WO1995003017A1

WO1995003017A1 - Ocular colorization process for changing eye color

Info

Publication number: WO1995003017A1
Application number: PCT/US1994/008242
Authority: WO
Inventors: Allan M. Robbins; James V. Aquavella
Original assignee: Robbins Allan M; Aquavella James V
Priority date: 1993-07-22
Filing date: 1994-07-22
Publication date: 1995-02-02

Abstract

A surgical process for changing the color of a human eyeball. In the first step of this process, substantially all of the epithelium of said human eyeball is removed, thereby exposing a layer of deeper corneal lamellae of the eyeball. Thereafter, water-insoluble stain is applied to the layer of the deeper corneal lamellae of the eyeball and the stain is fixed therein by contacting the layer of the deeper corneal lamellae with laser energy having a wavelength of from about 300 to about 1,064 nanometers. The treated eyeball is then washed.

Description

Ocular Colorization Process for Changing Eye Color

Technical Field

A surgical process of ocular colorization for changing the color of an eye in which the epithelial layer covering the cornea of the eye is displaced and water-insoluble stain is contacted with the Bowman's membrane or corneal stroma, which is thereafter contacted with laser energy.

Background Art

It is known that one's apparent eye color can be changed by the use of cosmetic contact lenses. However, these cosmetic contact lenses are not entirely satisfactory. Many patients cannot tolerate or are not comfortable wearing con¬ tact lenses for prolonged periods of time. Furthermore, the "color change" produced by these cosmetic contact lenses is not permanent and often does not appear to be very natural.

It is an object of this invention to provide a surgi¬ cal process for changing a patient's eye color which will permanently change such eye color.

Disclosure of invention

In accordance with this invention, there is provided a process for changing the color of an eye. In the first step of the process, the epithelium covering the cornea of the eye is removed. In the second step of the process, water-insolu¬ ble stain is contacted with one or more layers of the cornea below the basement membrane. In the third step of the inven¬ tion, the layer of the cornea is contacted with laser energy to create punctures of a predetermined size. Brief description of drawings

The details of our invention will be described in connection with the accompanying drawings, in which:

Figure 1 is a horizontal sectional view of a human eyeball;

Figure 2 is a sectional view of the cornea of a human eyeball;

Figure 3 is a flow diagram of a preferred process of the invention;

Figure 4 is a front view of a cornea with a center point marked thereon.

Figure 5 is a front view of the marked cornea of Fig¬ ure 4 with a central clear zone marked thereon.

Figure 6 is a front view of the marked cornea of Fig¬ ure 5 with a multiplicity of radial incisions made therein;

Figure 7 is preferred embodiment of an apparatus which may be used in applicant's process;

Figure 8 is a top view of a mask which may be used in one of the preferred processes illustrated in Figure 3;

Figure 9 is a side view of a device containing a mul¬ tiplicity of needles which may be used in conjunction with the apparatus of Figure 7;

Figure 10 is a front view of the device of Figure 9; and

Figure 11 illustrates a series of laser beams in a specified pattern impacting the stained layer of a cornea.

Best mode for carrying out the invention

Figure 1 is a horizontal section of the human eyeball 10. The eyeball 10 is a spherical, orbital sense organ that receives light and transmits visual information to the central nervous system. It is composed of three major layers (corneosclera, uvea, and retina) enclosing the agueous, lens, and vitreous.

Referring to Figure 1, it will be seen that outer clear layer 22 of eye 10 is comprised of the anterior epithel¬ ium layer 12 (hereinafter referred to as the "epithelium"), Bowman's membrane 14, the substantia propia 16 (hereinafter referred to as the "corneal stroma"), the Descemet's membrane 18, and the endothelium 20. Together these areas collectively comprise cornea 22.

Figure 2 is a microscopic cross-sectional view of cornea 22. Referring to Figure 2, it will be seen that the exterior layer of cornea 22 is comprised of epithelium 12.

As is known to those skilled in the art, the epitheli¬ um 12, which is often also referred to as the "corneal epi¬ thelium, " is comprised of multiple layers of cells that form the most superficial layer of the cornea; it rests on Bow¬ man's membrane 14.

The corneal epithelium is of uniform thickness (50 to 90 microns) with five to seven layers of nucleated cells di¬ vided into a superficial zone, usually formed by to or three layers of flat sguamous cells, a middle zone, formed by two or three layers of polyhedral wing cells, and a basal zone consisting of a single row of columnar cells.

Referring again to Figure 2, it will be seen that, in cornea 22, disposed below epithelium 12 is basement membrane 24. The basement membrane 24 is a thin membrane layer of connective tissue found at the base of every type of epitheli¬ al cell; it helps hold the cells in place. As is known to those skilled in the art, the basement membrane 24 is a pro¬ duct of the basal epithelial cells, approximately 30 to 60 microns wide. The posterior border of the basement membrane 24 often projects into the Bowman's zone 14 and consists of finely packed filaments embedded in a homogeneous matrix which can be regenerated by the basal cell layer after injury. Referring again to Figure 2, disposed below the base¬ ment membrane 24 is Bowman's membrane 14, which is one of the five corneal layers located just under the epithelium and above the corneal stroma 16. The corneal stroma 16 represents at least about 90 percent of the corneal thickness. The Bowman's zone 14, which is the most anterior zone of the corneal stroma 16, possesses resilient and mechanical proper¬ ties which are due to an interdigitating arrangement of colla¬ gen fibrils.

Referring again to Figure 2, the corneal stroma 16 is comprised of bundles of collagen fibers which are arranged in layers (or lamellae) separated by a ground substance of muco- polysaccharides. In the posterior region of the stroma 16, the layers are straight, but in the anterior region they may vary from a single row to several rows. Within the same layer, collagen fibers are parallel to each other, but fibrils in one lamella which traverse the entire cornea cross nearly at right angles to those in an adjacent lamella. This three- dimensional array acts as a diffraction grating.

