This invention is directed to an improved corneal onlay. More specifically the corneal onlay of the invention has a surface topography and a structure of the anterior surface which promote overgrowth with corneal epithelium and formation of a stratified epithelium following overgrowth, including the development of hemidesmosomes in basal cell layer of the epithelium.
The invention is particularly directed towards an implant for use for synthetic epikeratoplasty or as an implanted contact lens, where placed at an subepithelial site.
The objective of the invention is to provide a polymer surface that inherently supports tissue overgrowth without the need for an additional surface modification or biological coating. A further objective is to provide a polymer that combines this property with good biostability, optical properties, and mechanical properties that make the material suitable for the fabrication of epikeratoprostheses. Corneal onlays as such are known. One of the more recent findings, as disclosed in EP-A-729323, suggests that a corneal onlay needs to be porous to allow for through passage between anterior and posterior sides of the device of trophic factors and nutrients. Said EP-A-729323 is illustrative for a number of reasons, it is explaining the background state of the art, and definitions used therein do apply also to this invention, unless terms are expressly otherwise defined. A number of synthetic polymers have been proposed for a corneal onlay, or other corneal implant where epithelialisation is desired, such as hydrophobic materials, for example perfluoropolyether based materials, or collagen-hydrogel copolymeric materials.
However, the prior art examples do not teach, nor make predictable, the requirements as to the topography of the surface of a synthetic polymer for
(i) the processes of the migration of corneal epithelial tissue across the surface of an implant;
(ii) the processes of the assembly of a stratified corneal epithelium following movement of the tissue across the surface of the material. In considering this migration process, it needs to be recognized that there is a difference between the ocular epitzhelium and other epithelia for cellular migratory processes. In the case of the corneal epithelium, the epithelial cells that are found in the central region of the cornea arise initially from stem cells that lie in the limbal region (the zone that is the transition between the conjunctiva and the cornea). That is, there is a movement of epithelial cells from the limbal region to the central cornea. This compares with the situation of other epithelia, where the stem cells lie in the lower levels of the epidermis and cellular movement preceding, during, or to permit, stratification is towards the anterior surface;
(iii) the processes of the formation of hemidesmosomes (at the basal epithelial cells) at and into the near surface of the synthetic material;
other than to show that a topography that is supportive is possible.
The disadvantages of the prior art corneal onlays are overcome by the corneal onlay of this invention based on the surprising finding that for migration of the corneal epithelium to cover the onlay, it is not the pores which are relevant but a topography comprising a plurality of indentations.
The corneal onlay or corneal implant to be placed within or onto the surface of the cornea according to the disclosure herein has a surface topography in order to permit the overgrowth of a surface of the implant with corneal epithelium. The corneal epithelium tissue overlying the corneal onlay device shows characteristics of being a stratified corneal epithelium, including the presence in the basal epithelial cell layer of proteinaceous components of hemidesmosome structures.
The present invention is distinct from the prior art in that it arises from the recognition that the topography of the surface, independent of the porosity of the material, can promote the overgrowth of a corneal onlay with corneal epithelial tissue.
The invention provides a polymer surface for use in a corneal onlay, which surface has a topography that supports the overgrowth and migration of corneal epithelial tissue at a level that is superior to that seen for a smooth and non-porous form of the same synthetic polymer.
A further distinguishing feature from the prior art is that the surface according to the current invention combines this topography, with porosity.
The invention is therefore directed to a corneal onlay or corneal implant to be placed within or onto the surface of the cornea, being a biocompatible, optically transparent, synthetic and biostable polymeric material, said material comprising a surface that supports the attachment and growth of tissue cells, and where the exterior surface of the implant onto which epithelial tissue is to be attracted and to become attached, or in the case of a corneal onlay the anterior surface of the onlay, has a topography comprising a plurality of surface indentations.
A surface that supports the attachment and growth of tissue cells either provides said support directly, or said surface additionally has a surface coating that supports the attachment and growth of tissue cells.
It is important to note that the surface indentations may comprise pores, but pores alone are not within the meaning of surface indentation. In other words, the wording “topography comprising a plurality of surface indentations” includes surfaces having pores plus indentations, but excludes surfaces having pores without additional indentations. Apart from the fact that corneal onlays having pores, and no indentations, as disclosed in EP-A-729323, are not within the scope of the present invention, the indentations may have any suitable form and geometry.
