WO2014071408A1 - Systèmes et méthodes permettant de redonner une forme à une partie constitutive d'un œil - Google Patents

Systèmes et méthodes permettant de redonner une forme à une partie constitutive d'un œil Download PDF

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Publication number
WO2014071408A1
WO2014071408A1 PCT/US2013/068588 US2013068588W WO2014071408A1 WO 2014071408 A1 WO2014071408 A1 WO 2014071408A1 US 2013068588 W US2013068588 W US 2013068588W WO 2014071408 A1 WO2014071408 A1 WO 2014071408A1
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cross
cornea
linking
corneal
riboflavin
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PCT/US2013/068588
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English (en)
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David Muller
Marc D. Friedman
John Kanellopoulos
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Avedro, Inc.
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Priority claimed from US13/841,617 external-priority patent/US20130245536A1/en
Application filed by Avedro, Inc. filed Critical Avedro, Inc.
Publication of WO2014071408A1 publication Critical patent/WO2014071408A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/067—Radiation therapy using light using laser light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A61F2009/00861—Methods or devices for eye surgery using laser adapted for treatment at a particular location
    • A61F2009/00872—Cornea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/0079—Methods or devices for eye surgery using non-laser electromagnetic radiation, e.g. non-coherent light or microwaves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A61F9/00825—Methods or devices for eye surgery using laser for photodisruption
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0661—Radiation therapy using light characterised by the wavelength of light used ultraviolet

Definitions

  • the present invention relates generally to systems and methods for conducting an eye treatment, and more particularly to systems and methods for achieving corrective changes in corneal tissue and improving the stability of the changes to the corneal tissue.
  • LASIK Laser-assisted in-situ keratomileusis
  • LASIK eye surgery an instrument called a microkeratome is used to cut a thin flap in the cornea. The cornea is then peeled back and the underlying cornea tissue ablated to the desired shape with an excimer laser. After the desired reshaping of the cornea is achieved, the cornea flap is put back in place and the surgery is complete.
  • a system for treating an eye includes a cutting instrument configured to make incisions in selected areas of the cornea; a cross-linking treatment system, the cross-linking treatment system including an applicator that applies a cross-linking agent to the selected areas of the cornea, a light source that provides photo activating light for the cross-linking agent, and one or more optical elements that deliver the photo activating light to the selected areas of the cornea, the photo activating light acting on the cross-linking agent to initiate cross-linking activity in the selected areas of the cornea; and one or more controllers that determine the selected areas of the cornea for the incisions according to astigmatic keratotomy or radial keratotomy.
  • a method for treating an eye includes: selecting locations for making incisions in areas of the cornea according to astigmatic keratotomy or radial keratotomy; making, with a cutting instrument, incisions in the selected areas of the cornea; applying, with an applicator, a cross- linking agent to the selected areas of the cornea; and delivering, with one or more optical elements, photo activating light from a light source to the selected areas of the cornea to initiate cross-linking activity in the selected areas of the cornea.
  • FIG. 1 provides a block diagram of an example delivery system for delivering a cross- linking agent and an activator to a cornea of an eye in order to initiate molecular cross-linking of corneal collagen within the cornea.
  • FIG. 2A illustrates a graph of depletion and gradual replenishment of oxygen below a ⁇ corneal flap saturated with 0.1% Riboflavin during 3mW/cm 2 continuous wave (CW) irradiation.
  • FIG. 2B illustrates a graph of oxygen recovery under a ⁇ corneal flap saturated with 0.1% Riboflavin during 30 mW/cm 2 pulsed irradiation.
  • FIG. 3 illustrates a graph of absorbance of reduced Riboflavin before and after 30 mW/cm 2 CW irradiation for 3 minutes.
  • FIG. 4A illustrates a graph of fluorescence or Riboflavin samples at 450nm.
  • FIG. 4B illustrates a graph of relative fluorescence of cross-linked Riboflavin flaps at different Riboflavin concentrations and depths.
  • FIGs. 5A-5C illustrate graphs of force versus displacement curves for porcine cornea for various soak times and UVA illumination scenarios.
  • FIG. 6 illustrates a graph of fluorescence versus wavelength for porcine cornea 200 ⁇ flaps for various UVA illumination scenarios.
  • FIG. 7A illustrates a graph of cross-linking measured by fluorescence of the digested corneal flap at 450 nm for various UVA illumination scenarios.
  • FIG. 7B illustrates a graph of force versus displacement curve for porcine cornea for various UVA illumination scenarios.
  • FIG. 8 illustrates an example approach for stabilizing or strengthening corneal tissue by applying Riboflavin as a cross-linking agent according to aspects of the present invention.
  • FIG. 9 illustrates aspects of an eye anatomy.
  • FIG. 10 illustrates an example treatment that makes incisions to corneal tissue prior to an eye treatment that causes shape change in the cornea.
  • FIG. 1 1 illustrates an example system that makes incisions to corneal tissue prior to an eye treatment that causes shape change in the cornea.
  • FIG. 12 illustrates an example treatment that applies cross-linking treatments with intrastromal astigmatic keratotomy, according to aspects of the present invention.
  • FIG. 13 illustrates an example system that can be employed to apply cross-linking treatments with astigmatic keratotomy or radial keratotomy, according to aspects of the present invention.
  • FIG. 1 illustrates an example delivery system 100 for delivering a cross-linking agent 130 to a cornea 2 of an eye 1 in order to initiate molecular cross-linking of corneal collagen within the cornea 2.
  • the delivery system 100 includes an applicator 132 for applying the cross-linking agent 130 to the cornea 2.
  • the delivery system 100 includes a light source 1 10 and optical elements 1 12 for directing light to the cornea 2.
  • the delivery system 100 also includes a controller 120 that is coupled to the applicator 132 and the optical elements 1 12.
  • the applicator 132 may be an apparatus adapted to apply the cross-linking agent 130 according to particular patterns on the cornea 2.
  • the applicator 132 may apply the cross- linking agent 130 to a corneal surface 2A (e.g., an epithelium), or to other locations on the eye 1.
  • a corneal surface 2A e.g., an epithelium
  • Aspects for facilitating the delivery of the cross-linking agent 130 are described, for example, in U.S. Patent Application No. 14/062,467, filed October 24, 2013, the contents of which are incorporated entirely herein by reference.
  • the initiating element is ultraviolet-A ("UVA") light
  • UVA ultraviolet-A
  • the UVA light may be applied continuously (continuous wave or CW) or as pulsed light, and this selection has an effect on the amount, the rate, and the extent of cross- linking. If the UVA light is applied as pulsed light, the duration of the exposure cycle, the dark cycle, and the ratio of the exposure cycle to the dark cycle duration all have an effect on both the rate of cross-linking and the amount of resulting corneal stiffening.
  • Other factors that play a significant role in cross-linking include cross-linking agent concentration, temperature, specific conditions of the cornea (e.g., if any previous treatments have taken place), as well as other factors and parameters.
  • aspects of the present disclosure relate to the effect of each of these parameters on the rate and the amount of cross-linking, as well as the interrelations of these parameters among each other to optimize the conditions to achieve the desired amount, rate, and location (on the cornea 2) of corneal stiffening.
  • aspects of the present disclosure relate to monitoring the corneal response to a change in one or a plurality of parameters and adjusting the one or the plurality of parameters based on the received feedback.
  • the devices and approaches disclosed herein may be used to preserve desired shape or structural changes following an eye therapy treatment by stabilizing the corneal tissue of the cornea 2.
  • the devices and approaches disclosed herein may also be used to enhance the strength or bio mechanical structural integrity of the corneal tissue apart from any eye therapy treatment.
  • the optical elements 1 12 may include one or more mirrors or lenses for directing and focusing the light emitted by the light source 1 10 to a particular pattern on the cornea 2 suitable for activating the cross-linking agent 130.
  • the light source 1 10 may be a UVA light source that may also alternatively or additionally emit photons with greater or lesser energy levels than ultraviolet light photons.
  • the delivery system 100 also includes a controller 120 for controlling the operation of the optical elements 1 12 or the applicator 132, or both. By controlling aspects of the operation of the optical elements 1 12 and the applicator 132, the controller 120 can control the regions of the cornea 2 that receive the cross-linking agent 130 and that are exposed to the light source 1 10.
