Patent Application
20160151202
Exemplary embodiments of the present disclosure relate to a modification of optical and mechanical properties of the tissues using nonlinear photochemical processes such as two-photon induced crosslinking, and more particularly to methods, systems, computer-accessible medium and arrangements that provide refractive changes of the cornea by spatially-selective two-photon crosslinking of collagen fibers. Further exemplary embodiments of the present disclosure relate to methods, arrangements and systems that can alter the structural, optical and mechanical properties of the corneal tissue using photochemical processes, such as, e.g., light-mediated crosslinking of collagen fibers.
Collagen crosslinking is a procedure that involves a photosensitizing agent and light illumination that increases the strength of collagen fibers by inducing covalent crosslinks. Such procedure has become popular as a treatment for the cornea of patients affected by keratoconus or other ectatic disorders, i.e. conditions where the cornea is abnormally weak and therefore progressively thins and bulges.
Before 2003, therapeutic strategies for treating keratoconus included rigid gas-permeable contact lenses, thermal keratoplasty and intracorneal rings. However, all of these techniques aimed at managing the visual symptoms of keratoconus and were not able to arrest or even hinder the progression of keratoconus. In 2003, a clinical trial of Riboflavin/UVA cornea crosslinking (CXL) was reported for patients with moderate or advanced progressive keratoconus. (See, e.g., Ref 1).
CXL strengthens the cornea by inducing crosslinks among the collagen fibers of the corneal stroma. In all patients, the progression of keratoconus was arrested, and most patients experienced improved visual acuity. Subsequent studies confirmed these initial results and noted statistically significant improvements in long-term visual acuity. To date, CXL has been recognized as the only therapeutic approach that can arrest the progression of keratoconus.
The standard CXL protocol involves 1) epithelial debridement; 2) application of the photo sensitizer riboflavin (e.g., vitamin B2); and 3) irradiation with UVA light at 3 mW/cm2 for 30 minutes. (See, e.g., Refs. 2 and 3). The mechanism of CXL is known to involve the production of singlet oxygen when riboflavin is bleached by UVA light. Singlet oxygen then catalyzes the formation of covalent cross-links between primarily histidine residues in collagen. No collagen cross-linking was observed when CXL treatment was performed in the presence of sodium azide, a singlet oxygen quencher. (See, e.g., Ref. 4). This can suggest that the production of singlet oxygen by riboflavin is a key step in collagen-cross-linking.
Recently, CXL has found other applications alone or in combination with other ocular procedures to alter the structural, mechanical and/or refractive properties of the cornea. The crosslinking procedure is therefore destined to become the standard of care for patients with corneal ectasia and is conceivable that its application will extend to other ocular tissues such as conjunctiva, sclera and possibly more broadly to other human tissues.
Despite the demonstrated usefulness of the standard “one-photon” collagen crosslinking of the cornea using UVA light and riboflavin (CXL) a few important drawbacks limit the widespread use and effectiveness of the procedure. For example, the significant thinning induced by the Riboflavin solution during the procedure and the fear of endothelial cell damage make standard CXL only applicable to thick corneas (greater than about 350 μm). In this respect, two-photon-induced processes in optical imaging, spectroscopy and microfabrication have advantages over their one-photon counterparts in part due to the spatial selectivity associated with two-photon processes. The invention makes use of two-photon or other nonlinear optical processes to selectively cross-link corneal collagen with 3-dimensional resolution. A two-photon cross-linking (2P-CXL) protocol allows treatment of thin corneas (less than about 330 μm) that cannot currently be treated, and can improve cell viability by using near-IR light and irradiating only non-cellular regions. In addition, selective collagen cross-linking can alter the refractive power of the cornea, for increasing visual acuity of the individual by correcting myopia or aberrations including high-order aberrations induced after refractive surgery or conventional corneal crosslinking. Since the two-photon cross-linking procedure can be readily customized, and furthermore is non-invasive and permanent, such an application could be a viable alternative to femtosecond laser ablation, or lamellar laser refractive surgery (LASIK).
It is believed that two-photon collagen cross-linking procedure (2P-CXL) of the cornea has not been reported or described. Traditional CXL of the cornea, using one-photon irradiation, is well established worldwide. 2P-CXL brings numerous advantages over the traditional CXL protocol in the treatment of keratoconus, including use of a less phototoxic near-IR laser, ability to selectively irradiate non-cellular regions only, and treatment of thin corneas that cannot be currently treated in the clinic.
