Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~n~ 3B
-- 1 --
N~ .~OV~L~
FOR T~IR ~Fa~-, .JKk .
BACRGROUND OF THE~ lNV~ ON
Field of the Invention
The present invention relates to ocular implants
and methods for improving surfaces thereof.
Prior Art
Studies have shown that the surgical implantation
of ocular implants such as intraocular lenses (IOL),
etc., can result in the loss of significant corneal
_ 15 endothelial tissue unless great care is taken to ensure
a lack of contact between the device and the
endothelium. Most ocular implants are constructed of
hydrophobic polymethylmethacrylate (PMMA) polymers
because of their superior optical qualities, resistance
to biodegradation, etc. It has been found, however,
that PMMA surfaces adhere to endothelial cells upon
even casual contact and that separation of the surface
therefrom results in a tearing away of the endothelial
tissue adhered to the polymer surface. Similar
adhesive interactions with other ocular tissues, i.e.,
the iris, can also cause adverse tissue damage. Other
hydrophobic polymers which are used or have been
proposed for use in ocular implants (i.e.,
polypropylene, polyvinylidene fluoride, polycarbonate,
polysiloxane) also can adhere to ocular tissue and
thereby promote tissue damage.
2~8~
It is well documented in the prior art that a
significant disadvantage inherent in PMMA IOLs resides
in the fact that any brief, non-traumatic contact
between corneal endothelium ~nd PMMA surfaces results
in extensive damage to the endothelium. 8ee Bourne et
al, Am. J. Ophthalmol., Vol. 81, pp. 482-485 (1976).
Forster et al, Trans. Am. Acad. Ophthalmol.
Otolaryngol., Vol. 83, OP-195-0P-203 tl977); Ratz et
al, Trans. Am. Acad. Ophthalmol. Otolaryngol., Vol. 83,
OP-204-OP-212 (1977); Raufman et al, Science, Vol. 198,
pp. 525-527 11977) and Sugar et al, Arch. Ophthalmol.,
Vol. 96, pp. 449-450 (1978) for a discussion of the
problem associated with implant surface/endothelium
contact.
~ince it is extremely difficult to avoid any
contact between implant surface~ and endothelium during
surgical procedures, efforts have been undertaken to
_~ modify the PMMA ocular implant surfaces to reduce the
tendency thereof to adhere to and damage corneal
endothelium.
Ocular implant surfaces have been coated with
various hydrophilic polymer solutions or temporary
soluble coatings such as methylcellulose,
polyvinylpyrrolidone tRatz et al, supra, and Knight et
al, Chem. Abs., Vol. 92:203547f l1980)] to reduce the
degree of adhesion between the implant surfaces and
endothelial tissue cells. While offering some
temporary protection, these methods have not proven
entirely satisfactory since such coatings complicate
surgery, do not adhere adequately to the implant
surfaces, become dislodged or deteriorate after
implantation, dissolve away rapidly during or soon
after surgery or may produce adverse post-operative
complications. Moreover, it is difficult to control
the thicknesses and uniformity of such coatings.
2~
Yalon et al ~Acta: XXIV, International Congress of
Ophthalmology, ed. Paul Henkind (1983)] attempted to
produce protective coatings on PMM~ implant surfaces by
gamma-radiation induced polymerization of
5 vinylpyrrolidone thereon ~See also Rnight et al,
supra]. Their efforts were not altogether successful,
however, since their methods also presented problems in
controlling the optical and tissue protective qualitie~
of the coatings. Process conditions and parameters
10 (i.e., monomer concentration solvent, dose and dose
rate) were not specified. The resulting coatings were
of poor quality and non-uniform mechanical stability.
Gamma-PVP treatment of PTFE has been reported but
under severe process conditions requiring gamma doses
15 above 1 Mrad which are impractical in that both bulk
and surface properties of the PTFE are changed ~Boffa
et al, J. Biomed. Mater. Res., ~rol. 11, p. 317 (1977)].
Non-aqueous solutions of high monomer concentrations
(50% ~VP in pyridine) are required at relatively high
20 doses of gamma radiation (1-5 Mrad) resulting in a high
degree of grafting but with extensive changes in the
bulk and surface properties of the PTFE since PTFE is
readily degraded at gamma doses above 1 Mrad.
In U.S. Patent No. 4,806,382, issued February 21,
25 1989, there are described improved methods for
producing hydrophilic, gamma irradiation induced
polymerized and chemically grafted coatings on ocular
implants constructed of a variety of polymeric
materials, which methods overcome the above-noted
30 difficulties and disadvantages.
The invention described in that application is
predicated on the discovery of certain process
conditions and parameters that produce thin hydrophilic
gamma irradiation induced polymerized and chemically
35 grafted coatings of N-vinyl-pyrrolidone (NVP) ~PVP],
2~5~
- 4 -
copolymerized NVP and 2-hydroxyethylmethacrylate (HBMA)
lP(NVP-HEMA)], or HEMA tPHEMA] on the surfaces of
ocular implants constructed of materials including
polymethylmethacrylate (PMMA) and of other process
conditions and parameters which produce thin gamma
irradiation induced graft PVP, P(NVP-HEMA), or PHEMA
coatings on the surfaces of ocular ~rticles constructed
of materials including polypropylene (PP),
polyvinylidene fluoride (PVDF), polycarbonate (PC) and
silicone (P8i). The coatings increase the
hydrophilicity of the implant surface and minimize
adhesion between the surface and sensitive ocular
- - tissues such as corneal endothelium or iris thereby
minimizing tissue damage and post-operative
complications occasioned by contact between the implant
surface and ocular tissue. The coatings produced by
the improved method of the invention described in U.8.
Patent No. ~,806,382 are thin and reproducibly uniform.
Moreover, they are chemically bound to the surface of
the ocular implant and, therefore, far more durable and
les~ subject to removal, degradation or deterioration
during or following surgery than the coating~ produced
by prior art methods.
The improved gamma-irradiation induced graft
polymerization of NVP, HEMA or mixtures of NVP and HEMA
on ocular implant surfaces comprising PMMA to form
optimum PVP, P(NVP-HEMA) or PHEMA graft polymer surface
modification~ thereon comprises carrying out the graft
polymerization in an aqueous solution under specific
combinations of the following conditionR:
a) monomer concentration in the range of from
about 0.5 to about 50%, by weight;
b) total gamma dose in the range of from about
0.01 to about 0.50 Mrad:
2 ~ 3~3
- 5 -
c) gamma dose rate in the range of from about 10
to about 2500 rads/minute; and
d) maint~;n;ng the molecular weight of the
polymer in solution in the range of from about 250,000
to about 5,000,000.
