WO2020212802A1

WO2020212802A1 - Anterior lamellar keratoplasty

Info

Publication number: WO2020212802A1
Application number: PCT/IB2020/053308
Authority: WO
Inventors: Yavor Petrov ANGELOV; Alexander Angelov ANGELOV
Original assignee: Resbiomed Technologies Ltd.
Priority date: 2019-04-15
Filing date: 2020-04-07
Publication date: 2020-10-22

Abstract

A method for reshaping a cornea, including: placing a cornea on a cornea holder; dissecting the cornea to define boundaries of a cornea portion while the cornea is placed in the cornea holder; geometrically reshaping an outline of an external surface of the cornea portion while the cornea portion is placed in the cornea holder and is not separated from the cornea in the cornea holder.

Description

ANTERIOR LAMELLAR KERATOPLASTY

RELATED APPLICATION/S

This application claims the benefit of priority under 35 USC § 119(e) of U.S. Provisional Patent Application No. 62/833,869 filed 15 April 2019, the contents of which are incorporated herein by reference in their entirety.

FIELD AND BACKGROUND OP THE INVENTION

The present invention, in some embodiments thereof, relates to Lamellar Keratoplasty and, more particularly, but not exclusively, to Intrastromal Anterior Lamellar Keratoplasty.

Diseases affecting the cornea are a major cause of blindness worldwide, second only to cataract in overall importance. The globally quantified shortage of corneal graft tissue shows 1 cornea available for 70 needed. Corneal disease affects 12.7 million individuals globally, and the current gold standard therapy using a human donor cornea (HDC) in low risk patients or keratoprosthesis in high risk patients is prone to graft rejection.

SUMMARY OF THE INVENTION

Some examples of some embodiments of the invention are listed below:

Example 1. A method for reshaping a cornea, comprising:

placing a cornea on a cornea holder;

dissecting said cornea to define boundaries of a cornea portion while said cornea is placed in said cornea holder;

geometrically reshaping an outline of an external surface of said cornea portion while said cornea portion is placed in said cornea holder and is not separated from the cornea in said cornea holder. Example 2. A method according to example 1, wherein said cornea comprises an in-vitro formed cornea implant, a human donor cornea lenticule or a human donor cornea.

Example 3. A method according to any one of the previous examples, wherein said dissecting comprises dissecting said cornea to define a cornea portion after said dissecting having a maximal dimension of at least 7 mm.

Example 4. A method for replacing a portion of a cornea, comprising:

calculating a size of a cornea portion to be removed from a cornea;

removing said cornea portion to form an implantation site while keeping an upper layer of the cornea intact; implanting a cornea implant having a diameter which is smaller in at least 50 pm from a diameter of the implantation site into the implantation site and under the intact upper layer.

Example 5. A method according to example 4, comprising performing a Small Incision Lenticule Extraction (SMILE) surgery prior to said removing.

Example 6. A method according to any one of examples 4 or 5, comprising dissecting said cornea by a surgical laser device based on said calculated size.

Example 7. A method according to example 6, wherein said calculating comprises calculating thickness values of said cornea portion to be removed at one or more locations along an area of said cornea portion, and wherein said dissecting comprises ablating said cornea according to said calculated thickness values.

Example 8. A method for forming a treatment zone in a cornea, comprising:

activating one or more lasers to apply laser beams on a cornea in a subject, wherein said laser beams are configured to dissect and/or ablate said cornea;

forming a treatment zone having a maximal dimension larger than 8 mm but smaller than a maximal dimension of said cornea, in said cornea by said laser beams configured to dissect and/or ablate said cornea.

Example 9. A method according to example 8, wherein said one or more lasers comprise a femtosecond laser and/or an excimer laser.

Example 10. A method according to any one of examples 8 or 9, comprising removing tissue from said treatment zone in said cornea through an incision formed at a periphery of the cornea at a distance larger than 4 mm from a center of the cornea.

Example 11. A method according to example 10, wherein said incision extends in a circumferential direction and is smaller from a maximal dimension of a cornea implant.

Example 12. A cornea holder, comprising:

an elongated base having a longitudinal axis and an upper curved surface along at least 50% of the surface area, wherein said curved surface is shaped and sized to hold at least a portion of a cornea in a curved orientation.

Example 13. A device according to example 12, wherein said curved surface has a radius of curvature in a range of 7-9 mm along the entire curved surface.

Example 14. A device according to any one of examples 12 or 13, comprising an alignment portion located at or adjacent to said upper curved surface, wherein said alignment portion comprises one or more alignment markings shaped and sized to align said upper curved surface with alignment markings or a coordinate system of a laser surgical device. Example 15. A device according to example 14, wherein said alignment portion comprises one or more rotation orientation markings shaped and sized to be positioned near at least a portion of a cornea, wherein said rotation orientation marking are configured to allow marking of the cornea by forming a cut or a void in the cornea to set a rotation orientation of the cornea with respect to said rotation orientation marking of said holder.

Example 16. A device according to example 15, wherein said one or more rotation orientation markings comprises an opening or an indentation in said alignment portion.

Example 17. A method for removal of a damaged tissue region from the cornea, comprising: identifying a damaged region in the cornea;

calculating dimensions of at least a portion of said damaged region selected to be removed from the cornea;

removing said selected damaged portion from the cornea.

Example 18. A method according to example 17, comprising:

analyzing the cornea using optical coherence tomography (OCT), and wherein said calculating comprises calculated said dimensions based on said analysis results.

Example 19. A method according to any one of examples 17 or 18, wherein said calculating comprises calculating size and/or shape of a cornea implant to be inserted into said cornea instead of said removed damaged region.

Example 20. A control unit of system for laser surgery of an eye, comprising:

a memory comprising a treatment program, wherein said treatment program comprises a program for refractive correction and for dissecting and/or ablating a cornea to have a treatment zone having a maximal dimension in a range between 8 mm and a maximal dimension maximal value of the cornea;

a control circuitry configured to signal a laser device to dissect and/or ablate a cornea according to said treatment program.

Example 21. A system for laser surgery of an eye, comprising:

a femtosecond laser;

an excimer laser;

a control circuitry configured to signal said femtosecond laser and said excimer laser to dissect and ablate a cornea according to said treatment program. Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

As will be appreciated by one skilled in the art, some embodiments of the present invention may be embodied as a system, method or computer program product. Accordingly, some embodiments of the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, micro-code, etc.) or an embodiment combining software and hardware aspects that may all generally be referred to herein as a“circuit,”“module” or“system.” Furthermore, some embodiments of the present invention may take the form of a computer program product embodied in one or more computer readable medium(s) having computer readable program code embodied thereon. Implementation of the method and/or system of some embodiments of the invention can involve performing and/or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of some embodiments of the method and/or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware and/or by a combination thereof, e.g., using an operating system.

