(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`3 November 2011 (03.11.2011) (10) International Publication Number
`
`(43) International Publication Date
`
`WO 2011/137449 A2
`
`
`G1)
`
`International Patent Classification:
`A61F 9/008 (2006.01)
`A6IN 5/08 (2006.01)
`AGIN 5/067 (2006.01)
`A6IF 7/00 (2006.01)
`
`(74)
`
`Agents: LUPKOWSKI, Market al.; Squire, Sanders &
`Dempsey (US) LLP, 275 Battery Street, Suite 2600, San
`Francisco, California 94111 (US).
`
`(21)
`
`International Application Number:
`PCT/US201 1/034823
`
`(81)
`
`(22)
`
`International Filing Date:
`
`(25)
`
`(26)
`
`(30)
`
`(7)
`
`(72)
`(75)
`
`Filing Language:
`
`Publication Language:
`
`2 May 2011 (02.05.2011)
`
`English
`
`English
`
`Priority Data:
`61/330,168
`
`30 April 2010 (30.04.2010)
`
`US
`
`Applicant (for all designated States except US): SEROS
`MEDICAL, LLC [US/US]; 226 W. Edith Avenue, Unit
`#23, Los Altos, California 94022 (US).
`
`(84)
`
`Inventors; and
`Inventors/Applicants (for US only): HEREKAR,Satish
`¥V. [US/US]; 820 La Para Avenue, Palo Alto, California
`94306 (US). MANCHE, Edward E.
`[US/US]; 12005
`Moody Springs Court, Los Altos, California 94022 (US).
`EATON, Donald J. [US/US]; 226 West Edith Avenue,
`Los Altos, California 94022 (US).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, LD, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NL
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU,TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK,MT, NL, NO, PL, PT, RO, RS, SE, SL SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR,NE,SN, TD, TG).
`
`(54) Title: METHOD AND APPARATUS FOR TREATMENT OF OCULARTISSUE USING COMBINED MODALITIES
`
`[Continued on next page]
`
`
` A FORCE SENSIR
`
`DEFOGISER <7
`ILLUMINATIONS, =<
`GHILLED. WATER ae
`CHANMEL
`oe
`awe
`VACUUM CHANNEL va
`
`
`
`
`|
`LA
`
`SAPPHIRE LENS 7 we
`ee
`
`EYE"
`
`Figure 7
`
`(57) Abstract: An apparatus and a method
`are provided for treating a targeted area of
`ocular tissue in a tissue-sparing manner com-
`prising use of two or more therapeutic modal-
`ities, including thermalradiation source (such
`as an CW infrared fiber laser), operative in a
`wavelength range that has a high absorption
`in water, and photochemical collagen cross-
`linking (CXL),
`together with one or more
`specific system improvements, such as peri-
`operative feedback measurements for tailor-
`ing of the therapeutic modalities, an ocular
`tissue surface thermal control/cooling mecha-
`nism and a source of deuterated water/ ri-
`boflavin solution in a delivery system target-
`ing ocular tissue in the presence of the ultra-
`violet radiation. Additional methods of rapid
`cross-linking (RXL), are provided that further
`enables cross-linking (CXL)
`therapy to be
`combined with thermal therapy.
`
`
`
`
`
`wo2011/137449A2IMITINMINIITMTNANTAEA
`
`

`

`WO 2011/137449 A2 IfMMA TANTRA ANTM AOAMAAA
`
`Published:
`
`—_without international search report and to be republished
`upon receipt of that report (Rule 48.2(g))
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`METHOD AND APPARATUS FOR TREATMENT OF OCULAR TISSUE USING
`COMBINED MODALITIES
`
`BACKGROUND OF THE INVENTION
`
`This invention relates to apparatus and methodsfor treatment of ocular tissue and
`
`more particularly to altering opto-mechanical characteristics of targeted ocular tissue with the
`
`use of a continuous wave (CW)infrared laser in combination with other treatment modalities.
