JP2012502668A - Eye treatment system - Google Patents

Abstract

Heat is generated in the corneal fibrils of the cornea of the eye according to a selected pattern. The heat causes a morphological change of the corneal fibrils from the first form to the second form corresponding to the selected pattern. The second configuration provides the desired corneal remodeling. Next, the cross-linking agent is activated in the region corresponding to the selected pattern of corneal fibrils. The crosslinker prevents changes from the second form of corneal fibrils. As such, embodiments stabilize the corneal tissue and improve biomechanical strength after the desired shape change in the corneal tissue is achieved. Thus, embodiments help maintain the desired corneal remodeling.

Description

Cross-reference of related applications This application is a US Provisional Application No. 60 / 992,486 filed on Dec. 5, 2007, US Provisional Application No. 61 / 098,489 filed on Sep. 19, 2008, and Claims the benefit of US Provisional Application No. 61 / 101,509, filed Sep. 30, 2008, the disclosure of which is fully incorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to the field of keratoplasty, and more particularly to systems and methods for stabilizing changes in corneal tissue after applying energy to the corneal tissue.

2. Description of Related Art Various eye diseases such as myopia, keratoconus, and hyperopia are caused by the abnormal shape of the cornea. Keratoplasty is intended to correct such diseases by reshaping the cornea. For example, in myopia, the refractive power of the eye becomes excessively large due to the shape of the cornea, and the focal point of the image is in front of the retina. By flattening the shape of the cornea by keratoplasty, the refractive power of myopic eyes can be reduced, and the image can be properly focused on the retina.

  In order to reshape the cornea, invasive surgical procedures such as laser in situ keratoplasty (LASIK) can be employed. However, such invasive surgery generally requires a long treatment period after the operation. In addition, such surgery can cause dry eye syndrome by cutting corneal nerves.

On the other hand, keratoplasty is a non-invasive operation that can be used to correct the vision of a person with a disorder such as myopia, keratoconus disease, or hyperopia associated with the abnormal shape of the cornea.
Corneal thermoplasty can be performed by irradiating electrical energy in the microwave band or radio frequency (RF) band. Specifically, microwave corneal thermoplasty can use a near-field microwave irradiation device to irradiate the cornea with energy to raise the temperature of the cornea. At about 60 ° C., the collagen fibers in the cornea contract. The onset of contraction is rapid and the pressure resulting from the contraction reforms the surface of the cornea. Therefore, the present invention is not limited to this. For example, the shape of the cornea can be flattened and the visual acuity of the eye can be improved by irradiating the heat energy with a specific pattern such as a circular shape or an annular shape.

SUMMARY OF THE INVENTION Embodiments according to aspects of the present invention provide for stabilization of corneal tissue and increased biomechanical strength after a desired structural change in corneal tissue has been achieved. A system and method are provided. For example, this embodiment helps to maintain targeted corneal remodeling by performing corneal thermoplasty.

Thus, in some embodiments, heat is generated in the corneal fibrils of the eye's cornea according to the selected pattern. The heat causes the corneal fibrils to change from the first form to the second form corresponding to the selected pattern. The second form provides for the remodeling of the cornea. And in the area | region of the corneal fibril corresponding to the selected pattern, a crosslinking agent is activated. The cross-linking agent prevents corneal fibrils from changing from the second form.
In some embodiments, the cross-linking agent is applied according to a selected pattern. In other embodiments, an initiator for activating the cross-linking agent may be applied to corneal fibrils treated according to a selected pattern.

In certain embodiments, a system is provided that includes a source of cross-linking agent or initiating element. Crosslinkers maintain the structural changes in corneal fibrils generated by the application of heat to the eye. Initiators activate cross-linking activity in corneal fibrils.
The system includes a delivery device that can be placed between the eye and the source. The delivery device defines a selected pattern and delivers a crosslinker or initiator to the corneal fibrils according to the selected pattern. The initiator may be, for example, ultraviolet light. In some embodiments, the delivery device may be a mask that blocks ultraviolet light according to a selected pattern. In other embodiments, the transport device may be an optical device that redirects ultraviolet light emitted from the source to define the pattern. In certain embodiments, the delivery device may be an axicon capable of converting ultraviolet light as a collimated beam received from a source into concentric light.

