WO2002089709A1

WO2002089709A1 - Modified keratoprosthesis

Info

Publication number: WO2002089709A1
Application number: PCT/AU2002/000546
Authority: WO
Inventors: Traian V Chirila; Xia Lou; Celia Rachel Hicks; Ian Jeffrey Constable; Geoffrey James Crawford
Original assignee: The Lions Eye Institute Of Western Australia Incorporated
Priority date: 2001-05-04
Filing date: 2002-05-03
Publication date: 2002-11-14
Also published as: AUPR477201A0

Abstract

The invention provides a coloured keratoprosthesis comprising a one-piece core and skirt device having a transparent lenticular core portion and a peripheral skirt portion that is coloured to match the apparent colour of an iris in a patient. Preferably, the keratoprosthesis is coloured in such a manner wherein there is little or no bleeding of colouring agent from the peripheral skirt into the transparent lenticular core.

Description

Modified Keratoprosthesis'

Field of the Invention

This invention relates generally to an improved keratoprosthesis and to methods for its production.

Background Art

Australian patent 650156, and US patents 5300116 and 5458819, assigned to the present applicant, describe a keratoprosthesis and a method for its production. The prosthesis disclosed in these patents is a one-piece "core and skirt" device, comprised of intimately attached central and peripheral portions. The central portion or core is a transparent lenticular part and is a hydrogel composed essentially of a biocompatible hydrophilic polymer, while the peripheral portion, a porous annular skirt, is composed essentially of a like polymer but is a porous hydrogel sponge. A suitable material for both parts is a polymer of 2-hydroxyethyl methacrylate, commonly designated as PHEMA. The spongy periphery promotes and maintains cellular invasion from the host corneal tissue, thus providing a tight union between implant and recipient cornea, which prevents the post-operative extrusion of the implant.

Other unitary and composite keratoprostheses have been suggested in a wide range of references, and have generally utilised materials such as poly(methyl methacrylate) (PMMA), polytetrafluoroethylene (PTFE or Teflon^®), silicones and polyurethanes.

While prior art keratoprostheses such as those described in Australian patent 650156, and US patents 5300116 and 5458819 provide an artificial cornea replacement, when introduced into a patient's eye they produce an undesirable two phase colouration pattern due to he skirt obscuring the iris. This usually results in two clear and distinct bands in the iris wherein the skirt of the prosthesis appears almost white while the remainder of the iris remains its natural colour. Thus, prior art keratoprostheses provide patients with a white iris band which is aesthetically unpleasant to use, which in turn significantly diminishes their effective use. Methods for colouration of contact lenses and the like are well known in the art. An expansive description of such methodologies are presented in the prior art section of US patent 5,252,628. Significant problems in using such dyes with prior art keratoprostheses are expected to be encountered. In particular, the extractability in aqueous media of the colouring agent resulting in their release into the eye provides a significant impediment to the use of most colouring agents. Alternatively and or in addition, problems and difficulties may be encountered in applying colouring agents to the keratoprosthesis in a manner which does not lead to colouration of the central optical core of the keratoprosthesis.

The present invention seeks to provide a means for at least ameliorating these disadvantages with prior art keratoprosthesis without effecting the optical characteristics of a keratoprosthesis.

The preceding discussion of the prior art is intended to facilitate an understanding of the present invention only. It should be appreciated that the discussion is not an acknowledgement or admission that any of the material referred to was part of the common general knowledge as at the priority date of the application.

Throughout the specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Disclosure of the Invention

According to one form of the invention there is provided a coloured keratoprosthesis comprising a one-piece core and skirt device having a transparent lenticular core portion and a peripheral skirt portion that is coloured to match the apparent colour of an iris in a patient. Preferably, the keratoprosthesis is coloured in such a manner wherein there is little or no bleeding of colouring agent from the peripheral skirt into the transparent lenticular core. The keratoprosthesis may be conveniently formed from poly (2-hydroxyethyl methacrylate), commonly designated as PHEMA, or from mixtures of 2- hydroxyethyl methacrylate, commonly designated as HEMA, and other hydrophilic and/or hydrophobic monomers as disclosed in the patents of the background art that are herein incorporated by reference.