`
`This invention includes both the precise reshaping of corneal tissue for refractive correction
`
`and novel techniques for cross-linking the thermally treated corneal tissue to prevent such
`
`10
`
`tissue from regressing to its original shape.
`
`Overview of Current Cross-Linking Technology
`
`Cross-linking is a widespread method used to harden polymermaterials and to
`
`stabilize living tissue. More specifically in the medical arena, collagen cross-linking (CXL)
`
`and bonding technology has been used for many years in dentistry, orthopedics, and
`
`15
`
`dermatology.
`
`In 1998, a breakthrough occurred in ophthalmology when Theo Seiler, MD, PhD,of
`
`Zurich, Switzerland, used CXLto treat severe keratoconus (a progressive degenerative
`
`condition of the cornea wherethetissue thins and bulges forward). By 2000, after significant
`
`research into the safety aspects of this procedure by Dr. Seiler, Gregor Wollensak, MD,and
`
`Eberhard Spoerl, PhD (Germany), CXL was adopted by surgeons worldwide outside of the
`
`U.S.
`
`(In the US, clinical trials for the current version of CXLare underway.) In 2007 CXL
`
`received regulatory approval as a procedure in the European Union.
`
`The primary emphasis in the application of CXL for ophthalmologyhas been in the
`
`treatment of keratoconus, which is prevalent in about one in 2,000 people in the United
`
`States.
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`This condition is manifested by a weak cornea that becomestoo elastic and stretches,
`
`causing it to bulge outward. This condition changes the curvature of the cornea, which
`
`almost always leads to poor visual acuity (not correctable with glasses and/orsoft contact
`
`lenses) that requires the use of rigid gas permeable lenses. Thus, when the cornea begins
`
`losing its shape (i.e., becomes cone shaped instead of spherical), nearsightedness (myopia)
`
`and irregular astigmatism result, which causesthe blurring of vision. As this condition
`
`progresses, scarring and a very irregular corneal curvature may result. If a person cannot be
`
`helped with rigid contact lenses, then a corneal transplantation can be required.
`
`There are other conditions/corneal diseases where the cornea can becomestretched
`
`10
`
`and distorted, for example, such as surgically induced astigmatism. Another of these, where
`
`CXT is currently being utilized for correction, is in corneal ectasia. This condition involves
`
`stretching of the cornea (a collagen tissue) that occurs after refractive surgeries, such as laser
`
`in situ keratomileusis (LASIK) or photo-refractive keratectomy (PRK). Other corneal
`
`diseases in which CXLtreatment has been tried successfully include corneal ulceration
`
`15
`
`(possible sequelae to bacterial, viral or fungal infections) and bullous keratopathy (excess
`
`fluid accumulation causing corneal edema).
`
`The biomechanical basis of increased cornealstrength (i.e., stability and stiffness) is
`
`the result of the formation of covalent cross-links that occur when the photosensitizer,
`
`riboflavin (Vitamin B-2), is applied to the de-epithelialized surface of the cornea. This
`
`20
`
`excitation of the riboflavin by the UVAresults in the creation of free radicals that interact
`
`with aminoacids in neighboring collagen molecules to form strong chemical bonds.
`
`Known CXLproceduresare effective, but they are invasive and time-consuming,
`
`and they may havepotential safety issues. In knownprocedures, 0.1% riboflavin is
`
`formulated with a polysaccharide made of many glucose molecules such as dextran, and then
`
`25
`
`the surface layer of the cornea (epithelium) is surgically removed so the riboflavin can pass
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`(i.e., be absorbed) into the stroma (collagen layers) of the cornea. The riboflavin is applied
`
`with an eye dropper manually every 3 to 5 minutes for a total of 30 minutesprior to treatment
`
`(the pre-soak procedure). Following the pre-soak a continuous UVA light (wavelength of
`
`approximately 365-370 nm) is projected on the cornea for approximately 30 minutes, and
`
`there is no mechanism for measuring the depth of irradiation. During UVAirradiation
`
`riboflavin is continuously applied manually every 3 to 5 minutes with an eye dropper.