  These and other aspects of the invention will become more apparent by looking at the preferred embodiments of the invention described below in conjunction with the accompanying drawings.

FIG. 1 illustrates a system that applies heat to the cornea for remodeling the cornea. FIG. 2A shows a high resolution image of the cornea after heat has been applied. FIG. 2B shows another high resolution image of the cornea of FIG. 2A. FIG. 2C shows a tissue image of the cornea of FIG. 2A. FIG. 2D shows another tissue image of the cornea of FIG. 2A. FIG. 3A illustrates an approach for stabilizing corneal structure changes caused by application of energy according to an aspect of the present invention. FIG. 3B illustrates another approach for stabilizing corneal structure changes caused by application of energy according to aspects of the present invention. FIG. 3C illustrates yet another approach for stabilizing corneal structure changes caused by application of energy according to aspects of the present invention. FIG. 3D illustrates yet another approach for stabilizing corneal structure changes caused by application of energy according to aspects of the present invention. FIG. 4A illustrates a system that uses a mask to initiate cross-linking within the corneal tissue after application of energy according to an aspect of the present invention. FIG. 4B illustrates the starting pattern for the mask of FIG. 4A. FIG. 5A illustrates a system that uses an optical device to initiate cross-linking within corneal tissue after application of energy according to an aspect of the present invention. FIG. 5B illustrates a start pattern corresponding to the optical device of FIG. 5A. FIG. 6 illustrates another approach for stabilizing corneal structure changes caused by application of energy according to aspects of the present invention.

DETAILED DESCRIPTION OF THE INVENTION FIG. 1 illustrates a system that applies energy to the cornea 2 of an eye 1 to generate heat and reshape the cornea. Specifically, FIG. 1 shows an applicator 110 comprising an electrical energy conducting element 111 operably coupled to a source 120 of electrical energy, for example via a conventional conducting cable.
The electrical energy conducting element 111 extends from the proximal end 110A of the applicator 110 to the distal end 110B. The electrical energy conducting element 111 conducts electrical energy from the source 120 to the distal end 110B in order to apply thermal energy to the cornea 2 disposed at the distal end 110B. Specifically, the electrical energy source 120 may include a microwave oscillator for generating microwave energy. The oscillator may be operated, for example, in the range of microwave frequencies from 400 MHz to 3000 MHz, and more specifically at frequencies near 915 MHz or 2450 MHz that have been used safely in other applications. As used herein, the term “microwave” can generally correspond to frequencies from about 10 MHz to about 10 GHz.

  As further shown in FIG. 1, the electrical energy conducting element 111 may include two microwave conductors 111A, 111B extending from the proximal end 110A of the applicator 110 to the distal end 110B. Specifically, the conductor 111A is an outer conductor having a substantially cylindrical shape. On the other hand, the conductor 111B is a substantially cylindrical inner conductor that extends along an internal passage that penetrates the conductor 111A. The conductor 111A has an internal passage and has a substantially tubular shape. Inner and outer conductors 111A, 111B can be formed of, for example, aluminum, stainless steel, brass, copper, other metals, coated metals, metal-coated plastics, or other suitable conductive materials.

  Conductor 111A and conductor 111B are concentrically arranged, and a substantially annular gap 111C having a selected distance is defined between conductor 111A and conductor 111B. The annular gap 111C extends from the proximal end portion 110A to the distal end portion 110B. In order to separate the conductor 111A and the conductor 111B, a dielectric material 111D may be used in a portion of the annular gap 111C. The distance of the annular gap 111C between the conductor 111A and the conductor 111B determines the penetration depth of the microwave energy into the cornea 2 according to established microwave field theory. In this way, the energy conducting element 111 receives the electrical energy generated by the electrical energy generation source 120 at the proximal end portion 110A and directs the microwave energy toward the distal end portion 110B where the cornea 2 is disposed. Dodge.

