IE63102B1 - Uncrosslinked hydrogel, process for its preparation and its uses as an article for medical and/or surgical purposes such as tubes, filaments, films, joints, implants and the like, particularly in ophthalmology - Google Patents

Abstract

Non-cross-linked hydrogel, method for making it, and its uses in medicine and/or surgery, such as tubes, filaments, films, rings, implants and the like, especially in ophthalmolgy. The non-cross-linked hydrogel having a relatively high water content is made from a starting liquid composition (D) which comprises from 2 to 50 % of an acrylonitrile copolymer and of an olefinically unsaturated comonomer carrying anionic groups, optionally in salt form, the molar ratio of acrylonitrile to comonomer being between 90:10 and 100:0, a suitable solvent and a suitable non-solvent of the said copolymer, the solvent/non-solvent ratio being between 500:1 and 0.5:1 by weight, the said hydrogel having a microporous structure, an ionic capacity of between 0 and 500 mEq/kg of gel, a water content of between 50 and 98 %, and having a capacity for permanent deformation under stress, even at a temperature below 40 DEG C.

Description

UNCROSSLINKED HYDROGEL, PROCESS FOR ITS PREPARATION AND ITS USES AS AN ARTICLE FOR MEDICAL AND/OR SURGICAL PURPOSES SUCH AS TUBES, FILAMENTS, FILMS, JOINTS, · IMPLANTS AND THE LIKE, PARTICULARLY IN OPHTHALMOLOGY BACKGROUND OF THE INVENTION The present invention relates to an uncrosslinked hydrogel, to its process of preparation as well as to its applications as an article for medical and/or surgical purposes such as tubes, filaments, films, joints, implants and the like, particularly in ophthalmology.

It has already been proposed, to employ polymers in hydrogel form having a relatively high water content whilst having improved mechanical and optical properties (European patent n® 188 110 and American patents 4 379 864 and 4 543 371), for ophthalmic purposes.

However, the product described in American patents n° 4 379 864 and n® 4 543 371 do not show a high water content ; these polymers lose, in fact, the required mechanical properties, particularly for their use as an implant, when the water content is high.

As regards the hydrogel described in European patent application n° 188 110, they do not show properties of good tolerance, particularly required for an implant, to the extent that the ionic characteristics and in particular the electronegativity of the polymer does not permit good tolerance of the latter to be envisaged.

This is why Applicant has sought in another - 2 direction for a solution to the problem set, vhich is that of providing hydrogels having high biocompatibility for their use in the preparation of articles for medical or surgical purposes which are highly reliable and in particular ocular implants enabling a suitable permeability to be obtained to different biological molecules, said implants, not shoving, consequently, the drawbacks of known implants.

Patent FR 2 529 464 describes biocompatible materials in the form of hollow fibers or membranes. These biomaterials are treated by a plurality of drawings to produce a suitable permeability and showing for this reason, a different structure, namely of membranes or hollow fibers for hemodialysis and/or hemofiltration. .

Patent DE-A-2028956 describes a hydrogel which comprises many ionic groups, said hydrogel not showing the suitable biocompatibility sought by Applicant.

Applicant unexpectedly has found that certain biomaterials under particular conditions, have considerable advantages, especially in the field of ocular implants.

It is, in this respect, an object of the invention to provide an uncrosslinked hydrogel with improved mechanical properties and with a high water content as well as its method of preparation which responds better to the necessities of practice than the hydrogels of the prior art, particularly in that they have the advantage of confering on said hydrogels a character of inertia with respect to biological cells. - 3 It is also an object of the invention to provide articles constituted by or comprising said hydrogel. The use of said articles in surgery and in medicine is also an object of the invention.

Among said articles, may be mentioned especially ocular implants which show besides the character of Inertia with respect to biological cells : the following optical properties : perfect transparency in visible light, absorption of ultra-violet rays at 280 nm, refractive index close to that of the cornea, physico-chemical properties such as : high permeability to water, to physiological serum, to small and medium-sized molecules, assuring the migration of nutrient substances for the cornea as well as all of the metabolites, permeability to dissolved gases (θ£, θθ£), highly hydrophilic a chemical nature devoid of toxic groups, of heavy metals, of remaining catalysts and of free monomers and of solvent easy to use, dimensional stability, especially in a 0.9% chloride solution particular biological properties such as: be non-bioresorbable in the physiological medium, have good resistance to aging in this medium, that is to say not showing opacification, coloration or degradation of physical properties. show good tissue tolerance of the sites of - 4 implantations in the corneal stroma, without causing alteration of the epithelium and of the corneal endothelium - 5 have, if possible, a low affinity for proteins, be sterilizable and/or re-sterilizable.