`
`Limitations of Existing CXL
`
`In knownprocedures, there is no measurement as to how muchriboflavinis in the
`
`stroma during the treatment, and there is no meansto assure prevention of cell damagein the
`
`10
`
`corneal endothelium, or in the limbus, which contains vital corneal limbal stem cells.
`
`In short, the existing procedure employing CXL has beenclinically proven (in
`
`Europe) to be safe. However, in its current form, the procedure is very crude and exhibits a
`
`numberofsignificant limitations including but not limited to the following:
`
`the procedure
`
`takes too long (approximately one hour in total); removal of the corneal epithelium is
`
`required, making the procedure invasive and uncomfortable for the patient intra-operatively
`
`and for 3 to 4 days following surgery. These limitations clearly preclude the use of CXL for
`
`many corneal treatments that would require a fast and highly accurate process for stiffening
`
`and stabilizing the cornea.
`
`Overview of Corneal Thermal Reshaping
`
`20
`
`It is known that thermal treatment of the cornea with various laser devices can
`
`reshape the corneafor refractive correction. Although some of the known thermaltreatments
`
`have been FDA approvedin the USA,all have eventually failed because ofthe natural
`
`regression of the corneato its original shape. This regression may occur overtime periods of
`
`months to a few years. Companies knownto have been active in the field are Refractec
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`(Conductive Kerotoplasty — CK), Thermal Vision, aka Avedro (Keraflex), Rodenstock
`
`(Diode Thermal Kerotoplasty - DTK withdrawn) and Sunrise (Laser Thermal Kerotoplasty —
`
`LTK withdrawn). However, there remains a need to predictably re-shape andstabilize the
`
`cornea after the thermal treatment, to increase the long-term successrate.
`
`None of the aforementioned thermal treatments have been surface sparing, which
`
`meansthe outer layers of the cornea (epithelium and Bowman’s membrane) may be damaged
`
`by these treatments. There are a numberof negative outcomes that can occur from such
`
`damage:
`
`(1) there is pain and wound healing that can induce corneal haze and leave the
`
`cornea vulnerable to infection; (2) the structural integrity of the corneais negatively
`
`10
`
`impacted; (3) near-term predictability of refractive outcomes is poor. These negative
`
`outcomescanbe alleviated by a thermal procedure which spares the epithelium and
`
`Bowman’s membrane. The delivery ofthermal radiation in a surface-sparing fashion has
`
`been performed in dermatology applications for surface treatment. These applications
`
`involve heat transfer that occurs as a result of passing thermal radiation through a cooled
`
`custom contact windowonthe skin, thereby protecting the epidermallayer.
`
`SUMMARYOF THE INVENTION
`
`Embodiments of the present invention comprise combined treatment modalities that
`
`include an apparatus and a method for providing treatmentto targeted areas of oculartissue.
`
`These embodiments of the invention comprise the use of two or more therapeutic modalities,
`
`20
`
`including a thermal radiation source (such as a CW infrared laser), operative in a wavelength
`
`range that has a high absorption in water, and can be delivered with a surface heat extraction
`
`mechanism; temperature or thermal control mechanism; or cooling mechanism (such as an
`
`oculartissue surface thermal control/cooling device, ¢.g., with a sapphire lens). The thermal
`
`treatment modality is combined with photochemical collagen cross-linking, together with one
`
`25
`
`or more optional specific system improvements, such as feedback measurements using
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`optical coherence tomography (OCT), monitoring, amongstothers, for tailoring of
`
`therapeutic modalities. Another therapeutic modality is a collagen cross-linking promoting
`
`agent, in particular, a formulation of deuterated water and riboflavin solution (plus other
`
`possible excipients) in a delivery system targeting ocular tissue in the presence ofthe
`
`ultraviolet radiation. New methods of more rapid cross-linking than what occurs with
`
`existing CXL, and,in its non-invasive embodiment are provided. When the rapid cross-
`
`linking (herein “R-XL”) is combined with the thermal subsurface (herein ““TS”) technology
`
`described herein, this combination is defined as TS-RXL.