  In general, the outer diameter of the inner conductor 111B may be selected to achieve an appropriate change in corneal shape caused by irradiation of microwave energy, ie, a corneal curvature measurement method. On the other hand, the inner diameter of the outer conductor 111A may be selected to achieve the desired gap between the conductor 111A and the conductor 111B. For example, the outer diameter of the inner conductor 111B ranges from about 2 mm to about 10 mm, while the inner diameter of the outer conductor 111A ranges from about 2.1 mm to about 12 mm. In some systems, the annular gap 111C may be small enough to minimize exposure of the corneal endothelium layer (rear surface) and increase the temperature during application of energy by the applicator 110, for example about 0. It may range from 1 mm to about 2.0 mm.

The controller 140 may be used to selectively apply energy multiple times according to a predetermined or planned order. Also, any time heat may be applied. Further, the amount of heat applied may vary. By adjusting such parameters for applying heat, the degree of change caused inside the cornea 2 can be determined. Of course, the system may attempt to limit changes in the cornea 2 in accordance with the selected pattern in order to achieve an appropriate amount of collagen fibril contraction in the selected region.
In order to generate heat in the cornea 2 using microwave energy, for example using the applicator 110, low power (on the order of 40W), long pulse length (on the order of 1 second) of microwave energy is applied. However, other systems may apply short pulses of microwave energy. In particular, it may be advantageous for the duration of applying microwave energy to be shorter than the time of heat diffusion in the cornea. For example, microwave energy may be applied at a higher power in the range of 500 W to 3 KW, with a pulse duration in the range of about 10 milliseconds to about 1 second.

Referring again to FIG. 1, at least a portion of each of the conductors 111A, 111B is electrically insulated to minimize current density in the contact area between the corneal surface (epithelium) 2A and the conductors 111A, 111B. It may be covered by the body. In some systems, the conductors 111A, 111B, or at least some of them, may be coated with a material that can function as an electrical insulator and a thermal conductor.
A dielectric layer 110D may be used along the distal end 110B of the applicator 110 to protect the cornea 2 from current flowing into the cornea 2 through the conductors 111A, 111B. Such currents can cause undesirable temperature effects in the cornea 2 and can prevent the maximum temperature in the collagen fibrils in the mid-depth region 2B of the cornea 2 from being achieved.
Therefore, the dielectric layer 110 </ b> D is disposed between the conductors 111 </ b> A and 111 </ b> B and the cornea 2. Dielectric layer 110D is thin enough to minimize the effect on microwave emissions and is thick enough to prevent deposition of electrical energy on the surface due to conduction current flow. It may be a thing. For example, dielectric layer 110D may be a biocompatible material deposited to a thickness of about 0.002 inches.
In general, the conductor 111A, as long as it does not substantially affect the strength and penetration of the microwave radiation field, sufficient penetration of the microwave field in the cornea 2 and the intended heating pattern in the cornea 2. An intervening layer such as a dielectric layer 110 </ b> D may be used between 111 </ b> B and the cornea 2.
The dielectric may be an elastic material such as polyurethane or silastic, or may be an inelastic material such as Teflon (registered trademark) or polyimide. The dielectric may have a constant dielectric constant, or may have a dielectric constant that varies by mixing a plurality of materials or doping a sheet. Various dielectrics may be spatially dispersed to affect the microwave heating pattern in a customized manner.
The thermal conductivity of a substance may have a certain thermal characteristic (thermal conductivity or specific heat), or may vary spatially by mixing or doping of a plurality of substances. A means for changing the heating pattern is provided. Another approach for spatial modification of the heating pattern is to make dielectric sheet materials with various thicknesses. The thick region has a lower heating rate than the thin region and provides additional means for the spatial distribution of microwave heating.