For example, hardware for performing selected tasks according to some embodiments of the invention could be implemented as a chip or a circuit. As software, selected tasks according to some embodiments of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more tasks according to some exemplary embodiments of method and/or system as described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes a volatile memory for storing instructions and/or data and/or a non-volatile storage, for example, a magnetic hard-disk and/or removable media, for storing instructions and/or data. Optionally, a network connection is provided as well. A display and/or a user input device such as a keyboard or mouse are optionally provided as well.

Any combination of one or more computer readable medium(s) may be utilized for some embodiments of the invention. The computer readable medium may be a computer readable signal medium or a computer readable storage medium. A computer readable storage medium may be, for example, but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any suitable combination of the foregoing. More specific examples (a non-exhaustive list) of the computer readable storage medium would include the following: an electrical connection having one or more wires, a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), an optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the foregoing. In the context of this document, a computer readable storage medium may be any tangible medium that can contain, or store a program for use by or in connection with an instruction execution system, apparatus, or device.

A computer readable signal medium may include a propagated data signal with computer readable program code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electro magnetic, optical, or any suitable combination thereof. A computer readable signal medium may be any computer readable medium that is not a computer readable storage medium and that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.

Program code embodied on a computer readable medium and/or data used thereby may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, RF, etc., or any suitable combination of the foregoing.

Computer program code for carrying out operations for some embodiments of the present invention may be written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the "C" programming language or similar programming languages. The program code may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a local area network (FAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).

Some embodiments of the present invention may be described below with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems) and computer program products according to embodiments of the invention. It will be understood that each block of the flowchart illustrations and/or block diagrams, and combinations of blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.

These computer program instructions may also be stored in a computer readable medium that can direct a computer, other programmable data processing apparatus, or other devices to function in a particular manner, such that the instructions stored in the computer readable medium produce an article of manufacture including instructions which implement the function/act specified in the flowchart and/or block diagram block or blocks.

The computer program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.

Some of the methods described herein are generally designed only for use by a computer, and may not be feasible or practical for performing purely manually, by a human expert. A human expert who wanted to manually perform similar tasks, such as define freeform surface matrix and/or other characteristics of an implant, might be expected to use completely different methods, e.g., making use of expert knowledge and/or the pattern recognition capabilities of the human brain, which would be vastly more efficient than manually going through the steps of the methods described herein.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings and images. With specific reference now to the drawings and images in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced. In the drawings:

Fig. 1 is a flow chart of a process for reshaping a cornea implant prior to implantation and implantation, according to some embodiments of the invention;

Fig. 2 is a detailed flow chart of a process for reshaping a cornea implant prior to implantation and implantation, according to some embodiments of the invention;

Figs. 3A-3D are schematic illustrations describing reshaping a cornea implant, according to some embodiments of the invention;

Fig. 4A is a schematic illustration showing dissection of a cornea of a recipient, according to some embodiments of the invention;

Fig. 4B is a schematic illustration showing implantation of a reshaped implant into a dissected cornea, according to some embodiments of the invention;

Fig. 5A is a flow chart of a process for defining structural parameter values of a desired implant, according to some embodiments of the invention;

Fig. 5B is a flow chart of a process for transforming data collected by OCT to an ablation profile to be used by a laser device, according to some embodiments of the invention;

Figs. 5C-5E are schematic illustrations of a cornea lenticule holder, according to some embodiments of the invention; and

Fig. 5F is a schematic illustration of a cornea positioned on an upper curved surface of a cornea holder, according to some embodiments of the invention.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

An aspect of some embodiments relates to in-vitro reshaping, for example geometrical reshaping, a cornea, for example an in-vitro formed implant or a human donor cornea (HDC) lenticule. In some embodiments, the cornea implant is reshaped prior to implantation in a recipient cornea in-vivo. In some embodiments, the cornea implant is reshaped according to one or more of structural, anatomical or clinical parameters of the recipient cornea. Alternatively or additionally, the cornea implant is reshaped to fit a void formed in the recipient cornea.

According to some exemplary embodiments, reshaping of the cornea implant, for example geometrical reshaping, means reshaping of an external surface of the cornea that following implantation faces the external environment. In some embodiments, reshaping comprises modifying a thickness of the cornea implant, for example by removing tissue from the external surface of the cornea implant at one or more geometrical locations located on the external surface. Additionally, the reshaping is performed in an x-y-z coordinates system, having a reshaping range, in an x-y axis plane, which is larger than a reshaping range in a z-axis direction.

According to some embodiments, the cornea implant is dissected, for example cut while placed in a cornea holder. In some embodiments, the cornea implant is cut, for example to set boundaries of a cornea portion, for example a cornea lenticule, from the cornea implant, while the cornea implant is placed in the cornea holder. Optionally, the cornea implant is cut on the cornea holder using a femtosecond laser. In some embodiments, after cutting, the cornea portion is not separated from the rest of the cornea implant or from the cornea.

According to some exemplary embodiments, the cornea implant or the cornea portion is geometrically reshaped while placed in the cornea holder. In some embodiments, geometrically reshaping comprises reshaping of an outline of an external surface of the cornea implant or the cornea portion. In some embodiments, the geometrically reshaping is performed before, during or after the cutting.

An aspect of some embodiments relates to replacing a portion of a cornea, for example a human cornea or an animal cornea, with a cornea implant. In some embodiments, the replaced portion is an internal portion of the cornea. In some embodiments, the cornea implant comprises an in-vitro formed implant or a human donor cornea (HDC) lenticle implant. In some embodiments, the cornea implant shape, boundaries and/or size are adjusted according to the shape, boundaries and/or size of the replaced cornea portion. Optionally, a flap is not formed in the recipient eye for implantation of the cornea implant. As used herein, a flap is a layer of the eye that can be folded back to expose a working area that has a difference in area size of less than 30% compared to the area size of the folded layer covering the working area. In some embodiments, the portion of the cornea is replaced via an incision in the periphery of the eye. In some embodiments, the incision has an area size which is smaller in more than 70% from the area size of the replaced portion of the cornea. Is would talk about size of hole relative to size of area treated and/or angular size (surrounding center of treated area): <180 degrees.

According to some embodiment, the in-vitro formed implant comprises a bio-compatible scaffold. Optionally, the scaffold comprises one or more types of cells seeded on the scaffold and cultured in-vitro. In some embodiments, the one or more cell types comprise stromal cells, stem cells, mesenchymal stem cells, human embryonic stem cells, induced pluripotent stem cells, cells, placenta-derived cells, for example the PLX-PAD cells (a product of Pluristem Therapeutics Inc.) and/or endothelial cells. Alternatively or additionally, the bio-compatible scaffold comprises or is formed from extracellular matrix (ECM) proteins, for example collagen, recombinant human collagen type I (RHC I) protein, recombinant human collagen type II recombinant human collagen type III, recombinant human collagen type IV or any type ECM protein. Optionally, the scaffold is biodegradable.

According to some embodiments, the implantation of the HDC lenticule or the scaffold is used for stromal replacements, for example for the correction of the comeal shape and the refractive abnormalities of the eye in subjects with keratoconus I Grade 3, Grade, 4 and/or Grade PLUS according to the RETICS classification.