`
`According to this TS-RXLprocess, a thermal control/heat exchanging/cooling
`
`10
`
`modality is applied to the surface of the eye while injecting infrared radiation to invoke intra-
`
`stromal thermaleffects (i.e., shrinkage) that promote corneal reshaping accompanied by rapid
`
`cross-linking. The thermal control/cooling mechanism maybea target-surface-mountable
`
`lens of highly thermally conductive material, such as sapphire, that is juxtaposed to the ocular
`
`tissue. Methods operative in accordance with the invention produce intended subsurface
`
`lesions that reshape oculartissue resulting in a stable form, because this thermal reshaping is
`
`followed by the application of RXL, which prevents regression thereof.
`
`The invention will be better understood by reference to the following detailed
`
`description in connection with the accompanying drawings.
`
`20
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure | is a spectral graph showing absorption parameters and range of wavelengths
`
`that could be used according to the invention.
`
`Figure 2 is a sub-surface lesion schematic diagram illustrating the various layers of
`
`the cornea, and a specific region desirable for lesion application and rangesoflesionsrelative
`
`25
`
`to a surface.
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`Figure 3 is a side cross-sectional view of a schematic representation of an exemplary
`
`lesion-induced myopic correction.
`
`Figure 4 is a side cross-sectional optical coherence tomography (OCT) image of post
`
`thermal sub-surface lesions in a humancorneal application.
`
`Figure 5 is a TS system block diagram according to the invention.
`
`Figure 6 is a composite drawing of an entire exemplar apparatus suitable for
`
`practicing the invention, detailing key components.
`
`Figure 7 depicts side and cross-sectional views of a patient interface assembly cone
`
`that houses components for corneal applanation.
`
`10
`
`Figure 8 is a top view of the following system optics: telescope for magnification
`
`adjust, XY scanner, Collimator, Eye viewing and pupil monitoring camera.
`
`Figure 9 is a chart that illustrates the comparison of cornealstiffness achieved from
`
`cross-linking with and without the use of a chilled lens at the time of thermal delivery.
`
`Figure 10 shows exemplary thermal patterns that may be delivered for various
`
`15
`
`treatment conditions, which may be further individualized according to the specific
`
`characteristics of the treated patient, as well as through feedback, as described herein.
`
`Figure 11 is an example of the PC screen used during TS surgical setup and
`
`treatment.
`
`Figure 12 showsthe thermal laser beam path in the system CAD model
`
`20
`
`Figure 13 shows ray-tracing simulation at the sapphire meniscus lens — eye interface
`
`Figure 14 showssimulated positions of selected spots on sapphire lens.
`
`Figure 15 shows simulated OCT beam path collinear with the thermallaser through
`
`the XY scannerto the sapphire lens.
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The invention includes a method and apparatus for treatment of oculartissue that
`
`spares the outer layers (epithelium and Bowman’s membrane) of the cornea during the
`
`application of combined therapeutic modalities. The combined therapeutic modalities
`
`include subsurface thermal remodeling and rapid collagen cross-linking (TS-RXL). Thefirst
`
`therapeutic modality, thermal remodeling, pertains to the altering of the shape of targeted
`
`ocular tissue with the use of thermal energy, preferably in the form of a programmable XY-
`
`scanning continuous wave (CW)infrared fiber laser. This laser is operated at a wavelength
`
`range that has a high absorptionin water (penetration depth of 0.1 mm to 1 mm, 0.2 mm to
`
`10
`
`0.6, or 0.4 to 0.5 mm, for example, 0.5 mm penetration depth typically, see Figure 1) thereby
`
`also protecting the endothelium. The second therapeutic modality involves the peri-opcrative
`
`(whichis herein defined as pre-, intra-, and/or post- the application of thermal radiation)
`
`cross-linking of collagen tissue to enhancestiffness, shape and/orstability of the treated
`
`tissue, that may be effected through a photochemical process utilizing UVA andriboflavin.
