CA1173193A

CA1173193A - Opthalmic-grade keratoprosthetic polyurethane

Info

Publication number: CA1173193A
Application number: CA000370521A
Authority: CA
Inventors: Michael Szycher
Original assignee: Thermo Electron Corp
Current assignee: Thermo Fisher Scientific Inc
Priority date: 1980-02-11
Filing date: 1981-02-10
Publication date: 1984-08-21
Also published as: US4285073A; DE3104899A1; GB2070043B; GB2070043A; FR2477161A1; JPS56119245A

Abstract

Abstract of the Disclosure A polyurethane is disclosed which is the reaction product of methylene diisocyanate, polytetrsmethylene ether glycol and ethylene oxide-capped trimethylol propane. The resulting polyurethane is optically clear and suitable for use as an artificial cornea, or a permanently implantable lens.

Description

~73193 This invention relates to correction of injured or defective eyes, and more particularly to a synthetic corn`eal implant in the nature of a biologi-cal window which can be permanently substituted for the damaged area in corneal tissue. By virtue of its clarity and biological compatibility, the material of this invention can also serve as a permanently implantable lens.
Occasionally the corneal tissue which overlies the fore part of the human eyeball becomes injured or a growth forms therein which will create opaque areas in the cornea. If such opaque or lumpy areas occur over the pupil, then the person thus afflicted will be blind or at least have their vision partially obscured.
Presently, when a cornea has become diseased to a point where replacement is warranted~ the only truly effective method for such replacement is to perform a corneal transplant. Of course, the performance of a corneal transplant requires tbat a cornea be available and that the recipient be able to immunologically tolerate the transplant.
While the technique of making corneal transplants from eyes stored ;n so-called ~'eye banks~' is highly deYeloped, the percentage of successful operatlons is decidedly in the minority. Such operations are less than thirty (30) percent successful and the most reliable figures available indicate that in only sixteen ~16~ percent of the cases was there any improvement in visual acuity.
Present day practice in repairing damaged corneas involves replacing a carefully cut-out circular or square portion of the cornea with that of a donor which has been cut exactly to the same dimensions and configuration. The newly grafted cornea is then permitted to heal and form a transparent window through which the patient can see clearly. The operation is extremely critical and a high percentage of failures occurs because the corneal implant does not properly graft or will deteriorate, again becoming opaque. The major reasons for failure ~1731g3 are clouding of the graft and ingrowth of blood vessels and these failures have suggested the desirability of an artificial graft into which the blood vessels could not grow, and around which granulation tissue would not cloud the normal field of vision. Such clouding conditions greatly decrease the number of cornea transplants that can be performed.
Various attempts have been made to provide such grafts in the form of synthetic windows. In these windows, various transparent materials have been used but e~en when these weresufficiently inert to be tolerated, the grafts, although sutured in place, soon extruded. It is, of course, highly desirable to have a synthetic material that can be used as an artificial cornea for a cornea transplant.
In order for a synthetic material to be successful for use in Keratoprosthesis, the material must meet a number of criteria. For example, the material must be compatible with the tissue in the human eye. The material must be optically clear. It must also be tough and easy to fabricate. Up to the present time, such a material which meets all of the foregoing criteria has not been found.
In accordance with one aspect of the present invention, there is provided a polyurethane elastomer which is the reaction product of a hydro-genated methylene diisocyanate, a polytetramethylene ether glycol, and an ethylene oxide-capped trimethylol propane. The polyurethane is crystal clear and can be used as an artificial cornea.
Accordingly, another aspect of the invention provides an artificial cornea intended for implantation in a human eyeball, said cornea being formed from an aliphatic polyurethane elastomer which is the reaction product of:
(1) a hydrogenated methylene diisocyanate;
(2~ a polytetramethylene ether glycol having a molecular weight in the