A majority of the total refraction of the human eye is achieved by the cornea. (See, e.g., Ref 5). A number of refractive errors are due to abnormalities of the cornea, including astigmatism, hyperopia and myopia. In recent years, lamellar laser refractive surgery (LASIK) has emerged as an effective technique to modify the shape of the cornea and correct refractive errors associated with these disorders. In LASIK, a femtosecond laser is first used to etch a lamellar flap within the cornea stroma. The flap is then folded back, and an excimer laser is used to ablate and remodel the stroma. After ablation has been completed, the flap is repositioned to its original position, and left to heal naturally. Complications of LASIK include: lamellar keratitis induced by the femtosecond laser, dry eye due to severing of corneal nerves when the flap is created, displacement of the flap after surgery, and corneal ectasia, with similar clinical presentation of keratoconus.
U.S. Patent Publication No. 2010/0210996 describes a method for laser correction of refractive errors of an eye with a thin cornea by patterned crosslinking. Since this method relies on linear single-photon absorption of riboflavin, its spatial resolution, especially along the depth dimension, is inherently poor.
Another limitation of current CXL procedures is related to the requirement of de-epithelialization prior to the application of the drug. Human cornea has several layers, e.g., epithelium, Bowman's membrane, stroma, Descemet's membrane and endothelium. The stroma makes up the majority of corneal tissue and being rich in collagen fibers provides structural and mechanical strength of the cornea. CXL procedure aim to act on the corneal stroma and specifically on its collagen fibers.
The epithelial layer of the cornea, on the other hand, can be an extremely effective barrier against the diffusion of the photosensitizing agent into the corneal stroma. As CXL procedure's outcome is dependent on the effective delivery of the photosensitizing agent to the corneal stroma, by-passing the blocking function of the epithelium is truly a condicio sine qua non.
Standard protocols for collagen crosslinking address this issue by removing the epithelial layer prior to the application of the photosensitizer. For this reason, standard protocols can be generally referred to as “epi-off” CXL. However, removing the epithelium may have serious clinical drawbacks and side effects (see, e.g., Ref 21), e.g., (a) lengthening the post-operative recovery time, which may increase the pain involved with the procedure (that lasts about 5-7 days), (b) increasing the risk for infection, (c) losing corneal sensitivity for up to six months due to corneal nerve damage, (d) potential visual loss in the first days post-op, etc. Re-epithelialization takes a minimum of four days. It is typical that after CXL procedure antibiotics and steroids are prescribed for a week and patients need to be monitored during the first two weeks to assess corneal re-epitheliazation. (See, e.g., Ref. 21).
Thus, this is an important issue related to the CXL procedure, and an extremely active area of research. The clinical and research community has been exploring alternative procedures, usually referred to as “epi-on” procedures. The two major approaches currently investigated to achieve transepithelial delivery of the photosensitizer are, e.g. (a) Chemical loosening of the epithelial cell junctions (see, e.g., Ref. 22 and 23); and (b) Electrical driving of the photosensitizing solution into the cornea via iontophoresis (see, e.g., Ref 24). Both of these approaches have been shown to lack the necessary performance to replace the “epi-off” procedure; the evidence of their effectiveness is scarce and controversial, and therefore the clinical community has not adopted them. (See, e.g., Ref. 21). Although, as expected, the transepithelial “epi-on” delivery of photosensitizer reduces the side effects connected with epithelial debridment, the yield of delivery has been shown to be poor, which has produced decreased mechanical strengthening, and reduced clinical efficacy. (See, e.g., Refs. 21 and 25).
As a result, the growing field of collagen crosslinking has a clearly defined need to improve the delivery of the photosensitizer into the deeper layers of the cornea while not incurring in the clinical side-effects associated with the macroscopic removal of the epithelial layer. According to yet another exemplary embodiment of the present disclosure, the irradiation can be selectively controlled by the first arrangement(s) to provide a spatially-periodic pattern within the portion(s).
Accordingly, there may be a need to address at least some of the above-described deficiencies.