  As shown in FIG. 1, during operation, the distal end 110B of the applicator 110 is placed on or near the corneal surface 2A. The applicator 110 is preferably in direct contact with the corneal surface 2A. In particular, such direct contact may cause conductors 111A, 111B to substantially cornea surface 2A (or if there is a thin intervening layer between conductors 111A, 111B and cornea surface 2A). (Near the surface 2A). As a result, direct contact ensures the formation of a heating pattern by microwaves in corneal tissue having substantially the same shape and size as the gap 111C between the two microwave conductors 111A, 111B. To help.

  The system described in FIG. 1 is provided for illustrative purposes only, and other systems may be used for the application of heat to cause corneal remodeling. Other systems include, for example, U.S. Patent Application No. 12 / filed on Sep. 11, 2008, which is a continuation-in-part of U.S. Patent Application No. 11 / 898,189 filed on Sep. 10, 2007. 208,963, the contents of these applications are fully incorporated herein by reference. The applicator 110 and cooling system are used in combination to apply a coolant to the cornea 2 and determine the amount of energy to be applied to the cornea 2, as described in US Patent Application No. 12 / 208,963. May be.

  2A to 2D show examples of effects when heat is applied to corneal tissue using a heating system as shown in FIG. Specifically, FIGS. 2A and 2B show high resolution images of the cornea 2 after heat has been applied. As shown in FIGS. 2A and 2B, the damage 4 extends from the corneal surface 2A to the mid-depth region 2B of the corneal substrate 2C. Damage 4 is the result of a change in corneal structure caused by the heating described above. These structural changes lead to an overall remodeling of the cornea 2. However, it should be noted here that the application of heat does not cause any heat-induced damage to the corneal tissue.

Further, as shown in FIGS. 2A and 2B, the change in corneal structure is local and limited to the area and depth specifically defined by the applicator as described above.
FIGS. 2C and 2D are images of tissue structures in which the tissue shown in FIGS. 2A and 2B is colored to emphasize the structural changes caused by heat. In particular, the difference between the structure of the collagen fibrils in the mid-depth region 2B through which heat penetrates and the structure of collagen fibrils outside the mid-depth region 2B can be clearly seen. Thus, collagen fibrils outside of region 2B will generally be outside of region 2B, despite the formation and reconstitution of new bonds to form a completely different structure. Maintains an unaffected state by applying heat. In other words, the collagen fibrils in the region 2B are completely new, unlike a process such as corneal orthodontic treatment that compresses the corneal region and mechanically deforms the cornea.

That is, by applying energy to the cornea with an applicator such as the applicator 110 shown in FIG. 1, heat is generated to produce the desired corneal remodeling. Heat causes structural changes in the corneal collagen fibrils, but if the fibrillar change continues after the desired remodeling is achieved, the desired corneal remodeling effect is at least partially May decrease or may have the opposite effect.
Accordingly, aspects of the present invention provide a means for reshaping the cornea by applying heat and maintaining the desired corneal structure. Specifically, embodiments of the present invention provide for cross-linking of corneal fibril molecules to stabilize corneal tissue and improve its biomechanical strength after the desired corneal shape change is achieved. A means for initiating the bond is provided. Cross-linking is caused, for example, in the damaged corneal substrate 2C formed by heating as shown in FIGS.

  FIG. 3A illustrates an embodiment 300A according to aspects of the present invention. Specifically, in step 310, energy is applied to the corneal tissue to generate the structural changes and target shape changes caused by the heat already described. In step 320, the altered corneal tissue is treated with a crosslinker 322. Next, in step 330, the crosslinker 322 is activated by the initiating element 332. The activation of the crosslinking agent 322 can be caused thermally, for example, by irradiation with light or microwaves.

  As further shown by the embodiment 300B of FIG. 3B, in step 320, riboflavin is applied locally to the altered corneal tissue as a crosslinker 322 ′ and in step 330 in the corneal region treated with riboflavin. In order to initiate cross-linking, ultraviolet (UV) light may be irradiated as initiating element 332 ′. Specifically, ultraviolet light initiates cross-linking activity by activating the applied riboflavin to release reactive oxygen radicals in the corneal tissue.