`
`15
`
`As a key feature of the invention, the thermal and photochemical energy and dosing
`
`is subject to programmable customization based on integrated feedback and control from
`
`peri-operative measuring systems such as, topographic, wavefront, and/or optical coherence
`
`tomography (OCT) measurement. Both thermal and UVAtherapeutic modalities can be
`
`further augmented by employing these various measurements for customized treatments.
`
`Such measurements may provide feedback to more precisely tailor the therapeutic modalities
`
`for a particular condition or a specific patient need. For example, topographic, fluorescent
`
`(including auto-fluorescence) and/or OCT measurements maybe used to tailor the dosing,
`
`temperature, location, intensity, duration, or energy patterns of the two therapeutic
`
`modalities.
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`In addition to the combination of thermal and photochemical therapeutic modalities
`
`with feedback control, the invention encompasses one or more fundamental and enabling
`
`improvements that will provide a gentleness (such as minimal opacification) of treatment.
`
`For example: 1) surface cooling/thermal control of the cornea associated with thermal
`
`treatment, which enables epithelium-sparing thermal treatment; 2) a combination of
`
`controlled power and scanning speed of the thermal laser beam for customization of
`
`treatment; and, 3) real-time OCT guided thermal delivery. It is significant and surprising that
`
`cross-linking becomes more effective because of the surface (which includes both epithelium
`
`and Bowman’s membrane) cooling/thermal control/sparing application (See Figure 9). Peri-
`
`10
`
`operative control information is provided for both the thermal procedure and rapid cross-
`
`linking (as described herein). The end result of these combined modalities is to provide
`
`highly accurate thermal corneal reshaping, together with enduring stability of outcomes; plus,
`
`this procedure is performed in a minimally invasive manner.
`
`Rapid cross-linking (RXL) is herein defined as an effective (increasing stiffness by
`
`15
`
`at least 50%) level of collagen cross-linking in less than 5 to 15 minutes. Several techniques
`
`can contribute to more rapid cross-linking. One method of RXL comprises, in a further
`
`combination, the more rapid stabilization of corneal tissue by means of application of pulsed,
`
`fractionated ultraviolet radiation (as such feature is described in US Patent Application
`
`12/273,444 published
`
`20
`
`as US-2009-0149923-A1, which is hereby incorporated by reference herein in its entirety) in
`
`the presence of the application of a deuterated water solution of riboflavin to the corneal
`
`surface (as such feature is described in WO 2011/019940, which is hereby incorporated by
`
`reference herein in its entirety), the combination of which is an effective embodiment of
`
`RXL.
`
`25
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`Thermal Therapeutic Modality and Delivery
`
`In the thermal radiation technique, a preferred embodimentis shown in the
`
`exemplar apparatus of Figure 6, where a CWinfrared fiber laser beam is the source of
`
`thermal radiation, and is delivered to the ocular tissue via a fiber coupled XY scannerthat
`
`projects pre-selected patterns for delivering said thermal radiation onto ocular tissue. The
`
`XY scanner of the exemplar apparatus is shownin Figure 8. A key benefit of the XY
`
`scanneris to significantly increase the flexibility for customizing thermal energy patterns for
`
`a variety of ocular conditions. Such a scanner permits the inclusion of highly integrated
`
`(speed + power + position + depth) and precise patterns that are designed and programmed to
`
`10
`
`treat a variety of ocular conditions (myopia, astigmatism, glaucoma, presbyopia, hyperopia,
`
`keractoconus and ectasia). These patterns may be pre-programmed oradjusted during a
`
`given treatment procedure by the surgeon and/or throughthe use of feedback mechanisms, as
`
`will be detailed below. Figure 10 illustrates examples of such patterns.
