deliver light542 to the cornea. The light 542 can be focused to adesired treatment location and can be scanned to pro-duce the denervation treatment profile 120.[0054] Figures 5E shows an applicator 110 as in Fig.5A comprising an insulator 552 and at least one electrode550 to deliver electrical energy to the cornea outer portionof the cornea disposed peripheral to the inner portion,for example central portion.[0055] Figure 5E1 shows an applicator as in Fig. 5Acomprising at least two electrodes 556 to deliver electri-cal energy to the cornea. The applicator may comprisean electrode structure with the at least two electrodesshaped to define the treatment profile. For example, theelectrode may comprise an arcuate shape with the elec-trodes spaced apart by a distance so as to define thetreatment profile. The at least two electrodes can be ar-ranged in many ways to deliver RF electrical energy inaccordance with the treatment profile 120. The at leasttwo electrodes may comprise bipolar electrodes, for ex-ample. The insulator 552, for example a dielectric mate-rial, can extend between the electrodes to define thetreatment profile 120 with the spacing of the electrodes.The electrode spacing and energy to the electrodes canbe configured such that there is no substantial damageto endothelial cells with treatment profile 120 to dener-vate the nerves.[0056] Figure 5E2 shows an applicator as in Fig. 5Acomprising at least two electrodes 556 to deliver electri-cal energy to the cornea with a first nasal portion 550Aof the applicator and a second temporal portion 550B ofthe applicator. When the first portion and second portionare substantially symmetrical, the applicator can be usedon either eye, such that the nasal portion 550A can beused on the temporal portion of the opposite eye and thetemporal portion 550B can be used on the nasal portionof the eye.[0057] Figures 5E3A and 5E3B show an applicator asin Fig. 5E2 positioned on a cornea so as to define treat-ment profile 120 with the electrode fields 556E from thespacing of the at least two electrodes 556 and the profileof RF pulses. The electrodes can be spaced in manyways to achieve the desired depth penetration into tissue.[0058] Figures 5E4 shows circuitry 557 coupled to atleast two electrodes 556 of applicator 110 so as to gen-erate the profiled RF pulses and treatment profile. Theelectrodes can be coupled to the circuitry in many ways,for example with a flexible cable 558.[0059] Figures 5E5 shows RF pulses of the circuitry.The circuitry is configured to deliver short pulses of RFenergy with a low duty cycle so as to inhibit heating of

