Note: Descriptions are shown in the official language in which they were submitted.
13409 13
The preser..t 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, e.g., tubes, filaments, films, joints, implants
and the like, particularly in ophthalmology.
It has already been proposed to employ polymers in
hydrogel form which have relatively high water content
whilst having improved mechanical and optical properties
for ophthalmic purposes. (See European Patent No. 188 110
and U.S. Patent: Nos. 4,379,864 and 4,543,371).
However, the product described in U.S. Patents Nos.
4,379,864 and 4,.543,3'71 do not have a high water content;
in fact, these polymers lose the required mechanical
properties, particularly for their use as an implant, when
the water content is high.
The hydrogels described in European patent application
No. 198 110 do not have properties of good tolerance,
particularly required for an implant, to the extent that
the ionic characteristics. In particularly, the
electronegativity of the polymer does not permit good
tolerance of the: latter to be envisaged.
French Pat~=nt FH 2,529,464 describes biocompatible
materials in the form of hollow fibres or membranes. These
biomaterials are: treated by a plurality of drawing stages
to produce a suitable permeability. These show, for this
reason, a different :structure, namely, the structure of
membranes or hollow fibres for haemodialysis and/or
hemofiltration.
2 13409 13
German Patent DE-A-2028956 describes a hydrogel which
comprises many ionic groups, the hydrogel not possessing
suitable biocompatibilty.
This is why Applicant has sought for a solution to the
above problem in another direction, namely, that of
providing hydroc~els having high biocompatibility for their
use in the pre~parat~~_on of articles for medical and/or
surgical purposes which are highly reliable. In
particular, an .aim of this invention is the provision of
ocular implants enabling a suitable permeability to be
obtained to dif:Eerent biological molecules, the implants,
not showing, consequently, the drawbacks of known implants.
Applicant unexpectedly has found that certain
biomaterials, under' particular conditions, have
considerable advantages, especially in the field of ocular
implants.
Therefore, objects of aspects of this invention are to
provide an uncrosslinl~:ed hydrogel with improved mechanical
properties and with a high water content, as well as to
provide a process for its preparation, such hydrogel
responding bettE:r to 'the necessities of practice than the
hydrogels of the prior art, particularly in that they have
the advantage of conferring on the hydrogels a character of
inertia with re~.pect t:o biological cells.
An obj ect of another aspect of this invention is to
provide articles con;~tituted at least in part by such
hydrogel.
13409 13
An object of yet another aspect of this invention is
to provide for the use of such articles in surgery and in
medicine.
It is also an object of an aspect of the present
invention to provide am article for medical and/or surgical
use, e.g. , in th.e form of a tube, film, filament, joint, or
implant, or the like.
According t=o one aspect of the present invention, an
uncrosslinked h~~droge7_ is provided having a relatively high
water content, the h~~drogel being prepared from a liquid
starting composition which comprises from 2 to 50o by
weight of a copolymer of acrylonitrile and an olefinically-
unsaturated comonomer bearing anionic groups, which are
either unsalifi~=d or are salified, in a molar ratio of
acrylonitrile to comonomer of between 90:10 and 100:0, a
suitable solvent and a suitable non-solvent of the
copolymer comprising a.n aqueous solution of a salt, wherein
the solvent and the non-solvent are present in a ratio of
500:1 and 0.5:1 by weight, the hydrogel having a
microporous structure, an ionic capacity between 0 and 500
mEg of gel, a hydric content comprised between 50 and 980
and having an aptitude for permanent deformation under
stress, even at a temperature below 40°C.
According t.o one variant of such hydrogel, the molar
ratio of acrylo:nitrile to comonomer is between 95:5 and
99:1.
According t=o another variant of such hydrogel, the
solvent is selected from the group consisting of aprotic
13409 ~3
polar organic solvents and inorganic solvents. Such
solvents are known solvents of such copolymers, and are
preferably water-miscible. More specifically, examples of
such solvents inc:Lude N,N-dimethylformamide (DMF),
dimethylsulfoxide (DMSO), N-methylpyrrolidone (2NMP), and
concentrated solutions of zinc chloride or of calcium
chloride.