GENERAL DESCRIPTION OF THE INVENTION According to the present invention there is provided an uncrosslinked hydrogel with a relatively high water content, characterized in that it is constituted from a liquid starting composition (D) which comprises from 2 to 50 % of a copolymer of acrylonitrile and an olefinically unsaturated comonomer bearing anionic groups, possibly salified, the molar ratio acrylonitrile-comonomer being comprised between 90:10 and 100;0, a suitable solvent and a suitable non-solvent of said copolymer, the ratio solvent/nonsolvent being comprised between 500:1 and 0,5:1 by weight, said hydrogel having a microporous structure, an ionic capacity comprised between 0 and 500 mEq/kg of gel, a hydric content comprised between 50 and 98 % and showing an aptitude for permanent deformation under stress, even at a temperature below 40°C.

According to an advantageous embodiment of said hydrogel, the molar ratio acrylonitrile-comonomer is preferably comprised between 95:5 and 99:1.

According to another advantageous embodiment of said hydrogel, the solvent is selected from the group which comprises aprotic polar organic solvents and/or inorganic solvents.

The solvents prefered are known solvents of said copolymers, preferably water-miscible ; more specifically may be mentioned especially Ν,Ν-dimethyl formamide (DMF), dimethylsulfoxide (DMSO), Nmethylpyrrolidone (2NMP) ,7 concentrated solutions of - 6 zinc chloride or of calcium chloride.

Such solvents enable particularly the production of hydrogels whose structure is particulary suitable for opthalmological use and especially for keratophakia and epikeratophakia.

The hydrogels according to the invention have a residual content of solvent generally less than 1 % and preferably less than 0.1 % .

According to yet another advantageous embodiment of said hydrogel, the non-solvent is selected from the group which comprises water, aqueous solutions of a suitable inorganic salt and aqueous solutions of a suitable organic salt.

According to an advantageous disposition of this embodiment, when the non-solvent is an aqueous solution of salt, said solution is at a concentration comprised between 0.5 and 5%, so as to obtain in said composition (D), a salt concentration comprised between 0.03 and 1 %, preferably between 0.05 and 1 %.

The prefered mineral and organic salts are sodium or potassium chloride, sodium or potasssium iodate, sodium or potassium bicarbonate, sodium or. potassium, chlorate, sodium or potassium periodate, sodium or potassium nitrate, sodium or potassium citrate, sodium or potassium tartrate, sodium or potassium ascorbate, sodium or potassium acetate, sodium or potassium lactate .

According to a modality of this disposition, the prefered aqeous salt solution is a sodium chloride solution.

According to another preferred embodiment of the invention, the anionic groups are particularly selected from among the sulfonate, carboxyl, - 7 5 phosphate, phosphonate and sulfate groups.

The comonomer is advantageously sodium methallylsulfonate.

Such hydrogels, having a low electronegative charge, do not show interaction with the cells and hence have a distinctly improved tolerance.

It is also an object of the present invention to provide a process for the preparation of the uncrosslinked hydrogel according to the invention, characterized by the following steps : a) Lowering of the temperature of a liquid starting composition (D) comprising from 2 to 50 % of a copolymer of acrylonitrile and an olefinically unsaturated comonomer bearing anionic groups, possibly salified, the molar ratio acrylonitrilecomonomer being comprised between 90:10 and 100:0, a suitable solvent and a suitable non-solvent of said copolymer, the ratio solvent/non-solvent being comprised between 500:1 and 0.5:1 by weight; b) immersion of the product in the course of gelification in a first suitable bath ; c) then immersion of the hydrogel obtained in at least one suitable second bath, for a sufficient time to enable the stabilization of the hydrogel.