- 2 -11731~
range of 500 to 5000; and

(3) an ethylene oxide-capped trimethylol propane.
A further aspect of the invention provides a process for forming an artificial cornea for implantation in a human eyeball comprising:
~ a~ mixing together a hydrogenated methylene diisocyanate, a poly-tetramethylene ether glycol and an ethylene oxide-capped trimethylol propane to form a reactive mixture;
~ b) degassing the reactive mixture to remove entrained air;
(c~ forcing the reactive mixture into a mold having the configura-la tion of an artificial cornea;
~d) curing the mixture in the mold to form a polyurethane elastomer;
and (e) removing the cornea-shaped clear elastomer from the mold.
In the accompanying drawings:
~igure 1 is a schematic view of an eye shouing a cornea formed of material in accordance with the present invention;
Figure 2 is a diagram illustrating the process in accordance with the present invention for molding corneas from the elastomer of the pre-sent invention;
Figure 3 is a graph of light transmissive characteristics of the polymer of the present invention; and Figures 4 and 5 are infra-red spectra of the polymer of the present invention.
As indicated, the polyurethane elastomer of the present inven-tion is a rubbery reaction product of hydrogenated methylene diisocyanate, polytetramethylene ether glycol, and ethylene oxide-capped trimethylol propane.
In general, polyurethane polymers are the condensation products of reactions between diisocyanates and compounds containing active hydrogen _ 3 _ sites such as hydroxyl groups. A diisocyanate is an isocyanate compound having a functionality of 2. The polymerization takes place in the presence of a difunctional hydroxyl compound (this can be either a simple glycol or a macro-molecular glycol).

catalyst -1l 1l l ~

nO~C=N-R-N=C=O + n HO-R -OH ~ - -C-N-R-N-C-O-R -O _ (diisocyanate) (glycol) 1 L n (polyurethane) In the present invention, the diisocyanate is hydrogenated methy-lene diisocyanate which has the following structural formula:

O=CN ~ CH2 ~ N=C=O

The difunctional hydroxyl compound is polytetramethylene ether glycol (PTMEG) H-(O-CH2-CH2-CH2-CH2)n-OH. In general to be useful in the pre-sent invention, this glycol should have an average molecular weight from between 200 to 5000, preferably from lOOO to 3000. In the preferred embodiment of the invention, the PTMEG has a molecular weight of about 2000.
The polyurethane of the present invention also includes a chain extender (low molecular weight glycol). In accordance with the present inven-tion, the chain extender is ethylene oxide-capped trimethylol propane which has the following structural formula:

I

In preparing clear elastomeric polymers in accordance with the present inven-~7~1~3 tion, 2.2 equivalent weights of the hydrogenated methylene diisocyanate is reacted with 1.0 equivalent weight cf polytetramethylene ether glycol and 1.0 equivalent weight of ethylene oxide-capped trimethylol propane. The result of the reaction is a polyurethane elastomer having the following structural formula:

- 5 -~

~ A`J~

p ~ .
o=~

o = C~
1;--Z

0 2 ~ ~

~ ,~

1~73193 where nl, n2, and n3 are positive integers in the range of 25 to 30 and n4 is a positive integer in the range of 100 to 300.
To obtain fully cured polyurethane castings in areasonably short period of time, it is customary to incorporate into the reaction mixture, a suit-able catalyst to promote the polymerization reaction. Suitable catalysts in-clude N-methylmorpholine, trimethylamine~ triethylamine, zinc octoate and dibutyl tin dilaurate. Dibutyl tin dilaurate is the preferred catalyst.
An embodiment of the process for molding a cornea in accordance with the present invention is represented diagrammatically in Figure 2. In practicing the embodiment, the polyurethane is prepared from two components which can be referred to as part A and part B. Part A is the aliphatic diiso-cyanate, that is hydrogenated methylene diisocyanate. Part B comprises the remaining constituents, that is the polytetramethylene ether glycol, the ethylene oxide-capped trimethylol propane and the catalyst. To form a poly-urethane molded element, such as a cornea or a lens, the proper stoichiometric proportions of part A and part B are emulsified in a mixture at room temperature to form a moderately reactive thixotropic mixture having a viscosity below about 2500 cps.
Since the emulsification introduces air into the reactive mixture, the air must be removed. The air bubbles are removed, for example by placing a vessel containing the emulsion under a bell jar and evacuating the air from the bell jar with a suction device. The bell jar is evacuated to a pressure of about 0.3 microns and the mixture is kept under the bell jar for about 8 minutes causing the mixture to appear to boil. After the emulsion is taken from the bell jar, it is allowed to stand until the exothermic reaction that is taking place brings it to a temperature of about 40C. At that point, the emulsion is forced into a mold.