Preferred characteristics of the plurality of indentations are that they are equal or greater than 500 square nanometers in surface area and equal or less than 0.7 square microns in surface area in the plane of the surface, or that they are generally curvilinear or circular in shape at the plane of the surface and have minimum diameter(s) that is/are equal or greater than 0.025 microns in diameter and have maximum diameter(s) that is/are equal or less than 0.95 microns in diameter.
More preferred minimum diameters are equal or greater than 0.05 microns in diameter.
More preferred maximum diameters are equal or less than 0.80 microns in diameter, even more preferred equal or less than 0.50 microns in diameter and most preferred equal or less than 0.35 microns in diameter.
Another set of preferred features of the plurality of surface indentations is that they comprise the equivalent area in the plane of the surface as to be equal or greater than 0.10 % of the surface area in the plane of the surface and equal or less than 20% of the surface area. More preferred values in this context are that the surface indentations comprise the equivalent area in the plane of the surface as to be equal or greater than 2% of the surface area in the plane of the surface and equal or less than 15% of the surface area in the plane of the surface, and most preferred is a range from equal or greater than 3% of the surface area in the plane of the surface and equal or less than 10% of the surface area in the plane of the surface.
It may be appropriate to make a comment on terminology used herein: Some of the sizes of the indentations mentioned hereinbefore refer to the size of individual indentations, and there are a plurality of indentations of these sizes. Such indentations may not all be identical in size but would generally fit these size ranges. Sizes of this type are for example those referred to in claims 2 and 3. In contrast thereto, some of the sizes specified hereinbefore are for the totality of the indentations in aggregate. Sizes of this type are for example those referred to in claim 4. It is believed that the person skilled in the art will understand this differentiation taking into account the absolute magnitude disclosed.
It is also preferred that the mean depth of surface indentations below the plane of the surface is equal or greater than 0.1 microns.
It is further preferred that the surface indentations do not provide for the ingrowth of corneal epithelial tissue or cells or cellular processes to a depth of further than 20 microns from the plane of the surface of the implant, or more preferred the surface indentations do not provide for the ingrowth of corneal epithelial tissue or cells or cellular processes to a depth of further than 20 microns from the plane of the surface of the implant in the optical region of the implant.
The surface indentations as described hereinbefore may or may not have a coating or gel formed of biological molecules or synthetic analogues thereof placed upon or within said plurality of surface indentations.
A gel as mentioned hereinbefore may be made, for example, from collagen which is or is not chemically crosslinked to the surface and wherein the collagen molecules within the gel are crosslinked or uncrosslinked.
Furthermore, some or aH of the plurality of surface indentations as disclosed hereinbefore may have continuity with other indentations within the bulk of the material below the plane of the surface.
Also, the existence of pores, in addition to surface indentations, through the implant or onlay is possible. In such a case the pores are preferably curvilinear or circular and the diameter of the pores is in the range of equal or greater than 0.025 microns in diameter and equal or less than 0.95 microns in diameter. More preferred values in this context are 0.05 microns in diameter and equal or less than 0.35 microns in diameter.
A preferred corneal onlay has the following characteristics: It combines the elements of claims 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 8 and 10 and 11. Other combinations of preferred features of the invention are also possible and within the scope of this invention. This statement includes aspects of the invention disclosed hereinbefore and such aspects following hereinafter.
Further preferred aspects of the invention are in that the topography of the anterior surface of the onlay comprises indentations as defined hereinbefore and pores as defined hereinbefore and that said topography consists of a plurality of surface indentations that are equal or less than 10.000 square nanometers in surface area.
Another preferred aspect of the invention is in that the topography of the anterior surface of the onlay comprises indentations as defined hereinbefore and pores as defined hereinbefore and that said topography consists of a plurality of surface indentations which have a maximum diameter that is equal or less than 0.4 microns in diameter. More preferably said maximum diameter ie equal or less than 0.2 microns in diameter.
The disclosure of the invention hereinbefore has been made particularly with reference to intraepithelial corneal onlays and other corneal implant materials. However, this fact should not be understood as being limiting in any substantial way. A material that supports the overgrowth of epithelial tissue may also have applications as a component of other intra-epithelial implants, such as percutaneous access devices.