According to an advantageous method of practising the process according to the invention, the molar ratio acrylonitrile-comonomer is preferably comprised between 95:5 and 99:1.

According to another advantageous embodiment of the process according to the invention, the solvent is selected from the group which comprises aprotic polar organic solvents and/or inorganic solvents such as defined above. - 8 10 According to another advantageous embodiment of said process, the non-solvent is selected from the group which comprises water, aqueous solutions of inorganic salt and aqueous solutions of organic salt.

According to an advantageous disposition of this embodiment, when the non-solvent is an aqueous salt solution, it is at a concentration comprised between 0.5 and 5%, so as to have in said composition (D) a salt concentration comprised between 0. 03 and 1%, preferably between 0.05 and 1%.

The introduction of a non-solvent and particularly of the suitable aqueous salt solution, into the starting liquid composition can enable the production directly of a hydrogel whose structure and properties are entirely adapted to articles for surgical or medical use.

According to yet another embodiment of said process, the bath of step (b) comprises advantageously at least water and/or an aqueous salt solution identical with or different from the non-solvent, when the latter is itself an aqueous salt solution.

According to an advantageous disposition of this embodiment, the immersion of step (b) is performed in two steps, the first step being an immersion in a cold water bath for a suitable time, the second step being an immersion in a water bath at room temperature for a suitable time.

This immersion in a cold water bath, in the course of the gelification, has the advantage of preventing the crumpling -of the surface of the hydrogel during its formation, which would render the latter particularly useless in opthalmology ; in addition, the immersion of the gel in a water bath at room temperature enables the complete removal of the - 9 solvent.

According to yet another embodiment of the process according to the invention, prior to step · (c), the hydrogel is put into the form of a suitable article.

According to another method of practising the process according to the invention, the bath of step (c) is selected from the group which comprises water and an aqueous salt solution at a temperature comprised between 0.5 and 5 %, identical or different from the non-solvent when the latter is itself an aqueous salt solution.

According to an advantageous disposition of this embodiment, the immersion of step (c) is performed at a temperature comprised between room temperature and 70 °C.

According to yet another advantageous embodiment, prior to the gelification step, the composition (D) is prepared by dissolving said copolymer in the solvent and the non-solvent, at a solution temperature comprised between 40°C and 70°C.

According another advantageous embodiment of the invention, the temperature of cooling depends on the solvent and is advantageously comprised between -20°C and +20°C.

Step (c) of the process of preparation of the hydrogel, namely the stabilization by immersion in asuitable solution (salt or water), enables a dimensional stabilization of said hydrogel (accelprated contraction or shrinkage process) .

It is also an object of the present invention to provide an article for medical and/ or surgical use such as tube, film, filament, joint, implant and the like, -10characterized in that it is constituted by and/or comprises a hydrogel according to the invention. According to an advantageous embodiment of the invention said article is in the form of an ocular implant.

Ocular implants according to the invention find application as intraocular, epicorneal, corneal implants as well as in orbito-palpebral and lacrymal plastics.

According to the invention, said shaped article may, then, be sterilized by any suitable means such as ultra-violet rays, ethylene oxide or ionizing radiations.

It is also an object of the present invention to provide a process for the manufacture of articles according to the invention, characterized in that an article of the desired shape and size is shaped from the hydrogel according to the invention.

According to a method of practising this process, said article is shaped prior to step (c) of the process of preparing the hydrogel according to the invention.

According to an advantageous arrangement of this method of practice, the hydrogel is simultaneously prepared and shaped in a suitable mold.

According to another advantageous embodiment of this process, said article is shaped subsequent to step (c) of the process of preparation of the hydrogel according to the invention.

According to an advantageous arrangement of this embodiment, the hydrogel is heated to a temperature comprised between 50° and 90°C and cast in a suitable mold in two parts.

According to another arrangement of this -11embodiment, said article is shaped by machining.

By machining, is meant, both mechanical machining and physical machining (u.V. laser).

According to the invention, when the article is shaped by molding, the mold is advantageously composed of two parts defining the concave and convex surfaces of the article, characterized in that said parts are of plastics material compatible with the solvent.