Techniques for causing corneal cross-linking may require removal of the epithelium across the entire surface of the cornea prior to topical application of riboflavin to the corneal matrix. This technique is applied to all surfaces of the cornea. In addition, this technique typically requires epithelial debridement in order to activate the crosslinker by allowing the crosslinker to penetrate the matrix and bombard the substrate with ultraviolet light.
Epidermic debridement facilitates the transmission of crosslinkers and the transmission of ultraviolet light to the substrate. This is because the epithelium may at least partly act as a barrier. This technique actually initiates cross-linking in the substrate, but may have an undesirable effect. Specifically, application of a cross-linking agent over a wide range may cause corneal tissue hardening and unpredictable refractive power results across the cornea.

However, according to aspects of the invention, the embodiment does not apply cross-linking agents and activated ultraviolet light throughout the cornea. Rather, the cross-linking agent is initiated at a smaller portion of the cornea corresponding to the location of injury 4, for example as shown in FIGS. In fact, when the applicator 110 described above is applied to the cornea 2, energy is applied according to a pattern defined by the shape of the energy conducting element 111 at the distal end 110B.
Correspondingly, the cornea 2 experiences structural changes only in the region corresponding to the shape of the energy conducting element 111. As such, embodiments require that the cross-linking agent be applied only to a limited area of the cornea 2 that has experienced the desired structural changes. By applying the cross-linking agent according to a controlled pattern, the embodiment achieves more accurate cross-linking activity and minimizes unpredictable refractive power changes that may result from the application of the cross-linking agent to a wider range. Turn into.

Thus, as shown in embodiment 300B of FIG. 3B, in an embodiment, a cross-linking agent 322 ′, i.e. riboflavin, is applied in step 320, and in step 330, prior to irradiation with the starting element 332 ′, i.e. ultraviolet light, step At 315, the epithelium is removed in a pattern.
Embodiments do not remove the epithelium extensively across the entire cornea, but rather remove only the epithelium of a specific region of the cornea that has undergone a structural change according to the intended pattern. Limiting the removal of the epithelium to a smaller area will reduce patient pain after surgery and have the beneficial effect of reducing the duration of treatment and minimizing other complications associated with removal of the epithelium. Will be connected.

In areas where the epithelium has not been removed, the epithelium is at least partially a barrier to initiation of cross-linking, but in embodiments, a mask may be used to limit cross-linking activity to the target area of the cornea. Good.
As shown in the system 400 of FIG. 4A, a mask 410 may be placed on the corneal surface 2A prior to irradiating the starting element 332, ie, ultraviolet light from the light source 331, FIG. An example is shown. Specifically, the mask 410 may be an apparatus similar to a contact lens having a diameter of approximately 5 mm.
As described above, the energy conducting element 111 of the applicator 110 shown in FIG. 1 includes two concentric conductors 111A and 111B. The two concentric conductors 111A, 111B add energy to the cornea in a pattern corresponding to the annular gap 111C between them. As such, the region of the cornea 2 where the structure changes results in corresponding to the annular pattern. In order to stabilize these structural changes, it is usually necessary to initiate cross-linking only in regions along the circular pattern of the structural changes. As a result, the mask 410 of FIG. 3 only allows passage of ultraviolet light from the light source 331 to the cornea 2 and a cross-linking agent, such as riboflavin, is activated along the circular pattern 414. Specifically, the ultraviolet blocking material 412 defines the pattern 414 in the mask 410.
In other embodiments, the pattern 414 may be structurally defined as a cut out from the mask 410. Anyway, any ultraviolet light from the light source 331 outside this pattern 414 is blocked by the mask 410. Therefore, this mask 410 allows more accurate activation of the cross-linking agent.

