EP0830412A4

EP0830412A4 - Biocompatible optically transparent polymeric material based upon collagen and method of making

Info

Publication number: EP0830412A4
Application number: EP96919343A
Authority: EP
Inventors: Vladimir Feingold; Alexei V Osipov
Original assignee: Individual
Current assignee: Individual
Priority date: 1995-06-07
Filing date: 1996-06-07
Publication date: 1999-06-02
Also published as: KR19990022163A; JPH11507677A; EP0830412A1; AU6170196A; CA2223442A1; NZ310832A; WO1996040818A1; AU718546B2

Abstract

The present invention is a biocompatible polymer containing the copolymerization product of a mixture of hydrophobic and hydrophilic acrylic and/or allelic monomers, graft-polymerized with telo-collagen. The present material is useful in the production of deformable lenses, for example, intraocular lenses, refractive intraocular contact lenses, and standard contact lenses useful, for example, for correcting aphakia, myopia and hypermetropia.

Description

Title of the Invention

Biocompatible Optically Transparent Polymeric Material Based Upon

Collagen and Method of Making

Related Application

This application is a continuation-in-part application of U.S. patent application Serial No. 08/279,303, filed July 22, 1994, which application is incorporated by reference in its entirety.

Field of the Invention

This invention relates to a biocompatible polymer containing the copolymerization product of a mixture of hydrophobic and hydrophilic acrylic and/or allelic monomers, and telo-collagen preliminarily purified from glucoproteins and proteoglucanes. The material is useful for the production of soft intraocular lenses, refractive intraocular contact lenses, and standard contact lenses useful for example, in correcting aphekia, myopia and hypermetropia.

Background of the Invention

Ordinary polymers, based upon pure non-polyenic acrylates or allelic monomers, do not have on their surfaces water-solvent ionic layers on their surfaces which are buffered against the soφtion of proteins. Providing water-solvent ionic layers on the surface of the polymer is desirable because such layers will greatly improve the bio-compatibility of the lens with cell membranes of the recipient's eye.

Polyenic water-solvent ionic monomers may be used in order to produce a water-solvent layer. However, this decreases the resistance of such copolymers against swelling. For example, the system of polyenic copolymers, based upon acrylamid or acrylic acid with HEMA has a tendency towards excessive swelling beyond all bounds. This happens because pure homopolymers, polyacrylamide or polyacrylic acid, contained in this system, dissolve in water. Therefore, it is an advantage to produce a polymer which would be able to form such a vital water-solvent layer, and would not affect the polymer resistance against swelling.

References concerning graft-copolymers of collagen include U.S. Patent No. 4,388,428 (June 14, 1983) and U.S. Patent No. 4,452,925 (June 5, 1994). In these patents, a system of water-soluble monomers and A telo-collagen is used. However, this system is not hydrolytically stable and is not sufficiently optically transparent. In U.S. Patent No. 4,452,925, nothing is mentioned of special optical conditions needed for transparent polymer production. The water- solvent A telo-collagen disclosed in this patent does not have the capacity to form a gel in the organic monomer solution, and therefore the collagen precipitates or coagulates. Summary of the Invention

An object of the present invention is to provide a biocompatible optically transparent polymeric material based on telo-collagen.

A further object of the present invention is to provide a biocompatible polymer containing the copolymerization product of a mixture of hydrophobic and hydrophilic acrylic and/or allelic type-monomers and telo-collagen.

An object of the present invention is to provide a method of making a biocompatible, optically transparent, polymeric material based on collagen.

A further object of the present invention is to provide a method of making a biocompatible polymer containing the copolymerization product of a mixture of hydrophobic and hydrophilic acrylic and/or allelic type-monomers and telo-collagen.

The present invention is directed to methods of making a biocompatible polymeric material based on collagen for use in the produclion of deformable lenses.

The present invention is also directed to an deformable lens comprised of the present optically transparent, biocompatible, polymeric material.

The present invention is further directed to methods for making deformable lenses.

The present invention is also directed to methods for correcting aphekia (absence of the lens of the eye), myopia or hypermetropia in a patient by surgically implanting in the eye of the patient, the present deformable lens.

The biocompatible polymeric material according to the present invention is made as a copolymerization product of a mixture of hydrophobic and hydrophilic acrylic and/or allelic monomers graft polymerized with telo-collagen. For example, one or more hydrophobic acrylic and/or allelic monomers are mixed with one or more hydrophilic acrylic and/or allelic monomers, and the resultant solution is then mixed with telo-collagen dissolved in one or more hydrophilic acrylic and/or allelic monomers. The resulting material is then irradiated to form the present biocompatible optically transparent polymeric material.