There may be mentioned particularly among 10 plastics materials used poly-oxymethylene, polyolefines, polyamides, silicones and polytetrafluorethylene (PTFE).

Besides the preceding arrangements, the invention comprises yet other arrangements, which will emerge from the description which follows, which refers to examples of practising the process and of producing implants , as well as a description of experiments both in vitro and in vivo.

It must be well understood, however, that these examples of practice, of production and of reports, are given purely by way of illustration of the invention, of which they do not constitute in any way a limitation thereof.

DESCRIPTION OF PREFERED EMBODIMENTS Example 1: Preparation of a hydrogel according to the invention containing 73 % of water : 1. Starting liquid composition (D) : 9.6 % of a 90:10 copolymer, of acrylonitrile and sodium methallylsulfonate (dry extract), 86.6 % of dimethylformamide (DMF)f -123.8 X of 0.9 % NaCl, in water. 2. Preparation of the starting solution : The copolymer is dissolved in the form of a dry extract in DMF at a temperature of 70°C, by means of a ministirrer, for some minutes ( 5 minutes for 2 grams of solution, for example) then the 0.9 % NaCl is introduced . It is homogenized by means of an ultrasonic sonotrode, for some seconds. 3. Casting : Said starting solution, formed as specified at 2 is cast on a suitable support particularly a plate, at a temperature of 50°C. 4. Gelling : The whole is cooled to a temperature of about -15°C and - It is immediately dipped in a bath composed of 30 X C2H5OH, 0.5 X NaCl, 69.5 X H2O, at a temperature comprised between -10 and -5°C for 5 minutes.

After dimensional stabilization, a hydrogel is obtained which contains 78 X of H2O.

Example 2 : Preparation of a hydrogel according to the invention containing 80 X of water : 1. Starting composition : X of a 90:10 copolymer of acrylonitrile and of sodium methallylsufonate (dry extract), X of dimethylformamide (DMF), X of 0.9 X NaCl' in water -132. Preparation of the starting solution : The procedure is the same as that of Example 1, with the exception of the dissolving temperature which in this case is 40°C.

The procedure of step 3 is identical with that of Example 1. 4. Gelling : a) The whole is cooled to a temperature below or equal to 4°C for 20 -minutes. b) Immersion : First step : the whole is dipped in water at about 0°C - 4°C for 5 minutes.

Second step : then the whole is dipped for some minutes in water at room temperature, then the membrane obtained is separated and immersed for some hours in the same water.

. Stabilization : The membrane is dipped for three hours in a 0.9 % NaCl solution.

Example 3: Hydrogel according to the invention containing 90 % of water : 1. Starting composition: * of copolymer of acrylonitrile and sodium methallylsulfonate (dry extract), % of dimethylformamide (DMF) % of 0.9 % NaCl, in water. -142. Preparation of starting solution : Procedure is the same as that of Example 1.

Steps 3, 4 and 5 : the procedure is identical with that of Example 1.

Example 4 : Hydrogel containing 86,6% of water : - Starting composition : % homopolymer (polyacrylonitrile) 81,1 % of DMF 9,9 % of 0,9 % NaCl in water.

- The other steps are identical with those of example 1 Example 5 : Ocular implant : The starting composition of Example 1 is cast directly on a suitable mold having the following characteristics : The mold used in the present embodiment is a combination of polyamide - silicone. The mold is composed of a 6.6 polyamide support containing the concave part of unfilled silicone elastomer . The second part of the mold, convex, is a bead produced in elastomer-silicone of Shore A hardness 80, surface treated with an unfilled silicone, to improve the surface properties of said bead.

The concavity of the first portion of the mold was produced by the spin-casting method, by means of a rotating tray, specially designed and formed. The speed of rotation of the tray, variable and displayed, enables a desired height of a liquid meniscus to be obtained within a cylinder positioned on this plate.

Step 4 is identical with that of Example 1.

. Stabilization : The formed article is dipped for 3 hours in a 0.9 % NaCl solution. -156. Sterilization : Seven minutes by means of ultra-violet rays.

The implants must be checked both from the point of view of their optical qualities and their size and their tolerance both in in vitro and in vivo.