Thus, in the embodiment 300C of FIG. 3, in step 315, the limited pattern of epithelium is removed, and in step 320, a crosslinker 322, such as riboflavin, is applied to the area where the epithelium has been removed, and then in step 325. A mask 410 is applied to the eye.
When the crosslinker 322 is effectively applied to the substrate, the mask 410 more precisely defines where the applied riboflavin should be activated on the substrate.
Accordingly, at step 330, the eye is irradiated with an initiating element 332, eg, ultraviolet light, to initiate cross-linking according to the pattern of the mask 410.

Before the cross-linking agent such as riboflavin is effectively applied to the substrate, the epithelium covering the substrate is removed, but the cross-linking agent is chemically movable from the epithelium toward the substrate. I know. Indeed, riboflavin can also be transported to the substrate by being applied locally to the epithelium. Thus, in the embodiment 300D shown in FIG. 3D, it is not required to remove the epithelium. Further, in some examples, the epithelium may be used to facilitate the movement of the cross-linking agent by passing through the epithelium. Thus, in step 320 ′, the cross-linking agent may be applied directly to the epithelium.
With proper delivery of the cross-linking agent to the substrate, in step 325, the mask 410 is applied to the eye, and in step 330, an initiating element 332 for initiating cross-linking according to the pattern of the mask 410 is delivered.
The embodiment 300D shown in FIG. 3D advantageously eliminates post-operative pain, duration of treatment, and other complications associated with epithelial removal.

  Although the mask 410 is used to deliver the starting element 332 to the cornea according to a particular pattern, in some embodiments the mask 410 may be used to deliver a crosslinker according to a particular pattern. Good. Accordingly, the light source 331 of the starting element shown in FIG. 4A may be replaced with a source of crosslinker.

Furthermore, although the system 400 may use a mask 410, the means used for the patterned initiation of the cross-linking agent is not limited to the use of such a mask. Embodiments may further include general systems and methods for activating the cross-linking agent according to a precise pattern, regardless of the type of means that actually moves the initiating element to a specific region of the cornea. For example, as shown in FIG. 5A, the system 500 converts the starting element 332A, eg, ultraviolet light, emitted from the light source 331 to define the target pattern 514 shown in FIG. 5B.
In contrast to the system 400, the system 500 does not prevent the starting element 332 from the light source 331 from reaching the outside of the pattern. As shown in FIG. 5A, an optical device such as the Axicon 510 receives the ultraviolet light from the light source 331 as a parallel beam 332A and converts the parallel beam 332A into a light ring 332B. The annulus 332B thus carries ultraviolet light to the cornea 2, for example according to an annular pattern 514 corresponding to the structural changes caused by the applicator 110 described above. In other words, the pattern 514 coincides with the target region that initiates the binding of the crosslinker. In general, any number or type of optical device, such as a lens, beam splitter, etc., can be used as a means for transporting the starting element into the desired shape. Further, in some embodiments, a mask as shown in FIG. 4A may be used in combination with an optical device.

In the above-described embodiment, an example in which a bridging element such as riboflavin is directly applied to the cornea has been shown, but other techniques for delivering a cross-linking agent to the cornea may be used. For example, as shown in embodiment 600 of FIG. 6, in step 610, thermally sensitive liposomes having a crosslinker 622 therein may be applied to the treatment site of the cornea.
Specifically, thermally sensitive liposomes are applied to areas where heat is generally applied for corneal remodeling. In step 620, heat is applied to the cornea using, for example, the applicator 110 described above. As mentioned above, heat causes structural changes in the cornea. However, since thermally sensitive liposomes 612 have also been applied to the cornea, heat from the applicator causes the release of the crosslinker 622 from the thermally sensitive liposomes. Since heat is applied in the desired shape for the desired remodeling of the cornea, the thermally sensitive liposomes 612 in the area of the pattern are activated by the heat to release the crosslinker 322. . As such, only the region where the structure has changed, that is, the region where heat is applied, is in contact with the cross-linking agent 622. As with the other embodiments described herein, the cross-linking agent 622 is applied to a limited area where stabilization of structural changes in the cornea is desired.
As shown in FIG. 6, if further activation of the crosslinker 322 is required, then in step 630, an initiating element 332 is applied according to the techniques described herein. While the embodiments described herein may use a starting element, other embodiments may not require a starting element. In the embodiment shown in FIG. 6, the pattern of cross-linking activity is achieved by patterned delivery of the cross-linker 322 using thermally sensitive liposomes 612 rather than patterned delivery of the initiating element 332. Yes.