Any colouration agent that is non-toxic to the patient and capable of altering the colouration of the skirt without release from it may be used in the present invention. Most preferably, the colouration agent is selected so as not to interfere with the structural and or optical properties of the skirt. The colouring agent may be a dye or like-colouration composition, a tinting agent or a combination of these agents. Preferred colouring agents used in the present invention include those producing colours selected from a group consisting of: sky blue, light blue, dark blue, light green, emerald green, hazel, light brown, dark brown and grey.

The colouration of the keratoprosthesis may be performed at any temperature suitable for facilitating dyeing of the skirt. Those of ordinary skill will be familiar with the temperature required for each dye. Preferably the colouration process is carried out at room temperature.

The colouration of the keratoprosthesis may be performed for any period of time suitable for facilitating dyeing of the skirt. Those of ordinary skill will be familiar with the times required for each dye. Preferably the colouring agent is contacted with the keratoprosthesis for 10 seconds to 30 minutes.

Those skilled in the art will appreciate that there will be a number of methods of preparing the keratoprosthesis of the present invention.

In one form of the present invention there is provided a method for preparing a keratoprosthesis, said method comprising the steps of: a. treating the peripheral skirt of the keratoprosthesis with a colouring agent in such a manner that the agent is fixed to the skirt portion; and b. engaging the skirt portion with the core in such a manner that permits bonding of the skirt with the core while minimising bleeding of the colouration agent into the core.

In another form of the present invention there is provided a method for preparing a keratoprosthesis, said method comprising the steps of: a. introducing a first monomer mixture into a moulding unit and confining the mixture within a first annular peripheral moulding space;

b. allowing or causing the monomer mixture to polymerise;

c. successively treating the skirt with colouring agents and fixation/developing agents;

d. introducing a second monomer mixture into a second moulding space associated with the first, confined to the second space; and

e. allowing or causing the monomer mixture to polymerise, whereby to form the core or central portion of the two part construction.

In another form of the present invention there is provided a method for preparing a keratoprosthesis, said method comprising the step of: a. successively treating the skirt of a keratoprosthesis with colouring agents and fixation/developing agents wherein the keratoprosthesis is coloured in such a manner that there is little or no bleeding of colouring agent from the peripheral skirt into the transparent lenticular core.

b. allowing or causing the monomer mixture to polymerise;

c. introducing a second monomer mixture into a second moulding space associated with the first, confined to the second space; d. allowing or causing the monomer mixture to polymerise, whereby to form the core or central portion of the two part construction;

e. removing the keratoprosthesis from the moulding unit;

f. successively treating the keratoprosthesis skirt with colouring agents and fixation/developing agents wherein the keratoprosthesis is coloured in such a manner that there is little or no bleeding of colouring agent from the peripheral skirt into the transparent lenticular core;

In another form of the present invention there is provided a method for preparing a keratoprosthesis, said method comprising the steps of: a. introducing a first monomer mixture into a moulding unit and confining the mixture within a central moulding space;

b. allowing or causing the monomer mixture to polymerise;

c. introducing a second monomer mixture into a second moulding space associated with the first, confined to the second space;

d. allowing or causing the monomer mixture to polymerise, whereby to form the skirt or peripheral portion of the two part construction;

e. removing the keratoprosthesis from the moulding unit;

In one embodiment of the present invention, members of the moulding unit are assembled prior to introduction of the first monomer mixture, and confinement of the monomer mixture to the first annular peripheral moulding space is effected by inserting a first plunger into the moulding unit. That plunger and a head member are removed from the moulding unit to allow extraction of the skirt for colouring treatment, and these parts are reintroduced successively after reintroduction of the skirt back to the first moulding space. A second plunger is used to confine the second monomer mixture to the second moulding space for the subsequent polymerisation step.