The hydroge~ls according to aspects of this invention
have a residual content of solvent which is generally less
than 1 o and pref=erabl~~r is less than 0 . 1 0 .
According t.o yet another variant of the invention, the
non-solvent is selected from the group consisting of an
aqueous solution of a suitable inorganic salt and an
aqueous solution of a suitable organic salt. By a
variation thereof, the non-solvent aqueous solution of a
salt is at a concentration of between 0.5 and 5o by weight,
so as to obtain in the composition, a salt concentration of
between 0.03 and 1%, preferably between 0.05 and 1%.
Examples of suitable mineral and organic salts include
sodium or potas:~ium chloride, sodium or potassium 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, and sodium or potassium lactate. The
preferred aqueous salt. solution is an aqueous solution of
sodium chloride.
13409 13
According to another preferred embodiment of the
invention, the .anionic groups are selected from the group
consisting of sulfonate, carboxyl, phosphate, phosphonate
and sulfate groups.
5 The comonome:r is advantageously sodium
methallylsulfonate.
Such hydrogels, of various aspects of the present
invention, having a low electronegative charge, do not show
interaction with the cells and hence have a distinctly
improved tolerance.
Such solvents enable the production of hydrogels whose
structure is particularly suitable for ophthalmological use
and especially f:or keratophakia and epikeratophakia.
The introduction of the suitable aqueous salt solution
as a non-solvent int=o the starting liquid composition
enables the production of a hydrogel whose structure and
properties are entirely adapted to articles for surgical or
medical use.
By another aspect: of the present invention, a process
is provided for the preparation of the uncrosslinked
hydrogel the proces~> comprising the following steps:
lowering the temperature of a liquid starting composition
comprising from 2 to 50% by weight of a copolymer of
acrylonitrile and an olefinically-unsaturated comonomer
bearing anionic group~~, which are either unsalified or are
salified, in a molar ratio of acrylonitrile to comonomer of
between 90:10 and 100:0, a suitable solvent and a suitable
non-solvent for the copolymer, such suitable non-solvent
13409 13
being an aqueou:~ salt solution, wherein the solvent and the
non-solvent are present in a ratio of between 500:1 and
0.5:1 by weight; immE=_rsing the product in the course of
gelification in a fir~~t suitable bath to obtain a hydrogel;
and then immersing the hydrogel so obtained in at least one
suitable second bath, for a sufficient time to enable the
stabilization of= the lzydrogel.
According t:o one variant of the process aspect of the
invention, the molar ratio of acrylonitrile to comonomer is
between 95:5 and 99:1.
According t:o anot:her variant of the process according
to this aspect of the invention, the solvent is selected
from the group consisting of aprotic polar organic solvents
and inorganic solvent;, as described above.
According to yet another variant of the process aspect
of this invention, the non-solvent is selected from the
group consistin<~ of an aqueous solution of an inorganic
salt and an aqueous solution of an organic salt, as
described above.
By one variation thereof, the non-solvent aqueous salt
solution is at a concentration between 0.5 and 5% by weight
so as to have, in the composition, a salt concentration
between 0.03 anc. lo, preferably between 0.05 and lo/.
According to yet another variant of the process aspect
of the invention, the first bath advantageously comprises
at least water and/or an aqueous salt solution identical
to, or different from, the non-solvent aqueous salt
solution. The immersion in the first bath is preferably
7 13409 13
performed in two steps, the first step being an immersion
in a cold water bath for a suitable time, the second step
being an immers=Lon in a water bath at room temperature for
a suitable time.
This immer;~ion 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 ophthalmology. In addition, the immersion of
the gel in a water bath at room temperature, enables the
substantially-complete removal of the solvent.
According to yet another variant of the process aspect
of the invention, the: hydrogel is formed into a suitable
article prior to the .Last step.
According to another variant of the process aspect of
the invention, t:he se,~ond bath is selected from the group
consisting of water and an aqueous salt solution at a
temperature comb>rised between 0.5 and 5%, the aqueous salt
solution being identical to, or different from, the non-
solvent aqueous salt solution. By a variation of this
variant, the immersion in the second bath is preferably
performed at a temper=ature between room temperature and
70°C.