  • the controller 120 can control the particular regions of the cornea 2 that are strengthened and stabilized through cross-linking of the corneal collagen fibrils.
  • the cross-linking agent 130 can be applied generally to the eye 1 , without regard to a particular region of the cornea 2 requiring strengthening, but the light source 1 10 can be directed to a particular region of the cornea 2 requiring strengthening, to thereby control the region of the cornea 2 wherein cross-linking is initiated by controlling the regions of the cornea 2 that are exposed to the light source 110.
  • aspects of the present invention relate to modulating the specific regimes of the applied light to achieve a desired degree of corneal stiffening in selected regions of the cornea 2.
  • Another controller may be used to control the operation of the optical elements 112, and thereby control with precision the delivery of the light source 110 (i.e., the initiating element) to the cornea 2 by controlling any combination of: wavelength, bandwidth, intensity, power, location, depth of penetration, and duration (the duration of the exposure cycle, the dark cycle, and the ratio of the exposure cycle to the dark cycle duration) of treatment.
  • the function of the controller 120 can be partially or wholly replaced by a manual operation.
  • Embodiments may also employ aspects of multiphoton excitation microscopy.
  • the delivery system e.g., 100 in FIG. 1 delivers multiple photons of longer wavelengths, i.e., lower energy, that combine to initiate the cross- linking.
  • longer wavelengths are scattered within the cornea 2 to a lesser degree than shorter wavelengths, which allows longer wavelengths of light to penetrate the cornea 2 more efficiently than shorter wavelength light. Shielding effects of incident irradiation at deeper depths within the cornea are also reduced over conventional short wavelength illumination since the absorption of the light by the photosensitizer is much less at the longer wavelengths. This allows for enhanced control over depth specific cross- linking.
  • each photon may be employed, where each photon carries approximately half the energy necessary to excite the molecules in the cross-linking agent 130 that release radicals (Riboflavin or photosensitizer and oxygen).
  • radicals Radiboflavin or photosensitizer and oxygen.
  • a cross-linking agent molecule simultaneously absorbs both photons, it absorbs enough energy to release reactive radicals in the corneal tissue.
  • Embodiments may also utilize lower energy photons such that a cross-linking agent molecule must simultaneously absorb, for example, three, four, or five, photons to release a reactive radical.
  • the probability of the near-simultaneous absorption of multiple photons is low, so a high flux of excitation photons may be required, and the high flux may be delivered through a femtosecond laser.
  • aspects of the present disclosure can be employed to reduce the amount of time required to achieve the desired cross- linking.
  • the time can be reduced from minutes to seconds.
  • aspects of the present disclosure allow larger irradiance of the initiating element, e.g., multiples of 5 mW/cm 2 , to be applied to reduce the time required to achieve the desired cross-linking.
  • Highly accelerated cross- linking is particularly possible when using laser scanning technologies in combination with a feedback system.
  • the total dose of energy absorbed in the cornea 2 can be described as an effective dose, which is an amount of energy absorbed through an area of the corneal surface 2A.
  • the effective dose for a region of the corneal surface 2A can be, for example, 5 J/cm 2 , or as high as 20 J/cm 2 or 30 J/cm 2 .
  • the effective dose described can be delivered from a single application of energy, or from repeated applications of energy.
  • aspects of the present disclosure provide systems and methods for delivering pulsed light of specific duty cycle and frequency, especially when a cross-linking agent is applied to stabilize desired shape changes generated in corneal tissue.
  • Corneal cross-linking with Riboflavin is a technique that uses UVA light to photoactivate Riboflavin to stabilize and/or reduce corneal ectasia, in diseases such as keratoconus and post-LASIK ectasia. Corneal cross-linking improves corneal strength by creating additional chemical bonds within the corneal tissue.
  • systems and methods generate pulsed light by employing a digital micro-mirror device (DMD), electronically turning a light source on and off, and/or using a mechanical or opto-electronic (e.g., Pockels cells) shutter or mechanical chopper or rotating aperture.
  • DMD technology may be used to modulate the application of initiating light spatially as well as a temporally.
  • a controlled light source projects the initiating light in a precise spatial pattern that is created by microscopically small mirrors laid out in a matrix on a semiconductor chip, known as a DMD. Each mirror represents one or more pixels in the pattern of projected light. The power and duration at which the light is projected is determined as described elsewhere.
  • pulsed light may be generated in any suitable manner.
  • Riboflavin is deactivated (reversibly or irreversibly) and/or photo-degraded to a greater extent as irradiance increases. When Riboflavin absorbs radiant energy, especially light, it undergoes photo sensitization. There are two major photochemical kinetic pathways for Riboflavin photosensitization, Type I and Type II. Some of the major reactions involved in both the Type I and Type II mechanisms are as follows:
  • Rf represents Riboflavin in the ground state.
  • Rf * i represents Riboflavin in the excited singlet state.
  • Rf * 3 represents Riboflavin in a triplet excited state.
  • Rf " is the reduced radical anion form of Riboflavin.
  • RfH " is the radical form of Riboflavin.
  • RfH 2 is the reduced form of Riboflavin.
  • SH is the substrate. SH "+ is the intermediate radical cation.
  • S " is the radical.
  • S ox is the oxidized form of the substrate.
  • Rf ox is deutero flavin (7,8-dimethyl-10- (formylmethyl)isoalloxazine) having UVA absorption and sensitizer properties similar to those of Riboflavin (and unlike those of RfH 2 ).
  • Riboflavin is excited into its triplet excited state Rf 3 as shown in reactions (1) to (3). From the triplet excited state Rf 3 , the Riboflavin reacts further, generally according to Type I or Type II photomechanical mechanisms.
  • Type I mechanism above is favored at low oxygen concentrations, and Type II mechanism is favored at high oxygen concentrations.
  • the substrate reacts with the sensitizer excited state to generate radicals or radical ions, respectively, by hydrogen atoms or electron transfer.
  • the excited sensitizer reacts with oxygen to form singlet molecular oxygen. The singlet molecular oxygen then acts on tissue to produce additional cross- linked bonds.
  • Oxygen concentration in the cornea is modulated by UVA irradiance and temperature and quickly decreases at the beginning of UVA exposure.
  • the oxygen concentration tends to deplete within about 10-15 seconds for irradiance of 3mW/cm 2 (as shown, for example, in FIG. 2A) and within about 3-5 seconds for irradiance of 30mW/cm 2 .
  • Utilizing pulsed light of a specific duty cycle, frequency, and irradiance, input from both Type I and Type II photochemical kinetic mechanisms may be optimized to achieve the greatest amount of photochemical efficiency. Moreover, utilizing pulsed light allows regulating the rate of reactions involving Riboflavin.
  • the rate of reactions may either be increased or decreased, as needed, by regulating, one of the parameters such as the irradiance, the dose, the on/off duty cycle, Riboflavin concentration, soak time, and others.
  • additional ingredients that affect the reaction and cross-linking rates may be added to the cornea.
  • One aspect of the present disclosure relates to achieving photon optimization by allowing deactivated (reduced) Riboflavin to return to ground state Riboflavin in Type I reactions and allowing for reduced rate of oxygen uptake in Type II reactions where better photon conversion efficiency occurs.
  • the rate of return of deactivated (reduced) Riboflavin to ground state in Type I reactions and the rate of oxygen uptake in Type II reactions is determined by a number of factors. These factors include, but are not limited to, on/off duty cycle of pulsed light treatment, pulse rate frequency, irradiance, and dose. Moreover, the Riboflavin concentration, soak time, and addition of other agents, including oxidizers, affect the rate of oxygen uptake. These and other parameters, including duty cycle, pulse rate frequency, irradiance, and dose are optimized to achieve optimal photon efficiency and make efficient use of both Type I and Type II photochemical kinetic mechanisms for Riboflavin photo sensitization. Moreover, these parameters are optimized in such a way as to achieve an optimum chemical amplification effect.
  • the on/off duty cycle is between approximately 100/1 to approximately 1/100; the irradiance is between approximately 1 mW/cm 2 to approximately 500 mW/cm 2 average irradiance, and the pulse rate is between approximately 0.1 Hz to approximately 1000 Hz.
  • the on/off duty cycle is between approximately 1000/1 to approximately 1/1000; the irradiance is between approximately 1 mW/cm 2 to approximately 1000 mW/cm 2 average irradiance, and the pulse rate is between approximately 1000 Hz to approximately 100,000 Hz.