Figure 3 is a flow diagram of a preferred process within the scope of this invention. Referring to Figure 3, and in the preferred embodiment illustrated therein, it will be seen that, in step 26 of this process, the epithelium 12 of cornea 22 is preferably anesthetized.

In one aspect of this embodiment, a topical anesthetic is applied to epithelium 12. In this aspect, one may use topical anesthetics such as, e.g., cocaine hydrochloride, proparacaine hydrochloride (also known under the trade names of "AK-TAINE," "ALCAINE," and "OPTHAINE, " ), tetracaine hydro¬ chloride (also known under the trade names "ANACEL" and "PONTOCAINE" ) , and the like. These topical anesthetics are described on page 10 (see Table 14) of Edward R. Barnhart's "Physicians' Desk Reference for Ophthalmology," 18th Edition (Medical Economics Company Inc., Oradell, New Jersey, 1990). Alternatively, or additionally, one may apply a re¬ gional anesthetic to epithelium 12 such as, e.g., procaine, tetracaine, hexylcaine, bupivacaine, lidocaine, mepivacaine, prilocaine, etidocaine, and the like; see, e.g., Table 15 of said page 10 of Barnhart's "Physician's Desk Reference for Ophthalmology," supra. Such regional anesthetic may be ap¬ plied by peribulbar or retrobulbar injection.

As will apparent to those skilled in the art, it is not essential to applicant's process to apply anesthetic to the epithelium. Thus, e.g., one may use a general anesthetic. Because the amount of discomfort involved with the process is minimal, often only a few drops of topical anesthetic are reguired to minimize the patient's discomfort.

In one embodiment, after the epithelium 12 is anesthe¬ tized in step 26, or after other suitable means to minimize the patient's discomfort have been taken, the visual axis is preferably marked in step 28; alternatively, as described below, another desired center point may be marked.

The visual axis (which is often also referred to as the "line of fixation," or the "primary line of sight," or the "principal line of direction," or the "visual line"), or any other desired center point, may be marked by conventional means. By way of illustration and not limitation, and refer¬ ring to pages 63-65 of Benjamin F. Boyd's "Highlights of Ophthalmology," Volume II, 30th Anniversary Edition (High¬ lights of Ophthalmology, Coral Gables, Florida, 1987), "After 10 to 15 seconds of application of the soaked Weck-cel sponges on the limbus, the patient is asked to look at the illuminated filament of the Zeiss microscope. While the patient is doing this, you mark the visual axis (Fig. 3-1)....The surgeon closes his left eye and, fixating with the right eye, asks the patient to fixate on the center of the Zeiss filament; the surgeon then makes a small epithelial defect one filament- width below the left end of the image of the filament on the patient's cornea....To mark the visual axis, we use a small needle on a tuberculin syringe."

In one embodiment, instead of marking the center of the patient's visual axis, the center of the patient's pupil is marked instead by a process in which the area and geometry of the iris are of paramount importance. As will be apparent to those skilled in the art, the center of the patient's pupil may be marked by a visual process in which calipers may be used to measure the maximum and minimum dimensions of the pupil and the geometric center is thereafter calculated and marked.

In cases where the surgery is designed to both correct a visual defect (such as myopia) and to change eye color, it is preferred to mark the center of the visual axis. In cases of purely cosmetic surgery, it is preferred to mark the center of the pupil. As will be apparent to those skilled in the art, there may be a difference of up to from about 1 to about 2 millimeters between such center points. Depending upon the desired result(s), and the geometry of the patient's eye, different points may be chosen as the center point.

Figure 4 is a front view of a cornea 22 in which cen¬ ter point 23 has been marked. Figure 5 is a view of the cornea of Figure 3A in which a corneal clear zone 25 has been marked on cornea 22.

After the desired center point 23 has been marked, one may mark the corneal clear zone 25. The corneal clear zone is the area of the cornea which will not be affected by the surgical procedure. Thus, referring to Figure 6, which illustrates the radial incisions 27 which are commonly made in radial keratoto y ("RK"), the corneal clear zone 25 will be marked to demarcate the area which is not to be treated.

The corneal clear zone 25 will vary from patient to patient, depending upon the age of the patient, the patient's pupil size, whether other refractive surgery (such as radial keratotomy) is to be performed, and other factors. In gener¬ al, the corneal clear zone 25 is a substantially circular area with a diameter of from about 2 to about 8 millimeters and, preferably, from about 2 to about 5 millimeters. In one preferred embodiment, the diameter of the corneal clear zone 25 is from about 3 to about 4 millimeters.

By way of illustration and not limitation, and as is disclosed on page 66 of the aforementioned Benjamin F. Boyd book, "When the visual axis has been marked, the proper size marking trephine is selected to mark the corneal clear zone. We use the marking trephines manufactured by Katena. The formula for determining the desired optical clear zone is very simple: if the patient has between -2.00 and -3.12 diopters of myopia, we use a 4mm clear zone; conseguently the marking trephine should have a diameter of 4mm....If the patient has between -3.25 and -4.37 diopters we use a 3.5mm marking trephine. If he/she has from -4.50 to -8.00 diopters, we use a 3mm marking trephine. In essence, the larger the myopia, the smaller the optical clear zone, the longer the corneal cuts, and the closer they will be to the visual axis."

Where the surgery is done for purely cosmetic regions, the size of the corneal clear zone will be determined based upon the size of the patient's pupil and the degree of the color change desired. In this aspect, however, the corneal clear zone will generally be a substantially circular shape with a diameter ranging from about 2 to about 5 millimeters.