According to some exemplary embodiments, the implantation of the HDC lenticule or the in-vitro implant is directly into the stroma of the cornea with no access or minimal access of the transplanted tissue to the outer corneal surfaces. Additionally, cells from the comeal surface are optionally introduced into the stroma. In some embodiments, the volume of the implanted tissue is less in at least 10%, at least 20%, at least 50% or any intermediate, smaller or larger percentage value from the corneal volume transplanted in (D)ALK thus having a lower risk for antigen- presenting cells to be a factor in the indirect pathway of rejection.

According to some embodiments, the implantation of the HDC lenticule or the in-vitro implant is performed using a Small Incision Lenticule Extraction (SMILE) procedure. In some embodiments, a small incision having a length in a range of lmm-4mm, is performed in the cornea at a distance of at least 4 mm, for example at least 4.5 mm, at least 5 mm or any intermediate, smaller or larger distance a center of the recipient cornea. In some embodiments, a center of a cornea is a geometrical position located at equal distances from two locations on the periphery of the cornea that are also positioned on a maximal dimension of the cornea, for example on a diameter of the cornea. In some embodiments, the cornea implant is inserted through the incision into the recipient cornea.

An aspect of some embodiments relates to forming a stromal replacement treatment zone in a cornea, and/or a cornea implant, having a width larger than 7 mm, for example larger than 8 mm, larger than 9 mm or any intermediate, smaller or larger value. In some embodiments, the stroma replacement treatment zone is formed in a cornea of an adult eye. In some embodiments, the stromal replacement treatment zone comprises an implantation bed in a recipient cornea for the cornea implant.

According to some embodiments, a thickness of the formed treatment zone and/or the cornea implant varies in a range of 1 pm-500 pm, for example 1 pm -100 pm, 50 pm -150 pm, 120 pm -200 pm, 180 pm -300 pm, 250 pm-350 pm, 300 pm-500 pm, or any intermediate, smaller or larger range of values.

According to some embodiments, a software program controlling the operation of a femtosecond laser, for example the femtosecond laser VisuMax® 500 kHz by CZM AG is modified, for example to allow the formation of a treatment zone with a width or a maximal dimension, for example a diameter larger than 7 mm, for example larger than 8 mm, larger than 9 mm, larger than 10 mm or any intermediate, smaller or larger value. Additionally, the width or maximal dimension is larger than 7mm but smaller than a maximal width or a maximal diameter of the cornea. Additionally or alternatively, a software program controlling the operation of an excimer laser, for example MEL® 80 by CZM, is adjusted to allow an ablation profile larger than a width or a maximal dimension of 7mm.

According to some exemplary embodiments, at least one parameter of a software program controlling the laser is modified, for example a safety zone area or dimensions and/or a programmed ablation area defined by the software. In some embodiments, the at least one parameter is modified, for example automatically modified, when a cornea holder on which a cornea implant is positioned is visualized by the laser.

According to some exemplary embodiments, the formed treatment zone has a round, oval and/or a polygonal shape. In some embodiments, a cornea implant is shaped to match the dimensions and shape of the formed treatment zone.

According to some embodiments, an incision to insert a cornea implant is performed at the periphery of a recipient cornea at a distance larger than 4mm, for example larger than 4.5mm, larger than 5mm from the center of the cornea. In some embodiments, the incision is performed at a periphery of a visual field of the eye, for example at a distance of less than 8 mm, for example less than 7 mm, less than 5 mm from a border of the visual field.

An aspect of some embodiments relates to a cornea holder, for example a comeal button jig, shaped and sized for holding at least a portion of cornea. In some embodiments, the cornea holder is shaped and sized to hold at least a portion of a cornea, in a selected fixed curvature along the entire surface of the cornea. In some embodiments, the selected fixed curvature has a radius of curvature in a range of 6mm-9mm, for example 6mm-8mm, 7mm-8.5mm, 8mm-9mm or any intermediate, smaller or larger range of values. In some embodiments, the radius of curvature is selected based on the curvature of the recipient cornea, or the curvature of the implantation site formed with the recipient cornea.

According to some exemplary embodiments, the cornea holder comprises an alignment portion on an upper surface of the holder, or adjacent to the upper surface of the holder, for example to allow alignment between the upper surface of the holder comprising at least a portion of the cornea, and a coordinate system of a laser device, for example alignment markings of the laser device. Optionally the alignment marking of the laser device are viewable through an eyepiece of the laser device. In some embodiments, the alignment marking is a visual marking. Optionally, the visual alignment marking is used by the laser system.

According to some exemplary embodiments, the cornea holder comprises one or more rotation alignment markings on the upper surface of the cornea holder or adjacent to the upper surface of the holder, for example to mark a rotation orientation of the cornea during cutting or ablation when positioned on the curved surface of the holder.

An aspect of some embodiments relates to ablating a cornea implant positioned in a fixed curvature during the ablating. In some embodiments, the cornea implant is placed on a curved surface during the ablation process. In some embodiments, an ablating sequence of the cornea is applied based on translated coordinates of the fixed curvature.

A potential problem sometimes found with immunological rejection and customization of the anterior lamellar keratoplasty procedure is potentially addressed with the introduction of a Sutureless Intrastromal Anterior Lamellar Keratoplasty (sIALK) described herein. This laser refractive surgery procedure is performed with, for example, a combination of laser profiles of the femtosecond laser VisuMax® 500 kHz and the excimer laser MEL® 80 by CZM, for example for customized stromal exchange and replacement, through a very small single incision in the periphery of the cornea. Additionally, the surgical procedure is performed to compensate for the loss of tissue, while preserving the functioning endothelial cells. In some embodiments, ablation and cutting of the cornea implant are performed while the cornea implant is placed in a fixed curvature on the cornea holder.

A potential advantage of the suggested new customized sIALK with a free-form HDC lenticule or an in-vitro scaffold is that it replaces and compensates the lost corneal stoma and optionally regenerates the cornea to restore and establish the normal function of the eye. The sIALK procedure potentially allow customization of the anterior lamellar keratoplasty procedure.

A potential advantage of using mesenchymal stromal cells or stem cells seeded on a scaffold for intrastromal implantation, is that these cells may allow regeneration of at least some of the layers of the cornea, for example epithelium, stroma or endothelial layers and the extracellular matrix.

According to some embodiments, a cornea implant, for example a cornea implant lenticule is selected to include one or more of cornea layers. In some embodiments, an in vitro scaffold with cells is selected to include tissue having several layers of the cornea or, multiple in-vitro scaffolds are selected for implantation, each containing a different layer.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

Exemplary general process for reshaping and implantation

According to some exemplary embodiments, a stromal replacement surgery is performed on a human cornea, for example to replace at least a portion of the cornea with an HDC or with a bio-compatible scaffold. In some embodiments, each of the HDC or the bio-compatible scaffold are geometrically reshaped prior to implantation in the recipient cornea.