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tissue. The RF energy is within a range from about 1 kHzto about 1 GHz, for example from about 10 kHz to about100 MHz. Each pulse comprises a duration τ, and thepulses are separated by a delay Δ, such the waveformcomprises a period T. The frequency of the RF energycorresponds to many oscillations of the electric field perpulse. The duration of the pulse is from about 0.2 ms toabout 200 ms, and the frequency can be from about 50kHz to about 5 MHz. The duty cycle is no more than about10%, for example no more than about 5%, even 2% soas to inhibit heating of the tissue. For example, the pulseduration can be about 20 ms, and the delay betweenpulses about 48 ms, such that the pulses are deliveredat about 2 Hz.[0060] Work in relation to embodiments suggests thatthe electric field can produce sustained denervation with-out substantially heating of the nerve. A person of ordi-nary skill in the art can conduct experiments appropriateelectrode spacing, pulse duration, frequency and dutycycle based on the teachings describe herein so as todenervate the nerve without substantial heating of thenerve with treatment profile 120. Alternatively, the nervemay be heated with the electric field and current so asto form a lesion, and a person of ordinary skill in the artcan conduct similar experiments to determine appropri-ate parameters.[0061] Figure 5F shows an applicator as in Fig. 5Acomprising at least one transducer to deliver energy tothe cornea.[0062] Figures 5F shows an applicator 110 as in Fig.5A comprising a housing 560 and at least one transducer562 to deliver energy 564 to the cornea, for example ul-trasound energy. For example, the transducer 562 maycomprise ultrasound energy for sonoporation of one ormore of the corneal nerves or the corneal epithelium soas to deliver the substance as described herein.[0063] Figures 6A to 6C show an applicator 110 as inFig. 5A comprising a heat conduction apparatus 600 toconduct heat to or from the cornea. For example, appa-ratus 600 can be heated prior to application so as to heatthe cornea. Alternatively, apparatus 600 can be cooledprior to application so as to cool the cornea. Apparatus600 comprises a handle 620 and an annular portion 620to contact the cornea along an annular region of the cor-nea, such as outer portion 44. Apparatus 600 may com-prise a metal with high heat capacity and conduction tocool the cornea. Apparatus 600 can be cooled to an in-tended temperature prior to placement, and can beplaced on the cornea for an intended duration, such thatthe cornea is cooled with a targeted denervation treat-ment profile 120. The inner portion of the distal portionof the applicator can be shaped to inhibit contact with thecornea centrally when the end contacts the cornea atouter portion 42. The applicator 600 may be placedagainst a sphere having a radius of curvature corre-sponding to the cornea, for example a 7.94 mm radiusof curvature.[0064] Figures 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.[0065] Figure 7A shows an applicator 110 as in Fig.5A comprising an apparatus 700 configured to deliver asubstance 700S as described herein to an outer portionof the cornea. The apparatus 700 may comprise an outerportion 710 having the substance 700S disposed thereonand an inner portion 720, which inner portion may com-prise an opening or a portion of a substrate substantiallywithout the substance.[0066] Figures 7A1 and 7A2 shows an applicator 110as in Fig. 5A comprising apparatus 700 with outer portion710 comprising an annular ring with the substance 700Sdisposed thereon to deliver the substance to the outerportion of the cornea. The outer portion 710 may definean inner aperture 710A, and a handle may extend fromthe outer portion.[0067] Figures 7A3 shows the substance coated on asupport 702 along outer portion 710 so as to deliver thesubstance to the outer portion of the cornea.[0068] Figures 7A4 shows an applicator 110 with achannel 720 to deliver the substance 700S to the outerportion of the region cornea and a wall structure 722 toinhibit release of the substance. The applicator may com-prise a foam portion 724 disposed therein to retain theliquid in the channel. Alternatively or in combination, athin porous membrane can be disposed on the lower por-tion to the applicator to release the substance to the cor-nea. The apparatus may comprise a luer connector toconnect the applicator to an injection apparatus 728.[0069] Figures 7A5 and 7A6 show top and side andviews, respectively, of applicator 700 in which the appli-cator comprises micro-needles 716 to deliver the sub-stance 700S to outer portion of the cornea. The sub-stance can be coated on the micro-needles, for example.Alternatively or in combination, the substance can be in-jected with the micro-needles. The micro-needles maycomprise a length extending from a base located at thesupport to a tip, and the length can be sized to deliverthe substance to a target location. For example, thelength of the micro-needles may comprise no more thanabout 50 um to deliver the substance to the epithelium.Alternatively, the micro-needles may comprise a greaterlength to extend into the stroma.[0070] Figure 7A7 shows applicator 700 comprising acompartment 718 with the substance 700S disposedtherein to deliver the substance to the outer portion ofthe cornea. The substance 700S can be contained in thecompartment as a liquid, for example a liquid having aconcentration of the substance. A porous membrane 719can extend on toward the outer region of the cornea todeliver the substance. The compartment 718 may com-prise an annular compartment. A wall can extend sub-stantially around an inner perimeter of the compartmentand an outer perimeter of the compartment. For example,the wall can extend around outer perimeter of an annulusand the inner perimeter of the with an annular portionextending therebetween along an upper surface, with the