`
`In addition,
`
`flexibility is built into the apparatus to permit the surgeon the option to intervene and redirect
`
`15
`
`the apparatus to generate new orpatient-personalized pattern selections. This personalization
`
`capability illustrates the advantages and efficacy ofthe treatment.
`
`The thermal radiation in the exemplar apparatus of this method is delivered with
`
`adjustable scan speed and laser power through a temperature controlled/chilled custom
`
`applanation lens. This lens may be made of a material such as sapphire, diamond coated
`
`20
`
`glass, or clear YAG that provides high thermal conductivity, high heat capacity and optical
`
`transmission or by other meansfor thermal control/cooling the surface, such as a cryospray.
`
`This thermal control/cooling results in low collagen impact/disruption in the corneal stroma,
`
`and produces only a moderate sub-surface thermal temperature increase (i.e., less than about
`
`85 deg C). The result of this thermal control/cooling also provides protection to the
`
`25
`
`epithelium and Bowman’s layers of the cornea fromthe thermal application. Illustrations of
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`the thermal cone features of the examplar apparatus are depicted in Figure 7 and Figure 13.
`
`Figure 7 depicts side and cross-sectional viewsof a patient interface assembly cone that
`
`houses components for corneal applanation temperature. Figure 7 showsa sapphire lens
`
`whichis a thermal laser window as well as OCTlight delivery window, water channel for
`
`cooling water that is used to control the temperature of the sapphire lens, a lens defogger
`
`(pumped air nozzle) for defogging the sapphire lens, a suction ring labeled as vacuum
`
`channel, illuminator in for camera illumination, and a force sensor to sense force applied by
`
`the cone to the eye in excess of that by the suction ring.
`
`The exemplar apparatus uses a thermal radiation source, such as a CW infrared fiber
`
`10
`
`laser, which has a wavelengthin the range of 2013 nm (Tm: YAG). However, this apparatus
`
`may in the future be changed or upgraded whereby the CW infrared fiber laser may offer a
`
`tunable wavelength. This type of tunable CW fiber laser will enable a wavelength selection
`
`between 1.4 um to 1.54 um or 1.86 um to 2.52 um. These optical wavelengths provide an
`
`absorption length in water in the range of 200m to 600um,which is appropriate for the
`
`15
`
`intended application and may provide such a range of penetration depth in ocular tissue.
`
`Figure | shows absorption parameters and range of wavelengths that could be used. Other
`
`lasers could be included in this system which may have one or more fixed wavelengths or
`
`may be tunable. These laser features are presently embodied in the solid state lasers using the
`
`aforementioned Tm:YAGlaser crystal, or such laser features can also be obtained using Tm
`
`20
`
`fiber lasers or semiconductor lasers with electrical or optical excitation. The primary purpose
`
`of having this wavelength selection feature is to vary the penetration depth ofthe laser beam.
`
`Those skilled in the art will note that other methods of thermal radiation are
`
`available and knownin the field, encompassing other laser, microwave, radio-frequency
`
`(RF), electrical and ultrasound energy sources, and the invention is not here intended to be
`
`25
`
`limited to the aforementioned CW infrared fiber laser.
`
`10
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`Key Design Factors for Thermal Delivery
`
`The following are the design factors that distinguish the exemplar apparatus’
`
`thermal delivery from anyprior art, one or more such features being necessary to the practice
`
`of the invention:
`
`(1) A cornea- shaped, custom applanation lens (such as Plano-concave or meniscus,
`
`approximately 1 mm to 5 mm in thickness & 4mm to 20mmin diameter)is fitted on the
`
`ocular tissue (See Figure 13 for illustration and application oflens);
`
`(2) During the entire time or part of the time the thermal radiation source (e.g., a
`
`CWinfrared fiber laser) is applied, the ocular tissue surface and the stromal collagen tissue
`
`are temperature controlled, preferably by a sapphire contact lens. The lens surface may be
`
`maintained at a temperature ranging from 0 degrees to 20 degrees C, or from 8 to 18 degrees
`
`C and preferably about 8 to 11 degrees C, during the course of a thermal radiation treatment.