Optimally, the method may also be carried out under
one or more of the following conditions:
e) substantially excluding free oxygen from the
aqueous graft polymerization solution:
f) maint~; n; ng the thickness of the PVP or
P (NVP-HEMA) surface graft in the range of from about
looA to about 150 microns;
- - g) including a free radical scavenger in the
aqueous graft polymerization solution; and
h) including in the aqueou~ graft polymerization
solution a swelling solvent for PMMA or other polymer
substrate surface.
The improved gamma-irradiation induced graft
_~ .
polymerization of NVP, mixtures of NVP and HEMA or HEMA
on ocular implant surfaces comprising PP, PVDF, PC or
PSi to for~ optimum PVP or P(NVP-HEMA) surface grafts
thereon may also be carried out under specific
combinations of the process parameters as indicated
above for PMMA but also under conditions which involve
excluding free oxygen from the polymerization solution
for preferred surface modification of these ocular
implant polymer substrates.
It is an object of the present invention to provide
a still further improved method for producing
hydrophilic coatings on the surfaces of ocular
implants.
8UMMARY OF THE lNv~NlION
The present invention is predicated on the
discovery that, in order to produce the hydrophilic
2~5~83~3
coatings on the surfaces of ocular implants aceording
to the method aescribed in U.8. Patent No. 4,806,382,
the "maintenance of the molecular weight of the polymer
in solution in the range of from about 250,000 to about
5,000,000" is not a critical condition.
The present invention is further predicated on the
discovery that in order to successfully carry out the
method described in U.8. Patent No. ~,806,382, the
total gamma dose range may be extended to a minimum
value of 0.001 ~rad.
The success of the improved method of the present
invention is, however, predicated on strictly
- - maintaining the remainder of the conditions outlined in
~.S. Patent No. 4,806,382 for achieving the graft
polymerization coating on ocular implant surfaces.
BRIEF DESCRIPTION OF THE DRAWINGS
The drawings, FIGS. 1-3, depict examples of ocular
implants according to the present invention.
FIG. 1 depicts a top view of a one-piece intra-
ocular lens,
FIG. 2 depicts a top view of an intraocular lenswith fiber haptics which may be made of a different
substrate polymer than the optic, and
FIG. 3 depicts a top view of a keratoprosthesis.
DETAILED DESCRIPTION OF THE I-NV~N~1~10N
The maintenance of the molecular weight of the
polymer in solution at certain values, identified in
U.8. Patent No. 4,806,382 as a critical condition of
the method is not actually a ~condition~ of the method,
but rather, as stated in the specification, a result
which is dependent on the reaction conditions employed
in carrying out the graft polymerization process. It
is, therefore, not appropriate to specify the molecular
2 ~5~ 3
- 7 -
weight of the polymer in solution as the reaction
conditions used in this invention and may be widely
varied depending on specific gamma graft
monomer-substrate-process conditions. If a certain set
of fixed conditions are employed, namely: monomer,
monomer concentration, total gamma dose and gamma dose
rate, the molecular weight of the polymer formed in
solution cannot be independently varied but will be ~n
output of the process which is dependent upon the
values of the above-noted monomer concentration, total
gamma dose and gamma dose rate conditions. For
example, in the presence of certain ionic monomers,
- solvents or radical inhibitors, solution polymeri- -
zation may be inhibited significantly without
sacrificing efficient surface graft polymerization and
the resulting solution polymer molecular weight may
thereby be relatively low (i.e., as low as
5,000-10,000).
8ince the application which matured into
U.S. Patent No. 4,806,382 was filed, the inventors of
the subject matter defined therein conducted additional
research and unexpectedly found that although
relatively low doses of 0.01 to 0.20 Mrad are generally
preferred for the compositions of this invention, the
process could be conducted at a total gamma dose as low
as 0.001 Mrad.
The state of the art prior to the application which
matured into U.~. Patent No. 4,846,382 taught the use
of relatively high gamma doses, generally greater than
0.5 Mrad, for gamma polymerization grafting, and it was
therefore surprising to find that surface grafting
could be achieved at doses as low as 0.01 Mrad. The
achievement of effective grafting at doses as low a~
O.001 Mrad is consequently an even more unexpected
result of the process of this invention. Furthermore,
Z 05~ 8~3
~lthough grafting with monomer eoneentrations as low as
0.5 wt% was indieated in prior U.S. Patent
No. 4,806,382, further researeh has revealed that
monomer eoneentrationQ as low as 0.1 wt% may be
utilized in some embodiments of the graft process of
thi~ invention.
Yalon et al ~supra) and Rnight et al (supra)
diselose gamma-irradiation coatings on PMMA using
N-vinylpyrrolidone (NVP) and 2-hydroxyethylmethacrylate
~HEMA) and indieate poor dynamie ~abrasive) proteetion
of endothelium for these coatings. Dissolvable
coatings of polyvinyl-alcohol ~PVA) were regarded as
- - optimal for intraocular lenses ~IO~s) by ~night et al,
supra, and commercial development of a PVA-coated IOL
was attempted with unsatisfactory clinical results.
The gamma polymerization surface modifieations reported
were earried out under proees~ eonditions of monomer
concentration, solvent, dose and dose rate which were
not specified and which apparently yielded poor
quality, readily abraded coatings. Conditions for
producing useful permanent PVP or PHEMA coatings on
PMMA IOLs or any other plastic surface are not taught
in the prior art. Neither Rnight et al, Yalon et al or
the literature on gamma-graft polymerization of the
past 30 years suggest the process eonditions required
to achieve the complieated requirements for useful
coatings on plastics. These requirements include:
a) Thin, permanent, optically clear ~in the case
of contact lenses) and uniform graft coatings. The
literature generally discloses conditions which produce
distortion and degradation of the substrate due to the
use of high gamma-radiation dose (>1 Mrad) and
non-aqueous solvent media, and yield thick, eloudy,
non-uniform coatings (e.g., Chapiro, Radiation
Chemistry of PolYmeric Systems, John Wiley and Son~,
- 9 -
Inc., New York ~1962); Henglein et al, Angew. Chem.,
Vol. 15, p. 461 (1958).
b) Long-term biocompatibility in vivo.--
c) Low contact angle (high wettability) for water
or underwater air bubble (less than about 30-).
d) Non-adherent to tiSSUQ (adhesive force to
endothelium les~ than about 150 mg/cm2).
e) Non-dam~ging to endothelium (less than ca. 20%
damage for in vitro contact test~).
f) Measurable graft coating by BSCA or FTIR
analysis.
g) Abrasion resistance by sliding (dynamic)
- - friction testing showing no change in wetting (contact
angle) and confirming before and after presence of
graft coating.
h) Rapid hydration - change from dry state to
wetted lubricou~ state on immersion in water (within
five minutes).