According to some exemplary embodiments, the stromal replacement surgery comprises an Intrastromal Anterior Lamellar Keratoplasty (IALK), for example a sutureless IALK (sIALK). In some embodiments, the sIALK is an experimental refractive laser surgery procedure, through a very small laser assisted incision of at least 1.5 mm, for example at least 2 mm, at least 2.4 mm or any intermediate, smaller or larger value, in the peripheral cornea. In some embodiments, the stromal replacement surgery is used, for example, to correct one or more corneal protrusions and/or the loss of stroma in keratoconus. Additionally or alternatively, the surgery is used, for example, to correct the comeal shape and/or the refractive abnormality of the eye, for example by adding a HDC lenticule or a RHC I scaffold.

According to some exemplary embodiments, pre-operative data is collected at block 102. In some embodiments, the pre-operative comprises clinical information regarding the clinical condition of an eye and/or clinical condition of the cornea. Additionally or alternatively, the pre operative data comprises data regarding to one or more damaged regions in the cornea. In some embodiments, the pre-operative data comprises structural information regarding the one or more damaged regions, for example thickness of the cornea, width of the damaged region, diameter of the damaged region, area and/or size of the damaged region, axial length of the eye, crystalline lens anterior and posterior radius of curvature, thickness of the lens and/or diameter of the lens.

According to some exemplary embodiments, the pre-operative data is collected at block 102 using one or more imaging techniques, for example one or more imaging techniques of the eye and/or cornea. In some embodiments, the one or more imaging techniques comprise optical coherence tomography (OCT) and/or low resolution anterior segment Pentacam scheimpflug camera.

According to some exemplary embodiments, a cornea implant, for example a donor cornea or a bio-compatible scaffold is provided at block 104. In some embodiments, the donor cornea comprises a human donor cornea (HDC). Alternatively, the cornea implant comprises an animal cornea, for example a pig cornea. Optionally, the animal cornea is used in a xenotransplantation procedure, and is implanted in a human eye.

According to some exemplary embodiments, the bio-compatible scaffold comprises an in- vitro fabricated scaffold, for example using bioprinting techniques. In some embodiments, the bio compatible scaffold is formed by decellularization of a tissue, for example tissue of the eye or cornea tissue. In some embodiments, the scaffold comprises one or more extracellular matrix (ECM) proteins, for example collagen. In some embodiments, the scaffold comprises one or more cell types, seeded and cultured in-vitro on the scaffold. In some embodiments, the one or more cell types comprise primary cells, mesenchymal stromal cells, mesenchymal stem cells, induced pluripotent stem cells, embryonic -originated cells, placental-derived cells, immune system-related cells, and/or endothelial cells.

According to some exemplary embodiments, a free-form cornea implant, for example a free-form cornea lenticule implant, is formed at block 106. In some embodiments, the free-form cornea implant is formed in-vitro from the provided cornea implant. In some embodiments, the free-form cornea implant is formed by geometrical reshaping, for example in an X-Y plane of the external surface of the provided cornea implant. In some embodiments, the geometrical reshaping is used to adjust the thickness of the cornea implant, for example along the X-Y plane. Additionally, the dimensions, for example size, width and/or diameter, of the cornea implant are adjusted, for example by cutting the provided cornea implant along a z-axis. In some embodiments, the dimensions of the of the cornea implant are adjusted to fit or according to dimensions of a portion in a recipient cornea, selected to be replaced by the free-form cornea implant.

According to some exemplary embodiments, the geometrical reshaping is performed based on the pre-operative data collected at block 102, for example based on data related to the thickness of the cornea, width of the damaged region, diameter of the damaged region, area and/or size of the damaged region. In some embodiments, the geometrical reshaping is performed using an excimer laser. In some embodiments, the cornea implant is reshaped to have a width or a diameter larger than 7 mm, for example larger than 8 mm, larger than 9 mm or any intermediate, smaller or larger diameter.

According to some exemplary embodiments, an implantation site is created at a recipient cornea at block 108. In some embodiments, the implantation site is created based on the pre operative data collected at block 102, for example based on a thickness, size and/or shape of a damaged area in the recipient cornea. In some embodiments, the implantation site is generated to have a width or a diameter larger than 7 mm, for example larger than 8 mm, larger 9 mm or any intermediate, smaller or larger diameter. In some embodiments, the thickness of the implantation site generated at block 108 has a diameter or width which is larger than a diameter or width of the cornea implant in up to 100 pm, for example up to 90 pm, up to 80 pm, up to 70 pm, up to 50 pm, up to 40 pm, up to 30 pm or any intermediate, smaller or larger value.

According to some exemplary embodiments, the free-form cornea implant is implanted in a recipient cornea at block 110. In some embodiments, the cornea implant is implanted into the recipient cornea through an incision having a size in a range of 1.5 mm-5 mm, for example 2 mm- 2.6 mm, 2.4 mm-3 mm, 2.7 mm-3.5 mm, 3 m- 4.5 mm, 4 mm-5 mm or any intermediate, smaller or larger cut in the peripheral cornea. In some embodiments, the incision is formed at a distance of at least 4 mm, for example at least 4.5 mm, at least 5 mm from a center point of the eye.

Exemplary detailed process for reshaping and implantation of a cornea implant

According to some exemplary embodiments, an eye of a subject, for example a cornea of the eye, is diagnosed at 202. In some embodiments, the eye is diagnosed by one or more imaging techniques, for example using OCT. In some embodiments, the OCT comprises high-resolution anterior segment OCT diagnostics. In some embodiments, the eye is diagnosed to detect one or more damaged regions in the cornea. Alternatively or additionally, the eye is diagnosed, for example, in order to determine values of structural parameters of the cornea, for example thickness of the cornea, thickness of one or more damaged regions of the cornea, size, surface and/or shape of the one or more damaged regions and/or size, surface and/or shape of other cornea regions, for example regions surrounding the one or more damaged regions of the cornea. In some embodiments, data collected during diagnosis is used to customize the stromal replacement procedure for a specific cornea of a specific subject.

According to some exemplary embodiments, the eye is diagnosed at block 202 for example to determine corneal shape and/or for detecting refraction abnormalities of the eye. Additionally or alternatively, the eye is diagnosed, for example, to determine a class or a grade of keratoconus. In some embodiments, the eye is diagnosed to determine cell types of the cornea, and/or to determine the shape, thickness, size, width and/or length of various tissue layers of the cornea.

According to some exemplary embodiments, values of one or more parameters related to an area to be removed from the cornea, for example a treatment zone, are calculated at block 204. In some embodiments, the one or more parameters of the treatment zone comprise structural and/or anatomical parameters. In some embodiments, the treatment zone parameters comprise size, shape, curvature angle, surface area, width, diameter and/or depth of the treatment zone. In some embodiments, the calculated values related to the treatment zone are transmitted to a memory of control unit of a laser, for example a femtosecond laser, configured to form the treatment zone in the cornea based on the calculated values.