Example A : Macroscopic control of the intra-ocular Implant : After having been dipped in physiological serum, the implant is checked under a binocular lens (dimensions, relief, optical homogeneity) on a black background, in incident light. The thickness of the implant was measured by a raicrofeeler. The radii of curvature were measured by means of a microslide reader, modified, so as to enable placing under the objective lens of a cup containing the immersion liquid and the lens. The projection of the profile of the lens, focused on the median section, was traced and the radii measured with a compass.

The implants formed and tested had the following characteristics : diameter : 6 mm. central thickness of the order of 0.2 mm.

Example B Physicochemical properties of the implant : a) Linear shrinkage : The measurements were performed on specimens having as initial sizes : 75 x 25 x 0.8 mm.

The shrinkage of the hydrogel according to the invention is distinctly greater in the presence of a saline solution (0.9 % NaCl), as shown by Table 1 below : TABLE I INITIAL COMPOSITION shrinkage L/L . 100 (%) the mixture : P/S/NS -LN HaO IN Serum % 1 HaO - « HaO 5,3/83,5/11,2 3.9 94 27.6 86 7,0/82,5/10,5 5.2 91 27.6 82 9,0/81,0/10,0 6.6 88 24.3 81 11,0/80,0/9,0 7.9 86 21.7 80 13,0/79,0/8,0 9.2 85 18.4 79 19,0/75,0/6,0 15.7 78 17.0 72 rapid gelling 5,1/80,0/14,8 4.8 95 19.7 90 P : Polymer ; S : Solvent ; and NS : non-solvent.

This phenomenon has its limits and the shrinkage is only manifested up to a certain concentration of solute. For example, the gel dipped in 0.9 % NaCl solution (physiological serum) shows a shrinkage of 21.7 X. The same gel dipped in a 5 X NaCl solution has almost the same shrinkage of about 23 X. b) water permeability, to physiological serum, to small and medium molecules : This is one of the fundamental properties of materials for use in corneal refractive surgery and particularly for intracorneal implants. This permeability is an essential result for the maintenance of the corneal physiology on which the transparency of the cornea depends. Nutrient and metabolic flows, the transport of dissolved gases -17and (oxygen and carbon dioxide) / water migration must not be hindered by the presence of the lens.

The implants according to the present invention show through their particular structure very good permeability. The permeability to water, to physiological serum and to various dissolved substances, was measured by means of a test bench constituted by a tank provided with a stirrer. The membrane tested was placed in sealed manner in contact with a 6.6 polyamide support. Hence it separates the tank into compartments : that of the solution - that of the filtrate.

All the measurements were carried out on samples of hydrogel of copolymer, according to the invention, containing 80 % of H20, in the form of membranes of a thickness of 0.35 - 0.40 mm and of 18 cra^ surface.

They were packaged in physiological serum. The pressure gradient was maintained at 20 cm H2O. The permeablility to small and medium molecules 20 was evaluated by the transmittance coefficient K expressing the ratio of the concentrations of the substance in the filtrate and in the solution for a stable flow rate ; and at room temperature. C filtrate 25 K C solution Subs . Cone. FLOW KATE TRANSMITTANCE 9/1 10*5 ml/mn.cm2.mmHg CO EFF1 .CIENT 30 water 4.5 - NaCl (serum ) 0.09 3.5 - urea 0.7 4.0 1 creatinine 0.05 2.7 0-98 glucose 1.1 2.7 1 vitamin B12 2.10-2 3.2 1 albumine H 40.0 1.9-1.6 0-4 -18c) permeability to oxygen : Tests were carried out on specimens of membrane of hydrogel : - containing 80 X of water (hydrogel 5 according to the invention), - and 70 X of water, having a thickness of 0.15 - 0.25 and 0.37 mm.

The permeability to oxygen was : - 36.10 ml/cm^/cm.s.mm Hg, for 80 X water hydrogel, whilst it is only 29.10“^^/cm^/cm.s.mm Hg, for a 70 X ware hydrogel. d) Refractive index : It was measured by means of an ABBE refractometer (CARL ZEISS COMPANY, W-GERMANY). The results are shown in Table 2 below and relate to membranes of hydrogel.