Yalon et al (supra) disclose an in vitro technique
for measuring endothelium damage. Results for PMMA
were used to illustrate the method. Although it was
noted that PVP coatings reduced cell damage with less
damage at higher monomer concentrations, the conditions
for the experiment ~i.e., irradiation dose, dose rate,
etc.) were not disclosed nor were any of the critical
process-product relationships indicated.
The improved process conditions and parameters of
the invention described in U.S. Patent No. 4,806,382
which are necessary to produce useful
polymer~ having a surface modified by gamma-irradiation
induced graft polymerization therein of PVP,
P(NVP-HEMA) or PHEMA include: % monomer, gamma dose,
dose rate, penetration time or swelling time of monomer
into the ~ubstrate prior to polymerization and oxygen
~i
,..~
2~5~R~;
-- 10 --
(air) degassing. Other optimal proeess eonditions
inelude eatalysts, free radieal seavengers, polymer
swelling solvents and temperature. The solution
polymer moleeular weight and M.W. distribution, the %
eonversion and residual monomer, the graft polymer
thickness and surface properties, etc., are process
results whieh can change markedly as the proeess
variables change. For example, the surface modifica-
tion achieved for PVP on polymer surfaces will be
different when using 10% monomer and 0.1 Mrad if
prepared at low dose rates sinee low dose rate~ (~lower
polymerization) favor higher moleeular weights.
Similarly, degassed oxygen-free reaetion media result
in improved grafts at mueh lower doses. The presence
of free radieal seavengers sueh as eopper or iron salts
or organie redueing agents (i.e., aseorbie acid) also
greatly influenee~ other proeess parameters, generally
redueing solution polymer moleeular weight and
~-~ preventing solution gelation at high monomer
eoneentrations.
Eaeh of the above-deseribed proeess eonditions and
parameters of the method of the invention may be varied
within the ranges discussed below to produce certain
specific combinations which are particularly
advantageous for the surface modification of a
particular polymerie surface.
a) Monomer concentration: Inereasing monomer
concentration inereases polymer mol. wt. in the graft
solution and reduces contact angle (C.A.), i.e.,
renders the surface more hydrophilie. For example, in
the ease of forming PVP coatings on PMMA, in the range
of from about 3-15% NVP the PVP viscosity mol. wt. (Mv)
increases from 560,000 to 2,700,000 and the PMMA graft
C.A. deereases from 29- to 21- at 0.1 Mrad and 309
rads/min. ~owever, this effect is sensitive to dose
ZO SZ 8~3
rate and total dose. For example, at 1-10% NVP, but ~t
a lower dose rate of 6~ rads/min., the mol. wt.
increases from 400,000 to ~,590,000 and the C.A.
decrease~ from 49- to 18-.
In general, monomer concentrations in the range of
0.1-50% are preferred depending on other parameters.
Concentrations as low as 0.1 - 0.5% at low dose rate~
can yield hydrophilic surface grafts with C.A. below
30-40- under conditions of this invention. At monomer
concentrations greater than 20-30%, effective grafting
without solution polymer gelation requires low doses
and use of free radical scavengers. Monomer
- - concentration~ greater than 50% are feaqible but not
preferred since high concentrations of radical
scavengers must be used and polymer mol. wts. and
monomer conversion are lowered significantly by their
use. For producing PHEMA coatings, HEMA concentrations
of between 0.5% and-10%, by weight, are sufficient.
b) Dose: In general, increasing total gamma dose
increases mol. wt. of the polymer and reduces C.A.
~owever, an important practical limit exists in that at
higher dose~, lower dose rates and higher monomer
concentrations, reaction media becomes extremely
viscous or form gels which are very difficult to wash
and to remove (e.g., about 0.25 Mrad and 10% NVP at 309
rads/min).
It will be understood by those skilled in the art
that electron beam radiation will also induce graft
polymerization. Therefore, electron beam radiation of
energies equivalent to that described herein for gamma
radiation may be substituted for gamma radiation in the
practice of the method of the invention. Electron beam
voltages in the range of from about 50 KeV to about 10
MeV may be employed at currents of from about 5 mA to
about 100 m~. For electron beam initiated
- 12 - -~
polymerization grafting, conditions which produce dose
rates substantially higher than for gamma graft
polymerization, i.e., in the range of from about 10 to
about 108 rad~/min or more may be employed.
c) Dose rate: ~ecreasing gamma radiation dose
rate generally increases solution PVP M.W., e.g., from
1,150,000 to 5,090,000 at 10% NVP and 0.1 Mrad as dose
rate decreases from 1235 to 49 rads/min. The C.A. al~o
goes down at lower dose rates, i.e., from 31- to 15-.
As noted above, dose rates of up to 1o8 rads/min or
more are practical when employing electron beam
irradiation.
- - d) 801ution Polymer Mol. Wt.: The mol. wt. may
vary widely depending upon process conditions, monomers
and radical inhibitors used. Effective grafting with
low C.A. may therefore be achieved with even low mol.
wt. solution polymer (Mv as low as 5000-10,000 or
less). However, solution polymer Mv greater than
5,000,000 or gels which form during grafting are
generally impractical because of washing problems.
e) Degassing: Removal of oxygen from the graft
solutions by vacuum and/or inert gas (e.g., argon
purging) has an important effect: lower total doses are
required (practical grafting at less than 0.1 Mrad).
Oxygen degassing also has a large effect on PVP Mw and
% conversion of monomer. For example, with degassing,
good grafting of PVP on polypropylene (PP) is achieved
at O.05 Mrad and 10% NVP ~C.A. 15-). Without
degassing, little grafting occurs under these
conditions. Oxygen degassing i~ critical to hydro-
philic surface modification grafting where the
substrate polymer is PP, PVDF or PSi. It has been
found that graft polymerization is inefficient when
using these materials as substrates in the presence of
oxygen. Oxygen degassing is also beneficial for PMMA
- 13 -
ana PC substrates in that much lower radiation doses
~0.01-0.15 Mrad) become effective compared with
grafting these polymers in the presence of oxygen.
f) Graft thickness: ~urface grafts less than
100-200 angstroms, although non-adhesive and
hydrophilic, are useful but may exhibit somewhat less
mechanical "softness~ or compliant gel-like surfaces
than thicker coatings for reduced tissue-contact
trauma. Graft coatings greater than ca. 300-500 A (or
0.03 - 0.05 microns) up to 50 microns or more are
probably more desirable for many applications as long
as they are smooth, uniform, optically clear for optic
surfaces, and quickly hydrated.