According to some exemplary embodiments, values of one or more parameters related to a cornea implant, for example a cornea lenticule are calculated at block 206. In some embodiments, the parameters comprise lenticule axis degree, width, diameter, desired thickness along one or more regions on the external surface. In some embodiments, the calculated values of the cornea implant are calculated based on the calculated values of the treatment region parameters. In some embodiments, the calculated values related to parameters of the cornea implant are transmitted to a memory of a control unit of a laser, for example an excimer laser, configured to reshape, for example geometrically reshape the cornea implant based on the calculated values.

According to some exemplary embodiments, an artificial lenticel is grown at block 208. In some embodiments, the artificial lenticel comprises a scaffold, for example a bio-compatible scaffold. In some embodiments, the scaffold comprises one or more extracellular matrix (ECM) proteins, for example collagen proteins. In some embodiments, the scaffold comprises a recombinant human collagen type I (RHC I) scaffold. In some embodiments, the scaffold is a biomimetic, biocompatible and surgically transplantable for intrastromal replacement. In some embodiments, the scaffold is fabricated using Laser Induced Forward Transfer (LIFT) 3D printing technology.

According to some exemplary embodiments, the artificial lenticel comprises one or more cell types, for example primary cells, endothelial cells, stromal cells, stem cells, mesenchymal stem cells, stromal stem cells, induced pluripotent stem cells, and/or placenta-derived stem cells. In some embodiments, the cells are seeded on the scaffold and are cultured in-vitro, for example in a bio reactor, to form a tissue. In some embodiments, the scaffold with the cells is configured to allow regeneration of the three layers of the cornea and optionally also regeneration of the ECM.

According to some exemplary embodiments, the artificial lenticule is placed on a lenticule holder, for example a jig, at block 210.

According to some exemplary embodiments, the artificial lenticule is reshaped at block 212. In some embodiments, the artificial lenticule is reshaped using values calculated at block 206. In some embodiments, the artificial lenticule is reshaped, for example by geometrical reshaping of an external surface of the artificial lenticule. In some embodiments, the geometrical reshaping comprises removing of one or more tissue layers. Additionally or alternatively, geometrical reshaping comprises reshaping an outline of the external surface of the artificial lanticle. In some embodiments, the artificial lenticule is geometrically reshaped using an ablating laser. In some embodiments, the artificial lenticule is geometrically reshaped using an excimer laser, for example the excimer laser MEL® 80 by CZM.

According to some exemplary embodiments, an in an alternative approach, a cornea is extracted from a donor at block 216. In some embodiments, a cornea is extracted from a human donor, and is termed HDC. Alternatively, a cornea is extracted from an animal, for example from a pig. Alternatively, a cornea is provided from a cornea bank. In some embodiments, the cornea is provided as a whole cornea. Alternatively, at least 70%, for example at least 75%, at least 85%, at least 90%, at least 95% or any intermediate, smaller or larger percentage of cornea tissue is provided.

According to some exemplary embodiments, the cornea is placed on a cornea holder, for example a cornea jig, at block 216. In some embodiments, the cornea is placed on an upper surface of the cornea holder having a radius of curvature of at least 7 mm, for example at least 8 mm, at least 9 mm, at least 10 mm or any intermediate, smaller or larger radius of curvature.

According to some exemplary embodiments, the cornea is dissected at block 220. In some embodiments, the cornea is dissected while positioned in the cornea holder, for example to form a free-form lenticule at block 220. In some embodiments, the cornea is dissected using a laser, for example a femtosecond laser and/or an excimer laser. In some embodiments, the femtosecond laser comprises the femtosecond laser VisuMax® 500 kHz. In some embodiments, the excimer laser comprises the excimer laser MEL® 80 by CZM.

According to some exemplary embodiments, the cornea is dissected along a z-axis, for example to define a width or a diameter of the cornea implant, for example a lenticule implant. In some embodiments, the cornea implant is dissected into a depth of at least 30 pm, for example at least 50 pm, at least 70 pm, at least 100 pm, at least 120 pm, at least 150 pm, or any intermediate, smaller or larger value. In some embodiments, the cornea is dissected to form a lenticule implant having a diameter or width of at least 6 mm, for example at least 7 mm, at least 8 mm, at least 9 mm or any intermediate smaller or larger value. In some embodiments, the cornea is dissected based on values calculated at block 206.

According to some exemplary embodiments, the lenticule is reshaped, for example geometrically reshaped at block 222. In some embodiments, the lenticule is reshaped while positioned in the cornea holder. In some embodiments, the lenticule is reshaped during dissection, or following a dissection process. In some embodiments, the lenticule is reshaped by removing tissue or ablating tissue along the external surface of the lenticule. In some embodiments, the lenticule is reshaped by removing tissue or ablating tissue along an X-Y plane of the external surface of the lenticule. According to some exemplary embodiments, the lenticule is reshaped using a laser, for example an excimer laser. In some embodiments, the laser is configured to ablate a region having an area larger than 7 mm, for example larger than 8 mm, larger than 9 mm or any intermediate, smaller or larger area size. In some embodiments, the excimer laser comprises the excimer laser MEL® 80 by CZM.

According to some exemplary embodiments, a cornea implant is provided at block 214. In some embodiments, the cornea implant comprises a scaffold with or without cells, formed at block 212. Alternatively, the cornea implant comprises a lenticule implant formed at blocks 220 and 222.

According to some exemplary embodiments, a recipient cornea is dissected in a SMall Incision Lenticule Extraction (SMILE) surgical process, at block 224. In some embodiments, in the SMILE procedure a laser, for example a femtosecond laser is used to create a small, lens-shaped bit of tissue (lenticule) within the recipient cornea. Additionally, the laser is used to form a small incision, for example an arc- shaped incision in the surface of the cornea through which the created lenticule is extracted. In some embodiments, the incision has a length in a range of 1.5 mm-5 mm, for example 2 mm- 3.5 mm, 2.4 mm- 4mm, 3.2 mm-5 mm or any intermediate, smaller or larger incision length. In some embodiments, the femtosecond laser comprises the femtosecond laser VisuMax® by CZM AG. In some embodiments, the shape and size of the removed lenticule are determined based on the values calculated at block 204.

According to some exemplary embodiments, a damaged region of the recipient cornea is removed at block 226. In some embodiments, the damaged region is part of the lenticule, removed at block 224. In some embodiments, the damaged region is ablated using the femtosecond laser.

According to some exemplary embodiments, the lenticule removed at block 224 and/or the damaged region removed a block 226 define a treatment region in the recipient cornea. In some embodiments, a shape, size, area, width and/or diameter of the treatment region are determined based on the values calculated at block 204, the properties of the cornea implant and/or the diagnosis results of the eye. In some embodiments, the laser, for example the femtosecond laser is configured to form a treatment region that has a width or a diameter larger in up to 150 pm, for example up to 100 pm, up to 50 pm or any intermediate, smaller or larger value from the width or diameter of the cornea implant, for example to allow better implantation of the cornea implant within the treatment region.