The telo-collagen used in the present invention is essentially type IV collagen obtained from pig's eye sclera or cornea. The collagen is a naturally stable polyenic, which comprises hydrophobic, hydroxylic and polarized amino-acids (Matsumura, T., Relationship Between Amino-Acid Composition and Differentiation of Collagen, L t. J. Biochem. 5(75,1:265-274 (1972), and Traub W., and Piez K.A., The Chemistry and Structure of Collagen, Advances in Protein Chem 25:243-352, (1971). It is not advisable to use a modified collagen in the system according to the present invention since this collagen biodegrades with time (U.S. Patent No. 4,978,352, December 18, 1990).

The resulting biocompatible polymeric material is an elastic biopolymer, based upon the mixture of the hydrophobic and hydrophilic monomers and telo-collagen. The product of the hydrophobic and hydrophilic monomer copolymerization exhibits an elevated hydrolytic stability and a much higher index of refraction, if compared with a polymer which is based upon hydrophilic monomers alone.

The high molecular mass of telo-collagen molecules (320.000D), their size (up to 1000A), the disorientalion of molecules in space, the refraction index 1.47 (Hogan J. J. et. al. , Histology of Human Eyes, An Atlas and Textbook, Philadelphia, London, Toronto, (1971)), and other characteristics of collagen make it impossible to produce optically transparent hydrogel implants made of collagen alone. The refraction index of the hydrogel base substance, the aqueous number is equal to 1.336, which is substantially different from the refractive index of collagen 1.47, resulting in opacification of the gel, if a suspension of collagen in aqueous monomer is made. In order to produce an optically homogeneous gel in the mixture of organic monomers it is necessary to utilize telo-collagen containing telo-peptide. Telo-peptide is the basic element of interaction among collagen molecules. This produces a stable gel in the mixture of hydrophobic and hydrophilic monomers, and this gel neither precipitates nor coagulates.

For the purpose of increasing the optical transparency and homogeneity in this system,

the refraction index of polymer and of telo-collagen should be approximately equal, so that the intensity of light diffusion is close to zero, in accordance with Reley's equation (U.G. Frolof, Course of Colidle Chemistry, Moskva Chemia, 1989):

WHEREAS, I = I₀

I. = is intensity of incident light;

= is the intensity of diffused light as a unit of radiation volume;

P_f = distance to detector;

w = light diffusion angle; C = concentration of particles per volume unit;

λ = length of incident light wave;

N, = refraction index of particles;

N„ = refraction index of basal substance; and

V = volume of particles.

If N, = N„ then I_p = O. Thus, the intensity of light diffusion is zero.

A preferred hydrophilic acrylic monomer for use in the present invention is 2- hydroxyethyl melhacrylate (HEM A), and a preferred hydrophobic monomer for use in the present invention is 4-metharyloxy-2-hydroxybenzophenone. The telo-collagen is preferably produced from pig's eye sclera or cornea.

Detailed Description of the Preferred Embodiments

I. Definitions:

The below definitions serve to provide a clear and consistent understanding of th specification and claims, including the scope to be given such terms.

Telo-collagen. By the term "telo-collagen" is intended for the purposes of this inventio a naturally stable polyenic, that contains hydrophobic, hydroxylic and polarized amino-acid (Matsumura, T., Relationship Between Amino-Acid Composition and Differentiation of Collage Lut. J. Biochem 3(15):265-214 (1972).

The present telo-collagen is essentially type IV telo-collagen preferably made from pig' eye sclera or cornea, and has a viscosity of greater than or equal to lOOOcPs. The present tel collagen retains the telo-peptides and has a refractive index of about 1.44 to 1.48.

Biocompatible polymeric material. By the terminology "biocompatible polymeri material" is intended a material which is made by combining or mixing one or more hydrophobi monomers (acrylic and/or allelic monomers), and one or more hydrophilic monomers (acryli and/or allelic monomers), and graft-copolymerizing the resultant mixture with a telo-collagen/hydrophilic monomer/acid solution.

Monomer. By the term "monomer" denotes the molecular unit that by repetition, constitutes a large structure or polymer. For example ethylene CH₂=CH₂ is the monomer of polyethylene, H(CH₂)NH.

Allyl. By the term "allyl" is intended 2-propenyI, the monovalent radical,

CH = CHCH₂- .

Organic Acid. By the term "organic acid" is intended an acid made up of molecules containing organic radicals. Such acids include for example, formic acid (H-COOH), acetic acid (CH₃COOH) and citric acid (C₆H_gO₇), all of which contain the ionizable -COOH group.

Acrylic. By the term "acrylic" is intended synthetic plastic resins derived from acrylic acids.

Optically Transparent. By the terminology "optically transparent" is intended the property of a polymeric material to allow the passage of light at or above the threshold of visual sensation (i.e., the minimum amount of light intensity invoking a visual sensation). Preferably, the present biocompatible polymeric material including COLLAMER has a refractive index i the range of 1.44 to 1.48, more preferably 1.45 to 1.47, and most preferably 1.45 to 1.46. Th best mode of the present invention is the biocompatible polymeric material COLLAMER.