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porous membrane 719 disposed along the lower surface.[0071] Figure 7B shows an applicator as in Fig. 5A todeliver a substance to an inner portion of the cornea. Theapplicator 740 comprises an inner portion 742 having thesubstance disposed thereon. The applicator comprisesan outer portion 744 substantially without the substance.The applicator 740 can be applied to the epithelium be-fore PRK over the intended ablation zone. Alternatively,the applicator 740 can be applied to the ablated stromaafter ablation with direct applicator to ablated nerve con-tact, for example with direct contact of a noxious sub-stance such as comprising capsaicin to nerve comprisinga cation channel which mediates stimuli.[0072] Figure 7C shows an apparatus 750 comprisingapplicators as in Figs. 7A and 7B to deliver an inner sub-stance to the inner portion and an outer substance to theouter portion of the region of the cornea to denervate thecornea. The apparatus 750 comprises an inner applicator752 to apply an inner substance to the inner region andan outer applicator 754 to apply an outer substance tothe outer region. Work in relation to embodiments sug-gests that such combination of substances can be ben-eficial to obtain the denervation treatment profile as de-scribed herein. For example, the substance of the innerportion may comprise a noxious substance such as cap-saicin or a capsaicin analog, and the outer portion maycomprise an anesthetic such as a calcium channel block-er. Alternatively, the substance of the outer portion maycomprise the noxious substance such as capsaicin or acapsaicin analog, and the inner portion may comprisethe anesthetic such as a calcium channel blocker. Thisseparation of the calcium channel agonist from the cal-cium channel blocker can allow the agonist to effect thenerves substantially without inhibition from the calciumchannel blocker.[0073] The inner applicator 752 may be applied to thecornea before the outer applicator 754. Alternatively, theouter applicator can be applied to the cornea before theinner applicator. For example the outer applicator 754can be applied to cornea with an anesthetic comprisinga calcium channel blocker before the inner applicator 752is applied. The outer applicator 754 comprising the cal-cium channel blocker can be removed when a sufficientamount of calcium channel blocker has been deliveredto the cornea. The inner applicator 752 comprising thenoxious substance, for example a calcium channel ago-nist such as capsaicin, can be applied to cornea to re-lease the agonist to the inner portion without substantialinhibition from the blocker that has been previously ap-plied to the outer region. The inner applicator 752 canthen be removed. The eye may then be ablated with PRK.[0074] Figure 7D shows an apparatus 760 to deliver afirst substance to the inner portion 42 and the outer por-tion 44 of the region of the cornea to denervate the cor-nea. Figure 7E shows a side view of an applicator as inFig. 7A. Apparatus 760 comprise an inner portion 762with a first substance disposed thereon and an outer por-tion 764 with second substance disposed thereon. The

first substance of inner portion 762 may comprise a nox-ious substances such as a calcium channel agonist suchas a capsaicin and the second substance of the outerportion 764 may comprise a calcium channel blocker an-esthetic. Alternatively, the first substance of inner portion762 may comprise may comprise a calcium channelblocker anesthetic and the second substance of the outerportion 764 may comprise a noxious substances suchas a calcium channel agonist such as a capsaicin.[0075] A person of ordinary skill in the art can conductexperiments to determine empirically the inner or outerlocation of the noxious substance comprising the calciumchannel agonist such as capsaicin and the inner or outerlocation of the anesthetic comprising the calcium channelblocker, and also the concentration of the first and secondsubstances and duration of application.[0076] The first and second substances may be coatedon the inner and outer portions of the substrate with anamount per unit area.