According to some exemplary embodiments, the cornea implant is implanted within the target region in the recipient cornea at block 228. In some embodiments, the cornea implant is implanted in a ReLEx SMILE laser refractive surgery procedure. In some embodiments, during implantation the cornea implant is aligned with respect to the recipient cornea by aligning the peripheral incision with a rotation marking in the implant, for example a rotation marking formed at a 0 degrees mark of the cornea holder. Additionally, the cornea implant is dissected to have a width or diameter smaller in at least 50 pm, for example at least 70 pm, at least 100 pm, at least 120 pm or any intermediate, smaller or larger value, from a diameter or width of the implantation bed.

Exemplary reshaping a cornea implant

According to some exemplary embodiments, a sutureless Intrastromal Anterior Lamellar Kertoplasty (sIALK) procedure, as described in this application, is a laser refractive procedure to correct the loss of the comeal stroma and/or the refractive abnormalities of the eye the in keratoconus. In some embodiments, the procedure is based on imaging results, for example imaging results using high resolution Anterior Optical Coherence Tomography. Reference is now made to figs. 3A-3D depicting the formation of a free-form HDC lenticule, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, the HDC lenticule, for example an HDC button lamella is formed to have a constant spatial thickness. In some embodiments, a lamellar keratoplasty option of a femtosecond laser system, for example the femtosecond laser system VISUMAX 500 kHz by Carl Zeiss Meditec AG is used.

According to some exemplary embodiments, for example as shown in fig. 3A, an HDC button lamella, for example HDC button lamella 304, is dissected out from a donor cornea 302. In some embodiments, the dissected HDC button lamella 304 is placed on a cornea holder having a constant radius of curvature of at least 7 mm, for example at least 8 mm, at least 9 mm or any intermediate or smaller value. In some embodiments, the maximal radius of curvature of the cornea holder is up to 15 mm, for example up to 12 mm, up to 10 mm or any intermediate, smaller or larger value.

According to some exemplary embodiments, for example as shown in fig. 3B, the dissected HDC button lamella 304 comprises an upper epithelium layer 306 and a lower stroma layer 308. In some embodiments, a thickness 307 of the upper epithelium layer is in a range of 30pm- 100pm, for example 30pm-50pm, 40pm-70pm, 60pm- 100pm or any intermediate, smaller or larger range of values. In some embodiments, a thickness 309 of the stroma layer is in a range of lOOpm-500 pm, for example 100 pm -200pm, 150pm -300pm, 250pm-450pm, 350pm-500pm or any intermediate, smaller or larger range of values.

According to some exemplary embodiments, when placed in the cornea holder, the HDC button lamella is marked at 0° degree. In some embodiments, the HDC button lamella is marked at a selected location to set a specific rotational orientation of the HDC button lamella. In some embodiments, the marking is performed, for example, in order to be sure that there will be no induced rotation error mistake of the free-form lenticule at the time of the implantation.

According to some exemplary embodiments, the epithelium layer of the HDC button lamella is removed, for example by ablation. In some embodiments, the epithelium layer of the HDC button lamella is ablated with a constant spatial thickness in a range of 50pm- 90pm, for example 50 pm-70 pm, 60 pm-80 pm, 65 pm-75 pm, 74 pm-85 pm or any intermediate, smaller or larger range of values. In some embodiments, the epithelium layer is ablated with a constant thickness of 70pm. Alternatively, the epithelium layer is ablated with a varying thickness along the surface of the HDC button lamella. In some embodiments, the ablation thickness is calculated, for example at blocks 206 and/or 204 shown in fig. 2. In some embodiments, the epithelium layer is ablated using the excimer laser MEL-80 by Carl Zeiss Meditec AG.

According to some exemplary embodiments, for example as shown in figs. 3C and 3D, the HDC button lamella is ablated to achieve a cornea implant, for example a free-form HDC lenticule. In some embodiments, the HDC button lamella 308 is reshaped by ablating tissue 310 on the upper portion of the HDC button lamella, for example to form the free-form HDC lenticule 312. In some embodiments, an outline of the free-form HDC lenticule is reshaped according to the values calculated at block 206 shown in fig. 2. In some embodiments, the free-form HDC lenticule is reshaped using an excimer laser, for example the excimer laser MEL-80 by Carl Zeiss Meditec AG.

Exemplary implantation bed creation and implantation of HDC lenticule

Reference is now made to fig. 4 A depicting creation of the implantation bed, according to some exemplary embodiments.

According to some exemplary embodiments, a recipient cornea is dissected to create an implantation site, for example an implantation bed for the cornea implant, for example the free form HDC lenticule. In some embodiments, the recipient cornea is dissected according to values calculated for example at block 204 shown in fig. 2. In some embodiments, a width or a diameter of the implantation site is larger than a width or diameter of the cornea implant in up to 200 pm, for example up to 150 pm, up to 100 pm, up to 80 pm or any intermediate, smaller or larger value.

According to some exemplary embodiments, the implantation site 406 is formed using a femtosecond laser, for example the femtosecond laser system VISUMAX 500 kHz by Carl Zeiss Meditec AG. Optionally, the procedure for generating the implantation site is the ReLEx Smile procedure. In some embodiments, during the procedure a - 0.75D sphere manifest refraction correction is performed.

According to some exemplary embodiments, during the procedure a tissue lenticule having a diameter in a range of 7mm-9mm, for example 7mm-8mm, 7.5mm-8.5mm or any intermediate, smaller or larger range of values is generated by dissecting the cornea 404 of eye 402. In some embodiments, a cap diameter is in a range of 8mm- 10mm, for example 8mm-9mm, 8.5mm-9.5mm, 8.5mm-9mm or any intermediate, smaller or larger range of values. (8.7mm). In some embodiments, a tissue having a thickness in a range of 30 pm-50 pm, for example 40 pm, 42 pm or any intermediate, smaller or larger value is extracted from the center portion of the implantation site. Additionally, a tissue having a thickness in a range of 15 pm-30 pm, for example 20 pm , 25 pm or any intermediate, smaller or larger value is extracted from the edges of the implantation site.

According to some exemplary embodiments, an incision in the recipient cornea, for example in the periphery of the recipient cornea is performed. In some embodiments, the incision length is in a range of 2mm-4mm, for example 2mm-3mm, 2.3mm-3.2mm, 3mm-4mm or any intermediate, smaller or larger range of values. In some embodiments, the incision is performed, for example to allow the removal of the lenticule from the recipient cornea and the implantation of the cornea implant. In some embodiments, the incision is performed at a location selected to be aligned with the rotation orientation marking performed in the cornea implant, for example the marking performed at 0° degree.

According to some exemplary embodiments, for example as shown in fig. 4B, the free-form cornea implant, for example the free-form HDC lenticule 312 shown in figs. 3C and 3D is implanted into the recipient cornea 404. In some embodiments, the implantation of the free-form lenticule is performed by tweezers. In some embodiments, during the implantation the free-form lenticule is oriented in the center of the side cut. In some embodiments, in order to achieve a correct match between the HDC lenticule and the implantation bed, the width or diameter of the implantation bed is at least 0.05mm, for example at least 0.1mm larger than the implanted lenticule diameter width or diameter.