Polymerization. By the term "polymerization" is intended a process in which monomer combine to form polymers. Such polymerization can include "addition polymerization" wher monomers combine and no other products are produced, and "condensation polymerization" where a by-product (e.g. ater) is also formed. Known suitable polymerization processes ca be readily selected and employed for the production of the present biocompatible polymeri material by those of ordinary skill in the art to which the present invention pertains.

Polyene. By the term "polyene" is intended a chemical compound having a series o conjugated (alternating) double bonds, e.g., the carotenoids.

Refractive Index. By the terminology "refractive index" is intended a measurement o the degree of refraction in translucent/transparent substances, especially the ocular media. The "refractive index" is measured as the relative velocity of light in another medium (such as th

present polymeric material) as compared to the velocity of light in air. For example, in the case of air to crown glass the refractive index(n) is 1.52, in the case of air to water n = 1.33.

Tensile Strength. By the terminology "tensile strength" is intended the maximal stress or load that a material is capable of sustaining expressed in kPa. The present biocompatible polymeric material including COLLAMER has a tensile strength in the range of about 391-1778 kPa, preferably 591-1578 kPa, more preferably 791-1378 kPa, and most preferably in the range of from 991 kPa to 1178 kPa. The present material "COLLAMER" has a tensile strength of preferably 1085 ±. 493 kPa. The tensile strength of a polymeric material can be readily determined using known methods, by those of ordinary skill in the art.

Hypermetropia. By the term "hypermetropia" (h.) is intended farsightedness/longsightedness, i.e., long or far sight which is an optical condition in which only convergent rays can be brought to focus on the retina. Such conditions include: (1) absolute h.— that cannot be overcome by an effort of accommodation; (2) axial h.— h. that is due to shortening of the anteroposterior diameter of the globe of the eye; (3) curvature h.— h. which is due to the decreased refraction of the anterior diameter of the globe of the eye; (4) manifest.— h. that can be compensated by accommodation; (5) facultative h.~ manifest h.; (6) latent h.— the difference

between total and manifest h.; and (7) total h.~ that which can be determined after complete paralysis of accommodation by means of a cycloplegic; (8) index h.— h. arising from decreased refractivity of the lens.

Myopia. By the term "myopia" (m) is intended "shortsightedness; nearsighledness; near or short sight; that optical condition in which only rays a finite distance from the eye focus on

the retina. Such conditions include: (1) axial tn.-m. due to elongation of the globe of the eye; (2) curvature.— m. due to refractive errors resulting from excessive corneal curvature; (3) degenerative.— pathologic m.; (4) index m.- . arising from increased refractivity of the lens, as in nuclear sclerosis; (5) malignant.-palhologic m.; (6) night.— m. occurring in a normally emmetropic eye because long light rays focus in front of the retina; (7) pathologic— degenerative or malignant., progressive, marked by fundus changes, posterior staphyloma and subnormal corrected acuity; (8) prematurity m.,.~ m. observed in infants of low birth weight or in association with retrolental fibroplasia; (9) senile lenticular. -second sight; (10) simple m.-m. arising from failure of correlation of the refractive power of the anterior segment and the length of the eyeball; (11) space. -a type of m. arising when no contour is imaged on the retina; and (12) transient.— m. observed in accommodative spasm secondary to iridocyclitis or ocular contusion.

- 13 -

Hydrophilic allelic monomer. By the term "hydrophilic allelic monomer" is intended for the puφoses of the present invention any monomer containing an allyl group which monomer is soluble in water.

Hydrophilic acrylic monomer. By the terminology "hydrophilic acrylic monomer" is intended any monomer containing an acrylic group which monomer is soluble in water. For example, HEMA is a hydrophilic acrylic monomer because it is soluble in water even though it contains both hydrophilic groups and hydrophobic groups.

Hydrophobic allelic monomer. By the term "hydrophobic allelic monomer" is intended for the puφoses of the present invention, any monomer containing an allyl group, which monomer is not soluble in water.

Hydrophobic acrylic monomer. By the term "hydrophobic acrylic monomer" is intended for the puφoses of the present invention, any monomer containing an acrylic group, which monomer is not soluble in water.

Deformable lens. By the term "deformable lens" is intended any type of deformable lens, for example, for correcting hypermetropia or myopia, where the lens comprises the present material. Such lenses include those disclosed in U.S. Patent Application Serial Nos. 08/318,991 - 14 -

and 08/225,060. All of the foregoing are hereby incoφorated by reference herein. Such lense include: intraocular lenses for implantation into a patient's eye, for example, into the anterio chamber, in tlie bag or in the sulcas; refractive intraocular lenses for implantation into a patient' eye, for example, into the anterior chamber or in the sulcas; and standard soft contact lenses.