DESENSITIZING AGENTS

[0077] The desensitizing agent as described hereincan be delivered in accordance with treatment profile 120so as to denervate the target tissue, for example the cor-nea, for a plurality of days. As the substance is deliveredin accordance with the treatment profile 120, the amountof desensitizing agent delivered to the target tissue canbe increased substantially to achieve the desired amountof desensitization. The desensitizing agent may com-prise one or more of a noxious substance, a chemical,or a neurotoxin. The desensitizing agent may compriseBotulinum A toxin. The Botulinum A toxin may compriseone or more serotypes of Botulinum toxin such as Botu-linum type A, Botulinum type B. For example, the sub-stance may comprise Botulinum Toxin Type, commer-cially available as Botox(R), delivered in accordance withthe treatment profile 120 so as to treat the target tissuesafely. The Botulinum toxin may comprise one or moreof a heavy chain or a light chain of the toxin. The sub-stance may act upon a receptor of the corneal nerves,such as one or more of a sodium channel blocking com-pound, or a potassium channel blocking compound. Forexample the substance may bind to and activate the tran-sient potentially vanilloid receptor.[0078] The substance may comprise a neurotoxin,such as a pharmaceutically acceptable composition of along-acting sodium channel blocking compound, in whichsaid compound binds to the extracellular mouth of thesodium channel, occluding the channel by a mechanismseparate from that of local anesthetics, such as propa-racaine. The substance may comprise a toxins or ana-logs thereof that specifically bind to a site formed in partby an extracellular region of the alpha subunit of a sodiumchannel. For example, the substance may comprise theclass of toxins and analogs that specifically bind to a siteformed by the SS1 and SS2 extracellular regions of thealpha subunit of a sodium channel. The substance may

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comprise on or more of tetrodotoxin, saxitoxin and ana-logs thereof.[0079] The transient receptor potential vanilloid-1(TRPV1) is a capsaicin-responsive ligand-gated cationchannel selectively expressed on small, unmyelinatedperipheral nerve fibers (cutaneous nociceptors). WhenTRPV1 is activated by agonists such as capsaicin andother factors such as heat and acidosis, calcium entersthe cell and pain signals are initiated. After disease orinjury, cutaneous nociceptors may become persistentlyhyperactive, spontaneously transmitting excessive painsignals to the spinal cord in the absence of painful stimuli,resulting in various types of pain. When TRPV1 is con-tinuously activated through prolonged exposure to an ag-onist (e. g., capsaicin), excessive calcium enters thenerve fiber, initiating processes that result in long-termyet reversible impairment of nociceptor function. The ap-plication of capsaicin can provide relief from pain withthis mechanism.[0080] Figure 8A shows the chemical structure of Cap-saicin.[0081] The substance comprising desensitizationagent may comprise a substantially hydrophobic and li-pophilic substance such as Capsaicin. When deliveredto the surface of the epithelium as described above, thehydrophobic Capsaicin can be substantially localized tothe epithelium, with treatment profile 120 as describedabove. For example, the elevated concentration of Cap-saicin may be localized to the epithelium near the edgeof a debridement of the epithelium.[0082] Capsaicin may comprise a purified extract fromchili peppers (Genus Capsicum). Capsaicin comprisesan odorless, flavorless, lipophilic substance. Capsaicinis a capsaicinoid, a family of chemicals found in thesepeppers which can induce the feeling of heat upon in-gestion.[0083] Figure 8B shows Vanilloid Receptor 1 (VR1) re-ceptor, which comprises a Capsaicin receptor suitablefor use with a denervating substance. VR1 receptors arefound in the peripheral neurons in the skin and cornea,for example Aδ and C fibers. The primary receptors havesomata in the dorsal root ganglion and the trigeminal gan-glion. The VR1 receptor comprises a non selective cationchannel which mediates stimuli from both chemical andphysical triggers, including heat, low pH, capsaicin andsome chemical biproducts from inflammation. As capsa-icin is lipophilic, the binding site for capsaicin can be in-side or outside of the cell membrane.[0084] Capsaicin can induce a feeling of pain. Capsa-icin binds to nociceptors, which stimulate afferent thinly-myelinated Aδ and un-myelinated C fibers. When theVR1 receptor is not activated, the VR1 receptor remainsclosed. Upon activation, for example with capsaicin bind-ing, the VR1 channel opens. Since the VR1 receptor isa non-selective cation channel, when capsaicin binds,positive ions, for example calcium, can flow into the axonsand dendrites of the neurons. The substantial effect ofthe opening of the channel of the VR1 receptor is an influx