,~

It is preferred to force the emulsion from the bottom to the top of the mold by the use of a pressurizing gas such as dry nitrogen. After the mold is filled, it is placed in an oven and heated to a temperature of at least lloQC for four hours or more until the elastomer is cured. The mold is then removed from the oven, allowed to reach room temperature and the cornea or lens is demolded. It is anticipated that a single mold will actually be used to form several corneas or lenses which are ccnnected together. After being removed from the mold, the cornsas or lenses are trimmed. The cornea molds are designed such that a thickness of 250 micrometers or less can be achieved for a given cornea.
The invention is further illustrated by the following nonlimiting Examples.
Example 1 One Shot Technique A blend of polytetramethylene ether glycol, molecular weight 2000, and ethylene-oxide capped trimethylol propane is heated to 35 and degassed for several minutes. Mixing ratio by weight is 227.2 grams of polyether to 24.9 grams of triol. To insure proper cure, 0.015 grams of dibutyl tin dilaurate are added to the above mixture. To this blend is charged 67.9 grams of hydrogenated methylene diisocyanate, and both materials are intimately emulsified by mixing for three minutes. This is followed by a second degassing step to remove any en-trapped air in the blend.
The batch is forced into a suitable mold by means of nitrogen pressure and cured at 110C for 3 hours. This results in an optically clear, elastic polymer with the following physical properties: 320 psi ultimate ten-sile strength; 600% elongation; and a Shore A hardness of 65.

.

Example 2 Prepolymer Technique 68 Grams of hydrogenated methylene diisocyanate is charged into a four neck reaction flask which has been purged with dry nitrogen. The contents of the flask are held under a steady nitrogen stream and 227.2 grams of polytetramethylene ether glycol ~2000 MW) which had been previously dried is charged to the flask. The polyether is added slowly to the isocyanate to promote capping rather than extension. After all the polyether has been chargedJ 0.010 grams of dibutyl tin dilaurate are added.
The mixture is held at 80C under continuous agitation for four hours or until a theoretical NC0 percentage of 4.3% +1 has been reached. The prepolymer is then allowed to cool to room temperature and packed under a nitrogen atmosphere. Prior to chain extension the prepolymer is reheated to 85C and deaerated. This is followed by forcing the liquid mixture into a mold by means of nitrogen pressure, and curing for four hours at 110C. Ty-pical properties of the optically-clear resultant elastomer are: 3600 psi ultimate tensile strength; 680% elongation; and a Shore A hardness of 65.
An infrared spectrum of a polymer in accordance with the present invention is shown in Pigures 4 and 5. Figure 4 is the transmittance infrared spectrum and Figure 5 is the absorbance spectrum.
Material prepared by the procedures set forth in Example 1 has been inserted beneath the cornea of one eye of a rabbit. This was done by making a surgical incision in the cornea of the rabbit and slipping a piece of the material underneath the existing cornea. This test demonstrated that the rabbit was able to see out of the eye containing the material of the pre-sent invention, which remained clear and free of opacifying blood vessels for the entire implantation test period of 30 days.
_ 9 _ ~ .~