Using no swelling solvents and no prolonged monomer
contact with substrates prior to irradiation, surface
grafts which exhibit desired implant properties under
preferred process conditions have thicknesses of about
0.1 to 5 microns. However, using swelling solvents
~~ such as ethyl acetate, polymer grafts on PMMA of 100
microns or more can be prepared. For certain
applications it may be preferred to have thicker
~spongy~ coatings of 20-100 microns.
g) Free-Radical Scavengers: Free radical traps,
usually reducing agents such as Cu~, Fe~2 ascorbic
acid, etc., are known to inhibit radical polymerization
in solution and thus be effective ~especially at high
gamma doses, high dose rates and high monomer
concentrations) in slowing the onset of solution
gelation during grafting. However, under practical
grafting conditions, this may result in lower
mol. wts., high concentrations of unreacted monomer and
broad mol. wt. distributions. Use of metal salts may
also be objectionable where maximum biocompatibility is
critical.
2~
Although most preferred graft conditions avoid the
use of radical scavengers, useful conditions for graft
coatings of PVP, P(NVP-HEMA) or PHEMA have also been
defined using ~scorbic acid to limit high viscosity ~nd
gelation of the graft polymer solution. These
conditions use high monomer concentrations ~up to 50%)
and thicker grafted are obtained using ethyl acetate as
a swelling solvent (0.5-5%).
h) 8welling solvents: The use of substrate
polymer solvents in the aqueous monomer grafting
solution facilitates swelling and monomer diffusion
into the polymer before and during gamma
polymerization. Penetration of monomers into the
substrate increases graft coating thickness and
enhances bonding to the surface. 8O1vents such as
ethyl acetate have been shown to greatly facilitate
this process with some substrates such as PMMA.
Although the above-described method represents a
-~- significant improvement over prior art methods, optimum
results in each case depend upon the selection of a
combination of numerous process parameters and
conditions.
Where mixtures of NVP and HEMA are employed to form
graft copolymerized coatings of P(NVP-HEMA), the
mixtures may contain up to about 50% by weight of HEMA,
based on the weight of the monomer mixture. However,
above 20-30% HEMA, radical scavengers and low monomer
concentrations should be used to prevent gelation since
HEMA enhances the onset of gelation.
It will be understood by those skilled in the art
that the PVP, P(NVP-HEMA) or PHEMA graft coatings of
this invention may be modified by copolymerization with
various ionic monomers. Mixtures of hydrophilic and
ionic monomers may also be copolymerized therewith.
For example, graft copolymerization incorporating
~ ~ 5~ 3
vinylsulfonic acid, styrene sulfonic acid,
sulfoethylmethacrylate, sulfopropylmethacrylate or
other vinyl sulfonic acids or vinylcarboxylic acids
such as acrylic acid, crotonic acid or methacrylic acid
can afford surface modification~ ~hich are anionic.
8imilarly, graft copolymerization incorporating basic
or amino-functional monomers, e.g., vinylpyridines,
aminostyrenes, aminoacrylates or aminomethacrylates
such a~ dimethylaminomethylmethacrylate or -
dimethylaminostyrene afford surface modifications which
are cationic. It is also useful to use salts of ionic
monomers or to convert ionic grafts to the salt form by
- - post-treatment.
Amounts of ionic monomers up to about 50 wt. % of
the total monomer weight may be employed, it being
understood that the critical process parameters listed
above may be maintained.
Based on the foregoing considerations and the many
process studies conducted, preferred conditions for
various article substrate polymers by way of example
are provided in the examples below. 8Ome key points
may be summarized as follows:
8everal ranges of process conditions appear useful.
Choice of the "best" process will depend on such
factors as: molecular structure of substrate and
coating thicknes~ desired. In general, those
conditions which produce extreme solution viscosities
and gels or conditions which could produce solvent
stress cracking or crazing of the IOL polymers (e.g.,
higher conc. than about 20% for a PMMA swelling solvent
such as ethyl acetate) should be avoided. The
following four sets of process conditions appear most
practical for the preparation of improved surface
modified articles.
~ Q ~
- 16 -
(1) Agueous Monomer Concentration:
5-20% (preferred 10%)
Dose: 0.05-0.20 Mrad (preferred 0.10)
Dose Rate: 20-15,000 rads/min.
(preferred 50-2,000)
C.A. : <30-
(2) 8ame as (1) except that system i8 oxygen
degassed (vacuum or inert gas purge, e.g.,
argon) with Dose: 0.010.15 Mrad (0.05
preferred) and % NVP: 1-15% (5-10% preferred).
This system is generally preferred to (1).
(3) 8ame as (1) and (2) with swelling solvent
- - (e.g., ethyl acetate for PMMA) gives greater
monomer penetration of substrate and thicker
grafts.
(4) ~igh monomer concentrations (25-50%) using
<5.0% ethyl acetate swelling agent and radical
inhibitor such as ascorbic acid (0.1-1.0 mN)
at 0.100.20 Mrad and 20-5000 rads/min.
All percentages expressed in the examples are by
weight unless otherwise stated.
All contact angles (C.A.) and other surface
characteristic~ for gamma polymerization grafts, unle s
otherwise indicated, are for samples washed with water
or water-alcohol at room temperatures or elevated
temperaturQs to remove soluble residual monomer and
ungrafted polymer for the improved surface graft
processes of this invention. The resulting graft
polymers are stable and permanent for long-term use and
are not dissolvable by aqueous media.
It will also be understood by those skilled in the
art that the ocular implants to be graft coated may be
also constructed of materials other than PMMA, PP,
PVDF, PC or PSi to facilitate their use. It will be
understood by those skilled in the art that such
2~s~
- 17 -
materials may also be at least partially graft polymer
surface modified 80 as to improve their properties a~
implant materials.
The hydrophilie graft polymer surfaee modifieation~
of this invention are espeeially advantageous for
intraocular lenses (anterior ehamber, posterior ehamber
and phakie), but are also of great value in affording
improved tissue proteetion and improved
bioeompatibility for other oeular implants, sueh as
eorneal inlays, keratoprosthesis, epikeratophakia
deviees, glaucoma drains, retinal staples, seleral
buekles, ete.
EXAMPLE 1
This example illustrates the important effects
which result from varying the above-discussed proces~
conditions and polymerization parameters for
gamma-irradiated polymer graft surface modification of
PMMA with PVP.
PMMA slab sample~ were washed twice each by soap
solution and distilled water using a sonicator. After
complete drying, the samples were put into NVP
solutions in glas~ vials. The samples were then
r-irradiated at various conditions. After
T-irradiation, the surface modified PMMA samples were
rinsed several times with H20 and evaluated.