of calcium ions, resulting in a depolarization. This depo-larization can eventually induce an action potential.When the neurons containing these receptors are stim-ulated, the neurons release a neurotransmitter, sub-stance P. Substance P can communicate a messageeventually perceived as an itch, burning sensation, orpain, for example with release of substance P (SP) intothe cornea.[0085] Figure 8C desensitization with Capsaicin andmechanisms of desensitization. Desensitization withCapsaicin may comprise functional desensitization orpharmacological desensitization or both. Functional de-sensitization comprises the eventual reduction or loss ofresponsiveness of the neuron to other stimuli. Pharma-cological desensitization comprises the progressive de-cline in the size of subsequent responses to capsaicinafter prolonged or repeated exposures.[0086] Capsaicin can cause desensitization via multi-ple mechanisms. At least one mechanism involves thecalcium dependent activation of a protein phosphatasecalled calcineurin, which is mainly associated with acti-vating the T cell immune response. Capsaicin activationof the VR1 receptor can induce an increase in the intra-cellular calcium concentration. This increase in calciumions stimulates calcineurin, causing the calcium-depend-ent dephosphorylation of various proteins, ion channels,and enzymes. The dephosphorylation of one of cal-cineurin’s protein targets can result in a functional de-sensitizing effect.[0087] Capsaicin comprises a TRPV1 agonist, that canbe administered locally to the site of pain, for example tothe cornea. Two substantial types of pain sensing nervesare C-fiber neurons and A-delta neurons, for example ofthe cornea as described above. Long-lasting "noxiouspain" can be transmitted in the body by C-fiber neuronsand is associated with longer-term, dull, aching, throb-bing pain. In contrast, A-fiber neurons can transmit im-mediate "adaptive pain," such as that experienced milli-seconds after the slamming fingers in a door or aftertouching a hot surface. Capsaicin acts on TRPV-1 recep-tors expressed most densely in C-fiber neurons. TheseC-fiber neurons transmit long-term pain signal to thebrain, and Capsaicin acts as a TRPV-1 agonist so as tobind these pain receptors and open the calcium ion chan-nels as described above.[0088] After initial stimulation with Capsaicin, desensi-tization of the TRPV-1 receptors blocks noxious pain.This desensitization leads to a prolonged, reversible andlocalized desensitization of the pain fibers.[0089] 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.[0090] Capsaicin comprises a high safety profile suit-able for use with refractive surgery such as PRK.[0091] Because Capsaicin acts primarily on C-fiberneurons, Capsaicin may not to have an adverse effecton normal sensation such as temperature or touch, de-pending upon the dose based on the teachings as de-

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scribed herein.[0092] Figure 8D shows neural channels sensitive toCapsaicin and afferent transmission of acute pain to thecentral nervous system (hereinafter "CNS") and efferenttransmission neurogenic inflammation to the cornea. TheCapsaicin can trigger the release from the neuron of oneor more of substance P (SP), adenosine triphosphate(ATP) or calcitonin gene-related peptide (CGRP). In atleast some embodiments, the Capsaicin can be appliedto the epithelium to trigger the release of one or moreneuropeptides such as SP or CGRP and the epitheliumremoved, for example scraped away, so as to removethe neuropeptide with the epithelium.[0093] Capsaicin can be used for PRK. For example,the release of Capsaicin can be controlled with an appli-cator as described above. The controlled release maycomprise one or more of a quantity of release, a rate ofrelease, region of release such as to an inner portion ofthe cornea or an outer portion of the cornea, or both theinner portion and the outer portion. The quantity of cap-saicin may be determined with concentration of Capsa-icin applied to the cornea for an amount of time. For ex-ample, the covering, or shield, as described herein canbe provided with Capsaicin coated thereon for acceler-ated release and delivery of fixed amount of Capsaicinto a target location on the eye with the covering.

