Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Scleroproteins – e.g. – fibroin – elastin – silk – etc.
Reexamination Certificate
1999-01-18
2001-03-20
Borin, Michael (Department: 1631)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Scleroproteins, e.g., fibroin, elastin, silk, etc.
C514S801000, C522S068000, C128S858000
Reexamination Certificate
active
06204365
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
Photoablation eximer laser keratectomy is a ophthalmologic technique which employs an 193 nm excimer laser as a surgical tool to ablate or remove a precise amount of tissue from the anterior corneal surface of the eye. In addition to its usual application in correcting refractive errors (e.g. myopia, hyperopia and astigmatism) by altering the curvature of the cornea, this technique has more recently been applied, with success, in removing opacities and irregularities from the anterior corneal surface.
The application of eximer lasers in photoablation procedures have been described in the medical literature. See, for example, Sher, N. A. (1991)
Arch. Ophthal.,
Vol. 109, pages 491-498; Zabel, R. W. et al. (1990)
Refrac. Corn. Surg.,
Vol. 6, pages 329-334; Steinert, R. F. et al, ibid, page 352; Gaster, R. N. et al. (1989)
Invest. Ophthal. Vis. Sci.,
Vol. 30, pages 90-98; and Tuft, S. J., ibid, page 1769-1777. Typically, a far ultraviolet argon fluoride laser, emitting at 193 nm, is used in clinical procedures because of its minimal tissue interaction, ablative efficiency and ease of control of ablation depth. Moreover, irradiation at 193 nm shows less mutagenic potential in comparison to longer ultraviolet wavelengths. The laser, fitted with a series of apertures of varying diameter and shapes, is preprogrammed to deliver a series of pulses of a given duration and energy fluence settings. In general, eye movements are minimized during the ablating process and the eye is held with the visual axis fixated under the center of the laser beam.
The extent and depth of the ablation depends on a number of variables which include aperture, shape and diameter, laser energy fluence (mJ/cm
2
), duration of irradiation (nanoseconds), pulse rate (Hz) and number of pulses. Other factors would include intraoperative epithelium and corneal stromal drying during effluent removal. Eximer laser ablation of the anterior corneal lamellar tissue, in general, leaves behind a smooth surface that enables reepithelialization, a clearer cornea, and an appropriate refractive surface.
In certain situations, modulators are used during the procedure. As defined herein, the term “modulator” refers to a substance which, when applied to tissue, is capable of absorbing UV irradiation and modulating the degree of tissue ablation. Modulators are generally used as adjuncts to promote photoablative smoothing of irregular corneal surfaces and to protect adjacent corneal tissue where ablation is not desired. Examples which would benefit from the use of modulators include removal of corneal scars and opacities, often accompanied with an irregular or rough epithelial surface, due to post-infectious and post-traumatic causes, including herpes simplex virus, dystrophies (e.g. Salzmanns and Reis Buckler's syndrome), recurrent erosions and band keratopathy. Also, several types of corneal pathologies ablate more quickly than others, and this differential ablation may lead to increased irregularity of the corneal surface following ablation.
A number of photoablation modulators have been reported in the literature. See, for example, Sher, N. A. (1991), supra; Steinert (1990), supra; Kornmehl, E. W. et al. (1991)
Investigative Ophthalmology
&
Visual Science,
Vol. 31(4), Page 245, Abstract no. 1203; and Steinert, R. F. in “Eximer Laser Phototherapeutic Keratectomy: Strategies and Representative Cases,” 17th Cornea Research Conference, Sep. 19-21, 1991, Eye Research Institute and Massachusetts Eye and Ear Infirmary. Examples of known modulators include viscous aqueous solutions of methylcellulose, dextran 70, sodium carboxymethylcellulose and hydroxypropylmethylcellulose 2910 as well as 0.9% saline.
In general, conventional modulators suffer from a number of deficiencies which preclude their broader use in photoablation procedures. For example, modulators (1) are difficult to apply smoothly on the corneal surgical bed; (2) are susceptible to drying and rippling from the air flow from the effluent remover; (3) do not adequately absorb at 193 nm; and/or (4) do not adequately promote a smoother ablated corneal surface relative to a control situation (no modulator) because the modulator ablates at a different rate than corneal tissue. Accordingly, there is a need in the art for photoablation modulators which avoid one or more of the aforementioned deficiencies.
SUMMARY OF THE INVENTION
Surprisingly, it has now been discovered that certain collagen formulations are useful for preparing collagen modulators useful in photoablation procedures. These compositions not only fill in various imperfections on the corneal surface, but also ablate at approximately the same rate as the corneal stroma. The collagen modulators promote a smoother ablated surface, relative to a control situation (no modulator). The disclosed collagen formulations has enormous utility in clinical eximer laser photoablation procedures.
The present invention provides biologically compatible collagen solutions for use in photoablation procedures and methods for its preparation as well as application in therapeutic and refractive eximer laser photoablation.
In one embodiment of the invention, a neutralized, acid solubilized collagen, which remains in solution at physiological temperatures, is used to prepare a modulator gel coating or film on a corneal surface. These solutions must be extensively dialyzed against EDTA solutions and/or deionized water to reduce available cations and to prevent premature collagen fibrillogenesis. As the cations are removed, the pH of the collagen solution is increased to between about 6.8 and about 7.5 by adjusting the pH of the EDTA solution using 1 N sodium hydroxide. The collagen preparation does not undergo typical fibrillogenesis in the absence of added unbound or free cations.
When applied to a surface of a human cornea prior to photoablation keratectomy, the collagen formulation uniformly coats and readily adheres to the surface, filling surface depressions and other irregularities and provides a smooth surface for subsequent photoablation. The collagen coating is then instantly converted to a firm gel upon contact with a metal cation-containing solution. Metal cations are supplied in buffer solutions such as phosphate buffered saline or sodium chloride solution. The collagen gel readily absorbs UV irradiation, e.g. 193 nm, which is used in eximer laser keratectomy and exhibits ablation properties which resemble the human cornea. Upon completion of the photoablation procedure, any remaining residual collagen gel are readily removed from the corneal surface by dislodging the residue with water or physiological buffer solution.
In another embodiment of the invention, chemically modified polymerizable soluble collagen solutions having redox initiators are used in preparing modulator films. When applied to a corneal surface as a coating, the chemically modified collagen adheres to the surface, filling surface depressions and other irregularities. The coating is then subjected to polymerization conditions such as short wave UV to form a thin modulator film prior to photoablation. The film strongly adheres to the corneal surface and is physically removed during the photoablative procedure.
In a further embodiment of the invention, a glutaric anhydride modified collagen, preparable by reacting soluble collagen with glutaric anhydride in an amount ranging between about 20 and about 30 wt. % based on total collagen, is provided and which undergoes temperature-dependent sol/gel transformation. The glutaric collagen, at a collagen concentration ranging between about 5 and about 100 mg/ml, melts or liquifies at physiological temperature, e.g. 37° C., to form a viscous solution. When applied to a corneal surface as a coating at 37° C., the glutaric collagen adheres to the surface, filling surface depressions and other irregularities. The coating rapidly forms a gel upon cooling to room temperature without any addition of metal cation solution or induced polymerization. The collagen gel readily ab
DeVore Dale P.
Eiferman Richard A.
Borin Michael
Collagenesis Inc.
Darby & Darby
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