The polymerized NVP grafting solutions or gels were
freeze-dried under a vacuum. The solution PVP samples
were evaluated for molecular weight by viscosity
measurement (Mv) or gel permeation chromatography (Mw).
For Mv, PVP was dissolved in distilled water and
intrinsic viscosity t ~ ] wa~ measured at 30-C in a
capillary viscometer.
PVP grafted PMMA samples were evaluated by water
drop or underwater air bubble contact angle measure-
~2~
- 18 -
ments. The bubble technique is regarded as more
reliable for very hydrophilic surfaces. For air bubble
C.A., the grafted PMMA was held horizontally in
distilled water. An approximately 0.8 ~l air bubble
was formed ~nd positioned underneath the test surface.
Angles on opposite sides of the bubble were measured
~ssuring symmetry. Five measurement~ were usually made
for each sAmple. The result~ are set forth in the
following tables:
TABL~ 1
Dose Rate Effect on Solution Polymer
~ -Molecular Weiqht For T-Polymerized NVP
Concentration: 10% DVP in H2O
Total Dose: 0.1 hrads
Distance
-2 from co60Dose Rate Time Mol.
Wt. (Mv)~rads/min) (hrs.min) ~ ~ ] (x 106)
source
2~ 1235 1.21 1.48 1.15
4" 309 5.24 2.21 2.27
6~ 137 12.09 2.61 3.04
8~ 77 21.36 2.85 3.49
10~' 49 33.45 3.56 5.09
The effect of dose rate was evaluated by PVP
solution viscosity measurements. These results show
that the molecular weight increased as dose rate
decreased due to the slower and reduced initiation of
radicals and the increased time of polymerization while
maintaining the same total absorbed dose. At the
lowest dose rate in this experiment, 49 rads/min (at
10" from the Cobalt-60 gamma source), the highest
molecular weight PVP polymer, Mv = 5-09 x lo6, was
obtained.
2~5~
- 19 - ~'
TABLE 2
Total Dose Effect on Molecular Weight
r-Polymerized ~VP
Concentration: 10% ~VP in H2O
5Dose Rate: 309 rads/min (~" from r-source)
Total Dose Time Mol. Wt. (Mv)
(Mrad~) (hrs.min) ~ ~ l (x 106)
0.05 2.42 1.86 1.69
0.10 5.24 2.21 2.27
10 -0.25 13.30 * ---
0.50 27.00 * ---
* Polymer solution gelled.
Table 2 shows the effect of total ~-irradiation
dose on molecular weight at 309 rads/min. Increasing
the total dose gives a higher molecular weight. A
polymer gel was formed at a dose of 0.25 Mrad and
higher. These results show that a high irradiation
dose can cause gelation or cross-linking of the PVP
polymer.
2~5~
- 20 -
TABL~ 3
Molecular Weight of T-Polymerized NVP at
Different Solution Concentrations
Total Dose: 0.1 Mrads
Dose Rate: 309 rads/min.
r-Irradiation time: 5 hr~. 24 mins.
NVP Concentration Mol. Wt. (Mv)
(%) t 71 ] ~x 106)
3 0.97 0.56
6 1.58 1.29
1.94 1.82
2.45 2.70
These results show the relation between the
concentration of NVP monomer and the molecular weight~
of PVP at constant dose and dose rate. The result~
indicate that higher NVP concentrations give higher
molecular weight polymers. The importance of dose rate
iQ also indicated by the fact that even at lS% NVP, the
PVP molecular weight (Mv) was only 2.7 x 1o6 at 309
rads/min. compared to 5.0 x 1o6 at a lower dose rate of
49 rads/min.
%~8~
-- 21
TABLB 4
Contact Angle of PVP r-Grafted PM~5A
at Different Do~e Rate~
Concentration: 10% NVP
5Total dose: 0.1 Nrad
Distance
from Do~e Rate Time Contact
r-source~rad~/min) (hrs.min) Angle
Ungrafted
PMMA control --- --- 65-
PVP Grafted
PMMA
2~ 1235 1.21 31-
2~ 309 5.2~ 24~
lS 6" 137 12.09 21-
_~ 8~ 77 21.36 19-
10~ 49 33.~5 15-
The result~ in Table 4 show that the contact angle~
for PVP grafted PMM~ decreased due to hydrophilic PVP
20 grafting and that the lower dose rate~ give lower
contact angle~.
~ ~ S~ 3
- 22 -
TABLE 5
Contact Angle of PVP r-Grafted PMMA
at Different Total Dose~
Concentration: 10% NVP in H20
Do~e Rate: 309 rads/min.
Total Dose Contact
(Nrads) Angle
Ungrafted PNNA Control 65-
Grafted PNMA
0.05 27-
0.10 25-
0.25* 24-
0.50* 24-
* Polymer solution gelled.
. 15 These results show the effect of total dose on the
contact angle~ of PVP r-grafted PMMA. The contact
angle showed little change abo~e 0.05 Mrad at constant
dose rate of 30g rads/min.
~5~3~
- 23 -
TABLE 6
Contact Angle of PVP T-Grafted PMMA
at Different Monomer Concentrations
Total Dose: 0.1 Mrad
Dose Rate: 309 rads/min.
NVP Concentration Contact
t%) Angle
~ngrafted PMMA Control 65-
Grafted PMMA
10 3 29-
6 27-
25-
21-
_,~ The effect of different monomer concentrations was
evaluated for PVP ~-grafts on PMMA by contact angle
measurement. Even at 3% NVP and O.1 Mrad, a major
increase in hydrophilicity was observed as compared
with non-grafted PMMA. The contact angle decreased
slightly at monomer concentrations above 3%.
~ 0~ 3
- 24 -
TABLE 7
Molecular Weight of 7-Polymerized PVP
at Different Nonomer Concentrations
~otal Dose: 0.1 Mrad
Dose Rate: 64 rads/min.
NVP Concentration Mol. Wt. (Mv)
(%) t 71 ] (x 106) --,
1 0.79 0.40
3 1.65 1.38
2.23 2.30
3.35 4.S9
These results show the relationship between the
concentration of NVP monomer and molecular weight of
~~ PVP at a do~e rate of 6~ rads/min.
The molecular weight of PVP increases ~ignificantly
with increasing concentration of NVP monomer.
~ 8~3
- 25 -
TABLE 8
Contact Angle of PVP T-Grafted PMMA
at Different Nonomer Concentrations
Total Dose: 0.1 Mrad
SDose Rate: 64 rads/min.