INHIBITION OF PAIN WITH POST-OP ANESTHETIC

[0094] Figure 9 shows a method of treatment 900 witha covering 910 positioned on the eye over an epithelialdefect so as to inhibit delivery of an anesthetic to theepithelial defect when the covering conforms to a bound-ary of the epithelium and the defect and seals the cornea.The cornea 20 may ablated with PRK and the covering910 positioned over the ablation. The covering may com-prise a soft portion that conforms to the epithelium so asto seal the cornea. For example, the covering 910 maycomprise a conformable covering as described in USApp. No. 12/384,659 filed 04/06/2009, entitled "Thera-peutic Device for Pain Management and Vision," An an-esthetic, for example that alters function of calcium re-lease channels, can be applied 922 to the cornea with adrop 920. The drop of anesthetic spreads over the tearfilm of the eye. A the shield 920 conforms to the edge ofthe epithelium that defines the epithelial defect, the cor-nea is substantially sealed to inhibit swelling. The dropof anesthetic is absorbed preferentially by the epitheliumaway from the covering at location 924, as the covering910 can inhibit penetration of the anesthetic to the cor-nea. The anesthetic can treat the nerves of the corneaperipheral to the epithelial defect to inhibit pain and soas to inhibit effect of the anesthetic on the regeneratingepithelium near the defect, such that re-epithelializationis not delayed substantially with application of the anes-thetic.[0095] Figure 10 shows a method 1000 of treating aneye of a patient. A step 1005 provides an eye, for example

as described above. A step 1010 defines a region of theeye comprising an inner portion and an outer portion, forexample as described above. A step 1015 applies a top-ical anesthetic, for example as described above. A step1020 denervates one or of the outer portion of the innerportion with a delivery profile, for example as describedabove. A step 1025 removes the epithelium from the innerportion, for example as described above. A step 1030ablates the inner portion with a laser beam, for examplean excimer laser PRK as described above. A step 1035provides a covering for the eye, for example a siliconeshield with a wettable upper coating as described above.A step 1040 places the covering on the eye, for examplewhen the eye is dry, such that the covering conforms tothe epithelium so as to seal the cornea. A step 1045 re-generates the epithelium under the covering. A step 1050applies a topical anesthetic to the eye, for example withdrops, when the covering is sealed to the epithelium soas to inhibit delivery of the anesthetic to the epithelialdefect and the regenerating epithelium near the defect.A step 1055 inhibits the deliver of anesthetic over thedefect, for example with the covering and the seal, suchthat the anesthetic penetrates the epithelium near thelimbus and so as to denervate the nerve bundle disposedin the stroma and denervate the inner portion of the ab-lated region of the cornea. A step 1060 regenerates theepithelium under the covering to cover the ablated stro-mal tissue and close the epithelial defect. A step 1065removes the covering.

Experimental

[0096] Based on the teachings described herein, a per-son of ordinary skill in the art can conduct experimentsto determine empirically the parameters to denervate thecornea to decrease pain, for example pain following PRK.[0097] Figure 11 shows experimental cooling data andprofiles of corneal temperature at depths. For example,the cooling apparatus as described above can be chilledto a temperature such as 0 degrees C, or - 70 degreesC. The apparatus can be contacted to the cornea to de-termine the temperature of the cornea as a function oftime and depth. For example, a 0 degree C probe canbe placed on the cornea and the temperature of the eyedetermined over time at depths of 200, 400 and 600 mi-crons. A -20 degree C probe can be placed on the corneaand the temperature of the eye determined over time atdepths of 200, 400 and 600 microns. A -70 degree Cprobe can be placed on the cornea and the temperatureof the eye determined over time at depths of 200, 400and 600 microns. The temperature can be determinedexperimentally, or can be modeled with finite elementanalysis and non corneal heat transfer parameters, or acombination thereof. The denervation treatment profilecan be determined, and the parameters adjusted suchthat pain is inhibited and also such that corneal innerva-tion is restored after reepithelialization.[0098] Similar studies can be conducted with heat,