In a preferred form of the present invention there is provided a keratoprosthesis produced according to the methods of the invention.

Example

Further features of the present invention are more fully described in the following non-limiting Examples. It is to be understood, however, that the descriptions are included solely for the purposes of exemplifying the present invention. They should not be understood in any way as a restriction on the broad description of the invention as set out above.

Preparation of a keratoprosthesis with a coloured skirt was achieved via two consecutive polymerisations in a specially designed Teflon^® mould that allows for the each polymerisation to occur in a different portion of the mould. The mould comprised a Teflon^® base and Teflon^® lid whereby the lid was perforated with evenly spaced holes of a known diameter. The diameter corresponds approximately to the diameter of the clear core of the keratoprosthesis and each hole is the site of one keratoprosthesis. Each hole in the lid was fitted with a Teflon^® plunger that completely filled the hole and extended into the region between the base and the lid.

EXAMPLE 1

Keratoprostheses with a clear core and a coloured annular skirt (henceforth known as "coloured keratoprostheses") were produced via a multi-step process. The process involved polymerisation of the annular skirt, polymerisation of the clear core and dyeing of the skirt.

The first monomer mixture was introduced into the assembled mould described above and filled the voids around the Teflon plungers. The monomer mixture comprised HEMA or its mixtures with hydrophilic or hydrophobic monomers, of 5 to 25 % by weight concentration in water, crosslinking agent and initiator as disclosed in the patents of the background art. The monomer was caused or allowed to polymerise at room temperature for at least 22 hours.

After polymerisation, all of the Teflon^® plungers were extracted and any excess water on the surface removed from the mould via lint-free swabs. A second monomer mixture was introduced into the mould by pouring it across the lid, causing it to flow into the holes (i.e. the space formerly occupied by the plungers in the first polymerisation). The second monomer mixture comprised HEMA or its mixtures with hydrophilic or hydrophobic monomers, of 60 % to 95 % by weight concentration in water, crosslinking agent and initiator as disclosed in the patents of the background art. This mixture is suitable for forming the transparent lenticular core of the keratoprosthesis. The second monomer was caused or allowed to polymerise in a temperature-controlled oven at 50 °C for at least 24 hours.

After polymerisation, the mould was removed from the oven and the cast carefully removed from the mould. The cast was placed onto a clean cutting board and each keratoprosthesis cut from the cast using a clean, undamaged 10 mm trephine. The keratoprostheses were placed into a clean bottle containing a mixture of glycerol and water and the bottle placed into a temperature-controlled oven at 60 °C for 8 hours.

The keratoprostheses at this stage, which were purposely larger in size than required for implantation, were individually resized. Each keratoprosthesis was frozen to -70 °C and cut to the required size and curvature in a diamond-tool lathing machine. Each adjusted keratoprosthesis was then thoroughly washed in distilled water and stored in sterile phosphate buffer saline.

A resized keratoprosthesis, with a clear PHEMA core and a white PHEMA skirt, was introduced into a commercially available jig for tinting contact lenses. The jig is specifically designed for producing an annular tint. Specifically, the jig has two holes for insertion of the dye, neither of which are located at or near the centre of the cylindrical end of the jig (where the clear core of the keratoprosthesis will be positioned). Before closing the jig, any excess liquid was removed from the surface of the keratoprosthesis using an absorbent tissue.

The keratoprosthesis was fixed in place in the jig via a spring mechanism. Once fixed in place, the core of the keratoprosthesis was firmly pressed between two surfaces in the jig, shielding it from the introduced dye.

A commercially available dye typically associated with tinting PHEMA contact lenses (Spectratint™ grey, Lamda Polytech, 0.15 mL) was introduced into the jig via means of a syringe taking care to introduce the dye so that it filled the empty space in the jig from the circumference inwards. Care was also taken to keep the jig upright during this procedure, so that a symmetrical, annular tint was obtained.