TABLE II 20_ SPECIMEN REFRACTIVE INDEX Hydrogel 85 % HaO 1.347 Hydrogel 83 % HaO 1. 350 Hydrogel 78 % HaO 1.368 e) absorption of light (visible light and ultra-violet light) : This measurement was carried out on specimens of the hydrogel according to the invention, containing 80^ -19of water, by a spectrophotometric method.

Figure 1 shows the absorption of light by the implant.

The ordinate axis represents the absorbance : A = - log (If/Ii), If being the intensity of the light which has passed through and Ii, the intensity of the initial light.

The abscissae axis represents the the wavelength in ram.

It is seen that there is total absorption at 280 nm whilst there is no absorption for visible light (400 - 700 nm). f) Mechanical tests : Figure 2 shows that in spite of a high water content, the tensile strength is fairly high.

The abscissae axis represents the X elongation and the ordinates axis the load in kg/cm2.

Curve A corresponds to a hydrogel with 80 X water. Curve B corresponds to a hydrogel with 85 X water. Example C : In vitro evaluation of a hydrogel utilizable as an intra-corneal implant : Tissue used : Chicken embryo corneal endothelium of 14 days incubation.

Materials : Positive control (toxic) : a filtering disk (Millipore AP25 1300) soaked in a phenol solution with 64 mg/1 in culture medium (ph 1/100) ; _ Negative control (non toxic) : Thermanose (Lux Corpo.) plastic treated for cell cultures (THX). -20A hydrogel according to the invention (80 % to 90 % H20) sterilized with UV and tyndalised at the time of use (Hl).

A membrane of 22 (im thick polyacrylonitrile for hemofiltration (Hospal) (H2).

Culture Technique : The culture medium was DMEM mixed V/V with gelose and supplemented with 10 % of foetal calf serum. were cultivated on the contact with different Whole corneal fragments endothelial surface in materials and controls.

Evaluation Criteria : All the measurements were carried out on the same batch of 24 explants for each type of tissue and each material, after 7 days of culture. The following three properties were measured quantitatively : multiplication, migration and cellular adhesion by measurement of the surface area of migration of the cells and counting of cells of this migration web.

Cellular multiplication and migration : The results are expressed by the cell density as a function of the migration surface area.

Cell Adhesion : The technique of sensitivity of the cells to trypsin was used, which permitted calculation of the percentage of the cells detached as a function of time and the establishment of the corresponding curve.

From this curve, a static adhesion index (SAI) was defined which is the product of the area (A) comprised between the curve and the x axis and the total number of cells. The results are expressed by the area of the curve as a function of the SAI. -21Results and Interpretation The results are summarized In Table III belov : TABLE III NUMBER OF CELLS 1 dC A SAI X 106 THX 8150+3000 4.9+1.8 1800+1000 4600+600 0.36 + 0. 1 PH1/100 8100*3500 2.6±0.8 3000+350 4900*100 0.4±0.1 Hl 16603±245 6.6±0.4 2500+118 2500±315 0-42+0. 06 H2 39700+7000 23+9 1730+100 5170±300 205±0.9 The toxic control (ph 1/100) occurs in the limiting area of the diagram of multiplication and of migration.

It shows a slight toxicity vith respect to corneal endothelium and permits very average cell attachment.

The non-toxic control permits very slight multiplication of the endothelial cells of the cornea which adhere to a very moderate degree to its surface.

H2 facilitates a high migration of the endothelium and consequently low adhesion.

Hl enables multiplication of the endothelial cells superior to that of the negative control and shows a distinctly superior cell attachment to that of all the other materials which is very well demonstrated by Figure 3 (% of cells detached as a function of time), in which the abscissae axis represents time in min and the ordinates axis -2210 represents the percentage of cells detatched. In this figure, the curve (1) corresponds to H2, the curve (2) to the toxic control, curve (3) to the product according to the invention, curve (4) to the nontoxic control and curve (5) to PVC.

Example D : In vivo corneal tolerance test : Implants of copolymers according to the invention, were implanted unilaterally in the corneae of six cats and nine monkeys.

These implantations permitted the evaluation of bio-compatibility of the implants and their transparency.

The operational technique calls upon either an intra-stromal lamellar dissection, or, so far as possible, a lamellar dissection with the BARRAQUER micro-keratome.