  • the laser source may be an adjustable pulsed source, an LED system, arc sources or incandescents at very long on-time duty cycles, or any other suitable sources.
  • Pulse rates of 0.1 Hz to approximately 1000 Hz or 1000 Hz to approximately 100,000 Hz may be chosen based on the photochemical kinetics as detailed by Kamaev et al., Investigative Ophthalmology & Visual Science, April 2012, Vol. 53, No. 4, pp. 2360-2367 (April 2012), which is incorporated herein by reference in its entirety.
  • the pulse length may be long - on the order of one or several seconds - or short - on the order of fractions of a second.
  • pulsed light illumination can be used to create greater or lesser stiffening of corneal tissue than may be achieved with continuous wave illumination for the same amount or dose of energy delivered.
  • Light pulses of suitable length and frequency may be used to achieve optimum chemical amplification.
  • FIG. 2A illustrates a graph of depletion and gradual replenishment curve of dissolved oxygen below a ⁇ thick porcine corneal flap, saturated with 0.1% Riboflavin during 3 mW/cm 2 UVA irradiation at 25°C.
  • the oxygen concentration (mg/L) fell to zero at about 15 seconds and gradually started to increase after approximately 10 minutes, getting back to approximately one-tenth its starting value after 30 minutes.
  • FIG. 2B illustrates a graph of oxygen recovery under a 100 ⁇ thick corneal flap.
  • the corneal flap was saturated with 0.1% Riboflavin during 30 mW/cm 2 UVA irradiation.
  • the irradiation was pulsed at a 3 second on / 3 seconds off cycle. Riboflavin drops were added to the cornea every 90 seconds. In this example, it took about 3 minutes for the oxygen concentration to gradually start increasing and about 6 minutes for the oxygen concentration to increase to 0.1 mg/L.
  • UVA radiation is stopped shortly after oxygen depletion, oxygen concentrations start to increase (replenish) as shown in FIGs. 2A and 2B.
  • Excess oxygen may be detrimental in corneal cross-linking process because oxygen is able to inhibit free radical photopolymerization reactions by interacting with radical species to form chain-terminating peroxide molecules.
  • the pulse rate, irradiance, dose, and other parameters may be adjusted to achieve an optimized oxygen regeneration rate. Calculating and adjusting the oxygen regeneration rate is another example of adjusting the reaction parameters to achieve a desired amount of corneal stiffening.
  • Dissolved free oxygen is significantly depleted not only at the position of the oxygen sensor and below, but also throughout the corneal flap above. Oxygen content may be depleted throughout the cornea, by various chemical reactions, except for the very thin corneal layer where oxygen diffusion is able to keep up with the kinetics of the reactions. This diffusion-controlled zone will gradually move deeper into the cornea as the reaction ability of the substrate to uptake oxygen decreases.
  • Oxygen measurements in the cornea suggest that the predominant photosensitizing mechanism for cross-linking with Riboflavin is the Type I pathway after a very short initial Type II photochemical mechanism at the start of the illumination with UVA light. More than halfway through the period of illumination, the oxygen concentration in the cornea slowly increases, as shown in FIGs. 2A and 2B above, to a concentration at which a Type II mechanism may begin to play an additional role.
  • Reduced Riboflavin undergoes an oxidation reaction as shown in equation (6) above.
  • the oxidation of reduced Riboflavin by molecular oxygen is irreversible, autocatalytic, and involves generation of free radicals that can initiate radical polymerization (as in case of vinyl monomers, acrylamide with bis(acrylamide), etc.).
  • the autocatalytic oxidation of reduced Riboflavins by oxygen is accounted for by the reactions described in Massey, V., Activation of molecular oxygen by flavins and flavoproteins, J. Biol. Chem. (1994), 269, 22459-22462.
  • a number of parameters affect the reaction rate and cross- linking rate of the reduced Riboflavin.
  • Oxygen is the naturally occurring oxidizer and is used as the oxidizer according to aspects of the present disclosure. According to further aspects of the present disclosure, oxygen and/or other oxidizers are utilized; such oxidizers may be added to the formulation or administered to the cornea in a suitable way.
  • reduced Riboflavin may be soaked in a suitable agent that contains oxygen and is able to oxidize the reduced Riboflavin.
  • Vitamin B12 may be added in any suitable manner to the reduced Riboflavin and/or to the cornea.
  • Vitamin B12 contains a Cobalt molecule that is capable of holding oxygen, thereby creating an oxygen storage reservoir.
  • the reduced Riboflavin may be super-saturated with Vitamin B12 or another suitable oxygen carrying agent.
  • the suitable agent, such as Vitamin B12 may be provided in conjunction with application of pulsed light. The proper level of oxygen can be maintained with various reversible oxygen carriers. See Yang N., Oster G. Dye-sensitized photopolymerization in the presence of reversible oxygen carriers. J. Phys. Chem. 74, 856-860 (1970), the contents of which are incorporated entirely herein by reference.
  • Corneal stiffening may be applied to the cornea according to particular patterns, including, but not limited to, circular or annular patterns, which may cause aspects of the cornea to flatten and improve vision in the eye. For example, more or less corneal stiffening may be desired on the outer edges of the cornea as opposed to the center of the cornea. Aspects of the present disclosure relate to achieving more corneal stiffening on the outer diameter of the cornea and gradually decreasing the amount of corneal stiffening from the outer diameter toward the center of the cornea. Other aspects of the present disclosure relate to selecting regions of the cornea that require more corneal stiffening based on a predetermined set of characteristics and applying more corneal stiffening to those selected regions by varying the regime of the pulsed light.
  • pulsed light may be applied with different irradiance, dose and/or different duty cycle to different areas of the cornea, leading to areas of differing levels of corneal stiffening or corneal stiffening gradients.
  • Varying the regime of the pulsed light to achieve a desired level of corneal stiffening is another example of adjusting the parameters of the cross-linking reaction to achieve specific, targeted results.
  • varying the regime of the pulsed light to achieve a desired level of corneal stiffening at selected regions of the cornea allows for more precise and accurate control of the shape changes in the eye.
  • Riboflavin RFH 2 (with two hydrogen atoms supplied to the aromatic nucleus by the side chain) can be produced by anaerobic photolysis of Riboflavin (Holmstrom 1961) and observed by the reduction in absorption at 445 nm.
  • FIG. 3 a graph illustrating absorbance for 0.2 mm light path of an initial sample of Riboflavin versus absorbance for 0.2 mm light path of reduced Riboflavin RfH 2 after being irradiated for 3 minutes at an irradiance of 30 mW/cm 2 .
  • the absorbance of the initial sample is about 0.543, while the absorbance of the irradiated sample is about 0.340.
  • RFH 2 is autoxidizable and in the presence of oxygen yields the highly light-sensitive fluorescent and absorbing (445 nm) Deutero flavin (7,8-dimethyl-10- (formylmethyl)isoalloxazine).
  • Reduced Riboflavin solutions can be prepared under nitrogen by irradiation of Riboflavin with visible light in the presence of EDTA and stored in absence of oxygen. Reaction with oxygen completes during hundreds of msec (depending on the initial conditions), proceeds via free radicals (as described in Massey), and is able to initiate polymerization of vinyl monomers. The rate of the reaction with oxygen may be increased by dissolving oxygen in a flavin solution instead of in water.
  • RFH 2 was prepared by irradiation of Riboflavin solutions (with and without EDTA, 1% EDTA, 0.1% Riboflavin) and saturated with argon (to displace oxygen) in a shallow sealed quartz cuvette. Then, in the absence of additional UV light, porcine corneal flaps were immediately placed in those solutions. After 1-2 min this procedure was repeated with a fresh solution containing RFH 2 several times. Corneal flaps then were washed with distilled water, digested with papain buffer, and their fluorescence was measured.
  • the reducing agents may include, but are not limited to, EDTA, ascorbic acid, sugars, amines, amino acids, and any combination thereof. This is another example of modifying the parameters of the cross-linking reaction to achieve a desired level of cross-linking with the corneal fibrils.
  • Riboflavin concentrations between about 0.001% Riboflavin to about 1.0 % Riboflavin may be utilized.