It is preferred to use a trephine to mark the optical clear zone. As is known to those skilled in the art, a trephine is a surgical cutting tool that is capable of making a circular hole in tissue. See, e.g., United States patents 5,084,059, 4,913,143, 4,796,623, 4,336,805, and the like, the disclosure of each of which is hereby incorporated by reference into this specification.

By way of illustration and not limitation, one may use a suitably sized trephine sold by the Storz Ophthalmic Instruments of 3365 Tree Court Industrial Blvd., St. Louis, Mo. 63122 (see the 24th edition of the "Storz Ophthalmic In¬ struments" catalog which was published in 1988). Thus, e.g., one may use a trephine sold under the trade name of "PATON SEE-THROUGH TREPHINE," model number E3806 (see page 256 of said Storz catalog) . Alternatively, one may use the "CASTRO- VIEJO CORNEAL TRANSPLANT TREPHINE," model E3100 (see page 257 of the Storz catalog) .

It is preferred, when using the trephine to mark the clear zone, that one use substantially the same method for centering the cross-hairs of the trephine around the visual axis mark that was used to mark the visual axis itself. Thus, referring to page 66 of the aforementioned Benjamin F. Boyd Book, "With the Zeiss surgical microscope, I close the right eye because I am left eye dominant and once again the adjust the marking trephine on the cornea until I can no longer see any part of the inside walls of the trephine with my left eye (Fig. 3-5)."

It is preferred that, when the trephine is centered with the cross-hairs on the visual axis mark made previously by the surgeon, a very firm circular impression is made in the epithelium. Again referring to page 66 of the aforementioned Benjamin F. Boyd book, "I usually press the globe back a millimeter or two and make a guarter turn of the trephine with my hand so that the epithelial imprint will last for the duration of the case (Fig. 3-6) ....During this entire period, the assistant has been putting proparacaine drops on the cornea approximately every 10 seconds."

Referring again to Figure 3, and after the corneal clear zone has been marked in step 30, one may then optionally mask the corneal clear zone in step 32 or, alternatively, may omit optional step 32 and proceed to step 34, the removal of that part of the epithelium which does not comprise the cor neal clear zone.

In one embodiment, where the corneal clear zone is to be masked, one may dispose a masking material which is adapted to fit over the corneal clear zone over such zone. Thus, e.g., one may dispose a suitably sized contact lens over such corneal clear zone.

Contact lenses are well known to those skilled in the art and are described, e.g., on pages 209-226 of Edward R. Barnhart's "Physicians' Desk Reference for Ophthalmology," supra. In one preferred embodiment, the contact lens used consists essentially of polymethylmethacrylate (PMMA). Thus, e.g., one may use an "Storz" intraocular lens implant manufac¬ tured by Storz/Coburn Company of 1365 Hamlet Avenue, P.O. Box 2498, Clearwater, Florida 33618. Other suitable masking devices will be readily apparent to those skilled in the art.

It is preferred that the mask consist essentially of clear material so that the surgeon can determine whether the dye used is in the desired area(s) and does not invade the corneal clear zone.

The masking means may be disposed over the corneal clear area, contiguous therewith. Alternatively, one may removably adhere the masking means to the corneal clear zone by conventional adhesive means. Thus, e.g. one may use "AM- VISC PLUS" for this purpose; "AMVISC PLUS" is a sterile, nonpyrogenic solution of sodium hyaluronate which is sold by the IOLAB Corporation of 500 Iolab Drive, Claremont, Califor¬ nia. Thus, e.g., one may use methylcellulose, which is sold under the trade name of "OCCUCOAT" by the Storz company.

After the corneal clear zone has been masked in step 32 or, if this step is omitted, after the corneal clear zone has been marked in step 30, the area of the epithelium 12 outside of the corneal clear zone may be removed by conven¬ tional means. Thus, by way of illustration, one may remove the undesired portion of the epithelium by abrading it with a Q-tip, by mechanical debridement, with the use of an excimer or an equivalent laser, and the like. As is known to those skilled in the art, both the ultraviolet wavelength lasers as well as the frequency coupled yttrium aluminum garnet ("yag") lasers and the picosecond lasers have demonstrated an ability to ablate tissue and leave behind a smooth surface.

In one preferred embodiment, the unwanted portion of epithelium 12 is removed by curettage. As is known to those skilled in the art, a curette (which is also often referred to as a "curet") is an instrument, shaped like a spoon or scoop, for scraping away tissue.

Curettes are well known to those skilled in the art and are disclosed, e.g., in United States patents 5,090,907, 5,069,224, 5,024,600, 4,932,957, 4,838,899, 4,785,796, 4,777,947, 4,651,735, 4,641,662, 4,572,180, 4,044,770, 3,889,657, 3,670,732, 3,635,222, 3,542,031, 3,502,082, 3,491,747, D318,117, D312,310, and D275,127; the entire disclosure of each of these United States patents is hereby incorporated by reference into this patent application.

By way of illustration and not limitation, , one cur¬ ette which may be used in applicant's process is described on page 38 of the aforementioned Storz catalog as "HEATH CHALA- ZION CURETTE," model number E0801.

In applicant's process, when the epithelium 12 is re¬ moved, the basement membrane 24 is also preferably removed. As is known to those skilled in the art, the epithelium 12 is readily removed by mechanical abrasion; and the basement membrane 24, which is the bottom of the epithelium 12, is also readily removed by such means. However, because the Bowman's membrane 14 is substantially more resilient, it generally will not be removed by mere mechanical abrasion.

In one embodiment of the process, it is preferred not to re¬ move such Bowman's membrane 14.

Thus, in this embodiment, and after step 34, the unmasked and/or unmarked portions of the cornea 22 will preferably have been abraded down to the Bowman's membrane 14 of such stroma. The exposed areas of the Bowman's membrane then be stained in staining step 36.