NVP Concentration Mol. Wt. ~Mv)
~%) ~x 106)
~ngrafted PMMA Control 65-
Grafted PMMA
0 62-
1 49-
3 43-
31-
18-
The contact angle of PMMA was evaluated after
T-grafting with NVP at different solution concentra-
tions at a dose rate of 64 rads/min. These results
show thAt the contact angles of PVP-grafted PMMA
decreased with increasing concentration of NVP monomer.
This result, at 64 rads/min dose rate is qualitatively
similar to results at 309 rads/min (Table 6).
Hydrophilicity at 10% monomer appears to be favored
somewhat by the lower dose rate ~C.A. 18- vs. 25-).
Polar organic solvents or aqueous-polar organic
solvent mixtures may be useful for hydrophilic monomer
graft polymerization. Typical of such organic solvents
are alcohols or ethers such as methanol, ethylene
glycol, polyethylene glycols, dioxane, etc. However,
when such organic solvents act as radical traps or
radical chain transfer agents, they must be used at
concentrations lower than 50% or with high hydrophilic
- 26 -
monomer concentrations (i.e., >25%). For example,
methanol has some radical scavenger properties but may
be used for PVP gamma grafts on PNMA in water-methanol
mixtures up to 50-60% methanol for PVP grafts on PMMA
using 0.1 Mrad and 10% monomer (Table 9). Hydrophilic
grafts result although radical chain transfer by
methanol Appears to require low dose rates at 10%
monomer. In general these system~ yield low viscosity
solutions indicative of low molecular weight solution
polymer which forms in the presence of radical
inhibitors.
~ TABLB 9
Contact Angle of PVP ~-Grafted PMMA at Different
Dose Rates in 50% Methanol ~MeOH) Solution
Concentration: 10% NVP in 50% MeOH
Total Dose: 0.1 Nrad
Dose RateContact Angle
(rads/min)
No graft 65-
1065 36-
326 28-
157 27-
64 20-
EXAMPLE 2
This example illustrates the effect of swelling
solvents on the surface modification process.
For hydrophilic gamma grafts on PMMA as the
substrate, for example, addition of the swelling
solvent, ethyl acetate (EtOAc), to aqueous monomer
solutions is advantageou to achieve more efficient
2~5~
- 27 -
diffu~ion of monomer into the Y~NA surface. Although
EtOAc is not very soluble in water, a homogenous
reaction medium can be achieved in the presence of a
monomer such as NVP.
The thickness of the graft polymer surface
modification can be increased by higher ethyl acetate
concentrations and by longer diffusion times prior to
irradiation; i.e., the time of pre-swelling. In
general, without oxygen degassing, gamma radiation
doses of 0.10 - 0.15 Mrad are suitable to achieve
significant amounts of grafting.
The NVP-ethyl acetate-water solvent system is also
~ - a solvent for PVP and keeps the solution polymer phase
homogenous.
~Embedded grafting~ of PVP into the PMMA surface is
made possible by irradiating the PNMA after exposure
for various times to the monomer-swelling solvent-water
mixture.
-
In experiments using this proces~ techniques,
sample~ were cleaned by sonication in a 10% soap
solution followed by washing with distilled water.
Prior to surface modification, PMMA samples were dried
for 18 hours in a vacuum desiccator and weighed. NVP
monomer was purified by vacuum distillation and stored
at 4-C.
For gamma radiation grafting, the PMMA substrate
was immersed in aqueous monomer-solvent solutions and
exposed to gamma radiation. Typically, cleaned
substrates were immersed in NVP-ethyl acetate-H2
mixtures and irradiated in a 600 Curie Co-60 source.
The samples were exposed to the monomer solution for
various lengths of time. Gamma doses ranging from 0.01
- 0.15 Mrad as measured by Fric~e dosimetry were used
in this experiment. Dose rates were also varied.
After irradiation, samples were removed from the gamma
2~5~
- 28 -
polymer solution and washed several times with
distilled water and in deionized water with agitation.
80me samples were weighed hydrated after blotting with
filter paper to remove surface water and then dried for
2~ hours in a vacuum desiccator. The polymerization
solutions ranged from clear viscous solutions to gels.
The following parameters were measured.
One measure of the degree of grafting was obtained
from the weight increase of the substrate according to~0 the following equation:
percent grafting = Wl - WO x 100
WO
~ where WO is the initial weight of PMMA and Wl is the
weight of grafted PMNA. Likewise, percent hydration~5 was calculated according to the following equation:
percent hydration = W.~ - W~ x 100
~ d
where Ww is the weight of PMNA after equilibration in
water ~after blotting it dry) and Wd is the weight of
dry sample (after desiccation). In most cases, the
maximum water uptake was reached after 12 hours.
Captive air bubble and n-octane contact angles were
measured for the radiation grafted PMMA surfaces to
estimate the hydrophilicity of modified surfaces.
Static contact angles were measured on a Rame-Hart
contact angle goniometer. At least five measurements
on different surface regions of each sample were made.
IR/ATR surface analysis of the grafted and
ungrafted surfaces was made by using a Perkin-Elmer
Model 283B IR Spectrometer using attenuated total
reflectance.
Samples of 1 cm2 grafted and ungrafted PMMA were
analyzed using a Rratos ES 300 ESCA spectrometer
employing a magnesium R~ x-ray source. Graft analysis
3s consisted of N/C ratio determination.
~:~5;i~
- 29 -
The molecular weight~ of PVP solution polymers were
determined by solution intrinsic viscosity measurements
at 30-C in a ~bbelhode viscometer.
Radiation doses ranged from 0.01 to 0.15 Mrad and
monomer concentrations ranged from 5 to 15%.
Data for PVP grafting onto pMMa using EtOAc aQ a
swelling solvent are shown in Table 10. 8ince no pre~
radiation swelling time is used here, diffusion
penetration of the surface by EtOAc and monomer occurs
during gamma radiation. 80me pre-radiation swell-time
i-Q considered preferable. This system exhibits
behavior typical of a reaction which involves monomer
~ diffusion control. Partitioning of NVP monomer into
the hydrophobic surface of PMMA is favored initially
because of the presence of the ethyl acetate, which i8
a swelling solvent for PMMA.
By the use of a swelling solvent for the graft
substrate (i.e., EtOAc), the NVP-~tOAc-E2 system swellQ
the surface layers of PMMA and polymerization grafting
of monomer molecules in the vicinity of radiation
induced radical species near the surface is immediate.
Under such conditions, more efficient grafting is
achieved at lower doses and with deeper penetration of
the graft polymer into the solvent swollen surface.
Measurement of percent swelling of PMMA sampleQ in
NVP-ethyl acetate-H20 (1:1:8) vs. time shows that
swelling of about 6% is attained after 12 hours. In
this system, the thickness of the grafted layer could
be controlled by changing the time allowed for
diffusion prior to irradiation, thus controlling the
thickness of the grafted zone. Table 11 shows the
graft behavior after 24 hours of pre-swelling of PMNA
in 1:9 ethyl acetate: water cont~;ning 15% of NVP.