Implant. By the term "implant" is intended the surgical method of introducing th

present lens into the eye of a patient, for example, into the anterior chamber, in the bag or i the sulcas, by the methods described in U.S. Patent Application Serial Nos. 08/195,717 08/318,991, and 08/220,999 using for example, surgical devices disclosed in U.S. Paten Application Serial Nos. 08/197,604, 08/196,855, 08/345,360, and 08/221,013. All of th foregoing are hereby incoφorated by reference.

The present hydrophilic monomers and hydrophobic monomers must be selected such tha the hydrophobic monomer(s) is soluble in the hydrophilic monomer(s). The hydrophili monomer acts as a solvent for the hydrophobic monomer. Suitable monomers can be readil selected by those of ordinary skill in the art to which the present invention pertains.

Examples of suitable hydrophobic monomers, include:

1) 4-methacryloxy-2-hydroxybenzophenone (acrylic); - 15 -

2) ethyl-3 benzoil acrylate (acrylic);

3) 3-allyl-4-hydroxyacetophenone (allelic);

4) 2-(2'-hydroxy-3'-allyl-5'-melhylphenyl)-2H-benzotriazole (allelic);

5) N-propyl melhacrylate (acrylic); 6) allyl benzene (allelic);

7) allyl butyrate (allelic);

8) allylanisole (allelic);

9) N-propyl melhacrylate (acrylic);

10) ethyl-methacrylate (acrylic); 11) methyl methacrylate (acrylic);

12) n-heptyl methacrylate (acrylic).

Various examples of suitable hydrophilic monomers, include:

1) 2-hydroxyethyl methacrylate (HEMA) (acrylic);

2) hydroxypropyl methacrylate (acrylic);

3) 2-hydroxyethyl methacrylate (acrylic);

4) hydroxypropyl methacrylate (acrylic);

5) allyl alcohol (allelic); 6) poly(ethylene glycol)n monomethacrylate (acrylic); 7) 4-hydroxybutyl melhacrylate (acrylic);

8) allyl glucol carbonate (allelic).

//. Method of Making the Present Polymeric Material Based on Collagen

The following is a description of a preferred method of making the biocompatible polymeric material according to the present invention.

Step 1:

The hydrophilic monomer is mixed wilh an acid, in particular formic acid. The weight ratio of hydrophilic monomer to acid is preferably in the range of about 5: 1 to about 50: 1 , preferably 14:1 to 20: 1 , and most preferably, 14: 1. This solution is preferably filtered through a 0.2 microfilter.

Step 2:

In an independent step, an acidic telo-collagen solution is prepared by mixing telo-collagen with organic acid (preferably formic acid). The solution is preferably 2 % by weight telo-collagen in 1 M formic acid. Step 3:

The solutions resulting from steps 1 and 2 are then mixed together. The resultant solution is preferably mixed from about 10 minutes to 60 minutes, most preferably 20 minutes at a temperature of 15-30°C. The ratio of telo-collagen to hydrophilic monomer is about 1:2 to about 1:7, preferably 1:3 to 1:6, and most preferably 1:4.

Step 4:

In an independent step, the hydrophobic monomer and hydrophilic monomer are mixed together in a weight ratio of about 10: 1 to 1: 1, preferably 8:l^'to 3:1, and most preferably 5: 1. The monomers are mixed wilii stirring for about 30 to 90 minutes, preferably 60 minutes at 70 to 95°C, preferably 80-95°C, and most preferably 80-92°C. The resulting solution is preferably filtered through a 0.2 micron filler.

Step 5:

The solutions from steps 3 and 4 are mixed together in a weight ratio in the range of about 1 : 1 to 50: 1 , preferably 2: 1 to 5 : 1 , and most preferably 3:1. The solution is preferably mixed 20 minutes with no heating at a temperature of 25-40°C. Mixing is preferably performed with a homogenizer.

Step 6:

The resulting material from Step 5 is then preferably degassed (i.e., using centrifugation or other means well-known to those of ordinary skill in the art to which the present invention applies).

Step 7:

The resulting material from Step 6 is irradiated to form a final product that can be dried, and stored, (i.e., stored in a desiccator due to its hydroscopic nature). The material from Step 6 can also be stored in a refrigerator, for example at 5°C to 10°C, prior to irradiation.

A polymeric material according to the present invention is obtained from an interaction between a solution of telo-collagen complex, and the hydrophilic and the hydrophobic monomers under radiation of lMrad/hr for a total dose of from 0.20 to 0.80Mrad, preferably 0.30 to 0.60Mrad, and most preferably from 0.35 to 0.50Mrad (lMrad = 10 Kgray). A turbo-type mixer such as a homogenizer, is preferably employed for mixing the solutions of at least Steps 3 and 5, and the mixing times set forth above are based on using a turbo-type mixer. Those of ordinary skill in the art can readily select and employ other known

mixers and methods, as well as time ranges.

In a preferred embodiment the present polymeric material is made by mixing the hydrophobic monomer in two stages to increase the solution viscosity, where in stage one the telo-collagen complex and a mixture of formic acid with 2-hydroxyelhyl-methacrylate are used as a stabilizer of ultra-colloidal stale solution and in stage two a hydrophobic blend of at least one monomer is introduced into the gel produced.