In this embodiment, it is preferred to use a stain which will selectively stain only the Bowman's membrane 14 and/or have a substantially higher affinity for the Bowman's membrane 14.

Referring again to Figure 3, and in another preferred embodiment illustrated therein, after the anesthetic has been applied to epithelium 12 (in step 26), or after other suitable means have been taken to minimize the patient's discomfort, all or substantially all of the epithelium 12 is removed by the conventional means described elsewhere in this specifica¬ tion in step 38. Thereafter, the entire exposed corneal stroma surface (such as the Bowman's membrane 14) is then stained in step 40. Alternatively, portions of the exposed corneal stroma may be punctured with a multiplicity of needles and stained in step 41.

In this embodiment, after the entire exposed corneal stroma surface has been stained, a portion in the center of such stained stroma surface which corresponds in size to the desired clear corneal area (and generally has a diameter of from about 2 to about 8 millimeters) is treated by laser means to remove the stain. Thus, by way of illustration and not limitation, one may treat the center portion of the stained Bowman's membrane 14 with an excimer laser to excise the stained central area.

Thus, referring again to Figure 3, after the entire exposed area of the corneal stroma (or Bowman's layer) has been stained in step 40, in step 42 a suitable portion of the stained tissue may be excised. As will be apparent to those skilled in the art, the amount and shape of the portion of stained tissue to be excised will depend upon the goals of the surgery. If the surgery is purely cosmetic, then a sufficient clear area in the center of the Bowman's membrane will be excised to produce the desired appearance and to preserve the existing corneal curvature. Where the goal of the surgery is, at least in part, to correct some refractive error, then the laser parameters will be set to alter the corneal curvature. The advantage of this procedure is that, when corrective surgery is to be done, at the same time, with little addition¬ al effort, the eye color of the patient may be changed.

The stain may be applied to the exposed Bowman's mem¬ brane 14 by conventional means. Thus, by way of illustration and not limitation, one may use a "BARRAQUER SABLE BRUSH" (catalog number E0910, see page 263 of the aforementioned Storz Ophthalmic Instruments Catalog) to brush or "paint" the stain onto the ocular surface of the Bowman's membrane 14. Thus, by way of further illustration, one may use a "STORZ SUPERSORB MICRO EYE SPONGE" (see catalog item E0976 on page 290 of the aforementioned Storz catalog) to sponge the stain onto the ocular surface of the membrane. Thus, e.g., one may use a small eye dropper to apply the stain the Bowman's mem¬ brane 14. Other suitable means will be apparent to those skilled in the art.

In one preferred embodiment, illustrated in Figure 3, the color of the Bowman's membrane 14 and/or anterior stroma 16 is changed by a process of corneal tattooing.

As is known to those skilled in the art, the Bowman's membrane 14 is acellular, i.e., it is not composed of cells. Furthermore, the anterior stroma 16 disposed beneath the Bowman's membrane 14 is substantially acellular, containing few cells. The few cells which do appear in the anterior stroma 16 are substantially dormant, exhibiting little if any metabolic activity. Recent research with the excimer lasers and the results of refractive surgery indicate that the Bow¬ man's membrane 14 and the anterior stroma 16 can be ablated without causing structural damage to the cornea and without sacrificing its optical properties.

Because of the substantially acellular nature of both the Bowman's membrane 14 and the anterior stroma 16, one may use many conventional, commercially available dyes to stain either or both of these layers.

By way of illustration and not limitation, one may use the dyes commonly used in tattooing. As is known to those skilled in the art, the epidermis which is commonly treated in tattooing is also substantially acellular and is composed of collagen, water, and mucopolysaccharides (as is the Bowman's membrane 14 and the corneal stroma 16).

The tattooing process, and the dyes used therein, are well known to those skilled in the art. Thus, e.g., reference may be had to United States patents 4,392,493 of Niemeijer, 4,488,550 of Niemeijer, 4,582,060 of Bailey, 5,116,313 of McGregor, and the like. The disclosure of each of these United States patents is hereby incorporated by reference into this specification.

The dyes commonly used in the tattooing process may also be used in applicant's process. Colored tattoo pigments have been available since the end of the nineteenth century, with the predominant pigment being black India ink. Currently more than fifty different colors, including fluorescent shades, have been developed. All of the colors are derived from various mixtures of metallic salts; some of these mix¬ tures are supplied in liquid form, and others are supplied in powder form. Typically, commercially available pigments comprise a mixture of metallic salts slurried in alcohol and glycerine.

The commercially available tattoo pigments are gener¬ ally accepted as being harmless when used in human maxillo- facial surgery and dermatology; see, e.g., H. Muller et al., "Tattooing in Maxillo-Facial Surgery," Journal of Cranio- Maxillo-Facial Surgery, 16:382-384 (1988), and E.M. van der Velden et al., "Cosmetic tattooing as a treatment of port-wine stains," International Journal of Dermatology, 32:372-375 (1993) .

By way of illustration and not limitation, some of the commercially available tattoo "cosmetic colors" are sold, e.g., by Spaulding-Rogers Manufacturing Inc. of Route 85 New Scotland Road, Voorheesville, New York 12186. Thus, e.g., one may purchase from such company cosmetic colors which are black (catalog number 8001), gray (catalog number 8002), brown (catalog number 8003), light brown (catalog numbers 8004 and 8005), dark brown (catalog number 8006), white (catalog number 8007), "cherri berri" (catalog numbers 8008 and 8009), "lemon up" (catalog numbers 8009 and 8010), banana (catalog numbers 8012 and 8013), peach (catalog numbers 8014 and 8015), fire red (catalog number 8016), dusk (catalog numbers 8018 and 8019), sandstone (catalog numbers 8020 and 8021), flesh (catalog number 8022 and 8023), salmon (catalog number 8026), tan (catalog numbers 8027 and 8028), and the like.