According to yet another variant of the process aspect
of this invent=ion, the composition is prepared by
dissolving the copolymer in the solvent and the non-
solvent, at a solution temperature comprised between 40°
and 70°C, prior to the gelification step.
13409 13
According t=o another variant of the process aspect of
the invention, the temperature of cooling depends on the
solvent and is advantageously between -20°C and +20°C.
The final step of the process of preparation of the
hydrogel, namely the stabilization by immersion in a
suitable solution (sa.lt or water), enables a dimensional
stabilization o:= the hydrogel (accelerated contraction or
shrinkage proce:~s) .
By another aspect of this invention, an article is
provided for medical a.nd/or surgical use comprising a tube,
a film, a filament, a joint, or an implant, the article
being constituted at .Least in part by a hydrogel.
According ~~o anc>ther variant of this aspect of the
invention, the article is in the form of an ocular implant.
Such ocular implants according to aspects of the invention
find application as intraocular, epicorneal, and corneal
implants, as well as in orbito-palpebral and lachrymal
plastics.
According to a variant of this aspect of the
invention, the shaped article may then be sterilized by any
suitable means, e.g., by ultra-violet rays, or by ethylene
oxide or by ionizing radiations.
By yet another aspect of the present invention, a
process is provided for the manufacture of an article for
medical and/or :~urgic.al use comprising a tube, a film, a
filament, a joint, or an implant, the article of the
desired shape arid size being formed at least in part from
13409 13
9
the hydrogel according to aspects and variants of this
invention.
According t=o one variant of this process, the article
is formed prior to the step of the process of preparing the
hydrogel according to aspects and variants of the
invention. According to another variant of this process,
the hydrogel is heated to a temperature of between 50 and
90°C and is cast, in a suitable mold in two parts.
By another variant of this process, the article is
formed by molding, the mold is being composed of two parts
defining concave and convex surfaces of the article, and
wherein the mold parts are composed of a synthetic plastics
material which is compatible with the solvent. According
to yet another variant of this process, the article is
shaped by machining. By machining is meant, both
mechanical machining and physical machining (U. V. laser).
By another aspect of this invention, a process is
provided for the manufacture of an article for medical
and/or surgical use comprising a tube, a film, a filament,
a joint, or an implant, the article of the desired shape
and size being formed of a hydrogel but being formed prior
to, the process of preparing the hydrogel.
By a variant thereof, the hydrogel is prepared and
shaped simultaneously in a suitable mold.
Among plastic materials which may be used in various
aspects of this invention are polyoxymethylene,
polyolefines, polyamides, silicones and polytetrafluoro-
ethylene (PTFE).
13409 13
Among the articles of variants of this invention,
ocular implants are especially useful since they possess,
besides the character of inertial with respect tc
biological cell~~, the following optical properties : namely,
5 perfect transparency in visible light, absorption of ultra-
violet rays at 280 nm, and refractive index close to that
of the cornea.
They posse~~s the following physio-chemical properties,
namely: high permeability to water, to physiological serum,
10 to small and medium-sized molecules, assuring the migration
of nutrient substance~~ for the cornea as well as all of the
metabolites; permeability to dissolved gases (O2, COZ),
highly hydrophillic; a chemical nature devoid of toxic
groups, of heavy metals, of remaining catalysts and of free
monomers and of solvent; are easy to use; and dimensional
stability, especially in a 0.9o chloride solution.
Particular biological properties provided include:
non-bioresorbabl.e in the physiological medium; good
resistance to aging =Ln this medium, that is to say not
showing opacif_~catio:n, coloration or degradation of
physical properties; good tissue tolerance of the sites of
implantations in the corneal stroma, without causing
alteration of the epithelium and of the corneal
endothelium; if possible, a low affinity for proteins; and
can be steriliza.ble and/or re-sterilizable.