Figure 3 illustrates the clarity of the polymer of the present invention by comparing its light transmissivity with that of a high quality optical glass. Curve 3 represents the polymer of the present invention; and, curve 4 represents a high quality optical glass.
In order that the Keratoprosthetic procedure in accordance with the invention may be readily understood, reference is made to the fact that a cornea lO protrudes somewhat from the regular contour of the remainder of the eyeball. (See Figure 1). Other parts of the eyeball that are shown in Figure 1 are the lens 12, the iris 14, and the vitreous body 16. As is stated above, lens 12 can be formed of a polymer in accordance with the present invention and can be implanted in an eyeball.
Before detailing the implant 18 of Figure 2, it is to be noted that it is relatively thin and of concavo-convex form to approximate the contour of the affected cornea 10. To accommodate an implant in accordance with the invention, the cornea IO is divided by an incision, separating the cornea into anterior and posterior layers with the layers remaining inter-connected in the zone of the limbus, the zone usually being diametrically opposite to the area in which the incision was started.
After the completion of the incision, the anterior layer is laid back and the implant is then positioned on the posterior corneal layer. The layer is drawn over the thus located implant and sutured so that the implant is held in place between the corneal layers.
As has been stated above, the material of the present invention is suitable forfix~ming an artificial lens which can be surgically implanted in-to an eyeball. Often a lens becomes clouded resulting in vision impairment.
When such a condition occurs, a lens formed of the polymer in accordance with the invention can be used as a replacement for the patient's normal lens. In ,, ~173193 performing such a procedure, the existing lens 12 will be removed by known techniques. One such technique is to break up the lens into small pieces and remove the small pieces from the eyeball by a suction device. With the normal lens removed, a lens formed of the polymer in accordance with the present invention having about the same physical shape can be inserted into the eyeball and secured in place in a manner similar to that described above with regard to the placement of the artificial cornea.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considrered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description~ and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An artificial cornea intended for implantation in a human eyeball, said cornea being formed from an aliphatic polyurethane elastomer which is the reaction product of:
(1) a hydrogenated methylene diisocyanate;
(2) a polytetramethylene ether glycol having a molecular weight in the range of 500 to 5000; and (3) an ethylene oxide-capped trimethylol propane.

2. The artificial cornea as set forth in claim 1 wherein the molecular weight of the polytetramethylene ether glycol is in the range of 1000 to 3000.

3. A polyurethane elastomer which is the reaction product of a hydro-genated methylene diisocyanate, a polytetramethylene ether glycol, and an ethylene oxide-capped trimethylol propane.

4. The polyurethane elastomer as set forth in claim 3 wherein the molecular weight of said polytetramethylene ether glycol is in the range of 1000 to 3000.

5. A process for forming an artificial cornea for implantation in a human eyeball comprising:
(a) mixing together a hydrogenated methylene diisocyanate, a poly-tetramethylene ether glycol and an ethylene oxide-capped trimethylol propane to form a reactive mixture;
(b) degassing the reactive mixture to remove entrained air;
(c) forcing the reactive mixture into a mold having the configuration of an artificial cornea;
(d) curing the mixture in the mold to form a polyurethane elastomer;

and (e) removing the cornea-shaped clear elastomer from the mold.

6. The process as set forth in claim 5 wherein the mixture is cured in step (d) by being heated to a temperature of at least 110°C for at least four hours.

7. A polyurethane elastomer having the following formula:

wherein n1, n2 and n3 is each a positive integer from 25 to 30 and n4 is a positive integer from 100 to 300.

8. An artificial lens intended for implantation in a human eyeball, said lens being formed from an aliphatic polyurethane elastomer which is the reaction product of:
(1) a hydrogenated methylene diisocyanate;
(2) a polytetramethylene ether glycol having a molecular weight in the range of 500 to 5000; and (3) ethylene oxide-capped trimethylol propane.

9. The artificial lens as set forth in claim 8 wherein the molecular weight of the polytetramethylene ether glycol is in the range of 1000 to 3000.

10. A process for forming an artificial lens for implantation in a human eyeball comprising:
(a) mixing a hydrogenated methylene diisocyanate, a polytetramethylene ether glycol and an ethylene oxide-capped trimethylol propane to form a reactive mixture;
(b) degassing the reactive mixture to remove entrained air;
(c) forcing the reactive mixture into a mold having the configuration of an artificial lens;
(d) curing the mixture in the mold to form a polyurethane elastomer; and (e) removing the lens-shaped clear elastomer from the mold.

11. The process as set forth in claim 10 wherein the mixture is cured in step (d) by being heated to a temperature of at least 110°C for at least four hours.