Exemplary defining a desired shape of a corneal implant

According to some exemplary embodiments, pre-operative data is collected, for example using one or more imaging techniques, for example as described at block 202 shown in fig. 2, and block 102 shown in fig. 1. In some embodiments, the imaging technique comprises high resolution anterior segment optical coherence tomography using, for example, the OCT Casia 2 (Tomey GmbH) system. In some embodiments, Matlab (MathWorks, Inc.) is used to write one or more scripts for performing calculations based on the OCT data. Reference is now made to fig. 5A, depicting a process for manipulating OCT data, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, configuration of OCT is performed, for example in order to have better resolution on radial scans (B/C scans =256). Additionally or alternatively, configuration of OCT is performed, for example to reach fast speed of measurement (A/B scans=512). In some embodiments, fast speed of measurements is needed, for example to minimising errors due to the movement of patient eye.

According to some exemplary embodiments, data is imported from the OCT to an analysis and/or calculation software, for example a MATLAB software, at block 502.

According to some exemplary embodiments, OCT provides raw data maps in a polar coordinate system, for example maps with information about corneal SAG and/or thickness of the cornea. In some embodiments, a MATLAB Script takes this data and creates a grid matrix, for example a 256 by 256 grid matrix, at block 504. In some embodiments, following grid formation, the data undergoes an interpolation process at block 506.

According to some exemplary embodiments, in order to calculate a distribution of the normal comeal thickness we use information from the article by Ambrosio R Jr. et al. (J Cataract Refract Surg. 2006) with optionally statistically rich data. In some embodiments, a benchmark matrix (CTSP) is created with the same size as OCT data, for example in a size of 256 by 256, for example at block 508. In some embodiments, the script subtracts the patient corneal thickness matrix with the benchmark one (CTSP), and creates a new matrix with missing tissue (WTPM). Additionally, the matrix includes a hydration coefficient and the spatial thickness profile of the removed ReLEx Smile lenticule.

According to some exemplary embodiments, the free-form surface is transformed to Zemike Malacara polynomial at block 510.

According to some exemplary embodiments, the database is exported to a treatment planning software, for example a CRS-Master, at block 512.

Excimer laser management

According to some exemplary embodiments, the excimer laser operation is controlled by a treatment management software, for example by the CRS-Master software. In some embodiments, the CRS-Master is a treatment planning software for the MEL-80 (Carl Zeiss Meditec AG) excimer laser. In some embodiments, the CRS-Master is configured to plan conventional and customized laser vision corrections, for example LASIK, Femto-LASIK, PRK and LASER. The software has several options for laser vision correction with feedback from the ocular aberrometer WASCA (Carl Zeiss Meditec AG ) and the comeal topography ATLAS 9000 (Carl Zeiss Meditec AG).

According to some exemplary embodiments, the software is used for customized wavefront driven laser vision correction. In some embodiments, the Software represents ocular wavefront error using the Zemike Malacara polynomial notation to 6th order. In some embodiments, in most of the wavefront refractive surgery techniques is applied the phase conjugation principle. In some embodiments, compensation of all points of optical path difference of the total ocular aberration are done by topographic change of cornea.

According to some exemplary embodiments, a treatment profile of ablation for wavefront vision correction applied to the stroma tissue are scaled by a factor of 2.9631 from ocular aberration.

In some embodiments, from that point, to implement free-form ablation profile surface as wavefront error it will need (WTPM) to be divided by factor 2.9631. Additionally, in the next step, transformation of matrix (WTPM) to Zemike Malacara notation is performed, for example to match data submission for CRS -Master.

According to some exemplary embodiments, after that manipulation, a script creates a database via add-on Database explorer for Matlab. In some embodiments, the CRS-Master recognize database as ocular abberometer data and allows to create free-form lenticule with the excimer laser.

According to some exemplary embodiments, for example as shown in fig. 5B, data from OCT 514 is imported to an analysis software, for example MATLAB analysis software 516. In some embodiments, a database generated by the software is delivered to a treatment management software, for example the CRS-master software 518. In some embodiments, information regarding a treatment profile of ablation generated by the CRS master software is transmitted to a memory of a control unit of an excimer laser 520. In some embodiments, control unit of the laser is configured to activate the laser according to the treatment profile of ablation. Exemplary cornea lenticule holder

According to some exemplary embodiments, the lenticule holder is shaped and sized for dissecting and/or reshaping a cornea while the cornea is positioned on a curved surface of the lenticule holder. In some embodiments, the curved surface is curved along at least 50% of the surface area. In some embodiments, placing the cornea on a curved surface during dissecting and/or reshaping allows for example, to have accurate dissecting and/or reshaping by one or more of preventing movement of the lenticule in a z-axis during the procedure, maintaining a known thickness of the cornea along the entire cornea surface during the procedure, and keeping the cornea in a desired curvature that allows better functionally post implantation. Reference is now made to figs. 5C-5E, depicting parts of a cornea holder, according to some embodiments of the invention.

According to some exemplary embodiments, a cornea holder, for example a cornea lenticule holder comprises a cornea holder base 530, shaped and sized for holding a cornea in a fixed curvature during dissection and/or ablation. In some embodiments, the cornea holder base 530 comprises a body 532 having a longitudinal axis 533 and an upper curved surface 534. In some embodiments, the upper curved surface has a radius of curvature in a range of 7 mm-9 mm, for example 7 mm-8 mm, 7.5 mm- 8.5 mm, 7.8 mm- 8.3 mm, 7.9 mm- 9 mm or any intermediate, smaller or larger range of values. In some embodiments, the upper curved surface 534 is configured to hold a cornea or a portion of cornea, for example a cornea lenticule.

According to some exemplary embodiments, for example as shown in figs. 5D and 5E, the cornea holder comprises an alignment portion located near or adjacent to the curved surface 534. In some embodiments, the alignment portion is part of a cornea holder alignment cover 536, configured to be placed on top the cornea holder base 530. In some embodiments, the holder alignment cover is hollow, for example to allow placing the cover around the holder base. In some embodiments, the cornea holder alignment cover 536 comprises a base 538 having a longitudinal axis, and a central opening 540 at the upper surface of the cover 536. In some embodiments, the central opening 540 comprises a round or an oval opening. In some embodiments, the central opening 540 is shaped and sized to allow at least a partial penetration of a cornea positioned on the curved surface of the holder base from within a lumen of the cover 536. Alternatively or additionally. The central opening 540 is shaped and sized to allow at least a partial penetration of the curved surface 534 through the opening from within a lumen of the cover 536. Optionally, the central opening 540 and the upper curved surface 534 are co-axial, when the cornea holder base is positioned at least partially within the lumen of the holder alignment cover 536.