In the accompanying drawings,
Figure 1 is a graph showing the absorption of light by
the implant, wherein the ordinate axis represents the
11 13409 13
absorbence, and the abscissa axis represents the wavelength
in nm;
Figure 2 is a graph showing the tensile strength,
wherein the abscissa <~xis represents the o elongation and
the ordinate axis represents the load in kg/cmz; and
Figure 3 i:~ a graph showing o of cells detached as a
function of time, in which the abscissa axis represents
time in min and the ordinate axis represents the percentage
of cells detached.
Besides thf=_ preceding embodiments and variants, the
invention also includes other embodiments and variants,
which will emerge from the description which follows, which
refers to examples of practising the process of aspects of
this invention and the processes for producing implants, as
well as a descr__ption of experiments both in vitro and in
vivo.
It must be understood, however, that these examples of
practice, of production and of reports, are given purely by
way of illustration of. the invention.
Example 1: Preparation of a hydrogel according to the
invention containing 78% of water:
1. Starting liquid composition (D): 9.6 % of a 90:10
copolymer, of acrylon:itrile and sodium methallylsulfonate
(dry extract), t36.6o of dimethylformamide (DMF), 3.8% of
0.9 % of NaCl, in water.
2. Preparation. of tree starting solution:
The copolymer is dissc>lved in the form of a dry extract in
DMF at a temperature of 70°C, by means of a ministirrer,
12 13409 13
for a suitable length of time (5 minutes for 2 grams of
solution, for example); then 0.9 % NaCl is introduced. It
is homogenized by means of an ultrasonic sonotrode, for
several seconds.
3. Casting:
The starting so7_ution, 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 t.o a temperature of -15°C, and it is
immediately dipped in a bath composed of 30 o CZHSOH, 0.5 0
NaCl, and 69.5 °-<s H20, at a temperature comprised between -
10°C and -5°C for 5 minutes.
After dimensional stabilization, a hydrogel is obtained
which contains ~Oo of H20.
Example 2: Preparation of a hydrogel according to the
invention containing 800 of water:
1. Starting composition: 9% of 90:10 copolymer of
acrylonitrile and of sodium methallylsulfonate (dry
extract), 81 0 «f dim.ethylformamide (DMF), 10 % of 0.9
NaCl, in water.
2. Preparation. of the starting solution:
The procedure i:~ the same as that of Example 1, with the
exception of the dissc>lving temperature which in this case
is 40°C.
The procedure of: step 3 is identical with that of Example
1.
4. Gelling:
13409 13
13
a) The whole i:~ cool,?d to a temperature below or equal to
4°C for 20 minul~es.
b) Immersion:
First step: the' whole is dipped in water at 0°C - 4°C for
5 minutes.
Second step: thf=_n the whole is dipped for some minutes in
water at room temperature, then the membrane obtained is
separated and irnmersed for some hours in the same water.
5. Stabilizat__on: The membrane is dipped for three hours
in a 0.9 o NaCl solution.
Example 3: Hydrogel according to the invention containing
90 % of water:
1 . Starting composition: 5 0 of copolymer of acrylonitrile
and sodium met~hallylsulfonate (dry extract), 80% of
dimethylformamide (DMF)
15 % of 0.9 a NaCl, in water.
-14- 1340913
2. Prepartion of starting
solution .
Procedure is the same as that of
Example 1.
Steps 3, 4 amd 5 . the procedure is identical
with that of Example 1.
Example 4 . HydrogE~l containing 86,6$ of water .
- Starting composition
9 ~ homopolymer (polyacrylonitrile)
81 , 1 ~ of DMI?
9,9 $ c>f 0,9 $ NaCl in water.
- The otrier steps are identical with those of example 1.
Example5 : Ocular implant .
The starting composition of Example 1 is cast
directly on a suitable mold having the following
characteristics .
The mo~_d 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 wit'~in a cylinder positioned on this plate.
Step 4 is identical with that of Example 1.
5. Stabilization . The formed
article is dipped for 3 hours in a 0.9 ~ 'VaCl
solution.
-,5- 1340913
6. 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 microfeeler. The radii of
curvature wE~re mE~asured 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 rays measured with a compass.
The imp'Lants formed and tested had the following
characteristics
- diameter . b mm.
- central thickness of the order of
0.2 mm.