  • Example 2 Measurement of the Collagen Linked Fluorescence in Cross-Linked Corneal Flaps at Depths of 100 ⁇ m and 200 ⁇ m
  • Porcine whole globes (SiouxPreme Packing Co., Sioux City, IA; shipped in saline solution packed in ice) were warmed to room temperature (25°C). The corneas were then de- epithelialized with a dulled scalpel blade and 0.1, 0.25, or 0.5% riboflavin solution in 0.9% saline was applied to the top of each cornea during 20 minutes before cross- linking.
  • Corneas were pan-corneally irradiated with a top hat beam (3% root mean square) for a determined amount of time with 365-nm light source (UV LED NCSU033B[T]; Nichia Co., Tokushima, Japan) at the chosen irradiance (3 or 30 mW/cm 2 ) which was measured with a power sensor (model PD-300-UV; Ophir, Inc., Jerusalem, Israel) at the corneal surface.
  • 365-nm light source UV LED NCSU033B[T]; Nichia Co., Tokushima, Japan
  • a power sensor model PD-300-UV; Ophir, Inc., Jerusalem, Israel
  • Corneal flaps (each 100 ⁇ thick, one after another) were excised from the eyes with aid of Intralase femtosecond laser (Abbott Medical Optics, Santa Ana, CA). The average thickness of the corneal flaps was calculated as a difference between the measurements before and after the excision from the eyes with an ultrasonic Pachymeter (DGH Technology, Exton, PA). The flaps were washed with distilled water until Riboflavin in the washing waters was not detectable by absorbance measurement at 455 nm (Thermo Scientific Evolution 300/600 UV-Vis Spectrophotometer, Thermo Fisher Scientific, Waltham, MA). The flaps then were dried in vacuum until the weight change became less than 10% (Rotary vane vacuum pump RV3 A652-01-903, BOC Edwards, West Wales, UK).
  • Each flap (1 mg) was digested for 2 h at 65°C with 2.5 units/ml of papain (from Papaya latex, Sigma) in 0.5 ml of papain buffer [lx PBS (pH 7.4), 2 mM L-cysteine and 2 mM EDTA].
  • papain buffer [lx PBS (pH 7.4), 2 mM L-cysteine and 2 mM EDTA].
  • the fluorescence of the papain buffer was taken into account by measuring fluorescence in the absence of tissue and subtracting this value from the fluorescence of the samples.
  • FIG. 4B Fluorescence of the excised samples, which was a relative value to the non-cross- linked samples with the same thickness, is illustrated in FIG. 4B. It is shown that the corneal fluorescence after cross-linking (all samples were exposed to the same UVA dose, 5.4 J/cm 2 ) is greater for samples exposed to UVA for a longer duration with lower irradiance and lower concentration of Riboflavin. Corneal fluorescence is also greater at first 100 ⁇ than at the next 100 ⁇ in the cornea. The highest corneal fluorescence was observed at the first 100 ⁇ for the sample that was soaked in 0.1% Riboflavin solution and irradiated at 3 mW/cm 2 .
  • porcine eyes Upon arrival, porcine eyes have excess muscle tissue that was removed and placed in saline in the incubator (set to 37°C) for 30 minutes. Eyes were then de-epithelialized and placed in a 0.1% Riboflavin solution for 20 minutes at 37°C. Eyes were removed from solution and physiological IOP was applied. Eyes were then placed under a UVA source and shutter system and irradiated according to the indicated protocol as shown in FIGs. 5A-5C. Riboflavin drops were applied every 1.5 minutes during UVA application. After being irradiated, the corneal thickness was measured with a pachymeter. The sample was then placed under the femto second laser and a -200 ⁇ flap was cut.
  • the flap was positioned in a biaxial materials tester (CS-BIO TESTER 5000, CellScale, Waterloo, ON Canada) and stretched until failure. The sample was then rinsed with distilled water and frozen for future papain digestion and fluorescence analysis.
  • CS-BIO TESTER 5000 CellScale, Waterloo, ON Canada
  • FIG. 5A illustrates force versus displacement curves for porcine cornea for various soak times and UVA illumination scenarios.
  • FIG. 5A illustrates results of experiments that show dissimilar biomechanical stiffness of the 0.25% Riboflavin sample 2 irradiated with 3 mW/cm 2 continuous wave illumination vs. the sample 3 irradiated with 30mW/cm 2 continuous wave illumination for a total 5.4 J/cm 2 dose delivered.
  • the biomechanical stiffness of the 0.25 % Riboflavin sample 3 irradiated with 30 mW/cm 2 continuous for a total 5.4 J/cm 2 dose delivered was similar to the biomechanical stiffness of the 0.1% Riboflavin sample 4 irradiated under the same conditions.
  • the biomechanical stiffness of the 0.25 % Riboflavin sample 6 irradiated with 30 mW/cm 2 pulsed light with a 3 seconds on / 3 seconds off duty cycle was similar to the biomechanical stiffness of 0.25 % Riboflavin sample 7 irradiated with 60 mW/cm 2 pulsed light with a 2 seconds on / 4 seconds off duty cycle for a total 5.4 J/cm 2 dose delivered to each sample.
  • the biomechanical stiffness of the 0.1 % Riboflavin sample 8 irradiated with 30 mW/cm 2 pulsed light with a 3 seconds on / 3 seconds off duty cycle was higher than both the samples 6 and 7.
  • the biomechanical stiffness of the Riboflavin sample 5 irradiated with 30 mW/cm 2 continuous wave illumination for a total 35.1 J/cm 2 dose delivered was higher than that for samples 6, 7, 3, 4, and 1 (control sample with 0.25% Riboflavin concentration) and lower than that for sample 2.
  • Sample 4 was soaked with Riboflavin for 30 minutes, while all the other samples were soaked with Riboflavin for 1 hour.
  • FIG. 5A illustrates the effect of varying different parameters on corneal cross- linking. Different parameters - irradiance, continuous wave vs. pulsed illumination, on/off duty cycle of pulsed light illumination, Riboflavin concentration, and other parameters - all have an effect on biomechanical stiffness.
  • a DMD may be used for illumination. With the DMD one can perform topography guided cross-linking as described, for example, in U.S. Patent Application No. 13/438,705, filed April 3, 2012, and U.S. Patent Application No. 13/051,699, filed March 18, 2011, the contents of which are incorporated entirely herein by reference.
  • the algorithms associated with the topography may be created using several different spatial and temporal irradiance and dose profiles.
  • These spatial and temporal dose profiles may be created using continuous wave illumination but may also be modulated via pulsed illumination by pulsing the illumination source under varying frequency and duty cycle regimes as described above.
  • the DMD may be able to modulate different frequencies and duty cycles on a pixel by pixel basis to give ultimate flexibility using continuous wave illumination.
  • both pulsed illumination and modulated DMD frequency and duty cycle combinations may be combined. This allows for specific amounts of spatially determined corneal cross- linking.
  • This spatially determined cross-linking may be combined with dosimetry, interferometry, optical coherence tomography (OCT), corneal topography, etc., for real-time modulated corneal cross- linking.
  • OCT optical coherence tomography
  • corneal topography etc.
  • the pre-clinical patient information may be combined with finite element biomechanical computer modeling to create patient specific pre-treatment plans.
  • complex biomechanical stiffness patterns may be imparted to the cornea to allow for various amounts of refractive correction.
  • These refractive corrections may include combinations of myopia, hyperopia, astigmatism, irregular astigmatism, presbyopia and complex corneal refractive surface corrections because of ophthalmic conditions such as keratoconus, pellucid marginal disease, post-lasik ectasia, and other conditions of corneal biomechanical alteration/degeneration, etc.
  • a specific advantage of the DMD system and method is that it allows for randomized asynchronous pulsed topographic patterning, creating a non-periodic and uniformly appearing illumination which eliminates the possibility for triggering photosensitive epileptic seizures or flicker vertigo for pulsed frequencies between 2 Hz and 84 Hz as described above.
  • Flicker vertigo is an imbalance in brain-cell activity caused by exposure to low-frequency flickering (or flashing) of a relatively bright light. It is a disorientation-, vertigo-, and nausea-inducing effect of a strobe light flashing at 1 Hz to 20 Hz, which corresponds approximately to the frequency of human brainwaves.
  • the effects are similar to seizures caused by epilepsy (particularly, photosensitive epilepsy), but are not restricted to people with histories of epilepsy.