HI. Standardized Method for the Compounding of the present COLLAMER

A. Preparation of Acidic Collagen Solution

A 1M acid solution, preferably 1M formic acid is prepared. The quantity of acid solution required for dissolution of the swollen tissue is calculated using a ratio of swollen collagen tissue: (sclera or cornea) acid solution of about 40:0.5 to 55:2, preferably about 45:1 to about 52: 1.5, most preferably about 50: 1. The swollen tissue is then dispensed in a homogenizer for about 10 to 20 minutes, preferably about 15 minutes at 2 to 10 RPM, preferably 4-5 RPM, at room temperature. The produced solution is then filtered through a funnel glass filter with a pore size of 100-150 microns, the filtrate is then filtered througli a second funnel glass filter with a pore size of 75-100 microns. The produced homogenic solution is then transferred into a container.

B. Hydrophobic and Hydrophilic Solution Preparation

1. The hydrophilic monomer, preferably HEMA is mixed with the hydrophobic monomer, preferably MHBPH in a weight ralio of about 5: 1 and healed for one hour at 80°C to 92°C with stirring (e.g., using a stirrer hot plate). The heated solution is then filtered through 5.0 micron filter.

2. HEMA is mixed with an organic acid (preferably formic acid), preferably in a weight ratio of about 14: 1. This mixture is added to the collagen solution produced (A) in a weight ratio of HEMA solution:collagen solution of about 1:3, and mixed for about 20 minutes at room temperature. The mixing is preferably performed using a homogenizer at a rate of 6000 RPM.

3. The HEMA MHBPH solution of B.(l) is then mixed in small portions with the HEMA telo-collagen solution of B.(2). The mixing is preferably performed in a homogenizer for 10 minutes at room temperature.

C. Production of COLLAMER

Glass vials are then coated with approximately 7mm of paraffin wax. The solution of B(3) is then poured into the glass vials and degassed (e.g., centrifuged for 15 minutes to remove air). The vials are subsequently irradiated at 5 Kgray. (Note: prior to irradiation the vials can be stored in a refrigerator, for example at 5°C to 10°C.)

IV. Guidance for Selecting the Present Monomers

The following equation can be used to aid in the selection of the appropriate concentration of monomer necessary to result in the present polymeric material having an index of refraction in the present desired range (1.44 to 1.48, preferably 1.45 to 1.47, and most preferably 1.45 to 1.46).

The monomer of copolymerization with telo-collagen complex is selected such that:

N = (K, • NJ + (1 - K,)N_p = N_c ± 0.02

K, = coefficient of swelling

N, = refractive index of water (1.336)

N_p = refractive index of dry polymer

N_c = refractive index of telo-collagen (about 1.45 to 1.46)

where N_p = A

Nj = refractive index of i-monomer

C| = concentration of i-monomer A = coefficient of increase in refractive index due to polymerization n = number of monomers i = monomer number

The hydrophobic and hydrophilic monomers must be selected such that the hydrophilic monomer is a solvent for the hydrophobic monomer, i.e., the hydrophobic monomer is soluble in the hydrophilic monomer.

The manner and method of carrying out the present invention may be more fully understood by those of skill in the art to which tlie present invention pertains by reference to the following examples, which examples are not intended in any manner to limit the scope of the present invention or of the claims directed thereto.

Examples

Example I: Compounding COLLAMER

A. Preparation of acidic collagen solution

Under an exhaust hood, 1 liter of distilled water was measured into a 3 liter glass beaker. 52 grams of formic acid was then added to the beaker and mixed until dissolved. Swollen collagen containing tissue (from pig's eyes) was then added to the acid solution in the below ratios of swollen tissue: acid solution.

Swollen Tissue Acid Solution

1. 517.00 grams 10.21 grams

2. 50.64 grams 1.00 grams

The mixture was then slored in a refrigerator al a lemperalure of 5°C, and was thereafter dispersed in a homogenizer for 15 minutes at 4-5 RPM at room lemperalure.

The produced solution was then fillered through a funnel glass filler with a pore size of 100-150 microns. Thereafter, the filtrate was fillered through a funnel glass filter with a pore size of 75-100 microns. The final homogenic solution was then transferred into a 250ml container.

B. MHBPH and HEMA solution preparation

1. 527.4g of HEMA was mixed with 106.2g of MHBPH and healed for one hour at 80°C using a stirrer hot plale. The healed solution was fillered through an Aero 50-5.0 micron filter. 2. 1 15.6g of HEMA was then mixed with 99.4g of formic acid in a hermetic glass container with a Teflon lid. lOOg portions of tlie IIEMA/acid solution were added into 333g of lelo-collagen solution and mixed for 20 minutes at room lemperalure. The mixing was performed in a homogenizer at a rate of 6000 RPM.