The BARRAQUER micro-keratome, to be realisable, necessitates the fixing of the eyeball by a pneumatic ring. This dissection has the advantage of sectioning in totality the Bowman membrane and of permitting the deformation of the front layers of the cornea on the implant. 1. Implantation in the cat : Lamellar dissections were carried out with the manual disciser.

Operational Procedure : General anesthesia is performed by sub-cutaneous injection of ketamine (about 30 mg/kg weight) and oxybuprocaine is instilled systematically into the eye.

A slightly arc-shaped incision with internal concavity is made at 0.25 mm depth and to 2 mm into the limb, over about 8 mm length. This incision -23necessitates the use of a micrometric knife with a diamond blade. The lamellar dissection is continued with a Beaver dissecter and with a Paufique ^}ssec^e&ver about 9 to 10 mm.

The intraocular implants were placed in position by means of a metal spatula. The sutures were done with 10/0 monofilament of polyamide and left in place for 10 days.

After placing the implants in position, a collyrium containing dexamethasone and neomycine was instilled daily into the operated eye for a month.

The cats were examined daily throughout the duration of the experiment.Technical characteristics of the implants : the water content of the implants was % water ; - the implants had a diameter of 5.5 to 6.3 mm, their thickness ranging from 0.20 to 0.2 mm.

The results observed in the cat were good tolerance of the keratoprothesis, without necrosis of the receptor cornea. 2. Implantation in the primate : Operational.procedure : Nine female papio cynocephalus monkeys (baboons) were operated on.

In three cases, a lamellar dissection was performed by a technique identical with that used in the cat ; they were in fact small sized monkeys, not permitting the fixation of the eyeball by a pneumatic ring. In the six other cases, lamellar dissection with the micro-keratorae was possible.

Technical Caracteristics of the Implants : the water content of the implants was -2460, 70 and 80 X water ; the diameter of the Implants range from 4.8 to 7 mm ; thickness of the implants ranged from 0.16 to 0.27 mm.

Results : The transparency of the cornea and the transparency of the implant were remarkable.

As emerges from the foregoing the invention is in no way limited ot those of its embodiments, methods of practice and use which have just been described more explicitly : it encompasses thereof on the contrary all modifications which may come to the spirit of the technician skilled in the art, without departing from the range or the scope of the present invention.

Claims (30)

1. Uncrosslinked hydrogel with a relatively high water content, characterized in that it is constituted from a liquid starting composition which comprises from 2 to 50 X of a copolymer of acrylonitrile and an olefinically unsaturated comonomer bearing anionic groups, possibly salified, the molar ratio acrylonitrile-comonomer being comprised between 90:10 and 100:0, a suitable solvent and a suitable nonsolvent of said copolymer, the ratio of solvent/nonsolvent being comprised between 500:1 and 0.5:1 by weight, said hydrogel having a microporous structure, an ionic capacity comprised between 0 and 500 mEq/kg of gel, a hydric content comprised between 50 and 98 X and having an aptitude for permanent deformation under stress, even at a temperature below 40°C.

2. Hydrogel according to claim 1, wherein the molar ratio acrylonitrile-comonomer is preferably comprised between .95:5 and 99:1. 20

3. Hydrogel according to claim 1 or claim 2, wherein the solvent is selected from the group which comprises aprotic polar organic solvents and inorganic solvent s.

4. Hydrogel according to any one of claims Ito 3, 25 wherein the non-solvent is selected from the group which comprises water, aqueous solutions of suitable inorganic salt and aqueous solutions of suitable organic salt. -265. Hydrogel according to any one of claims 1 to 4 wherein the non-solvent is an aqueous salt solution, said solution being at a concentration comprised between 0.

5 and 5 % , so as to obtain in said composition, a salt concentration comprised between 0.03 and 1 %, preferably between 0.05 and 1 %.

6. Hydrogel according to claim 4 O r claim 5, wherein the non-solvent is a sodium chloride solution.

7. Hydrogel according to any one of claims 1 to 6, wherein the anionic groups are particularly selected from among sulfonate, carboxyl, phosphate, phosphonate and sulfate groups.