  • websites provided by federal agencies are governed by section 508 of the Rehabilitation Act. The Act says that pages shall be designed to avoid causing the screen to flicker with a frequency between 2 Hz and 55 Hz.
  • FIG. 5B illustrates force versus displacement curves for samples of porcine cornea irradiated with pulsed light having various exposure times, as well as a curve for a sample irradiated with continuous wave illumination, and a curve for a control sample.
  • All the samples that were irradiated with pulsed light had a 0.1% Riboflavin concentration and were irradiated with 30 mW/cm 2 pulsed light with a 3 seconds off cycle and a varied exposure ("on") cycle.
  • the sample 2 having a 4.5 second exposure cycles had slightly lower biomechanical stiffhess than samples 3 or 1.
  • the duration of the exposure cycle affects the amount of corneal stiffening at the same irradiance and dark phase duration. Therefore, aspects of the present disclosure affect the displacement per unit force ratio. This is yet one more parameter that may be altered in optimizing cross-linking.
  • FIG. 5C illustrates force versus displacement curves for samples of porcine cornea illuminated with pulsed light having varied dark phase durations, as well as curves for samples irradiated with continuous illumination, and a curve for a control sample.
  • the graphs in FIGs. 5A-5C show that varying different parameters - applying pulsed instead of continuous wave illumination, varying on/off duty cycles, irradiance, dose, Riboflavin concentration, and soak times - all have an effect on biomechanical stiffhess. These parameters may be modified in such a way as to achieve an optimum or desired amount of corneal stiffness anywhere on or within the cornea.
  • Corneas were pan-corneally irradiated with a top hat beam (3% root mean square) for a determined amount of time with 365-nm light source (UV LED NCSU033B[T]; Nichia Co., Tokushima, Japan) at the chosen irradiance of 30 mW/cm 2 with either continuous wave illumination or pulsed illumination 3 seconds on/3 Seconds off.
  • Corneal flaps (200 ⁇ thick) were excised from the eyes with aid of Intralase femtosecond laser (Abbott Medical Optics, Santa Ana, CA). The average thickness of the corneal flaps was calculated as a difference between the measurements before and after the excision from the eyes with an ultrasonic Pachymeter (DGH Technology, Exton, PA).
  • FIG. 6 a graph of fluorescence versus wavelength curves is shown. At 455 nm, fluorescence was the highest - about 20,000 counts/s - for the sample irradiated with 30mW/cm 2 pulsed light illumination with a 3 seconds on / 3 seconds off cycle. The fluorescence for the sample irradiated with 30mW/cm 2 continuous illumination was about 40% less, or about 12000 counts/s. This is yet another example demonstrating that applying pulsed light illumination as opposed to continuous wave illumination affects cross-linking in the cornea.
  • Pig eyes from an abattoir (SiouxPreme, Sioux City, IA) were rinsed in saline. Eyes were cleaned and the epithelium was removed. Eyes were placed on a stand in the middle of a large beaker filled part way with water with a tube bubbling compressed oxygen into the water. The oxygen was turned on at certain times during the experiment to create a humid oxygenated environment for the eye. Eyes were soaked for 20 minutes with 0.1% Riboflavin, dH 2 0 solution in an incubator set at 37°C by using a rubber ring to hold the solution on top.
  • Corneas were pan-corneally irradiated with a top hat beam (3% root mean square) for a determined amount of time and irradiance (3 minutes CW at 30 mW/cm 2 with one drop of solution added every 30 seconds, or 30 minutes CW at 3 mW/cm 2 with one drop of solution added every minute, or 9 minutes for pulsed light - 1.5 seconds on / 3 seconds off - using a shutter system (Lambda SC Smart Shutter, Sutter Instrument, Novate, CA) at 30 mW/cm 2 with one drop of solution added every minute) with a 365-nm light source (UV LED NCSU033B[T]; Nichia Co., Tokushima, Japan). The irradiance was measured with a power sensor (model PD-300-UV; Ophir, Inc., Jerusalem, Israel) at the corneal surface.
  • a power sensor model PD-300-UV; Ophir, Inc., Jerusalem, Israel
  • Corneal flaps (approximately 380 ⁇ thick) were excised from the eyes with aid of Intralase femtosecond laser (Abbott Medical Optics, Santa Ana, CA). The average thickness of the corneal flaps was calculated as a difference between the measurements before and after the excision from the eyes with an ultrasonic Pachymeter (DGH Technology, Exton, PA). The flaps were washed with distilled water 15 times and then dried in a vacuum until the weight change became less than 10% (Rotary vane vacuum pump RV3 A652-01-903, BOC Edwards, West Wales, UK).
  • Each flap (2 mg) was digested for 2.5 h at 65 °C with 2.5 units/ml of papain (from Papaya latex, Sigma) in 1 ml of papain buffer [lx PBS (pH 7.4), 2 mM L-cysteine and 2 mM EDTA].
  • the fluorescence of the papain buffer was taken into account by measuring fluorescence in the absence of tissue and subtracting this value from the fluorescence of the samples.
  • FIG. 7A illustrates a graph of the amount of cross-linking measured by fluorescence of the digested corneal flaps at 450 nm.
  • Eyes were de-epithelized, soaked for 20 minutes with 0.1% Riboflavin, put in a regular air environment or a humid oxygenated environment, and illuminated with 30 mW/cm 2 or 3 mW/cm 2 of UV light for 3 minutes CW with one drop of solution every 30 seconds, or 30 minutes CW with one drop of solution every minute, or 9 minutes pulsed (1.5 seconds on / 3 seconds off) with one drop of solution every minute.
  • the following treatments shown in TABLE 1 below were applied to each of the samples shown in
  • FIG. 7A is a diagrammatic representation of FIG. 7A.
  • 3 mW CW Eyes were illuminated with 3mW/cm CW of UV light for 30 minutes.
  • Pulsed Light Eyes were illuminated with 30mW/cm of pulsed UV light (1.5 seconds on / 3 seconds off) for 9 minutes with oxygen on during soak and UV exposure.
  • a humid oxygenated environment with pulsed UV light greatly increases the amount of cross-linking taking place in the cornea.
  • Applying a combination of Riboflavin and ultraviolet (UV) light sterilizes a surface of the cornea.
  • the Riboflavin acts as a photosensitizer that increases the absorption of UV light.
  • the resulting absorption of UV light can induce DNA and RNA lesions, and as a result, is effective in killing viruses, bacteria, and other pathogens in the field.
  • a humid oxygen environment and pulsing UV light increase the amount of cross- linking to a certain degree when done separately, while they increase the amount of cross- linking to a significantly greater extent when done in conjunction.
  • Increased cross-linking involves creation of an increased number of radicals. Radicals help to eliminate harmful bacteria present in the eye. Accordingly, a humid oxygenated environment and pulsing UV light result in more efficient elimination of viruses, bacteria, and other pathogens in the cornea, creating a sterile environment while minimizing any damage or other unwanted effects in the tissue. This is yet another example demonstrating that applying pulsed light illumination as opposed to continuous wave illumination affects the amount of cross-linking in the cornea.
  • FIG. 7B illustrates force versus displacement curves for samples of porcine cornea illuminated with pulsed light of irradiance with oxygen, as well as curves for samples irradiated with continuous illumination, and a curve for a control sample.
  • the sample 3 irradiated with 30 mW/cm 2 pulsed light illumination with oxygen and a 3 seconds on / 3 seconds off duty cycle had the highest biomechanical stiffness, followed by sample 4 irradiated with 45 mW/cm 2 pulsed light illumination with oxygen and an identical on/off duty cycle.
  • the samples irradiated with 3 mW/cm 2 and 30 mW/cm 2 continuous wave illumination had lower biomechanical stiffness, followed by the control sample.
  • a treatment such as LASIK surgery, is applied in step 210 to generate structural changes in the cornea and produce a desired shape change.
  • the corneal tissue is treated with a cross-linking agent 222.
  • the cross-linking agent may be applied directly on the treated tissue and/or in areas around the treated tissue.
  • the cross-linking agent may be an ophthalmic solution that is broadly delivered by a dropper, syringe, or the like.
  • the cross-linking agent may be selectively applied as an ophthalmic ointment with an appropriate ointment applicator.
  • the cross- linking agent 222 is then activated in step 230 with an initiating element 232.