Comparing this data with Table lo ~no swelling time),
it is clear that the % graft is significantly higher
~ 3
- 30 -
for pre-swelling PMMA. At a given ethyl acetate
concentration, this difference i~ generally more
pronounced at lower monomer concentrations, e.g., 5%
monomer compared to 15% monomer.
In this system, NVP i~ the monomer but also acts a~
a mutual solvent to maintain a homogeneous phase of
otherwise poorly miscible solvents, i.e., ethyl acetate
and water. At ~ given monomer concentration (e.g.,
10%), it i~ necessary to keep the concentration of
ethyl acetate below 10% to avoid phase separation to a
microemulsion. Variation of the ethyl acetate
concentration, being a swelling agent, affects graft
~ - yield. Table 12 summarizes the observations made by
varying the concentration of ethyl acetate while
keeping other factors constant showing that the percent
grafting doe~ increase with higher ethyl acetate
concentration~. Greater grafting efficiency is also
indicated by the significant % grafting and reduction
of C.A. in the ~olvent swelling monomer system at low
doses. For example, up to 0.05 Mrad, little grafting
occurs in a simple aqueous monomer system. In
contrast, at only 0.01 Mrad C.A. is reduced to 35-
(Table 11, 24 hr. pre-swell) and to 23~ at 0.03 Mrad.
Technique~ used for the chemical analysis of bulk
polymers are usually not very satisfactory for analysi~
of the surfaces of polymers. The surface region, which
i-~ significantly different in structure and/or
chemistry from the bulk, is present only as a fraction
of the mass of the polymer. Thus, the traditional
techniques of chemical analysis are inadeguate.
8pecial surface analysis techniques are required for
graft copolymer~ since the surface region is a complex
mixture of graft, substrate, cross-linking groups and
chain transfer products. Two spectroscopic methods,
ATR-IR and ESCA are the most useful methods now
~5~3~i
- 31 -
available for this purpose and were used to help
characterize grafted surfaces.
The re~ults for ATR-IR (attenuated total reflection
infrared) ~hown in Table 13 indicate that the ration of
C=O (ester) and C=O (amide) group-~ in the surface
changes from 7.67 to 1.68 a~ the gamma dose increases
from 0.01 to 0.10 Mrad and then levels off which is
con-~istent with PVP grafting on PMMA.
E8CA analyses are shown in Table 14 and indicate
increasing nitrogen composition with increasing dose
(and grafting) as expected for a PVP graft.
SC~nni ng electron microscopic examinations of the
- grafted samples were performed in order to observe
their surface morphologies. All of the coated surface-~
appeared smooth even at lO,OOOX. The graft polymer
surface modifications appear to provide uniform
coverage across the surface of PMMA substrate. This is
important to insure excellent retention of optical
propertie~ for an optical implant such a~ an intra-
ocular lens.
Major conclusions to be drawn from the results of
this example are:
The NVP-ethyl acetate-water system produces uniform
hydrophilic graft polymer surfaces with controllable
graft penetration using PMMA as the substrate.
The monomer-ethyl acetate-water grafting front
gradually penetrates into the substrate and may be
controlled by varying the concentration of swelling
agent and the time of pre-swelling.
The presence of the PVP surface graft was confirmed
by gravimetric, contact angle, ATR-IR and ESCA
measurement~.
Unusually low radiation doses are required to
achieve significant grafting. Hence, any possiblo
radiation damage to the surface or substrate is
minimized.
o o o o o o
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o I
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. N ~ ~.o ~l ~ o~
C.) ~ ~ ,~ 7 N
.~
P~
o -n a~
~ ~- ~
- 'Z S ~ IO ~lo N ~ 10
~ X ~
~ O N O O O O O O
O ~ -
~-
~: ~ ~ O
~1 ~ ¦ ~ ~ N c3 N In
¦ ~ ~7 ~ ~ ~ N
E- N
.,~ ~ a
~ ~j
_S ~., ~,
~I
03 ~ J~
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:~ o ul o u~ ~ o
-rl
u~ o
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h
, V ~~ ~ ~ ~ ,i -
3 U
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~Y~ O ,~ :
O 'I ~ h
~- ~1 ~ O ~ U7 0 0
. p, a~ ~ . . . .
~ ~1
O ~7 ~ 0 ~ ~' ~D O
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o u~
O O O O ~1 ~i
O O O O O
o
34
TABLE 12
Graft Polymerization of NVP on PMMA
Effect of Ethyl Acetate : 12 hours Swelling
10% NVP, 309 rads/min
3% EtOAc 6% EtOAc 10% EtOAc
Total dose C.A. % Graft C.A. % Graft C.A. % Graft
(Mrads)
0.01 43 0.2 44 0.4 48 0.6
0.03 38 0.3 26 0.5 25 1.7
0.05 23 0.3 21 0.5 22 1.9
0.10 18 0.5 17 0.5 18 2.2
0.15 15 0.5 17 0.6 18 2.2 ~J
.~
2~,5~8 ~
-- 35 --
TABLB 13
ATR-IR Spectral Analy~i~ of PVP Grafted PMMA Sample~*
Total Dose Vc = ~ tester)
(Nrad) Vc = ~ (amide)
0.01 7.67
0.03 6.51
0.07 4.61
0.10 1.68
0.15 1.66
* Reaction mixture 5% NVP in 9:1 mixture of water-
ethyl acetate, dose rate 1065 rads/min - Swelling
time: 17 hour~.
~~ TABLE 14
ESCA Analysi~ of PVP Grafted PMMA Samples*
Total Do~e N/C at 0~C
~Mrad)
0.03 2.2 x 10-2
0-05 3.1 x 1o~2
0.07 4.5 x 10-2
0.10 4.7 x 10-2
* Reaction mixture - 5% NVP in 9:1 mixture of water-
ethyl acetate. Dose rate 1065 rads/min - Swelling
time: 17 hour~.
2 0 ~ 3
- 36 -
EXAMPLE 3
The following experiment de~onstrates the very
significant influence of oxygen on gamma polymerization
and gamma grafting and the important beneficial effects
of carrying out graft polymerizations in the substan-
tial absence of oxygen.