3. The HEMΛ/MHBPH solution was then added in small portions to the HEMA telo-collagen solution. The mixing was performed in a homogenizer for 10 minutes at room temperature.

C. Production of COLLAMER

Glass vials were coaled with approximately 7mm of paraffin wax. The resultant solution

of Step B(3) was then poured into the glass vials and centrifuged for 15 minutes to remove air. The vials were then irradiated at 5Kgray to polymerize and cross-link the present material.

Example 2: Preparation of a Biocompatible Polymeric Optically Transparent Material

In this example, pig's eye sclera was used. 300g of 2-hydroxyelhyl melhacrylate was mixed with 16g of formic acid. 50g of telo-collagen was filtered purified from sclera using alkaline hydrolysis with 200g NaOH and 200g of Na,SO_« in 2.5 liters of water, and filtered through a 100 micron filter. The telo-collagen was mixed wilh 2-hydroxyelhyl melhacrylate and the formic acid solution containing 2-hydroxyelhyl melhacrylale. 20g of 4-methacryIoxy-2- hydroxybenzophenone (MHBPH) dissolved in HEMA was then added. This mixture was radiated wilh gamma radiation in the range of 3.5-5.0 Kgray to polymerize and cross-link all the components.

Hydrophobic monomers were used in Ihis system lo reduce the absoφlion of water and swelling of the polymerized material when introduced into the aqueous media of the eye. In addition, the hydrophobic monomer was chosen so that the refraclive index of the resultant polymer increased to be approximately equal lo the refraclive index of telo-collagen.

Example 3:

The same procedure in Example 2 can be utilized, except the following monomers can be substituted:

1) ethyl-3-benzoilacrylate (hydrophobic acrylic monomer), plus

2) 2-hydroxyelhyl melhacrylate (HEMA), (hydrophilic acrylic monomer). Example 4:

1) 3-allyl-4-hydroxyacetophenone (hydrophobic allelic monomer), plus

2) 2-hydroxyethyl melhacrylate (HEMA), (hydrophilic acrylic monomer).

Example 5:

The same procedure in Example 2 can be utilized, except the following monomers can be subsliluled:

1) 2-(2*-hydroxy-3'-allyl-5'-methylphcnyl)-2H-benzolriazole (hydrophobic allelic monomer), plus

2) hydroxypropyl melhacrylate, (hydrophilic acrylic monomer). Example 6:

1) methyl melhacrylate (hydrophobic acrylic monomer), plus

2) hydroxypropyl melhacrylate (hydrophilic acrylic monomer).

Example 7:

1) 2-(2'-hydroxy-3'-allyI-5'-melhylphenyl)-2II-benzotriazole (hydrophobic allelic monomer), plus

2) hydroxypropyl methacrylate (hydrophilic acrylic monomer). Example 8:

A. Tensile Strength Testing of COLLAMER Material

The puφose of this lest was to determine the lensile properties of the present collamer material. This includes tensile strength, Young's modulus, and percent elongation at failure. The data collected was used to construct standards for inspection. The tensile test is similar lo the silicone lensile test. The sample geometry is different but the stress fundamentals remain the same.

B. Materials

COLLAMER samples Inslron tensile tester (Model 1 122) forceps log book

C. Procedure

1. Sample Preparation

a. The dry material samples were cut into rings. The dimensions are: Oulside diameter = 10 _t .1 mm, inside diameter = 8 _J_, .1 mm, thickness = 1.0 jh .01 mm. The material was prepared following the procedures used to manufacture lenses. Lenses were hydraled following MSOP /H 13ΛG.

Testing

a. The inslron leslcr was set up for tensile specimens, following

ESOP 202, RMX-3 Slab Pull Test, Rev B. The fixtures were

placed into the jaws and the fixtures were brought together so that the lop and bollom portion touched, by moving the crosshead up or down. When the fixtures were touching, there was

approximately 8 mm between Ihe two pins. This was the starling position of jaw separation, so the Inslron position coordinates were set to zero.

b. The load dial was set lo 2 kg full scale output, the crosshead speed

to 500 mm/min and Ihe chart recorder lo 500 mm/min. The chart

speed corresponded lo and recorded jaw separation. The chart buttons marked "PEN" and "TIME" were depressed.

c. The wet lest sample was removed from its vial and placed so it was almost stretched between the two pins. When the sample was in place, the "UP" button on the crosshead control panel was

immediately pressed. This sample was then loaded lo failure.

d. When Ihe sample failed, the "STOP" button on the crosshead control panel was pressed. The chart buttons marked "PEN" and "TIME" were then depressed so that they were in the up position, the return on the crosshead control panel was then pressed to

return Ihe crosshead to starting position. e. The failure point in the chart was then marked by noting the load at failure (in kg) and jaw separation.

f. Sleps 2a through 2e were repealed until all samples were all tested.