Thus, to address at least such issues and/or deficiencies, exemplary embodiments of methods, systems, computer-accessible medium and arrangements that provide refractive changes of the cornea by spatially-selective two-photon crosslinking of collagen fibers can be provided. For example, using two-photon photochemical cross-linking to tune the refractive power of the cornea has not been reported. The exemplary embodiments of systems, methods and arrangement can provide a nonlinear corneal crosslinking provides a beneficial paradigm in the treatment of refractory disease without invasive ablation and creation of corneal flaps.
Thus, systems, methods, arrangements and non-transitory computer-accessible according to exemplary embodiments of the present disclosure can be provided for, e.g., affecting refractive changes of the cornea by spatially-selective two-photon crosslinking of collagen fibers. For example, it is possible to obtain at least one property of at least one portion of the eye using at least one first arrangement. Based on the at least one property, data indicating a plan of affecting the portion(s) of the eye can be generated. Further, it is possible to control at least one electromagnetic-radiation-providing second arrangement to execute the plan and irradiate the at least one portion based on the plan, affecting at least one property. The irradiation can be selectively controlled to be delivered to at least one selective depth within the portion(s).
The second arrangement(s) can include a laser source configured to excite multi-photon transitions. The laser source can be a pulsed femto-second laser source which can be configured to deliver near an infra-red light radiation. The propert(ies) can include (i) refractive index, (ii) elastic or visco-elastic property, (iii) microstructure, (iv) radius of curvature, (v) collagen content and organization, and/or (vi) scattering effect of the at least one portion. The propert(ies) can be obtained by (i) OCT, (ii) Brillouin imaging modality (iii) Raman, (iv) laser speckle, (v) multi-photon imaging modality, (vi) photo-acoustic modality, (vii) confocal microscopy modality, (viii) florescence modality, and/or (ix) pentacam. For example, the change(s) can effect at least one optical property of the eye. The optical propert(ies) can include (i) a refractive property, (ii) a transmission property, (iii) a polarization filter, (iv) a reflection property, (v) a color filter, and/or (vi) a refractive error within the eye. The refractive error can include a myopia, a hyperopia, an astigmatism and/or a high-order aberration. The high-order aberration can include a spherical aberration and/or a coma aberration.
According to an exemplary embodiment of the present disclosure, the irradiation can be delivered to a specifically controlled volume within the portion(s), e.g., without effecting further sections of the portion(s) through which the irradiation is provided. The specifically controlled volume can be as small as a diffraction-limited spot delivered by the second arrangement up to less than the volume of the portion(s). For example, the specifically controlled volume can be approximately 1 μm3.
According to another exemplary embodiment of the present disclosure, at least one third arrangement can be provided which is configured to affect a further property of the eye (i) prior to and/or (ii) during the delivery of the irradiation to the portion(s). For example, the arrangement(s) can be configured to applanate the cornea or counteract the intrinsic refractive power of the cornea to facilitate cross-linking, and includes at least one of (i) a contact lens (ii) a concave lens, (iii) a convex lens, (iv) an applanating transparent window or (v) a prism. The portion(s) can contain a photo-activatable agent. The first arrangement(s) can activate the photo-activatable agent so as to cause a selective cross-linking. The first arrangement(s) can utilize the selective cross-linking to treat keratoconus in the portion(s). Alternatively or in addition, the first arrangement can obtain information regarding keratoconus in the portion(s), and can be used to change a refractive property of the portion(s) based the information using the selective cross-linking. The refractive property can include a high-order aberration, and the high-order aberration can include a spherical aberration and/or a coma aberration.
Further, or in addition, upon the execution of the plan and the delivery of the irradiation to the at least one portion based on the plan, (i) a refractive error and/or (ii) an imperfection of the eye can be improved, and/or at least one separation within the eye can be reconnected.
Turning to another exemplary embodiment of the present disclosure, a first step of the above-described CXL procedure, i.e. the de-epithelialization of the cornea prior to the procedure, can be modified. Thus, such exemplary embodiments can be broadly applicable to different photosensitizers and illumination strategies for CXL.
Thus, system, method and arrangement according to such exemplary embodiment of the present disclosure can address the issue of improving a delivery of the photosensitizer into the deeper layers of the cornea while not incurring in the clinical side-effects associated with the macroscopic removal of the epithelial layer. Thus can be done, e.g., by introducing microscopic spatially patterned debridement of the epithelium. Removing and/or ablating small localized zones of the epithelial layer can leave intact enough surrounding normal tissue which facilitates very quick re-epitelialization. Further, the localized “micro-holes” created in the epithelium can enhance a diffusion of the photosensitizing agent through the epithelium into the stroma.