As is known to those skilled in the art, these tattoo dyes are comprised of water-insoluble metal compounds such as hydroxides, chlorides, oxides, sulphates, or sulfides of metals such as gold, aluminum, calcium, barium, silver, or titanium.

In one embodiment of the process, a dye is generated in situ by chemical reduction of metallic salts (e.g., gold chloride or platinum black). See, e.g., Biomedical Founda¬ tions of Ophthalmology, T. Duane et al. (3) 9:41.

Referring to Figures 3 and 7, in one preferred process of the invention, the color of the eye is changed, in whole or in part, by a process of corneal tattooing, one preferred means of which is illustrated in Figure 7.

Referring to Figure 7, it will be seen that tattooing device 42, which is shown schematically, is comprised of a needle 44 comprised of an orifice 46 though which stain may be dispensed. The tip 48 of needle 44 preferably has a diameter of from about 50 to about 1,000 microns and, more preferably, of less than about 500 microns (such as, e.g., from about 200 to about 500 microns; such tip 48 may be used to puncture the corneal stroma 16.

Referring to Figure 3, and in the preferred embodi¬ ment illustrated therein, after one has removed part of the epithelium 12 (in step 34), or all of the epithelium (in step 38), one may then use such tip 48 to produce a multiplicity of punctures in that area of the exposed corneal stroma 16 which is outside of where the corneal clear area is desired to be. It is preferred that, in general, at least about 90 percent of such punctures have a maximum cross-sectional dimension (which will correspond to the maximum cross-sectional dimen¬ sion of tip 48) from about 20 to about 500 microns and, more preferably, from about 50 to about 250 microns. It is also preferred that, in general, at least about 90 percent of such punctures have a depth which is less than about 100 microns and, preferably, which is less than about 50 microns (and, most preferably, less than about 20 microns).

In another portion of this specification, another preferred process is described in which the punctures are created by laser energy rather than by the use of one or more needles 44. However, in this laser process, it is preferred that at least about 90 percent of such laser punctures have a maximum cross-sectional dimension of from about 20 to about 500 microns and, more preferably, from about 50 to about 250 microns. It is also preferred that, in general, at least about 90 percent of such laser punctures have a depth which is less than about 100 microns and, preferably, which is less than about 50 microns (and, most preferably, less than about 20 microns). It should be noted that the preferred laser process differs from the needle process described hereinabove in that, in the laser process, it is preferred to apply to water-insoluble stain to the area to be treated prior to the time the laser creates punctures in such area.

Referring again to Figure 7, after each such puncture, one may dispense a measured amount of stain from reservoir 50 into the site of the puncture.

Any conventional means of dispensing measured amounts of fluid to the site of the puncture may be used. Thus, e.g., a device similar to that disclosed in United States patent 5,170,779 may be used; the disclosure of this patent is hereby incorporated by reference into this specification. Thus, by way of further illustration and referring to Figure 4, device 42 is comprised of a switch 52 which is operative- ly connected to pump 54 which, in turn, is hydraulically connected to reservoir 50. By reference to flow meter 56, one can monitor the amount of fluid dispensed into each puncture site.

It will be apparent to those skilled in the art that more than one device 42 can be used in the process, more than one stain may be delivered to some or all of the puncture sites, and one may create puncture sites of different sizes or of the same size. Alternatively, or additionally, the device 42 may be connected to a multiplicity of needles (see Figure 9) arranged in a desired circular pattern to impress stain around a central clear corneal area; such a device in il¬ lustrated in Figures 9 and 10. Thus, for example, the multi¬ plicity of needles may be so configured and disposed that they simultaneously inject all points desired to create the pattern illustrated in Figure 8.

In the embodiment where a multiplicity of needles are used to create a pattern around a central clear zone, the device may be comprised of means for delivering different amounts of dye and/or different dyes and/or dye(s) at differ¬ ent flow rates to various of the needles. Thus, with this embodiment, the color at various points of the corneal treat¬ ment zone may be varied at will.

Referring again to Figure 3, and in one of the pre¬ ferred embodiments illustrated therein, one may dispose a specially designed transparent mask over epithelium 12 in step 51, puncture epithelium 12 in portions of such mask where puncturing is allowed to the desired depth in step 53, and then dispense stain below the epithelium 12 in step 55.

Figure 8 is a sectional view of mask 60 which may be used in the process of Figure 3. Referring to Figure 8, it will be seen that mask 60 preferably consists essentially of a plastic material which is transparent, such as transparent polymethylmethacrylate. The mask 60 is adapted to fit over the cornea 22 of an eye (see Figure 2); and many different mask 60's, each with a differently sized clear area and/or a different curvature and/or a different number of orifices and/or a different size of orifices may be used.

Referring to Figure 8, it will be seen that mask 60 is comprised of a central corneal clear area 62, which generally will be from about 2 to about 8 millimeters in diameter. This central clear area 62 will serve the function of a mask.

The mask 60 also is comprised of a multiplicity of orifices 64 through which the needle 44 (see Figure 7) may be placed.

Once the mask 60 has been disposed over the cornea 22, needle 44 may be placed through one of said orifices 64. It is generally preferred to insert needle 44 within the cornea 22 to a depth of less than about 100 microns and, preferably, less than about 50 microns. In one preferred embodiment, the depth of puncture is less than about 20microns. As will be apparent to those skilled in the art, different punctures may be made to different depths or the same depth; and the same or different amounts and/or types of stain may be delivered to different punctures. The mask 60 may contain orifices 64 of different di¬ mensions, and different portions of the mask may have differ¬ ent densities of such orifices 64. In general, from about 20 to about 100 percent of the unmasked portion of mask 60 (which is all of the mask 60 with the exception of section 62) is defined by a multiplicity of orifices 64.