  • Activation of the cross-linking agent 222 may be triggered thermally by the application of microwaves or light from a corresponding energy or light source.
  • the resulting cross-linking between collagen fibrils provides resistance to changes in corneal structure.
  • Riboflavin is applied as a cross-linking agent 222 to the corneal tissue in step 220.
  • light from an UV light source may be applied as an initiating element 232 in step 230 to initiate cross-linking in the corneal areas treated with Riboflavin.
  • the UV light initiates cross-linking activity according to the mechanisms described above.
  • aspects of the present disclosure relate to monitoring and optimizing the parameters of applying the cross-linking agent to the eye and of activating the cross-linking agent.
  • a large variety of factors affect the rate of the cross-linking reaction and the amount of biomechanical stiffness achieved due to cross- linking. These factors include Riboflavin concentration, conditions on the cornea, temperature, presence of oxidizing agents, the type of illumination applied to activate the Riboflavin, the irradiance, the dose, the on/off duty cycle of the applied illumination, as well as other factors.
  • Riboflavin concentration include Riboflavin concentration, conditions on the cornea, temperature, presence of oxidizing agents, the type of illumination applied to activate the Riboflavin, the irradiance, the dose, the on/off duty cycle of the applied illumination, as well as other factors.
  • a number of these factors are interrelated, in other words, changing one factor may have an unexpected effect on another factor.
  • aspects of the present disclosure relate to determining the effect of each of these parameters on the rate and the amount of cross-linking, as well as the interrelations of these parameters among each to optimize the conditions to achieve the desired amount, rate, and location of corneal stiffening.
  • aspects of the present disclosure relate to monitoring the corneal response to a change in one or a plurality of parameters and adjusting the one or the plurality of parameters based on the received feedback.
  • the embodiments described above may employ stepwise on/off pulsed light functions, it is understood that other functions for applying light to the cornea may be employed to achieve similar effects.
  • light may be applied to the cornea according to a sinusoidal function, sawtooth function, or other complex functions or curves, or any combination of functions or curves.
  • the function may be "substantially" stepwise where there may be more gradual transitions between on/off values.
  • irradiance does not have to decrease down to a value of zero during the off cycle, and may be above zero during the off cycle. Effects of the present disclosure may be achieved by applying light to the cornea according to a curve varying irradiance between two or more values.
  • Cross-linking is known to require suitable concentrations of agents including actinic radiance, photosensitizer, and dissolved oxygen for radicals generation and maintenance near the targeted tissue/protein substrate for the duration of the treatment.
  • concentrations of these agents change in tissue with depth.
  • One of the aspects of the present invention relates to formulating extensive relationships where the rates/concentrations of photo-bleaching, oxygen consumption/radicals generation, and photosensitizer/oxygen re-diffusion are used to construct multi-wavelength pulsing regimes (i.e., irradiance/duty cycle/synchronizing wavelength exposure) based on real time feedback of oxygen and photosensitizer consumption and concentrations as a function of depth.
  • an optimized way of delivery of the agents may include maximal oxygen pre-loading of the photosensitizers, multiple wavelength matching a mix of photo sensitizers or a single photosensitizer for calibrated radical generation and potentially using elasticity mapping feedback for 3D pattern optimization.
  • the localized cross-linking exposure duration required is approximated by the experimentally determined rate equations and can be factored into the delivery (pulsing) protocol, so that the system can target for depth and degree of cross-linking.
  • the delivery system of FIG. 1 is modified such that the light source 110 includes multi- wave length LED printed circuit boards (PCBs) and achromatic optics.
  • PCBs printed circuit boards
  • Example 6
  • a patient presents with a 300-350 ⁇ thick cornea and is desirous of a 1.25 D spherical flattening having 0.5 D cylinder (manifest refraction spherical equivalents (MRSE)).
  • MRSE manifest refraction spherical equivalents
  • a modeling analysis based nomogram generator (which combines elasto-fine element analysis and accelerated sub-surface cross-link density modulation) prescribes, for example, a UVA Riboflavin treatment in the central (5mm) zone for a 200 ⁇ treatment depth and a 1mm transition zone in the periphery at 250 ⁇ depth where the cornea is thicker. An average of 20 ⁇ shrinkage is targeted.
  • a pulsed spot illumination with fluorescence dosimetry feedback is implemented so that the dosimetry depth profile confirms adequate Riboflavin concentration at 200-250 ⁇ and is sequenced by a bowtie pattern for the 0.75 D cylinder correction. The shape/axis of the bowtie is entirely derived from the topography and is registered by an iris tracker during treatment. Delivery may be topographically guided or topographically optimized.
  • one of the aspects of the present invention relates to creating more efficient and controlled cross-link densities at depth.
  • Several sequences that perform feedback-controlled micro-volume cross-link sub-steps when attempting a bulk exposure were evaluated.
  • An example regime includes:
  • each sub-step of the sequence may include a different number of pulses.
  • the duration of each exposure may vary between the pulse trains.
  • the duration of a dark period following each exposure may vary as well. Alternatively, there may be no dark periods or pauses in between different pulse trains.
  • the wavelength may vary between the pulse trains.
  • the wavelength may increase for each pulse train, decrease for each pulse train, or the wavelength may be alternated between the different pulse trains.
  • the wavelength may be selected based on a predetermined pattern.
  • the irradiance may vary between the pulse trains.
  • the irradiance may increase for each pulse train, decrease for each pulse train, or the irradiance may be alternated between the different pulse trains.
  • the irradiance may be selected based on a predetermined pattern.
  • a sequence of pulse trains is applied, followed by a pause of a predetermined duration, and followed by an application of another sequence of pulse trains.
  • a sequence includes a brief sequence of high irradiance pulses followed by lower irradiance pulses repeating while under maximally hyperoxic conditions.
  • the tissue may be inducted by any sequence of oxygen in normoxic, hyperoxic, or hypoxic conditions, followed by addition of nitrogen prior to or during any of the pulsing train sequences discussed above.
  • Photo sensitizers including Riboflavin and Indocyanine green (ICG) may be used in combination with any of the sequences discussed above.
  • NIR near infrared light
  • UVA ultraviolet light
  • Formulations may include agents (chaperones) configured to improve wound healing and to protect the eye from unwanted side effects such as apoptosis or haze.
  • agents chaperones
  • Pulsing parameters may be selected based on target micro-volume fluorescence to increase safety and efficiency.
  • Zonal bleaching based bulk oxygenation can also be used for increased safety and efficiency.
  • One or more chemical accelerators and/or chemical quenchers (such as ascorbic acid) of various concentrations may be added before and/or during the pulse sequence to control the depth of cross-linking.
  • chemical quenchers and quenching methods are discussed in U.S. Patent Application No. 13/475,175, filed May 18, 2012 the disclosure of which is incorporated entirely herein by reference.
  • Rinsing with hyper, hypo or isotonic non-photo reactive solutions may also be used to vary the concentration profile of the photosensitizer within the tissue.
  • rinsing may protect against damage to the superficial corneal nerve plexus which is known to be destroyed following conventional cross- linking.
  • any combination of the permutations discussed above may be applied to achieve a desired effect of creating a more efficient and/or specific cross-linking profile through the tissue.
  • different parameters may be varied to achieve a desired depth and density of cross- linking.
  • different parameters may be varied to achieve a particular method of cross-linking.
  • the different parameters that may be varied include wavelength, irradiance, duration, on/off duty cycle, oxygenation conditions in the tissue, photo sensitizer selection, presence of additional agents and solutions.
  • eye treatments such as LASIK surgery, involve procedures to the anterior corneal tissue. While the procedures achieve a direct change in the shape of the anterior corneal tissue, the posterior corneal tissue generally does not change shape in a corresponding fashion. Accordingly, after such procedures, the posterior corneal tissue may exert a force on the anterior corneal tissue that counters or inhibits the desired changes to the corneal tissue affected by the procedures. The forces applied by the posterior corneal tissue on the anterior corneal tissue may prevent the procedure from achieving the desired structural change.
  • corneal tissue As a result, for example, more severe ablation of corneal tissue, greater amounts of thermal energy, and/or greater amounts of cross-linking agents may be required to account for the force applied by the posterior corneal tissue on the anterior corneal tissue and achieve a desired change to the corneal tissue.