`
`Dueto the proximity and thermal conductivity of the epithelium and stroma, an effect of the
`
`surface thermal control/cooling is to enable the precise control of temperature in the stroma.
`
`15
`
`The surface temperature is continuously monitored and displayed on the PC screen. The
`
`inventionis not limited to this method of temperature control. Other methods of temperature
`
`control may be used, including other methodsof direct thermal contact of the tissue surface
`
`with heated or cooled solids, liquids, or gases, as well as indirect methods, such as through
`
`the use of thermal radiation sources and may be used in the present invention.
`
`20
`
`(3) A custom suction ring applanates the ocular tissue to the sapphire lens in a
`
`gentle mannerprior to, throughout, and following the thermal procedure, which enables a
`
`precise thermal control/cooling effect on the anterior most membranesto be protected (such
`
`as epithelium and Bowman’s membranes and conjunctiva or blood vessels). The suction ring
`
`also provides greater laser registration and resistance to patient saccadic type movement. (See
`
`25
`
`Figure 7 for illustration of an exemplar cone with vacuum suction ring assembly.)
`
`11
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`Noninvasive Application of Thermal Lesions
`
`Based uponthe design factors set forth above, the exemplar apparatus is capable of
`
`transmitting thermal radiation through the epithelium and Bowman’s membranes(or
`
`conjunctiva, during scleral treatment) into the anterior ocular tissue (such as the stroma or
`
`sclera), while minimally disrupting these membranes. The result is that, such novel
`
`controlled thermal radiation is able to reach collagen fibers beneath these protected
`
`membranes, thus sparing the epithelium from adverse effects, such as reduced rates of wound
`
`healing, morbidity, scarring and haze formationor susceptibility to infections.
`
`Figure 2 is a schematic diagram of sub-surface lesions illustrating the various layers
`
`10
`
`ofthe cornea, and the specific region in the stroma desirable for lesion application and ranges
`
`of lesions relative to a surface. See,Vangsness, C, et al., Clinical Orthopaedics and Related
`
`Research, Number 337, pp 267-271; Gevorkian, S.G., et al., 102, 048101 (2009), both of
`
`whichare incorporated by reference herein. The thermal radiation creates a subsurface lesion
`
`in the collagen fibers that is preferably controlled to begin approximately 80 um to 100 ym
`
`15
`
`below the surface. The targeted collagen fibers affected by the lesion begin at this subsurface
`
`level and may continue to a typical depth of approximately 300 um (and preferably within a
`
`range of 100 um to 400 pm). The typical annular lesion created by an annular scan ofthe
`
`thermal radiation may have a width or thickness of the annulus of approximately 0.2mm to
`
`Imm. The primary impactof the lesion is controlled at a desired depth and width within the
`
`20
`
`targeted ocular tissue, and will not induce lesions in or adversely affect the Descemet or
`
`endothelium membranes.
`
`The precise control of the depth, shape and size of such thermallesions is a key
`
`benefit of the invention. Such precise control is a crucial advantage over previous methods.
`
`For the targeted lesion volume, the apparatus is pre-set (via nomograms, Real-Time-OCT,
`
`12
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`and temperature feedback) to create lesions that provide only controlled limited shrinkage of
`
`the collagenfibers.
`
`The system of the inventioncontrols the temperature as a function of depth to
`
`induce thermal remodeling or a change in shape of the cornea surface while sparing the
`
`surface layers. The temperature is also controlled to obtain the desired remodeling in a short
`
`time frame to reduce the treatment time for the patient. The thermal remodeling is induced
`
`through thermally induced shrinkage of collagen in the subsurface regions, specifically, the
`
`stroma.