8. Process for the preparation of an uncrosslinked hydrogel according to any one of claims 1 to 7, said process comprising : a) lowering of the temperature of a liquid starting composition comprising 2 to 50 % of a copolymer of acrylonitrile and an olefinically unsaturated comonomer bearing anionic groups, possibly salified, the molar acrylonitrile-comonomer ratio being comprised between 90:10 and 100:0, a suitable solvent and a suitable non-solvent of said copolymer, the ratio solvent/non-solvent being comprised between 500:1 and 0.5:1 by weight ; b) immersion of the product in the course of gelification in a suitable first bath ; c) then immersion of_the hydrogel obtained in at least one suitable second bath, for a sufficient time to permit the stabilization of the hydrogel. -279.

Process according to claim 8, wherein the molar ratio acrylonitrile-comonomer is preferably comprised between 95:5 and 99:1.

10. Process according to claim 8 or claim 9 » wherein the solvent is selected from the group which comprises aprotic polar organic solvents and inorganic solvents.

11. Process according to any one of claims 8 to 10, wherein a non-solvent is selected from the group which comprises water, aqueous inorganic salt solutions and aqueous organic salt solutions.

12. Process according to any one of claims 8 to 11, wherein the non-solvent is an aqueous salt solution, said solution being at a concentration comprised between 0.5 and 5 X, so as to have s in said composition^ a salt concentration comprised between 0.03 and 1 %, preferably between 0.05 and 1 %.

13. Process according to any one of claims 8 to 12, wherein the bath of step (b) advantageously comprises at least water and/or an aqueous salt solution identical or different from the non-solvent when the latter is itself an aqueous salt solution.

14. Process according to claim 13, wherein the immersion of step (b) is performed in two steps, the first step being an immersion in a cold water bath for a suitable time, the second step being an immersion in a bath of water at room temperature for a suitable time. -2815.

Process according to any one of claims 8 to 14, wherein, prior to step (c), the hydrogel is put in the form of a shaped article.

16. Process according to any one of claims 8 to 15, wherein the bath of step (c) is selected from the group which comprises water and an aqueous salt solution at a concentration comprised between 0.5 and 5 % , identical with or different from the known solvent when the latter is itself an aqueous salt solution.

17. Process according to claim 16, wherein the immersion of step (c) is performed at a temperature comprised between room temperature and 70°C.

18. Process according to any one of claims 8 to 17, wherein, prior to the gelification step, the composition ID) is prepared by dissolving said copolymer in the solvent and the non-solvent, at a dissolution temperature comprised between 40°C and 70°C.

19. Process according to an Y one claim s 8 wherein the cooling temperature depends on the solvent and is advantageously comprised between -20°C and +20°C.

20. Article for medical and/or surgical use such as tube, film, filament, joint, implant and the like, characterized in that it is constituted by and/or comprises a hydrogel according to any one of claims 1 to 7. -2921.

Article according to claim 20, which is in the form of an ocular implant.

22. Article according to claim 20 or claim 21, which can be sterilized by any suitable means such

5. As ultra-violet rays^ ethylene oxide, or ionizing radiations.

23. Process for the manufacture of articles according to any one of claims 20 to 22, wherein an article of the desired shape and size is formed from the hydrogel according to any one of claims 1 to 7.

6. 10 24. Process according to claim 23, wherein said article is formed prior to step (c) of the process of preparing the hydrogel according to any one of claims 8 to 19.

25. Process according to claim 24, wherein

7. 15 the hydrogel is prepared simultaneously and shaped in a suitable mold.

26. Process according to claim 23, wherein said article is formed subsequent to step (c) of the process for preparing the hydrogel according to any

8. 20 one of claims 8 to 19.

27. Process according to claim 26, wherein the hydrogel is heated to a temperature comprised between 50 and 90°C and cast in a suitable mold in two parts.

28. Process according to claim 26, wherein said article is shaped by machining. -3029.

Process according to any one of claims 23 to 27, wherein said article is formed by molding, the mold is advantageously composed of two parts defining concave and convex surfaces of the article, and 5 said parts are of a plastics material compatible with the solvent. as defined in Claim 8

30. Process/for the preparation of an uncrosslinked hydrogel, substantially as described herein by way of Example.