Figure 9 is a side view of a device 70 for simultane¬ ously applying dye to a multiplicity of points within the corneal stroma 16. This device 70 is connected via chamber 72 to pump 54 (not shown in Figures 9 and 10) which, in turn, is connected to reservoir 50 (not shown in Figures 9 and 10).

Referring again to Figure 9, the bottom portion of device 70 is comprised of a curved surface 74 which has a curvature similar to the curvature of the outer clear area 22 of eyeball 10 (see Figure 1). There is a central area 76 on the bpttom portion of device 70 which contains no needles 44; this central area 76 is adapted to designed to be aligned with the corneal clear zone 25 (see Figures 5 and 6).

The peripheral area 78 of the bottom portion of device 70 is comprised of a multiplicity of needles 44 which, prefer¬ ably, each have substantially the same depth. Thus, when the curved surface 74 is pressed against the outer clear area 22 of eyeball 22, each of the needles 24 will penetrate the eyeball 10 to substantially the same extent.

Each of the needles 44 is comprised of an orifice 46 and a needle tip 48 (not shown in Figure 9, but see Figure 7). To assure uniform application of dye, each of the orifices 46 is of substantially the same size. When switch 52 is activat¬ ed, and dye is caused to flow from reservoir 50 in the direc¬ tion of arrow 71 through chamber 72 (see Figure 7), substan¬ tially the same amount of liquid will be dispensed from each of needles 44 in the direction of arrows 80.

A variety of techniques may be used to provide a clear zone in the cornea centrally. One option is the use of the laser to ablate a central area and provide a clear path for vision. A mask may be utilized to prevent the dye from stain¬ ing the central corneal area. A neutralization agent may be employed to clear the visual axis.

In another embodiment, a technique is provided for performing a lamellar keractectomy and dissecting a pocket within the corneal stroma. A disc of artificial material of a given power is then placed in this space. The disc may be manufactured to correct nearsightedness or farsightedness as well as astigmatism. The disc can be tinted in a manner similar to that used with contact lenses to mask or alter the color of the underlying stroma. A central clear zone may be incorporated to maintain normal vision and appearance and to thereby produce a natural looking change in the color of the iris.

The process can also be applied to patients undergoing automated lamellar keratoplasty (ALK) or in situ keratomileu- sis. Either the corneal surface or the corneal button may be stained with available dyes. A central clear zone would be maintained either via the method of application of dye to the corneal stroma or by applying the dye prior to shaving of the corneal tissue. The central area removed can also have remov¬ al of the dyed corneal tissue. Use of laser energy to change eye color

In one especially preferred embodiment of applicant's invention, a laser beam energy is used to fix stain upon the target tissue. This embodiment may be used in tattooing collagen tissue in general; and it is especially useful in precisely and safely effecting change of eye color in ocular tissue.

This process is a variation of one of the processes illustrated in Figure 3. Referring to Figure 3, after the entire exposed corneal stroma has been contacted with the stain in step 40, a certain portion of the stained stroma is then contacted with a pattern of laser energy adapted to fix the stain the collagen tissue in such stroma only in said pattern (see step 43); alternatively, or additionally, this procedure may be applied to the Bowman's membrane. The stain thus contacted by the laser energy is permanently bonded to the collagen target tissue. The stain not contacted by the laser energy is removed by washing in step 45.

The cross-sectional size of the puncture wounds made by the laser process will be substantially identical to the cross-sectional size of the puncture wounds made by the needle process. The depth of the puncture wounds made by the laser process will be substantially identical to the depth of the puncture wounds made by the needle process. The width of the puncture wounds made by the laser process will be substantial¬ ly identical to the width of the puncture wounds made by the needle process.

In the laser process, it is preferred that, on aver¬ age, each puncture be separated from each adjacent puncture by from about 10 to about 1,000 microns and, more preferably, from about 20 to about 500 microns. It is also preferred that the maximum cross-sectional dimension of each puncture, on average, be from about 20 to about 500 microns and, more preferably, be from about 50 to about 250 microns.

Furthermore, in this preferred laser process, the depth of penetration of each puncture, on average, is less than 100 microns and, preferably, less than about 50 microns. In one especially preferred embodiment, the average depth of penetration of each puncture is less than about 20 microns.

In the laser process, it is preferred to use laser energy with a wavelength above 300 nanometers, preferably within the range of from about 300 to about 1,064 nanometers. In one preferred embodiment, the wavelength of the laser energy used is from about 450 to about 650 nanometers.

As will be apparent to those skilled in the art, the advantage of the use of such laser energy is that, with modern opthamological lasers, one is able create punctures with specified depths of penetration, cross-sectional sizes, and degrees of separation and to fix the stain in a speci¬ fied, predetermined pattern (which, for example, can corre¬ spond to the mask of Figure 8) using a specified amount of energy for a specified amount of time; see, e.g.. Figure 11, in which a multiplicity of laser beams 84 contacts the stained corneal stroma in a concentric area outside of the clear zone 76.

By means of illustration and not limitation, in ap¬ plicants' process one may use as model 2001 MPL laser system which is often referred to as the "Nd:YLF LASER FOR OPHTHAL¬ MOLOGY" and is manufactured by Intelligent Surgical Lasers, Inc., 4520 Executive Drive, San Diego, California. The opera¬ tor's manual furnished with this system is identified as 0520001 Rev. A., published on June 22, 1992.