`
`It is known that collagen shrinkage is induced by thermaltreatment(i.e., heating or
`
`increase in temperature). The rate of shrinkage or generally time dependence and the manner
`
`10
`
`of modification of collagen are known to depend on the temperature range. Little or no
`
`collagen shrinkage is expected to occur below 40 deg C or 50 deg C. Collagen shrinkage
`
`may occur above 50 deg C, however, in the 50 to 60 deg C range, the shrinkage occurs at a
`
`relatively slow rate. In addition, thermally induced collagen shrinkage may belinear up to
`
`about 70 to 75 deg C. Above about 75 to 80 deg C collagen shrinkage is rapid and non-
`
`15
`
`linear, resulting in the unraveling the collagentriple helix.
`
`In the present invention, the temperature of the epithelium and Bowman’s layeris
`
`preferably controlled to be less than 40 deg C, 40 to 50 deg C, or more narrowly, less than 18
`
`deg C. Asa result, no collagen shrinkage is expected or preferred to occurin these regions.
`
`However, the temperature in these surface layers can be above 40 deg C in some
`
`20
`
`embodiments with minimal shrinkage.
`
`In some embodiments, it is preferred to induce local shrinkage in a slow but linear
`
`manner for improved near term predictability. Therefore, in the present invention, the stroma
`
`is preferably exposed to temperatures of 50 to 75 deg C, or more narrowly, 60 to 65 deg C, 65
`
`to 70 deg C, or 70 to 75 deg C. In such embodiments, it is desirable to control the
`
`temperature to be sufficiently low to obtain collagen shrinkage in a linear manner and also
`
`13
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`controlling the temperature to be sufficiently high to obtain desired thermal remodeling in a
`
`short treatment time. However, the invention can further include exposing the stromato
`
`temperatures above 75 or 80 deg C and can further include inducing shrinkage in a rapid and
`
`nonlinear manner. Additionally, the temperature of layers below the stroma, the endothelium
`
`and Descemetlayers, is controlled so that there is little or no shrinkage, for example, to be
`
`less than 50 deg C, or 40 deg C. Furthermore, the creation of lesion boundaries (“edges”) can
`
`be more accurately defined by using a CW infrared fiber laser beam that is tightly focused.
`
`For example, using a laser with a high quality beam which allows for a focal diameter of
`
`about 100 um to about Imm at the desired working distance.
`
`10
`
`Functions of Subsurface Lesions
`
`The sub-surface lesions in the oculartissue are designed to produce one or a
`
`combination of the following effects:
`
`1) The thermal lesions generate collagen shrinkage that cause specific programmed
`
`re-shaping ofthat tissue. Specifically, the reshaping can include flattening or steepening of
`
`15
`
`the cornea corresponding to specific ranges of increase or decrease in diopter, respectively.
`
`For example, such re-shaping mayflatten (up to or over 5 Diopters) or steepen (up to or over
`
`5 Diopters) the cornea. Additionally, High Order Aberrations (IIOA’s) may be induced(e.g.,
`
`by over 2 um). Figure 3 illustrates an exemplary anterior corneal surface change due
`
`tomyopic correction showing the corresponding cross-section and lesion location. Figure 10
`
`20
`
`illustrates examples of refractive radiation energy treatment patterns for such myopia
`
`treatments.
`
`2) The thermal lesions can be applied in sequential patterns which can induce
`
`controlled directed tissue translocation (over 1 mm).
`
`3) The thermal lesions can modulate tissue elasticity (i.e., soften ocular tissue by
`
`14
`
`

`

`WO 2011/137449
`
`PCT/US2011/034823
`
`more than 90% of its pre-operative state).
`
`4) The thermallesions may cause shrinkage of ocular tissue (collagen fibers) that
`
`can force the opening of adjacent drainage channels, such as Schlemm’s canal and thereby
`
`reduce intra-ocular pressure (IOP).
`
`In summary, sub-surface lesions can be produced in ocular tissue that are
`
`s