Thus, according to certain exemplary embodiments of the present disclosure, an inscribing arrangement can be provided to produce microscopic injury with a pattern on the epithelium of a cornea. Such exemplary arrangement can include, e.g., a micro-needle array, an optical arrangement to generate at least one pattern, energy source (e.g., a pulsed laser, such as, e.g., femtosecond laser), mask/scanner, lens, etc. Various patterns can be achieved with such exemplary configuration (e.g., array pattern, patterned area, spacing, diameter, shape, depth, etc.).
According to yet another exemplary embodiment of the present disclosure, a drug delivery system can be provided which can include the above described arrangement, and utilize certain exemplary and chemical agents. Such exemplary agents can include certain chemical agents delivered/diffused through the injury produced by the tool, Riboflavin, Photosensitizer and/or eye drugs.
In still a further exemplary embodiment of the present disclosure, an apparatus for corneal treatment by microscopic epithelium debridement can be provided. Such exemplary apparatus can utilize the following, e.g., CXL, including CXL light, refractive correction, CXL light, and/or PDT, excitation light. A chemical agent can be used with chemical structure optimized for an efficient transport through microscopic debridement. The exemplary properties of the chemical agent can be further optimized to work in combination with other strategies, such as iontophoresis, for more rapid and effective diffusion.
These and other objects, features and advantages of the present disclosure will become apparent upon reading the following detailed description of exemplary embodiments of the present disclosure, when taken in conjunction with the appended drawings and claims.
Further objects, features and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings showing illustrative embodiments of the present invention, in which:
Throughout the drawings, the same reference numerals and characters, if any and unless otherwise stated, are used to denote like features, elements, components, or portions of the illustrated embodiments. Moreover, while the subject disclosure will now be described in detail with reference to the drawings, it is done so in connection with the illustrative embodiments. It is intended that changes and modifications can be made to the described exemplary embodiments without departing from the true scope and spirit of the subject disclosure and the appended claims.
An exemplary production of singlet oxygen by riboflavin occurs as follows. Here, we describe riboflavin as the photo-initiator, but there are several photo-initiator dyes known in the fields, including riboflavin derivatives and Rose Bengal, which has single-photon absorption in the green wavelength. Excitation of riboflavin can be accomplished with one-photon absorption, with use of UVA light (315-400 nm), or two-photon absorption (2PA) with use of a femtosecond laser that delivers near-IR light (800 nm). Although 2PA can follow different selection rules, two-photon photosensitized production of singlet oxygen has been demonstrated. (See, e.g., Refs. 7 and 8). 2PA generally relies on the simultaneous absorption of two photons, each with half the energy that is used in the one-photon process. A spatial selectivity of 2PA can arise because the probability of absorption is dependent on the square of the incident laser power. In addition, 2PA requires extraordinarily high peak laser intensities. As a result, two-photon absorption is confined to the laser focus (Δx<1 μm), which can minimize an excitation of molecules in the out-of-focus regions. This phenomenon contrasts with one-photon absorption, which can be linearly dependent on incident laser intensity, and can occur throughout the incident light cone.
In general, crosslinking can result in a local change of the refractive index. This can be used to produce a spatial refractive grating in the cornea. An exemplary pattern is shown in
2P-CXL can provide certain important benefits over standard CXL treatment. First, a prolonged illumination of corneas with UVA light in CXL can cause cell death and tissue toxicity. 2P-CXL can use a near-IR laser at about 810 nm, which is less phototoxic. (See, e.g., Ref 9). Second, the 2P-CXL procedure can be tailored to avoid keratocytes in the cornea, which are known to disappear from the anterior stroma soon after CXL treatment with UVA irradiation. (See, e.g., Ref 2). While the keratocytes can eventually repopulate the anterior stroma, the effects of their initial insult on cornea morphology may not be well understood. CXL treatment can also stimulate an inflammatory cell activation in the corneal stroma. At present, the long-term effects of CXL treatment on the cornea may not be known, due to a lack of long-term follow-up studies. By minimizing or reducing cell damage with 2P-CXL, long-term side-effects can be mitigated. Third, the 2P-CXL procedure would allow treatment of thin corneas (<330 μm) that cannot be treated with current CXL procedures. Typically, CXL treatment requires a minimal corneal thickness of 400 μm to prevent damage to the underlying endothelium. An exemplary protocol, which can use a hypo-osmolar riboflavin solution, can induce swelling of the cornea thereby extending this limit, while the protocol still uses a thickness of 330 μm. Since 2PA generally occurs at the laser focus, which is typically less than about 1×1×4 μm3, 2P-CXL can treat thin corneas without damaging the endothelium beneath the stroma. Fourth, 2P-CXL can be used in conjunction with Brillouin microscopy (see, e.g., Ref 11 and 12), or other imaging modalities that can provide spatially-resolved information regarding the local properties, optical and/or mechanical, of the cornea to select and cross-link corneal areas most distorted by keratoconus, thereby minimizing the overall irradiation.