This laser system, and comparable laser systems, pro¬ duces a beam of infrared light at a wavelength of 1053 nanome¬ ters. It can produce such beam of light in a desired pattern, such as a circle (see page 4.15 of the operator's manual), a spiral (see page 4.17 of manual), and the like. Thus, refer¬ ring to page 4.17 of such manual, "The spiral pattern moves the beam in a three-dimensional series of ever increasing (or decreasing) concentric circles. The completed pattern resem¬ bles a disc. "

In addition to being able to provide the beam of laser energy in a desired pattern, it can also provide such light at a desired intensity. Thus, by referring to page 4.2, the amount of energy emitted per pulse may be varied from about 40 to about 350 microjoules. The spot size may be varied by overlaying laser pulses (see page 4.4 of the manual).

By way of further illustration, one may use a "System 900 Photocagulator with Argon Laser and Zeiss Slit Lamp", which is sold by the Coherent Radiation Company of 3270 West Bayshore Road, Palo Alto, California 94303.

In the System 900, selection of the laser retinal im¬ age size is accomplished by rotating the Spot Size Selector ring. The spot size is continuously adjustable from 50 to 2,000 microns. The spot sizes are clearly marked on the se¬ lector ring and their locations are fixed by detents.

The System 900 is also comprised of a laser tele¬ scope/manipulator assembly. This micromanipulator enables precise placement of each lesion.

The laser power output of the System 900 can be set from 0 to 2.0 watts at the cornea and is continuously adjust¬ able over this range. The laser exposure time can be set for 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, or 5 seconds. The depth of penetration of the lesions created by the laser can be varied by varying the power output and/or the exposure time.

Referring again to Figure 8, one may use the mask 60_ of such Figure after having applied stain to the corneal layer to be treated. Thereafter, laser energy will be manually directed by the surgeon through apertures 64 of such mask and will only fix the stain in the area of these apertures. After this treatment, unfixed stain may be removed by washing.

In one preferred embodiment, which is analogous to the embodiment of Figure 10, the laser is first used to pierce the epithelium, preferably in a predetermined pattern. Stain is then applied to the multiplicity of punctures thus formed by conventional means, such as the means described elsewhere in this specification. Thereafter the laser is used to bond the dye to the underlying tissues. Tattooing of skin

In one embodiment of this process, a "stick-on tat¬ too," which applies a predetermined pattern to skin, is applied to a patient's skin. Thereafter, laser energy is fixed onto this pattern to bond it to the collagen tissue of the skin .

In another embodiment, laser energy in a certain pat¬ tern is used to provide a multiplicity of punctures within the skin. Thereafter, stain is topically applied and fixed to the skin by a second application of laser energy.

The following examples are presented to illustrate the claimed invention but are not to be deemed limitative thereof. Unless otherwise specified, all parts are by weight and all temperatures are in degrees Centigrade. Example 1

In the procedure of this Example, an argon laser sys¬ tem (a "System 900 Photocoagulator with Argon Laser and Zeiss Slit Lamp", which is sold by the Coherent Radiation Company of 3270 West Bayshore Road, Palo Alto, California 94303) was used. A laser wavelength of 440 nanometers was used, with a 2.0 second exposure time, a 500 micron spot size, and an energy level of 0.5 watts. This laser energy was applied two times to each spot in the cornea where a puncture was desired.

Two New Zealand White female rabbits, each with a weight of from about 2,500 to about 3,000 grams, were obtained from Hazelton Research Products of Denver, Pennsylvania.

The rabbits were first euthanized and then, within two minutes, the eyes of each rabbit were removed intact by surgical enucleation means. A 38.1 millimeter Barraquer wire speculum (obtained from Xomed-Treace Company of Jacksonville, Florida) was carefully placed in each eye, and about 0.5 milliliters of a sterile balanced salt solution (obtained from IOLAB Pharmaceuticals of Claremont, California) were dropped into the eye to keep it moist. The eye was held with a 0.3 millimeter Colibri corneal utility forceps (obtained from the Storz Instrument Company of St. Louis, Missouri), and curved delicate eye scissors with 27 millimeter blades (obtained from the Storz Instrument Company) were used to ease the conjuncti¬ va away from the globe and dissect off the muscle fibers. After this was done, the optic nerve and vessels were cut. The whole eye was then placed in a 100 milliliter plas¬ tic sterile specimen bottle (Simport, Beloeil, Quebec, Canada) on 3 pieces of gauze and about 10 milliliters of the IOLAB balanced salt solution, and it was kept at 4 degrees centi¬ grade until lazed.

Thereafter, each of the eyes was placed in a Petri dish under a Topcon OMS-70 operating microscope manufactured by the Tokyo Optical Company of Japan.

The balanced salt solution was dropped on the eye to keep it moist, and the eye was then marked with a 6.5 milli¬ meter disposable trephine (available from the Storz Instrument Company) . The corneal epithelium was removed from the surface with a surgical curette (a No. 3, 2.5 millimeter cup Meyer- hoefer Chalazion curette available from the Storz Instrument Company) by scraping until fluorescein strips (obtained from IOLAB Pharmaceuticals of Claremont, California) indicated that the entire epithelium had been removed. About 0.5 milliliters of the balanced salt solution was dropped onto the tip of the fluorescein strip, the excess was rinsed and then absorbed with surgical sponge spears (manufactured by Katena Products Inc. of Denville, New Jersey), and a black filter pen light was used to check the completeness of the debridement. If the area stained clearly, the eye was ready for laser work. If the area did not stain clearly, more epithelium was debrided and thereafter rechecked.

The surface of the corneal stroma was then cleansed by irrigating with 0.9 volume percent normal saline solution and was dried with the Katena sponge spears by wiping the surface.

A ring of Chloromycetin ophthalmic ointment (manufac¬ tured by the Parke Davis Corporation of Morris Plains, New Jersey, N0071-3070-07) was placed on the corneal stroma in a ring-like fashion at the external perimeter of the cornea, thereby creating a dam encompassing approximately 100 square millimeters of corneal surface area, thereby preventing the applied dye from running off the cornea and maintaining con¬ tact between the dye and the corneal surface.