According to some exemplary embodiments, the alignment portion comprises at least one, for example at least two alignment markings located on the upper curved surface 534 or adjacent to the upper curved surface 534. In some embodiments, the alignment markings are shaped as elongated indentations or channels. Optionally, the alignment markings comprises at least two straight lines or channels, shaped and sized to allow alignment of the upper curved surface with alignment marking or a coordinate system of a laser surgical device. Additionally or alternatively, the alignment portion comprises one or more rotation orientation markings located on the upper curved surface 534 or adjacent to the upper curved surface 534. In some embodiments, the rotation orientation marking is shaped as an opening or an indentation, and configured to mark a selected orientation position of the cornea or the cornea implant placed on the upper curved surface. In some embodiments, the orientation position of the cornea implant is marked to maintain a fixed rotation orientation of the cornea implant with respect to the cornea holder during the cutting and/or reshaping procedure. Additionally, the rotation orientation marking allows rotational alignment between the cornea implant and a marking in the eye, for example a peripheral incision formed in the eye to allow, for example implantation of the cornea implant into a recipient cornea.

According to some exemplary embodiments, the cover 536 comprises at least two alignment channels on the upper surface, crossing through the central opening 540 and positioned at a known angle relative to each other. Optionally, the at least two channels, for example channels 542 and 544 are perpendicular to each other. In some embodiments, the two alignment channel form a cross. In some embodiments, the center of the cross is positioned at a center of the central opening 540. In some embodiments, the alignment channels are shaped and sized to allow alignment with a cross-shaped marking in an eye-piece of a laser device, for example to allow better focusing and/or accurate dissection or ablation.

According to some exemplary embodiments, the cover the upper surface of the cover 536 comprises one or more marking indentations or marking openings on an edge of the central opening 540, for example marking opening 546. In some embodiments, the marking is positioned at an intersection between an alignment channel, for example an alignment channel 542 and the central opening 540.

According to some exemplary embodiments, the cover 536 and the base 530 are fixed relative to each other when the base 530 is positioned within the cover 536, for example to prevent relative movement between them during laser activation.

According to some exemplary embodiments, for example as shown in fig. 5F, a cornea 552 is placed on top a curved surface 534 of a cornea holder base 530. In some embodiments, the curved surface 534 allows to maintain a constant thickness of the cornea throughout the entire surface area of the cornea. It is expected that during the life of a patent maturing from this application many relevant methods for dissecting and ablating a cornea will be developed; the scope of the terms dissecting and ablating is intended to include all such new technologies a priori.

As used herein with reference to quantity or value, the term“about” means“within ± 10 % of’.

The terms“comprises”,“comprising”,“includes”,“including”,“has”,“having” and their conjugates mean“including but not limited to”.

The term“consisting of’ means“including and limited to”.

The term“consisting essentially of’ means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

As used herein, the singular forms“a”,“an” and“the” include plural references unless the context clearly dictates otherwise. For example, the term“a compound” or“at least one compound” may include a plurality of compounds, including mixtures thereof.

Throughout this application, embodiments of this invention may be presented with reference to a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as“from 1 to 6” should be considered to have specifically disclosed subranges such as“from 1 to 3”,“from 1 to 4”,“from 1 to 5”,“from 2 to 4”,“from 2 to 6”,“from 3 to 6”, etc.; as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein (for example“10-15”,“10 to 15”, or any pair of numbers linked by these another such range indication), it is meant to include any number (fractional or integral) within the indicated range limits, including the range limits, unless the context clearly dictates otherwise. The phrases“range/ranging/ranges between” a first indicate number and a second indicate number and“range/ranging/ranges from” a first indicate number “to”,“up to”,“until” or“through” (or another such range-indicating term) a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numbers therebetween. Unless otherwise indicated, numbers used herein and any number ranges based thereon are approximations within the accuracy of reasonable measurement and rounding errors as understood by persons skilled in the art.

As used herein the term“method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

As used herein, the term“treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting. In addition, any priority document(s) of this application is/are hereby incorporated herein by reference in its/their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method for reshaping a cornea, comprising:

placing a cornea on a cornea holder;

geometrically reshaping an outline of an external surface of said cornea portion while said cornea portion is placed in said cornea holder and is not separated from the cornea in said cornea holder.

2. A method according to claim 1, wherein said cornea comprises an in-vitro formed cornea implant, a human donor cornea lenticule or a human donor cornea.

3. A method according to any one of the previous claims, wherein said dissecting comprises dissecting said cornea to define a cornea portion after said dissecting having a maximal dimension of at least 7 mm.

4. A method for replacing a portion of a cornea, comprising:

calculating a size of a cornea portion to be removed from a cornea;

removing said cornea portion to form an implantation site while keeping an upper layer of the cornea intact;

implanting a cornea implant having a diameter which is smaller in at least 50 pm from a diameter of the implantation site into the implantation site and under the intact upper layer.

5. A method according to claim 4, comprising performing a Small Incision Lenticule Extraction (SMILE) surgery prior to said removing.

6. A method according to any one of claims 4 or 5, comprising dissecting said cornea by a surgical laser device based on said calculated size.

7. A method according to claim 6, wherein said calculating comprises calculating thickness values of said cornea portion to be removed at one or more locations along an area of said cornea portion, and wherein said dissecting comprises ablating said cornea according to said calculated thickness values.

8. A method for forming a treatment zone in a cornea, comprising:

9. A method according to claim 8, wherein said one or more lasers comprise a femtosecond laser and/or an excimer laser.

10. A method according to any one of claims 8 or 9, comprising removing tissue from said treatment zone in said cornea through an incision formed at a periphery of the cornea at a distance larger than 4 mm from a center of the cornea.

11. A method according to claim 10, wherein said incision extends in a circumferential direction and is smaller from a maximal dimension of a cornea implant.

12. A cornea holder, comprising:

13. A holder according to claim 12, wherein said curved surface has a radius of curvature in a range of 7-9 mm along the entire curved surface.

14. A holder according to any one of claims 12 or 13, comprising an alignment portion located at or adjacent to said upper curved surface, wherein said alignment portion comprises one or more alignment markings shaped and sized to align said upper curved surface with alignment markings or a coordinate system of a laser surgical device.

15. A holder according to claim 14, wherein said alignment portion comprises one or more rotation orientation markings shaped and sized to be positioned near at least a portion of a cornea, wherein said rotation orientation marking are configured to allow marking of the cornea by forming a cut or a void in the cornea to set a rotation orientation of the cornea with respect to said rotation orientation marking of said holder.

16. A holder according to claim 15, wherein said one or more rotation orientation markings comprises an opening or an indentation in said alignment portion.

17. A method for removal of a damaged tissue region from the cornea, comprising: identifying a damaged region in the cornea;

removing said selected damaged portion from the cornea.

18. A method according to claim 17, comprising:

19. A method according to any one of claims 17 or 18, wherein said calculating comprises calculating size and/or shape of a cornea implant to be inserted into said cornea instead of said removed damaged region.

20. A control unit of system for laser surgery of an eye, comprising:

21. A system for laser surgery of an eye, comprising:

a femtosecond laser;

an excimer laser;

a control circuitry configured to signal said femtosecond laser and said excimer laser to dissect and ablate a cornea according to said treatment program.