After a period of 15 seconds, the jig was opened and the keratoprosthesis removed and rinsed in distilled water for approximately 10 seconds. The keratoprosthesis was placed into a solution consisting of 4 parts distilled water, 1 part Activator solution (Spectratint™ Activator Solution) and 1 part Developer solution (Spectratint™ Developer Solution) at a temperature of between 50 and 60 °C. The keratoprosthesis was swirled in the solution for one minute and removed and placed into a stirred solution of phosphate buffer solution (approximately 70 mL) for no less than six hours.

The finished, coloured keratoprosthesis was sterilized by autoclaving at 120 °C for 20 minutes stored in sterile phosphate buffer saline until implantation.

EXAMPLE 2

Keratoprostheses with a clear core and a coloured annular skirt (henceforth known as "coloured keratoprostheses") were produced in bulk via a multi-step process. The process involved polymerisation of the annular skirt, dyeing of the skirt and subsequent polymerisation of the clear core.

The first monomer mixture was introduced into the assembled mould described above and filled the voids around the Teflon^® plungers. The monomer mixture comprised 2-hydroxyethyl methacrylate (HEMA) or its mixtures with hydrophilic or hydrophobic monomers, of 5 to 25 % by weight concentration in water, crosslinking agent and initiator as disclosed in the patents of the background art. The monomer was caused or allowed to polymerise at room temperature for at least 22 hours.

Once the monomer was polymerised, the porous annular skirt was treated successively with colouring agents and fixation/developing agent whilst still in the mould. Firstly, the polymer was immersed in a commercially available dye typically associated with tinting PHEMA contact lenses (Spectratint™ grey, Lamda Polytech). The polymer and mould were immersed for approximately 1 minute and rinsed with distilled water for approximately 30 seconds. The polymer and mould were then immersed into a solution consisting of 4 parts distilled water, 1 part Activator solution (Spectratint™ Activator Solution) and 1 part Developer solution (Spectratint™ Developer Solution) at a temperature of between 50 °C and 60 °C for one minute before being removed and placed into a stirred solution of phosphate buffer solution at room temperature for no less than six hours.

The mould was removed from the phosphate buffer solution and any excess water on the outside of the mould removed via towelling with a lint-free cloth. All of the Teflon^® plungers were extracted from the lid of the mould and any excess water on the surface removed from the voids left by the plungers in the polymer via lint-free swabs. A second monomer mixture was introduced into the mould by pouring it across the lid, causing it to flow into the holes (i.e. the space formerly occupied by the plungers in the first polymerisation). The second monomer mixture comprised HEMA or its mixtures with hydrophilic or hydrophobic monomers, of 60 % to 95 % by weight concentration in water, crosslinking agent and initiator as disclosed in the patents of the background art. This mixture is suitable for forming the transparent lenticular core of the keratoprosthesis. The second monomer was caused or allowed to polymerise in a temperature-controlled oven at 50 °C for at least 24 hours.

The keratoprostheses at this stage, which were purposely larger in size than required for implantation, were individually resized. Each keratoprosthesis was frozen to -70 °C and cut to the required size and curvature in a diamond-tool lathing machine. Each adjusted keratoprosthesis was thoroughly washed in distilled water and sterilized by autoclaving at 120 °C for 20 minutes. The keratoprosthesis and stored in sterile phosphate buffer saline until implantation.

EXAMPLE 3

Colouration of the skirt may be achieved by any method that permits colour fixation/development to and or in a polymer matrix suitable for use in a keratoprosthesis, which is non-toxic and which will not bleed out of the polymer matrix during ligation of the skirt with the transparent lenticular core. For example, colouration of the skirt may be achieved by treating the porous annular skirt with Pylam™ dyes supplied by Pylam Products of the United States followed by fixation of the dyes. An exemplary treatment might involve maintaining the formed skirt after extraction from the aforementioned moulding unit in the aqueous solution of selected dye (0.5 to 10 % by weight) for approximately 10 to 60 seconds. The skirt is then rinsed with distilled water and treated with a phosphate fixing solution, comprising 3 parts by weight trisodium phosphate and 6 parts by weight sodium chloride dissolved in 150 parts by weight deionised water, for approximately 5 to 10 minutes. The skirt is then boiled in saline solution for approximately 25 to 35 minutes to remove any residual colouring agent.