An exemplary ability to selectively cross-link the cornea can be used for certain applications, e.g., in modifying the refractive power of the cornea. The cornea can be modeled as a simple two-surface optical system and/or a positive meniscus lens. The refractive power can be calculated and/or determined with the refractive indices of the multiple regions (e.g., air, cornea, aqueous), and the radii of curvature of the anterior corneal surface and the posterior corneal surface 13. By altering the radius of curvature of the cornea globally or locally, e.g., on the anterior surface, with 2P-CXL, the refractive power of the cornea can be altered. The refractive index and thickness of cornea (stroma) can also be altered by 2P-CXL procedure. These and other exemplary physical and chemical effects can be considered when determining the exemplary crosslinking pattern. The incident laser power, cross-linking duration, photosensitizer concentration can also be optimized to achieve the desired effect of 2P-CXL.
Abnormal shape of the cornea can result in refractive errors such as low-order aberrations including myopia, hyperopia and astigmatism, and high order-aberrations such as spherical aberrations and coma.
The exemplary system, method and/or arrangement (e.g., 2P-CXL) according to various exemplary embodiments of the present disclosure can also be performed at a low enough power such that the major effects of the procedure are alterations in the cornea's refractive index rather than changes in curvature. Spatially patterned crosslinking at low power can also be used for higher order aberrations, which is a common side-effect of LASIK.
In addition, 2P-CXL can facilitate a modulation of the refractive index within the cornea in a periodical, quasi-periodical, or a-periodical manner in 3D. This can empower the eye with color filtering, polarization filtering (e.g., by modulating birefringence) and visual acuity previously not possessed by the eye. For example, the 2P-CXL procedure can induce a local increase in refractive index from the natural stroma value of 1.37 to up to 1.5. In this case, the periodic modulation of refractive index within parallel thin layers (e.g. N>10) of the corneas (see, e.g.,
An exemplary ability to alter with spatial selectivity the radius of curvature and refractive index of the cornea, allows the exemplary 2P-CXL technique to take advantage of diagnostic and structural information provided by existing measurements and/or modalities of the cornea. These can include, but not limited to, optical coherence tomography (OCT), pentacam and numerous imaging techniques such as laser speckle, Raman, photo-acoustic, multi-photon, photo-acoustic and fluorescence. Information provided by these measurements before the exemplary techniques of 2P-CXL to be performed can be used to generate an optimized three-dimensional plan for cross-linking the patient's eye to correct the patient's vision. For example, an exemplary 2P-CXL procedure can include: a) an exemplary analysis of three-dimensional OCT image and/or a Pentacam of the patient's cornea demonstrating myopia caused by excessive curvature in the anterior portion of the cornea, b) an exemplary computation/determination of an exemplary pattern used and/or required to correct patient's vision (e.g. a ring around the anterior portion of the cornea) and of the operational parameters which can be used to achieve the desired changes; c) an exemplary application of riboflavin to the cornea, and/or d) an exemplary two-photon cross-linking of a ring around the anterior portion of the cornea, at an optimized depth within the anterior portion of the cornea, e.g., to flatten or reverse the excessive curvature and restore optimal vision.