A 0.5 ounce bottle of black "cosmetic color" dye was obtained (as catalog number 8001) from the Spaulding-Rogers Manufacturing company of Route 85 New Scotland Road, Vorhees- ville. New York 12186. One milliliter of this colorant was drawn into a Terumo "NEOLUS" syringe (0.050 x 16 millimeters, with a tuberculin needle), manufactured by the Terumo Corpora¬ tion of Tokyo, Japan.

Thereafter, about 0.05 milliliters of the dye within the syringe was slowly applied over the surface of each cornea over a period of 10 seconds.

Each of the eyes so treated, together with the cup holder in which it was disposed, was then transported to the laser and placed under the laser microscope; magnification settings between 12 and 14 times were used, and laser energy was applied using the laser settings described above. Each pulse of the laser delivered with these settings caused a depth of pitting of 0.027 microns.

After two such laser pulses had been delivered to each spot to be treated on each cornea, the eyes were removed from the laser, the ointment around the perimeter of the eyes was removed with a sponge, and the eye surfaces were again irri¬ gated with about 1 cubic centimeter of the 0.9 volume percent normal saline solution.

Thereafter, the cornea of each eye was removed from the globe using a 0.9 millimeter trephine (obtained from the Storz Instrument Company) . Corneal specimens were prepared in standard fashion for examination by light microscopy and scanning electron microscopy.

The tissues were examined under a scanning electron microscope (model number EM902, available from the Carl Zeiss, Inc of One Zeiss Drive, Thornwood, New York 10594. It was found that the black pigment was fixed within the corneal tissue. Even after such tissue was washed, the spots treated by the laser were clearly marked with pigment.

Microscopic analysis of the tissue indicated that a clear layer of pigment, about 10 microns thick, rested on and was bonded to the surface of the anterior stroma. Example 2

The procedure of Example 1 was substantially repeated with the exception that, instead of the black dye, gray dye (catalog number 8002, obtained from the Spaulding-Rogers Manufacturing company) was used. Similar results were ob¬ tained, the gray dye being securely fixed within the corneal tissue. Example 3

The procedure of Example 1 was substantially repeated with the exception that, instead of the black dye, brown dye (catalog number 8003, obtained from the Spaulding-Rogers Manufacturing company) was used. Similar results were ob¬ tained, the brown dye being securely fixed within the corneal tissue. Example 4

The procedure of Example 1 was substantially repeated with the exception that, instead of the black dye, fire red dye (catalog number 8016, obtained from the Spaulding-Rogers Manufacturing company) was used. Similar results were ob¬ tained, the fire red dye being securely fixed within the corneal tissue.

It is to be understood that the aforementioned de¬ scription is illustrative only and that changes can be made in the apparatus, in the ingredients and their proportions, and in the sequence of combinations and process steps, as well as in other aspects of the invention discussed herein, without departing from the scope of the invention as defined in the following claims.

Claims

1. A surgical process for changing the color of a human eyeball, comprising the steps of seguentially:

(a) removing substantially all of the epithelium of said human eyeball and exposing a layer of deeper corneal lamellae of said human eyeball selected from the group consisting of the basement membrane of said human eyeball, the Bowman's membrane of said human eyeball, and the corneal stroma of said human eyeball;

(b) contacting said layer of said deeper corneal lamellae of said human eyeball with water-insoluble stain comprised of water-insoluble metal compound;

(c) creating a multiplicity of punctures which have maximum cross-sectional dimensions of less than about 500 microns, are separated from each other by a dis¬ tance of at least about 10 microns, and have a depth of less than about 100 microns, within said layer of said deeper corneal lamellae and fixing said water- insoluble stain on said layer of said deeper cor¬ neal lamellae by contacting said layer of deeper corneal lamellae with laser energy with a wavelength of from about 300 to about 1,064 nanometers; and

(d) after said water-insoluble stain is fixed onto said layer of said deeper corneal lamellae with said laser energy, said layer of said deeper corneal lamel¬ lae is washed to remove unfixed stain.

2. The process as recited in claim 1, wherein said water- insoluble stain is contacted with only a specified portion of said layer of said deeper corneal lamellae.

3. The process as recited in claim 1, wherein anesthetic is applied to said human eyeball prior to the time said epitheli¬ um is removed.

4. The process as recited in claim 2, wherein substantially the entire surface of said layer of said deeper corneal lamel¬ lae is contacted with said water-insoluble stain.

5. The process as recited in claim 2, wherein a central zone of said layer of said deeper corneal lamellae is not contacted with said laser energy.

6. The process as recited in claim 5, wherein said central zone has a substantially circular cross-section.

7. The process as recited in claim 6, wherein a multiplicity of laser beams is used to contact said specified portion of said layer of said deeper corneal lamellae in a concentric area around said central zone.

8. The process as recited in claim 1, wherein, prior to the time said laser energy is applied to said layer of said deeper corneal lamellae, a mask which prevents the transmission of laser energy to a specified portion of said layer of said deeper lamellae is applied to the surface of said layer of said deeper lamellae, thereby providing a masked layer of said deeper lamellae.

9. The process as recited in claim 8, wherein said laser energy is applied to said masked layer of said deeper lamellae in the pattern of a circle.

10. The process as recited in claim 8, wherein said laser energy is applied to said masked layer of said deeper lamellae in the pattern of a spiral.

11. The process as recited in claim 1, wherein overlaying laser pulses of said laser energy are applied to said layer of said deeper lamellae.

12. The process as recited in claim 1, wherein said punctures have maximum cross-sectional dimensions of from about 50 to about 250 microns.

13. The process as recited in claim 1, wherein said punctures have depths of less than about 50 microns.

14. The process as recited in claim 1, wherein said punctures have depths of less than about 20 microns.