It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text. All of these different combinations constitute various alternative aspects of the invention.

Claims

Claims defining the Invention:

1. A keratoprosthesis comprising a one-piece core and skirt device wherein the keratoprosthesis comprises a transparent lenticular core portion and a peripheral skirt portion that is coloured to match the apparent colour of an iris in a patient.

2. A keratoprosthesis according to claim 1 wherein the keratoprosthesis is coloured in such a manner such that there is little or no bleeding of colouring agent from the peripheral skirt into the transparent lenticular core.

3. A keratoprosthesis according to claim 1 or 2 wherein the keratoprosthesis may be conveniently formed from poly (2-hydroxyethyl methacrylate), commonly designated as PHEMA or from mixtures of 2-hydroxyethyl methacrylate, commonly designated as HEMA, and other hydrophilic and/or hydrophobic monomers.

4. A keratoprosthesis according to any of the preceding claims wherein the colouration agent is substantially non-toxic and capable of altering the colouration of the skirt without release from it.

5. A keratoprosthesis according to any of the preceding claims wherein the colouring agent is selected so as not to interfere with the structural and or optical properties of the skirt.

6. A keratoprosthesis according to any of the preceding claims wherein the colouring agent is a dye or like-colouration composition, a tinting agent or a combination of these agents.

7. A keratoprosthesis according to any of the preceding claims wherein the colouring agents used include those producing colours selected from a group consisting of: sky blue, light blue, dark blue, light green, emerald green, hazel, light brown, dark brown and grey.

8. A method for the preparation of a keratoprosthesis, said method comprising the steps of:

a. treating the peripheral skirt of the keratoprosthesis with a colouring agent in such a manner that the agent is fixed to the skirt portion; and b. engaging the skirt portion with the core in such a manner that permits bonding of the skirt with the core while minimising bleeding of the colouration agent into the core.

9. A method for the preparation of a keratoprosthesis, said method comprising the steps of:

a. introducing a first monomer mixture into a moulding unit and confining the mixture within a first annular peripheral moulding space;

b. allowing or causing the monomer mixture to polymerise;

e. allowing or causing the monomer mixture to be polymerise, whereby to form the core or central portion of the two part construction.

10. A method for the preparation of a keratoprosthesis, said method comprising the step of:

a. successively treating the skirt of a keratoprosthesis with colouring agents and fixation/developing agents wherein the keratoprosthesis is coloured in such a manner that there is little or no bleeding of colouring agent from the peripheral skirt into the transparent lenticular core.

11. A method for the preparation of a keratoprosthesis, said method comprising the steps of: a. introducing a first monomer mixture into a moulding unit and confining the mixture within a first annular peripheral moulding space;

b. allowing or causing the monomer mixture to polymerise;

d. allowing or causing the monomer mixture to be polymerise, whereby to form the core or central portion of the two part construction;

e. removing the keratoprosthesis from the moulding unit;

12. A method for the preparation of a keratoprosthesis, said method comprising the steps of:

a. introducing a first monomer mixture into a moulding unit and confining the mixture within a central moulding space;

b. allowing or causing the monomer mixture to polymerise;

d. allowing or causing the monomer mixture to be polymerise, whereby to form the skirt or peripheral portion of the two part construction;

e. removing the keratoprosthesis from the moulding unit;

13. A method for the preparation of a keratoprosthesis wherein the colouration is performed at room temperature.

14. A method for the preparation of a keratoprosthesis wherein the colouring agent is contacted with the keratoprosthesis for 10 seconds to 30 minutes.

15. A keratoprosthesis produced according to the method of claims 8 to 12.

16. A process for the preparation of a keratoprosthesis substantially as hereinbefore described with reference to the examples.