The exemplary embodiment of the system, method and arrangement according to the present disclosure can further utilize and/or include monitoring device(s). For example, photobleaching of riboflavin two-photon fluorescence during the exemplary 2P-CXL procedure, as shown in
To demonstrate the feasibility of the exemplary 2P-CXL procedure, system and arrangement according to an exemplary embodiment of the present disclosure, two-photon photobleaching experiments have been performed on riboflavin. For example, a Ti:Sapphire femtosecond laser delivering 810 nm, 150-fs, 80 MHz pulses was used to measure the reduction of riboflavin fluorescence over time. It was confirmed that riboflavin could be bleached using two-photon photoactivation. The photobleaching rate can be expected to depend quadratically on the laser power, much like two-photon absorption (I˜powern, where n=2). It was also determined that the photobleaching rate were dependent on even higher order photon interactions (n>2). Similar results with other fluorophores have been reported, although the mechanism of these higher order interactions is not well understood. (See, e.g., Ref 16). Nevertheless, the added non-linearity of two-photon induced riboflavin photobleaching provides superior spatial selectivity for the purposes of 2P-CXL.
Furthermore, a two-photon crosslinking procedure of porcine corneas has been performed in accordance with the exemplary embodiments of the present disclosure using an exemplary beam-scanning illumination system according to an exemplary embodiment of the present disclosure.
To determine the focal length of the cornea, according to one experiment, an excised ex vivo bovine cornea was mounted on a custom-made transparent aqueous chamber (see
2P-CXL remodeling of the cornea according to an exemplary embodiment of the present disclosure can be a suitable alternative to (or used in addition to) LASIK, since the exemplary procedure(s) which can be implemented by such exemplary embodiments is non-invasive, permanent and customizable for the patient's needs. The exemplary systems, methods and arrangements according to the present disclosure which utilize 2P-CXL do not require ablation of tissue or creation of a corneal flap. In comparison to LASIK, 2P-CXL delivers much lower peak laser intensities are delivered to the tissue. For example, in femtosecond laser cutting of corneal flaps, 2-3 μJ can be delivered per laser pulse (see, e.g., Ref. 17), while only 0.75 nJ can be delivered per laser pulse with use of our 2P-CXL procedure, assuming an average laser power of about 60 mW and repetition rate of about 80 MHz. In cases where LASIK may be preferable, 2P-CXL can also be used in conjunction with LASIK for the purposes of selective corneal flap bonding since the flap can be displaced after LASIK surgery.
CXL treatment with riboflavin is used clinically. The 2P-CXL protocol is relatively simple, and does not require expensive equipment other than a femtosecond laser, which is often available for clinical use. For these reasons, the exemplary systems, methods and arrangement of the present disclosure which implement 2P-CXL can be effective, and used not only for the treatment of keratoconus, but also as a viable alternative to LASIK for the treatment of various refractive disorders such as astigmatism, hyperopia and myopia.
In addition to collagen crosslinking, the exemplary systems, methods and arrangement of the present disclosure may utilize different nonlinear processes, such as, e.g., two-photon induced local release of chemicals. For example, molecules can be encapsulated by nano carriers, such as hollow gold nano-cubes coated with thermally sensitive polymers (see, e.g., Ref. 18), and illumination of femtosecond pulses release the molecules, such as collagenase, to induce physical and chemical changes of the cornea.
According to yet further exemplary embodiments of the present disclosure, the size of the small zones of removed epithelium can be varied. For example, the lower limit can be on the order of magnitude of the molecular size of the photosensitizing agent, and therefore the little holes can be as small as what diffraction-limited lasers can produce or even smaller, The upper limit for the size of the zones of epithelium removal is expected to be as big as, e.g., about 200 microns or more, which can be limited by the size that hinders the fast mode of re-epithelialization. Within these exemplary limits, the methods, arrangements and devices according to certain exemplary embodiments of the present disclosure can be customized and/or optimized.
For example, an estimation on exemplary improvements which can be associated with the methods, arrangements and devices according to exemplary embodiments of the present disclosure can be performed involving micro-injuries formation on skin through a technique, fractional photothermolysis, which is currently used with success for many purposes including scar removal and tissue rejuvenation. (See, e.g., Ref. 27). However, certain exemplary differences exist with respect to the skin application. For example, one such exemplary difference can relate to the depth of the treatment, e.g., in skin applications, the micro-holes or micro-injuries can usually run deep into the dermal layer, beyond the epithelium, because generally the intended purpose is tissue remodeling; on the other hand, according to an exemplary embodiment of the present disclosure, in the ocular tissue, only the epithelium needs to be removed, and removing deeper layers may represent a contra-indication.