  In other embodiments, the cross-linking agent may be delivered using thermally sensitive liposomes, but the heat that activates the thermally sensitive liposomes is the heat that causes corneal remodeling. There is no need to match. For example, thermally sensitive liposomes may be applied after the cornea has been reshaped, and a second heating may be performed to release the crosslinker. In some embodiments, the second heating does not cause a change in the shape of the cornea. In other embodiments, the second heating may cause an additional (desired) corneal shape change. As described above, heating may be performed according to a specific pattern in order to limit the region to which the cross-linking agent is applied to a region where stabilization of the shape change of the cornea is desired.

In the embodiment described here, the cross-linking in the cornea is initiated according to an annular pattern defined by an applicator such as the applicator 110 shown in FIG. 1, but in other embodiments the initiation pattern is a specific shape. It is not limited to. Indeed, energy may be applied to the cornea in a non-annular pattern, and cross-linking may be initiated in regions corresponding to the resulting non-annular changes in corneal structure.
Examples of non-annular shapes of energy that may be applied to the cornea are disclosed in US Pat. No. 12 / 113,672, filed May 1, 2008, the contents of which are hereby incorporated by reference. Fully captured.

The use of riboflavin as a cross-linking agent and the use of UV light initiating elements in the above embodiment is given as an example only. In general, other types of cross-linking agents may be used in accordance with aspects of the present invention. For example, the cornea is a collagen fibril that is uniformly spaced to form orthogonal sheets to obtain the required combination of light transmission and mechanical elasticity for cornea function. An extracellular matrix containing may be employed.
Fibrils associate collagen with interrupted triple-stranded helical structures (FACIT collagen). Leucine rich repeat (LRR) proteoglycans are natural binding polymers that play an important role in determining the structure and function of collagen fibrils.
FACIT collagen generated in the cornea includes, for example, type VI, type XII, and type XIV collagen. On the other hand, LRR proteoglycans that occur in the cornea include decorin, lumican, keratocan, and osteoglycin. FACIT collagen and LRR proteoglycan bind to collagen fibrils and control the fibril diameter. In addition, these macromolecules form a bond between fibrils that can bridge between fibrils and can provide some degree of elasticity while regulating the relative movement of fibrils. . Since FACIT collagen and LRR proteoglycan have the property of binding fibrils, they may be used as elements of a cross-linking agent applied to the embodiment of the present invention.

  In some embodiments, the crosslinker is formulated as an eye drop that can deliver the crosslinker to the target corneal fibrils underlying the epithelium and can be delivered to the corneal surface. May be used. For example, in order to prepare the composition, FACIT collagen and / or LRR proteoglycan dissolved in a compatible physiological buffer such as phosphate buffer may be used. The concentration of the corresponding solution can be from about 10 μg / ml to about 500 μg / ml.

Alternatively, the cross-linking agent may be selectively applied as an eye ointment, for example with a petrolatum base.
In order to deliver the shape-retaining substance to the structurally changed region under the corneal surface, for example, the mid-deep region 2B, the pH of the cross-linking agent is a suitable value, for example, about 7.6 to 8.0 to open the collagen matrix. May be adjusted.
As described above, the cross-linking agent is applied according to a specific pattern corresponding to the altered region of the corneal structure. For example, a mask similar to the mask 410 described above may be employed to carry the crosslinker according to a particular pattern.