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substances, ultrasound, light, photodynamic therapy andcutting as described herein.[0099] While the exemplary embodiments have beendescribed in some detail, by way of example and for clar-ity of understanding, those of skill in the art will recognizethat a variety of modifications, adaptations, and changesmay be employed. Hence, the scope of the present in-vention should be limited solely by the appended claims.

Claims

1. An apparatus to treat a cornea (20) of an eye, thecornea having an epithelium, an inner portion (42)and an outer portion (44) radially disposed outwardof the inner portion (42), the apparatus comprisingan applicator (110), wherein:

the applicator (110) is shaped to contact at leastthe outer portion (44) of the cornea (20);the applicator (110) is configured to stun or severthe nerves (30) of the outer portion (44) of thecornea (20) to denervate the nerves (30) of theouter portion (44) of the cornea (20) extendinginto the inner portion (42) of the cornea (20) andinhibit pain of the inner portion (42) of the cornea(20), wherein the applicator is in the shape of anannular ring comprising an insulator and at leasttwo annular, spaced apart, arcuate, bipolar elec-trodes within the annular ring; andcircuitry coupled to the at least two bipolar elec-trodes to define a treatment profile with an elec-tric field disposed between the at least two bi-polar electrodes to, wherein the circuitry is con-figured to deliver pulses of RF energy to dener-vate the outer portion (44) of the cornea (20)with the electrical field applied to the nerves (30),characterised in that the circuitry is further con-figured to deliver pulses of RF energy at a fre-quency within a range from 1 kHz to 1 GHz, apulse duration within a range from 0.2 ms to 200ms, and a duty cycle of no more than 10%.

2. The apparatus of claim 1, wherein the circuitry isfurther configured to deliver pulses of the RF energyat a frequency within a range from 10 kHz to 100MHz, or within a range from 50 kHz to 5 MHz.

3. The apparatus of either claim 1 or claim 2, whereinthe circuitry is further configured to deliver pulses ofthe RF energy at a duty cycle of no more than 5%,or of no more than 2%.

Patentansprüche

1. Apparat zur Behandlung einer Hornhaut (20) von ei-nem Auge, wobei die Hornhaut Folgendes aufweist:

ein Epithel, einen inneren Teil (42) und einen äuße-ren Teil (44), der vom inneren Teil (42) radial nachaußen angeordnet ist, wobei der Apparat einen Ap-plikator (110) umfasst, wobei:

der Applikator (110) zum Kontaktieren von min-destens dem äußeren Teil (44) der Hornhaut(20) geformt ist;der Applikator (110) zum Betäuben oder Durch-trennen der Nerven (30) des äußeren Teils (44)der Hornhaut (20) konfiguriert ist, um die Nerven(30) des äußeren Teils (44) der Hornhaut (20),die in den inneren Teil (42) der Hornhaut (20)verlaufen, zu denervieren und die Schmerzendes inneren Teils (42) der Hornhaut (20) zu in-hibieren, wobei der Applikator in der Form einesanulären Rings vorliegt, umfassend einen Iso-lator und mindestens zwei anuläre, mit Zwi-schenraum angeordnete, gebogene, bipolareElektroden in dem anulären Ring; undeine an die mindestens zwei bipolaren Elektro-den gekoppelte Schaltungsanordnung zum De-finieren eines Behandlungsprofils mit einemelektrischen Feld, das sich zwischen den min-destens zwei bipolaren Elektroden befindet, wo-bei die Schaltungsanordnung zur Abgabe vonRF-Energieimpulsen zum Denervieren des äu-ßeren Teils (44) der Hornhaut (20) konfiguriertist, wobei das elektrische Feld auf die Nerven(30) aufgebracht wird, dadurch gekennzeich-net, dass die Schaltungsanordnung weiter zurAbgabe von RF-Energieimpulsen bei einer Fre-quenz in einem Bereich von 1 kHz bis 1 GHz,einer Impulsdauer in einem Bereich von 0,2 msbis 200 ms und einem Arbeitszyklus von nichtmehr als 10 % konfiguriert ist.