Data

Calculation for Ultimate Tensile Strength

(1) σ = F/Λ

Where:

σ = Ultimate Tensile Strength, Pascals, (Pa). F = Force required lo break Ihe lest specimen, Newlons, (N)

A = Hydrated cross sectional area of specimen, square meters, (m²).

6 - Swell Factor, 1.17

w= width, mm t = thickness, mm Given:

F = .29 kg x 9.81 m/s² = 2.84 N

A = 2[δ(w) x δ(t)] =2[(1. 17 x 1.0) x (1.17 x 1.0)] = 2.74 mm² Conversion from mm² to m²: 2.74 mm² = 2.74 x 10"* m² A = 2.74 x 10⁶ m²

Find:

Ultimate Tensile Strength, a

Solution:

σ = F/A = 2.84N/2.74 x 10 * m² = 1038.3 kPa To convert kPa to psi, multiply by 145.04 x 10³

1038.3 kPa x 145.04 x 10³ = 150.6 psi

a = 1038.3 kPa or σ = 150.6 psi

Calculation for Percent Elongation

(2) δ = 200[L/MC_σS)]

Where:

δ = elongation (specified), percent,

L = increase in jaw separation at specified elongation, (mm), and MC_frs₎ = mean circumference of test specimen, mm, circumference = 7rd

Given:

L = 41.5 mm MC_frs₎ = (ird, + τrd₂)/2 = (ιr x 10 mm + r x 8 mm)/2 = 28.27 mm

Find:

Elongation, δ Solution:

δ = 200[IJMC_σs)] = 200[41.5 mm/28.27 mm] = 293.6% δ = 293.6%

Calculation for Young's Modulus

(3) E = Pl/Ae

Where:

E = Young's Modulus, Pascals, (Pa)

P = Force, Newlons, (N)

1 = length of sample, meters (m)

A = Cross Sectional Area, square meters, (m²) e = Gross Longitudinal Deformation, meters, (m).

Given:

P = .29 kg x 9.81 m/s² = 2.84 N

1 = .008 m

A ^ώ A = 2[δ(w) x δ(t)] = 2 [(1.17 x 1.0) x (1.17 x 1.0)] = 2.74 mm²

Conversion from mm² to m²: 2.74 mm² = 2.74 x 10 * m² e = .0415 m

Find:

Young's Modulus, E

Solution:

E = Pl/Λe = (2.84 N x .008 m)/(.0415 in x 2.74 x 10* m²) = 200.2 kPa To convert kPa lo psi, multiply by 145.04 x 10³ 199.8 kPa x 145.04 x 10³ = 29.0 psi E = 199.8 kPa or 29.0 psi E. Discussion

The Inslron was set up and calibrated according to ESOP #202. The testing fixtures were brought together so the centerlines were aligned and there was approximately 8 mm between the posts. This was designated zero and the fixtures returned to this position every time after the

test. Crosshead speed and the chart recorder speed were set lo 500 mm/min.

The chart recorder was set at zero load and deflection before every test. The chart recorder recorded kilograms-force load and jaw separation. Load is used to determine the ultimate tensile strength (see formula 1, Test Data Section), the stress at which the sample fails.

The sample was not set up lo test elongation using a standard gage length but a formula in the

ASTM D412 standard is used to calculate Ihe elongation (see formula 2, Data Section).

The performance of the specimen proved Ihe material to be elastic and wilh the stress increasing at a linear rale until failure. The linear increase can be one of two things: (1) it is possible the specimens have stress risers on the inside diameter. Stress risers would be caused by the milling process, because^il doesn't have the surface finish of the lalhe-turned outer diameter; this may not allow the material (o neck down during the plastic deformation stage of

the test. The majority of the stress is concentrated on Ihe internal circumference, which loads the stress risers more than if they were on the oulside circumference; (2) the material may not - 38 -

neck down (plastic deformation) as do other plastic materials such as Kapton film. It reacts like RMX-3, with the cross sectional area gelling smaller as elongation increases, which is indicative of Hooke's law.

The present material showed COLLAMER good resistance to tear propagation, which would happen at any stress risers. The cross sectional area of the failed part was flat, which was indicative of elastic failure.

E. Conclusion

The combined data from the present COLLAMER samples gave an average tensile slrenglh of 1084.6 kilopascals (kPa), and an average elongation of 324.9 percent (%). The tolerance for average tensile slrenglh was calculated as ±_ 3 limes the standard deviation, giving an upper tolerance of 1578 kPa (229 psi) and a lower tolerance of 591 kPa (86 psi). The tolerance for the elongation is calculated in the same manner. The upper tolerance is 395 % elongation and the lower tolerance is calculated as 255 % elongation. See Appendix 3 for the calculations. The tensile slrenglh standard is 1085 ± 493 kPa (157 ± 71 psi) and the elongation is 325% ± 70. Young's modulus standard is 189 ± 25 kPa (27 ± 11 psi).