In addition, the cross-linking agent may be applied before and / or after heat is applied to the cornea. The length of time that the cross-linking agent is applied depends on the cross-linking agent. If the cross-linking agent is applied before heat is applied, additional heat may have to be applied to eliminate the inhibition of fibrillary motion resulting from the application of the shape-retaining material. .
However, after all, the presence of, for example, FACIT collagen and / or LRR proteoglycans carried with a crosslinker is caused by heat, regardless of whether the crosslinker is applied before and / or after heat is applied. Helps maintain structural changes.
The application of the cross-linking agent in an embodiment of the present invention aims to maintain a new structural arrangement of the corneal fibrils and is mechanically pressed against the corneal structure that does not change during the treatment, such as corneal orthodontic treatment. It should be noted that it is not intended to maintain a specific deformation.
In fact, any process of corneal remodeling that involves mechanical deformation is stressed because the structure of the cornea resists mechanical deformation, and its application is time consuming or invalid. It seems to avoid applying shape-retaining materials before. On the other hand, it is easier to apply heat to eliminate such resistance.

  Although the present invention has been described in connection with a number of exemplary embodiments and implementations, the present invention is not limited and covers various other modifications and equivalent arrangements.

Claims (19)

A method applied to the treatment of the eye,
According to the selected pattern, heat is generated in the corneal fibrils of the cornea of the eye, and the heat causes a change from the first form to the second form of the corneal fibrils corresponding to the selected pattern, and the second form Provides remodeling of the cornea,
A method of activating a cross-linking agent in a region of corneal fibrils corresponding to the selected pattern, wherein the cross-linking agent prevents changes in the corneal fibrils from the second form.   The method of claim 1, further comprising applying a cross-linking agent to the corneal fibril region according to the selected pattern.   Providing the cross-linking agent according to the selected pattern comprises removing the corneal epithelium according to the selected pattern and applying the cross-linking agent directly to a region of corneal fibrils below the epithelium. The method of Claim 2 including a process.   Activating the cross-linking agent according to the selected pattern comprises applying an initiating element to a region of the corneal fibril according to the selected pattern, the initiating element activating the cross-linking agent; The method of claim 1.   The method of claim 3, wherein the initiation element comprises ultraviolet light.   4. The method of claim 3, wherein applying the starting element according to the selected pattern includes applying a mask, the mask restricting application of the starting element according to the selected pattern. Applying the starting element according to the selected pattern comprises applying at least one optical device;
The method of claim 3, wherein the at least one optical device guides the starting element to the eye according to the selected pattern.   4. The method of claim 3, wherein the cross-linking agent is riboflavin.   The method of claim 1, further comprising applying a cross-linking agent to a region of corneal fibrils prior to the step of generating heat.   The method according to claim 1, further comprising applying a thermally sensitive liposome containing the cross-linking agent to a region of corneal fibrils.   2. The step of applying the thermally sensitive liposome occurs prior to the step of generating heat, wherein the heat releases the crosslinker from the thermally sensitive liposome. the method of.   The method of claim 1, wherein the cross-linking agent comprises collagen associated with fibrils by at least one of an interrupted triple-stranded helical structure (FACIT collagen) and a leucine rich repeat (LRR) proteoglycan.   The method according to claim 1, wherein the crosslinking agent is present in eye drops or eye ointment. A system for stabilizing the pattern of structural changes in corneal fibrils generated by the application of heat to the eye,
A cross-linking agent that maintains the structural changes of corneal fibrils generated by the application of heat to the eye, or a source of initiating elements that activate cross-linking activity in the corneal fibrils;
A delivery device that is positionable between the source and the eye and defines a selected pattern and carries the crosslinker or the initiation element to corneal fibrils according to the selected pattern; Including system.   The system of claim 14, wherein the transport device is a mask.   The system of claim 14, wherein the source supplies ultraviolet light as the starting element.   The system of claim 15, wherein the transport device is a mask that blocks the ultraviolet light according to the selected pattern.   The system of claim 15, wherein the transport device is an optical device that redirects ultraviolet light emitted from the source to define the selected pattern.   18. The system according to claim 17, wherein the optical device is an axicon that receives ultraviolet light emitted from the source as a parallel beam and converts the parallel beam into a ring of light.

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