Example B . Phys:icochemical properties of the
implant .
a) linear shrinkage
The measuremE~nts 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 (t).9 ~ VaC1), as shown by Table 1
below
-13409 13
16
TABLE
1
INITIAL SHRINKAGE .
L/L 100
(o)
COMPOSITION
in the mixture : ITi o IN o H O
Hz0 HZO SERUM z
P/S/NS
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 1.5.7 78 17.0 72
rapid gelling
5.1/80.0/14.8 4.8 95 19.7 90
P . ;3 Solvent; NS:
Polymer; . non-solvent.
This phenomenon has its limits and the shrinkage is
only manifested up tc> a certain concentration of solute.
For example, t:he gel dipped in 0.9o NaCl solution
(physiological ~;erum) shows a shrinkage of 21.70. The same
gel dipped in a 5o NaCl solution has almost the same
shrinkage of 23°..
b) Water permeaioility, to physiological serum, to
small and mediur~i molecules
This is one of th~~ 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 (oxygen
and carbon dio~:ide), and water migration, must not be
hindered by the presence of the lens.
The implants according to aspects of the present
invention possess, through their particular structure, very
17 '13409 13
good permeability. The permeability to water, to
physiological s~srum and to various dissolved substances,
was measured by means of a test bench constituted by a tank
provided with a stirrE~r. 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, and that of the filtrate.
All the measurements were carried out on samples of
hydrogel of copolymer, according to aspects of the
invention, containing 800 of HZO, in the form of membranes
of a thickness of 0.:35 - 0.40 mm and of 18 cm2 surface.
They were packaged in. physiological serum. The pressure
gradient was maintained at 20 cm HZO.
The permeability to small and medium molecules was
evaluated by the transmittance coefficient (K) expressing
the ratio of th.e concentrations of the substance in the
filtrate and in the solution for a stable flow rate and at
room temperature.
C filtrate
K -
C solution
Subs. C:onc.
FLOW RATE
TRANSMITTANCE
c~/1 10-5 ml
. mn/cm' .
mmHg COEFFICIENT
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
-18- 1340913
c) permeability to oxygen:
Tests were carried out on specimens of membrane of hydrogel:
- containing 80% of water (hydrogel
according to the invention),
- and 70% of water,
having a thickness of 0.1!5 - 0.25 and 0.37 mm.
The permeability to oxygen was:
35 - 36.10 -" ml/cmz,icm.s.~:nm Hg, for 80% water hydrogel, whilst
it is only 29.10-"/cm2/cm.:~.mm Hg, for a 70% ware hydrogel.
d) Refractive index:
It was measured by means of a refractometer known by the
generic name ABBE (CARL ZE7CSS COMPANY, GERMANY) . The results are
shown in Table 2 below and relate to membranes of hydrogel.
TABLE II
SPECIMEN REFRACTIVE INDEX
Hydrogel 85% HZO 1.347
Hydrogel 83% HZO 1.350
Hydrogel 78 % HZO 1. 368
e) absorption of light (visible light and
ultra-violet light):
This measurement was carried our on specimens of the
hydrogel according to the invention, containing 80% of water, by
a spectrophotometric method.
- 19 -
13409 13
Figure 1 shows the absorption of light by the implant.
The ordinate axis represents the absorbence:
A = - log (If/Ii),
wherein If is the intensity of the light which has passed through
and Ii is the intensity of the initial light.
The abscissae a:~is represents the wavelength in mm.
It is seen that there is total absorption of 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 i'airly high.
The abscissae axis represents the % elongation and the
ordinates axis the load in kg/cm2.
Curve A corresponds to a hydrogel with 80% water.
Curve B corresponds to a hydrogel with 85% water.
Example C: "In 'vitro" evaluation of a hydrogel utilizable
as an intra-corneal _Lmplant:
- Tissue used:
Chicken embryo c:ornea:l endothelium of 14 days incubation.
Materials:
Positive control (toxic): a filtering disk (known by the
trade-mark MILLIPORE.~M AP2!5 1300) soaked in a phenol solution
with 64 mg/1 in culture medium (pH 1/100);
- 20 - 13409 13
Negative control (non toxic): Plastic treated for cell
cultures (known by the trade-mark THERMANOSETM THX of Lux
Corporation).