2. Apparat nach Anspruch 1, wobei die Schaltungsan-ordnung weiter zur Abgabe von RF-Energieimpul-sen bei einer Frequenz in einem Bereich von 10 kHzbis 100 MHz oder in einem Bereich von 50 kHz bis5 MHz konfiguriert ist.

3. Apparat nach entweder Anspruch 1 oder Anspruch2, wobei die Schaltungsanordnung weiter zur Abga-be von RF-Energieimpulsen bei einem Arbeitszyklusvon nicht mehr als 5 % oder nicht mehr als 2 % kon-figuriert ist.

Revendications

1. Appareil pour traiter la cornée (20) d’un oeil, la cor-née ayant un épithélium, une partie interne (42) etune partie externe (44) disposée radialement versl’extérieur de la partie interne (42), l’appareil com-prenant un applicateur (110), dans lequel :

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l’applicateur (110) est façonné pour entrer encontact avec au moins la partie externe (44) dela cornée (20) ;l’applicateur (110) est configuré pour désensi-biliser ou trancher les nerfs (30) de la partie ex-terne (44) de la cornée (20) pour énerver lesnerfs (30) de la partie externe (44) de la cornée(20) s’étendant jusque dans la partie interne (42)de la cornée (20) et inhiber la douleur de la partieinterne (42) de la cornée (20), dans lequel l’ap-plicateur est sous la forme d’une bague annu-laire comprenant un isolant et au moins deuxélectrodes bipolaires, annulaires, arciformes,écartées l’une de l’autre au sein de la bagueannulaire ; etune circuiterie couplée aux au moins deux élec-trodes bipolaires pour définir un profil de traite-ment avec un champ électrique disposé entreles au moins deux électrodes bipolaires, danslequel la circuiterie est configurée pour distri-buer des impulsions d’énergie RF pour énerverla partie externe (44) de la cornée (20) avec lechamp électrique appliqué sur les nerfs (30),caractérisé en ce que la circuiterie est confi-gurée en outre pour distribuer des impulsionsd’énergie RF à une fréquence comprise dansune plage de 1 kHz à 1 GHz, une durée d’im-pulsion comprise dans une plage de 0,2 ms à200 ms, et un cycle de service de pas plus de10 %.

2. Appareil de la revendication 1, dans lequel la circui-terie est configurée en outre pour distribuer des im-pulsions de l’énergie RF à une fréquence comprisedans une plage de 10 kHz à 100 MHz, ou dans uneplage de 50 kHz à 5 MHz.

3. Appareil soit de la revendication 1 ou de la revendi-cation 2, dans lequel la circuiterie est configurée enoutre pour distribuer des impulsions de l’énergie RFà un cycle de service de pas plus de 5 %, ou de pasplus de 2 %.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the Europeanpatent document. Even though great care has been taken in compiling the references, errors or omissions cannot beexcluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 4381007 A [0003]• WO 9207617 A [0005]

• US 12384659 B [0094]

Non-patent literature cited in the description

• MÜLLER LJ ; VRENSEN GFJM et al. Architectureof human corneal nerves. Invest Ophthalmol Vis Sci.,1997, vol. 38, 985-994, 991 [0016]

• MÜLLER LJ ; VRENSEN GFJM et al. Architectureof human corneal nerves. Invest Ophthalmol Vis Sci.,1997, vol. 38, 985-994, 992 [0018]