- 39 -

F. References

ASTM D412 Properties of Rubber in Tension ESOP 202 - RMX-3 Slab Pull Test, Rev B. Mark's Standard Handbook for Mechanical Engineers, Ninth Edition

All references cited are hereby incoφoraled by reference. Now having fully described this invention, it will be understood by those of skill in the art that the scope may be performed within a wide and equivalent range of conditions, parameters, and the like, without affecting the spirit or scope of the invention or of any embodiment thereof.

Claims

Wc Claim:

1. A biocompatible, optically transparent, polymeric material based on collagen, comprising:

one or more hydrophilic acrylic or allelic monomers, and one or more hydrophobic acrylic or allelic monomers; and

telo-collagen containing telo-peptides,

wherein said one or more hydrophilic acrylic or allelic monomers and said one or more hydrophobic acrylic or allelic monomers, are graft-polymerized with said telo-collagen to form a biocompatible, optically transparent, polymeric material based on collagen.

2. The polymeric material of claim 1 , wherein said telo-collagen has a viscosity of greater

than or equal to lOOOcPs.

3. The polymeric material of claim 1 , wherein said one or more hydrophilic acrylic or allelic monomers are selected from the group consisting of: HEMA (acrylic); 2-hydroxyethyl melhacrylate (HEMA) (acrylic); hydroxypropyl melhacrylate (acrylic); 2 - h y d r o x y e t h y l melhacrylate (acrylic); hydroxypropyl methacrylate (acrylic); allyl alcohol (allelic); poly(elhylene glycol)n monomethacrylate (acrylic); 4-hydroxybutyl melhacrylate (acrylic); allyl giucol carbonate (allelic);

said one or more hydrophobic acrylic or allelic monomers are selected from the group consisting of: 4-methacryloxy-2-hydroxybenzophenone (MHBPH) (acrylic); allyl benzene (allelic); allyl butyrate (allelic); 4-allylanisole (allelic); 3-allyl-4-hydroxyacetophenone (allelic); 2-(2'-hydroxy-3'-allyl-5'-melhyIphenone-2H-benzotriazol) (allelic); N-propyl methacrylate (acrylic); elhyl-melhacrylale (acrylic); melhyl melhacrylate (acrylic); ethyl-3-benzoil acrylale (acrylic); and n-heplyl melhacrylate (acrylic); and

wherein said one or more hydrophobic monomers are soluble in said one or more hydrophilic monomers.

4. The polymeric material of claim 3, wherein said hydrophilic monomer is HEMA and said hydrophobic monomer is MHBPH.

5. The polymeric material of claim 1, wherein said biocompatible, optically transparent, polymeric material has an index of refraction in Ihe range of from 1.44 to 1.48.

- 42 -

6. The polymeric material of claim 5, wherein said index of refraction in the range of from 1.45 to 1.47.

7. The polymeric material of any one of claims 1 or 4, wherein said biocompatible, optically transparent, polymeric material has an index of refraction in the range of from 1.45 to 1.46.

8. The polymeric material of claim 1 , produced by the process comprising:

dissolving an acid-telo-collagen solution in one or more hydrophilic monomers lo form a collagen/hydrophilic solution;

dissolving one or more hydrophobic monomers in one or more hydrophilic monomers to form a hydrophobic/hydrophilic solution;

combining said collagen/hydrophilic and said hydrophobic/hydrophilic solution to form a resultant solution; and

graft-polymerizing said resultant solution to form the present biocompatible, optically transparent, polymeric material based on collagen. 9. A method for producing a biocompatible, optically transparent, polymeric material, comprising:

dissolving an acid-lelo-collagen solution in one or more hydrophilic monomers to form

a collagen/hydrophilic solution;

combining said collagen/hydrophilic and said hydrophobic/hydrophilic solution lo form a resultant solution; and

graft-polymerizing said resultant solution lo form the present biocompatible, optically

transparent, polymeric material based on collagen.

10. The method of claim 9, wherein said step of graft-polymerizing comprises irradiating said

resultant solution.

11. A deformable lens comprising:

the biocompatible, optically transparent, polymeric material based on collagen of claim 1

12. The deformable lens of claim 11 , wherein said deformable lens is a contact lens.

13. The deformable lens of claim 11 , wherein said deformable lens is a soft intraocular lens

14. The deformable lens of claim 11 , wherein said deformable lens is a refraclive intraocula lens.

15. A method for correcting aphekia, myopia or hypermetropia in a patient sufferin therefrom, comprising:

implanting in the eye of said patient, the intraocular lens of any one of claims 13 or 14.

16. The polymeric material of claim 1 , wherein said polymeric material has a tensile strengt of from about 591 kPa to about 1578 kPa.

17. The deformable lens of claim 1 1 , wherein said deformable lens has a tensile strength of from about 591 kPa to about 1578 kPa.

18. A deformable lens comprising:

the biocompatible, optically transparent polymeric material of claim 4.