A hydrogel according to the invention (80% to 90% HZO)
sterilized with W and tyndalised at the time of use (H1).
A membrane of 22 ~cm thick polyacrylonitrile for
hemofiltration (known by t:he trade-mark HOSPALTM H2).
Culture Technique:
The culture medium 'was DMEM mixed V/V with gelose and
supplemented with 10% of foetal calf serum. Whole corneal
fragments were cultivated on the endothelial surface in contact
with different materials a.nd 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 fol_Lowing three properties were measured
quantitatively: multiplication, migration and cellular adhesion
by measurement of the surf<~ce area of migration of the cells and
counting of cells of this migration web.
Cellular multiplication and migration:
The results are expre;ased 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.
13409 13
- 20a -
From the curve, a static <~dhesion 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 a~ a f»nr-tine of t~ho caT
-zl- 1340913
Results and Interpretation
The results are summarized in Table III below .
TABLE III - __ ._ __ _
NUMBER
OF CELL,
1 dC A SAI X 106
THX 81503000 4,91,8 18001000 4600600 0
360
1
.
.
PH1/100 8100!3!i00 2.60, 3000350 49001100 0. 410.
8 1
H1 16603:?45 6. 6~0, 2500118 25001315 0. 420.
4 06
H2 397007000 239 1730100 51701300 205_0.9
The toxic control (ph 1/100) occurs in the
limiting area of the diagram of multiplication and of
migration.
It show: a slight toxicity with respect to
corneal endot.heliurn and permits very average cell
attachment.
The non-toxic control permits very slight
multiplication of the endothelial cells of the cornea
which adhere t.o a very moderate degree to its surface.
H2 facilitates a high migration of the
endothelium ar.~d consequently low adhesion.
H1 enables multiplication of the endothelial
cells superio:c 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 (X of cells detached as a
function of time), in which the abscissas axis
represents tj.me in min and the ordinates axis
22 1 3 4 0 9 ~ 3
represents the percentage of cells detached. In this
figure, curve (1) corresponds to H2, curve (2) to the toxic
control, curve (3) to the product according to the
invention, curves (4) to the non-toxic control and curve (5)
to PVC.
Example D: In yivo corneal tolerance test:
Implants of copolymers according to aspects of the
invention, were implanted unilaterally in the corneae of
six cats and nine monkeys.
These implantations permitted the evaluation of bio-
compatibility of the _Lmplants and their transparency.
The operational technique calls upon either an intra
stromal lamella:r dis:~ection, or, so far as possible, a
lamellar dissection vaith a micro-keratome, known by the
trade-mark BARRF,QUERTM
The BARRAQUERTM 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 anaesthesia is performed by sub-cutaneous
injection of ket:amine (30 mg/kg weight) and oxybuprocaine
is instilled systematically into the eye.
23 1 3 4 0 9 13
A slightly arc-shaped incision with internal concavity
is made at 0.25 mm depth and to 2 mm into the limb, over 8
mm length. Tlzis incision necessitates the use of a
micrometric knife with a diamond blade. The lamellar
dissection is continued with a dissector, known by the
trade-mark BEAVERTM and with a dissector known by the
PACIFIQUETM over 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 polyarnide and left in place for 10 days.
After placing the implants in position, a collyrium
containing dexarnethso:ne and neomycin 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 80% water; and
the implants had a diameter of 5.5 to 6.3 mm, their
thickness rangir..g 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 as performed by
a technique identical with that used in the cat; they were
in fact small si:aed monkeys, not permitting the fixation of
24 1 3 4 0 9 13
the eyeball by ~~ pneumatic ring. In the six other cases,
lamellar dissection with the micro-keratome was possible.
Technical C:haraci=eristics of the Implants:
The water content of the implants was 60, 70 and 80%
water; the diameter of the implants range from 4.8 to 7 mm;
and the thickne:~s of t:he implants ranged from 0.16 to 0.27
mm.
Results:
The transparency of the cornea and the transparency of
the implant werE~ remarkable .