  • Embodiments also relate to systems and processes for conducting an eye treatment that address such problems.
  • embodiments involve a procedure to cut one or more dissection planes or regions in the cornea to at least partially disassociate or separate the anterior corneal tissue from the posterior corneal tissue to provide one or more areas of stress relief.
  • embodiments reduce the extent of eye treatment required to achieve a desired change in corneal tissue and improve the stability of changes to the corneal tissue as part of eye treatment.
  • FIG. 9 illustrates a cornea 2 of an eye 1, including an anterior corneal tissue 2C and a posterior corneal tissue 2D.
  • FIG. 10 illustrates an example process 500 for performing a treatment on an eye.
  • the anatomy of a patient's eye 1 is determined using a measurement device.
  • the determination of the eye 1 anatomy may include, for example, a determination of the curvature and the thickness of the anterior corneal tissue 2C and the posterior corneal tissue 2D.
  • measurement devices that are suitable to assist in determining the anatomy of the eye 1 include a tonometer, an ultrasound pachymeter, an optical pachymeter, and/or an imaging device. Aspects of systems and approaches for making such measurements are described in U.S. Application No. 13/051,699, filed March 18, 2011, and U.S. Application No. 13/438,705, filed April 12, 2012, referenced above.
  • one or more locations, sizes, and depths are determined for one or more incisions to be formed in the posterior corneal tissue 2C.
  • the locations, sizes, and depths of the one or more incisions to the posterior corneal tissue 2D depend on the anatomical structure of the patient's eye (e.g., cornea 2), the particular optical condition that is to be corrected (e.g., myopia, keratoconus, or hyperopia), and/or the type of eye treatment to be applied (e.g., themokeratoplasty or LASIK) to reshape the cornea 2.
  • the anatomical structure of the patient's eye e.g., cornea 2
  • the particular optical condition that is to be corrected e.g., myopia, keratoconus, or hyperopia
  • the type of eye treatment to be applied e.g., themokeratoplasty or LASIK
  • the location, size, and depth of the one or more incisions are determined so as to at least partially disassociate or separate the anterior corneal tissue 2C from the posterior corneal tissue 2D without weakening the structural integrity of the eye 1.
  • the one or more incisions may take the form of one or more dissection planes or regions.
  • the one or more dissection planes or regions can be optimized for particular applications by, for example, localizing the one or more incisions to a specific region or providing the one or more incisions in a particular pattern depending on the anatomical structure of the patient's eye, the optical condition corrected, and/or the method of eye treatment employed.
  • the location, size, and depth of the one or more incisions are generally determined so that the incisions do not penetrate through the full thickness of the cornea 2 (i.e., from the posterior corneal tissue 2D through the anterior corneal tissue 2C).
  • the one or more incisions may be determined to have a location, size, and depth such that the one or more incisions formed in the posterior corneal tissue 2D do not penetrate into any portion of the anterior corneal tissue 2C.
  • the one or more locations, sizes, and depths for the one or more incisions may be determined and/or optimized by a controller (e.g., a computer processing system that reads instructions on computer-readable storage media).
  • the one or more incisions are formed in the posterior corneal tissue 2 by an incision device according to the one or more locations, sizes, and depths determined at step 520.
  • the incision device can be a femtosecond pulsed laser that is configured or controlled (e.g., by one or more controllers) to form the desired one or more incisions.
  • the one or more incisions at least partially disassociate or separate the posterior corneal tissue 2D from the anterior corneal tissue 2C so as to provide for one or more areas of stress relief.
  • An eye treatment (e.g., LASIK surgery or cross-linking treatment) is applied at step 540 to generate structural changes in the anterior corneal tissue 2C and produce a desired shape change.
  • the system for applying the eye treatment may include any device that is suitable for applying, for example, LASIK surgery.
  • a device for applying LASIK is an excimer laser.
  • the eye treatment applied to the eye 1 may take into account the reduced forces that the posterior corneal tissue 2D exerts on the anterior corneal tissue 2C due to the one or more incisions. As a result, the extent of eye treatment required to achieve a desired change in corneal tissue may be reduced.
  • a more moderate ablation of anterior corneal tissue 2C may be required to achieve a desired change in the corneal shape.
  • a reduced amount of cross-linking agent or lower dose of UV light may be required to achieve a desired reshaping of the corneal shape.
  • the precise amount of treatment to be applied to the eye e.g., laser ablation, magnitude of electrical energy, size of electrical energy pattern, number of electrical pulses, amount of cross-linking agent, and/or dose of UV light
  • the precise amount of treatment to be applied to the eye can be determined and controlled by one or more controllers that take into account the anatomy of the patient's eye and the one or more incisions to the posterior corneal tissue 2D.
  • the resulting shape of the anterior corneal tissue 2C may exhibit greater stability as the one or more incisions provide area(s) of stress relief against the forces applied by the posterior corneal tissue 2D to the anterior corneal tissue 2C.
  • a cross-linking agent can be further applied to the cornea 2 to stabilize the corneal tissue 2 and improve its biomechanical strength, e.g., in combination with LASIK surgery, as described above.
  • incisions are employed to promote desired shape change in corneal structure.
  • incisions are not limited to posterior corneal tissue.
  • a cutting instrument such as a femtosecond laser, may be employed to make incisions in any portion of the cornea to create slip planes that allow aspects of the corneal structure to move more easily relative to each other and to allow desired reshaping to take place when combined with other eye treatments, such as LASIK surgery or cross-linking treatment.
  • LASIK surgery a reshaping to take place when combined with other eye treatments, such as LASIK surgery or cross-linking treatment.
  • some particular shape changes would not be otherwise possible without the creation of one or more slip planes.
  • the location, size, depth of the slip planes depends on the desired shape change.
  • FIG. 11 illustrates an example integrated system 600, in which the components can be employed to manipulate varying aspects of the corneal structure in order to achieve customized shape change.
  • a cutting instrument 610 e.g., femtosecond laser
  • the components of the system 600 can be controlled by one or more controllers 640, which make measurements, provide monitoring, and/or drive the components, e.g., based on feedback from the monitoring.
  • the cutting instrument is employed to create incisions in selected areas of the cornea.
  • One of the eye therapy systems applies reshaping forces to the cornea.
  • the LASIK surgery system 620 ablates the corneal tissue with an excimer laser to apply the reshaping forces after a microkeratome creates a corneal flap or the cross-linking treatment system 100 applies a cross-linking agent, e.g., Riboflavin, and photoactivating light, e.g., UV light, to initiate cross-linking activity in selected areas of the cornea and apply the reshaping forces.
  • a cross-linking agent e.g., Riboflavin
  • photoactivating light e.g., UV light
  • the controller(s) 640 can determine the selected areas of the cornea for the incisions and the reshaping forces from the eye therapy system, such that the reshaping forces and the incisions combine to achieve a predetermined corrective reshaping of the cornea.
  • the cross-linking system 100 may control one or more parameters to achieve the desired amount, rate, and location (on the cornea 2) of corneal stiffening.
  • the controller(s) 640 may be employed to control with precision the delivery of photoactivating light to the cornea 2 by operating the corresponding optical elements according to any combination of: wavelength, bandwidth, intensity, power, location, depth of penetration, and duration (the duration of the exposure cycle, the dark cycle, and the ratio of the exposure cycle to the dark cycle duration) of treatment.
  • cross-linking treatments described herein may be applied in combination with any eye therapy that may require additional stabilization of the corneal tissue.
  • the eye therapy may include selective incision of one or more sections of the cornea.
  • cross-linking treatments are combined with astigmatic keratotomy eye surgery (AK).
  • AK is a surgical procedure for correcting astigmatism, where incisions are made in the steepest part of the abnormally shaped cornea to relax the cornea into a rounded shape.
  • AK is often employed in combination with cataract surgery.
  • the resulting shape change from AK can be stabilized with cross-linking treatment.
  • a form of AK is called intrastromal astigmatic keratotomy (ISAK).
  • ISAK is performed in steps 710 and 720.
  • a cornea with astigmatism is measured and analyzed to determine the location(s) for intrastromal incision(s) that will relax the cornea into the desired shape.
  • a femtosecond laser is used to make incisions in the stroma of the cornea without breaking Bowman's or Descemet's membranes.