As a result, the methods, arrangements and devices according to exemplary embodiments of the present disclosure are present which prevent a deeper injury. This can be done, e.g., by an exemplary optical engineering configuration and/or mechanically. For example, in skin, where micro-injuries are usually designed to be more significant, complete re-epithelialization can be observed in one day.
Thus, exemplary system, method and device according to the exemplary embodiments of the present disclosure can improve a post-op recovery time compared to current methods relying on macroscopic epithelial debridement. Further, in terms of yield of delivery of photosensitizer, if about 20-50% of surface area is open and accessible, performances comparable to macroscopic epithelial debridement can be achieved with minimal adjustments to the second step of the CXL procedure, i.e., the application/diffusion/soaking time of the photosensitizer, especially if the diffusion properties of the photosensitizer can be optimized for the intended application.
Further, the localized epithelium removal can be achieved, e.g., optically and/or mechanically. For example, different lasers or other light sources can be used for such purpose with varying pulsed duration, wavelength and/or energy (with much lower requirements with respect to the skin or other tissue application). Appropriate performances can be achievable because, e.g., a) in terms of retinal exposure safety, the natural divergence of the focused beam used to create the small holes can project a large unfocused beam onto the retina; and b) in terms of cornea thermal safety, only a small localized area of tissue is affected, the surrounding tissue can be unexposed and continuous perfusion of corneal tissue can be obtained through the aqueous humor.
Alternatives to optical arrangements/configurations, mechanical arrangements and/or configurations can be used. For example, in skin and other tissues, it has been recently shown that, similar healing/recovery performances to fractional photothermolysis can be obtained by a patterned array of sharpened micro-needles that extract ˜100-micron-sized columns of tissue. (See, e.g., Ref 28). This can represent a proof-of-principle for the exemplary embodiments of the present disclosure as showing that microscopic epithelium removal can be obtained mechanically in a controlled manner. This can be done, e.g., with patterned array of microneedles, robotically-driven scanned needles, and/or other devices that replicate the biopsies procedure at a microscopic scale and with more limited depth.
The foregoing merely illustrates the principles of the disclosure. Various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein. Indeed, the arrangements, systems and methods according to the exemplary embodiments of the present disclosure can be used with and/or implement any OCT system, OFDI system, SD-OCT system or other imaging systems, and for example with those described in International Patent Application PCT/US2004/029148, filed Sep. 8, 2004 which published as International Patent Publication No. WO 2005/047813 on May 26, 2005, U.S. patent application Ser. No. 11/266,779, filed Nov. 2, 2005 which published as U.S. Patent Publication No. 2006/0093276 on May 4, 2006, and U.S. patent application Ser. No. 10/501,276, filed Jul. 9, 2004 which published as U.S. Patent Publication No. 2005/0018201 on Jan. 27, 2005, and U.S. Patent Publication No. 2002/0122246, published on May 9, 2002, the disclosures of which are incorporated by reference herein in their entireties. It will thus be appreciated that those skilled in the art will be able to devise numerous systems, arrangements and methods which, although not explicitly shown or described herein, embody the principles of the disclosure and are thus within the spirit and scope of the present disclosure. It should be understood that the exemplary procedures described herein can be stored on any computer accessible medium, including a hard drive, RAM, ROM, removable disks, CD-ROM, memory sticks, etc., and executed by a processing arrangement and/or computing arrangement which can be and/or include a hardware processors, microprocessor, mini, macro, mainframe, etc., including a plurality and/or combination thereof. In addition, certain terms used in the present disclosure, including the specification, drawings and claims thereof, can be used synonymously in certain instances, including, but not limited to, e.g., data and information. It should be understood that, while these words, and/or other words that can be synonymous to one another, can be used synonymously herein, that there can be instances when such words can be intended to not be used synonymously. Further, to the extent that the prior art knowledge has not been explicitly incorporated by reference herein above, it can be explicitly incorporated herein in its entirety. All publications referenced herein can be incorporated herein by reference in their entireties.
The present application relates to U.S. Patent Application Ser. No. 61/856,479, filed Jul. 19, 2013, the entire disclosure of which is incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US14/47412 | 7/21/2014 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 61856479 | Jul 2013 | US |