  • the length, height, and shape (e.g., arc radius) of the incisions, for example, may vary to achieve the desired corneal shape.
  • Riboflavin of a known concentration and quantity is then injected into the intrastromal incisions with a tiny needle and allowed to soak for a prescribed amount of time.
  • cross-linking activity is then initiated where photoactivating light may be titrated to get variable amounts of energy delivered to control the amount of astigmatic correction desired.
  • concentration and soak time for the application of Riboflavin and the irradiance, dose, and patterning for the delivery of the photoactivating light may be varied to achieve the required amount of cross- linking.
  • cross-linking treatments may be combined with radial keratotomy (RK), which is a surgical procedure for correcting myopia, where radial incisions are made to the cornea to make corrective shape changes.
  • RK radial keratotomy
  • the effect of applying the cross-linking agent may also allow smaller incisions to be used during AK or RK.
  • FIG. 13 illustrates an example system 800 that can be employed to apply cross- linking treatments with AK or RK, according to aspects of the present invention.
  • a cutting device 810 such as a femtosecond laser, is employed to create the desired incisions to the corneal tissue to make corrective shape changes according to AK or RK.
  • a cross-linking agent applicator 820 such as a syringe or needle, is employed to apply cross-linking agent (e.g., Riboflavin) to the area of the incisions.
  • cross-linking agent e.g., Riboflavin
  • Optical elements 840 such as a digital micro- mirror device (DMD) and/or other devices described herein, are employed to deliver photoactivating light from a light source 830, such as a UV light source, to the area of the incisions.
  • the optical elements 840 allow the photoactivating light to be precisely and accurately delivered to the areas treated with the cross-linking agent and to initiate the desired amount of cross-linking activity as described above.
  • One or more controllers 860 may be employed to control the operation of aspects of the system 800.
  • the controller(s) 860 may control the optical elements 840 to deliver photoactivating light according to any combination of: wavelength, bandwidth, intensity, power, location, depth of penetration, and duration (the duration of the exposure cycle, the dark cycle, and the ratio of the exposure cycle to the dark cycle duration) of treatment.
  • An eye-tracking and/or monitoring system 850 may be employed to provide feedback to the controller(s) 860 to control dynamically the progress of the incisions, the application of the cross-linking agent, and/or the application of the photoctivating light.
  • the pattern of the photoactivating light may be controlled through eye tracking and real-time monitoring of the procedure through fluorescence dosimetry, optical coherence tomography (OCT), interferometry, abberometry, etc.
  • systems may include one or more controllers (e.g., a computer processing system that reads instructions on computer-readable storage media) to process the information determined for the anatomy of the eye, determine the locations, sizes, and depths for incisions to the corneal tissue, control the incision device in forming the incisions, and/or control the eye treatment systems in applying the eye treatment to the eye.
  • the one or more controllers may be implemented as a combination of hardware and software elements.
  • the hardware aspects may include combinations of operatively coupled hardware components including microprocessors, logical circuitry, communication/networking ports, digital filters, memory, or logical circuitry.
  • the one or more controllers may be adapted to perform operations specified by a computer-executable code, which may be stored on a computer readable medium.
  • the one or more controllers may be a programmable processing device, such as an external conventional computer or an on-board field programmable gate array (FPGA) or digital signal processor (DSP) that executes software, or stored instructions.
  • FPGA field programmable gate array
  • DSP digital signal processor
  • physical processors and/or machines employed by embodiments for any processing or evaluation may include one or more networked or non-networked general purpose computer systems, microprocessors, field programmable gate arrays (FPGA's), digital signal processors (DSP's), micro-controllers, and the like, programmed according to the teachings of the exemplary embodiments, as is appreciated by those skilled in the computer and software arts.
  • the physical processors and/or machines may be externally networked with the image capture device(s), or may be integrated to reside within the image capture device.
  • Appropriate software can be readily prepared by programmers of ordinary skill based on the teachings of the exemplary embodiments, as is appreciated by those skilled in the software art.
  • the devices and subsystems of the exemplary embodiments can be implemented by the preparation of application-specific integrated circuits or by interconnecting an appropriate network of conventional component circuits, as is appreciated by those skilled in the electrical art(s).
  • the exemplary embodiments are not limited to any specific combination of hardware circuitry and/or software.
  • the exemplary embodiments may include software for controlling the devices and subsystems of the exemplary embodiments, for driving the devices and subsystems of the exemplary embodiments, for enabling the devices and subsystems of the exemplary embodiments to interact with a human user, and the like.
  • software can include, but is not limited to, device drivers, firmware, operating systems, development tools, applications software, and the like.
  • Such computer readable media further can include the computer program product of an embodiment for performing all or a portion (if processing is distributed) of the processing performed in implementations.
  • Computer code devices of exemplary embodiments can include any suitable interpretable or executable code mechanism, including but not limited to scripts, interpretable programs, dynamic link libraries (DLLs), Java classes and applets, complete executable programs, and the like. Moreover, parts of the processing of exemplary embodiments can be distributed for better performance, reliability, cost, and the like.
  • interpretable programs including but not limited to scripts, interpretable programs, dynamic link libraries (DLLs), Java classes and applets, complete executable programs, and the like.
  • DLLs dynamic link libraries
  • Java classes and applets Java classes and applets
  • complete executable programs and the like.
  • parts of the processing of exemplary embodiments can be distributed for better performance, reliability, cost, and the like.
  • Common forms of computer-readable media may include, for example, a floppy disk, a flexible disk, hard disk, magnetic tape, any other suitable magnetic medium, a CD- ROM, CDRW, DVD, any other suitable optical medium, punch cards, paper tape, optical mark sheets, any other suitable physical medium with patterns of holes or other optically recognizable indicia, a RAM, a PROM, an EPROM, a FLASH-EPROM, any other suitable memory chip or cartridge, a carrier wave or any other suitable medium from which a computer can read.
  • Riboflavin may be employed as a cross- linking agent
  • other substances may be employed as a cross-linking agent.
  • Rose Bengal 4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein
  • Rose Bengal has been approved for application to the eye as a stain to identify damage to conjunctival and corneal cells.
  • Rose Bengal can also initiate cross-linking activity within corneal collagen to stabilize the corneal tissue and improve its biomechanical strength.
  • photoactivating light may be applied to initiate cross-linking activity by causing the Rose Bengal to form radicals and to convert 0 2 in the corneal tissue into singlet oxygen.
  • the photoactivating light may include, for example, UV light or green light.

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Abstract

La présente invention concerne des systèmes et des méthodes de traitement d'un œil consistant à choisir des emplacements pour pratiquer des incisions dans des zones de la cornée correspondant à une kératotomie astigmatique ou une kératotomie radiale, pratiquer les incisions dans les zones choisies de la cornée, appliquer un agent de réticulation aux zones choisies de la cornée, et administrer une lumière de photoactivation à partir d'une source de lumière vers les zones choisies de la cornée afin d'initier une activité de réticulation dans les zones choisies de la cornée.
PCT/US2013/068588 2012-11-05 2013-11-05 Systèmes et méthodes permettant de redonner une forme à une partie constitutive d'un œil WO2014071408A1 (fr)

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US201261722613P 2012-11-05 2012-11-05
US61/722,613 2012-11-05
US13/841,617 US20130245536A1 (en) 2009-10-21 2013-03-15 Systems and methods for corneal cross-linking with pulsed light
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US11135090B2 (en) 2010-09-30 2021-10-05 Cxl Ophthalmics, Llc Ophthalmic treatment device, system, and method of use
US10575986B2 (en) 2012-03-29 2020-03-03 Cxl Ophthalmics, Llc Ophthalmic treatment solution delivery devices and delivery augmentation methods
US10729716B2 (en) 2012-03-29 2020-08-04 Cxl Ophthalmics, Llc Compositions and methods for treating or preventing diseases associated with oxidative stress
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EP2967986A4 (fr) * 2013-03-14 2016-11-16 Cxl Ophthalmics Llc Dispositif de traitement ophtalmique, systeme et procede d'utilisation
US11207410B2 (en) 2015-07-21 2021-12-28 Avedro, Inc. Systems and methods for treatments of an eye with a photosensitizer
EP4009928A4 (fr) * 2019-08-06 2023-08-02 Avedro, Inc. Systèmes et méthodes de photoactivation pour des traitements de réticulation cornéenne

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