Gamma radiation induced polymerization of NVP was
carried out in 10% NVP aqueous solution as follows:
~ a) polymerization in presence of oxygen (air);
~b) polymerization in absence of oxygen using
argon degassing; and
~ c) polymerization in absence of oxygen. For
- - Group (a), aqueous 10% NVP solutions were irradiated to
total doses of 0.01, 0.05, 0.10, 0.20 and 0.25 Mrad in
each case at 213 rads/min in the presence of air. An
argon purge for 10 minutes was used in the case of
Group (b). A vacuum freeze-thaw (FT) method was
employed for degassing in the case of Group (c). In
the freeze-thaw experiments, the monomer solution was
frozen in liquid nitrogen and then vacuum (0.3 mm) was
applied to eliminate oxygen. The frozen solution was
thawed and brought to room temperature before irradia-
tion. Some samples were subjected to three
freeze-thaw cycles (3 FT). Experiments were run in
duplicate to establish reproducibility.
To determine the oxygen degassing effects on gamma
radiation grafting and polymerization, monomer
conversions and molecular weights were determined for
the different NVP solutions irradiated at 0.01 Mrad to
0.25 Mrad at 213 rads/min.
A method used for determining unreacted NVP after
irradiation was as follows: 5 ml of the gamma
irradiated NVP solution was extracted using 50 1
acetonitrile. NVP is soluble in acetonitrile, but PVP
is not. The PVP precipitate was centrifuged and the
2i~5~8~
- 37 -
supernatant solution was analyzed for NVP. The NVP
monomer solution (10% NVP/aqueou~) was used as a
control. NVP analysis was a~ follows: The 10% by
weight aqueou~ ~olution was diluted with acetonitrilo
to appropriate concentrations (O.S g/ml to 5.0 ~g/ml).
The U.V. absorbance was measured for each solution at
323 nm to develop a standard curve of NVP concentration
vs. U.V. absorbance. The regres~ion coefficient was
0.99 for this curve. GPC was used for molecular weight
; 10 measurement~ and gives Mw as well as molecular weight
distribution.
The % NVP conversion tamount of monomer reacted) is
- - significantly affected by Ar purge deoxygenation and by
FT oxygen degas~ing. At the very low dose of 0.01
Mrad, virtually no polymerization occurs in the
non-degassed oxygen (air) containing solutions.
However, 46%, 61% and 63% conversion to PVP occurred
for the AR-purged, lFT and 3FT samples, respectively.
Even at 0.10 Mrad, samples irradiated in air showed
only 90% conversion (10% unreacted NVP monomer)
compared to virtually complete conversion (99%) for
oxygen degassed sy~tems. This i8 important for
biological implants where unreacted monomers can cause
serious adverse toxicological behavior.
To demonstrate more efficient grafting of PVP on
PMMA at low gamma doses in the oxygen degassed system,
10% aqueous NVP was argon purged to remove oxygen and
irradiated with PMMA samples at 157 rads/min to 0.05
Mrad. The re~ulting hydrophilic surface modification
had C.A. 20 an~ was stable (no change in C.A.) to
mechanical abrasion. As indicated above, this
mechanically stable and very hydrophilic graft of PVP
on PMMA graft is achieved with high monomer conversion
(98%) and a high degree of polymerization for the
solution polymer (1.65 x 1o6 mol. wt.). In the
~1~5~3~'~
- 38 -
presence of air (oxygen), higher radiation dose~ ~0.1
Mrad) and/or higher monomer concentration (15% or more)
are required to achieve low C.A. with high conversion
And high molecular weight. For hydrophilic monomer
gamma polymerization grafts on other substrate
polymera, i.e., polypropylene, fluorocarbons (e.g.,
PTF~ or PVDF) or silicones, the beneficial effect of
oxygen degassing can be even greater. Oxygen removal
may also be used for improved gamma grafting in
combination with the use of substrate swelling solvent~
and free radical inhibiting agents such as oxidizable
metal salt~ or organic compounds (e.g., ascorbic acid).
- In the presence of radical inhibitors effective
grafting may be achieved but solution polymer may be of
lS low mol. wt.
PVP molecular weight is also greatly affected by
oxygen degassing. The Ar-purged and FT sample~ yield
PvP polymers with molecular weights of about 1.6 x 1o6
at only 0.01 Mrad. In sharp contrast, the non-degassed
sample~ do not form high mol. wt. polymer. At 0.05
Mrad, oxygen degassed samples yield PVP with molecular
weights of 1.65-1.8 x 1o6 compared with only about 0.35
x 106 in air. At 0.10 Mrad, all samples have molecular
weights of about 1.8 to 2.0 x 106.
EXAMPLE 4
The following experiments were carried out to
demonstrate the advantageous effects of free radical
scavengers in inhibiting solution polymerization and
gelation during the graft polymerization process,
especially at high monomer concentrations.
PMMA sample~ were surface grafted with PVP using
gamma irradiation a-~ in Example 1. Ascorbic acid
(AscA) was used as a radical inhibitor in these
2 ~ 3
- 39 -
experiment~. The irradiation conditions are set forth
in Table 15.
TABLE 15
a) 30% NVP/0.5mM AscA/2.5%EtoAc/0.2 Mrad*
b) 30% NVP/0.5mN AscA/2.5%EtoAc/0.15 Mrad
c) 40% NVP/l.OmM AscA/O.l Nrad
d) 50% NVP/l.OmM AscA/O.l Mraa
e) 50~ NVP/l.OmM AscA/0.2 Mrad~
* 0.1 Mrad initial dose: additional 0.1 Mrad after
washing sample free of monomer and soluble polymer.
- - C.A. for all PMMA samples in Table 15 were 18-24-
indicating very high hydrophilic grafts. Dose rate~
used were 33 rads/min. A dose rate of 667 rads/min for
(b) was al~o used. Solution polymer gelation can occur
under these conditions at these monomer concentrations
(30-50%) if a radical inhibitor such as AscA is not
used. The AscA significantly inhibits solution
polymerization without interfering with grafting
yielding low mol. wt. solution polymer. In addition to
C.A., PVP grafting was verified by ESCA and FTIR-ATR
analysis showing the presence of surface nitrogen and
the PVP imide carbonyl group. Good mechanical
properties were demonstrated by an abrasion test
showing little change in C.A. or surface nitrogen after
abrasion.
EXAMPLE 5
This example demonstrates the large favorable
effect of hydrophilic gamma graft surface modification
on reducing tissue adhesion by measuring corneal
endothelium adhesion and cell adhesion using fibroblast
cells. These are important factors in demonstrating
the improved biocompatibility and minimal tissue
~1~5~
- 40 -
irritation or damage afforded by the hydrophilic graft
surface modifications of this invention.
An apparatus which measures the force of adhesion
(mg/cm2) between contacting polymer and tissue surface~
wa~ used to determine adhesion between rabbit corneal
endothelium and polymer surface~. Adhesion force
values of about 250-400 mg/cm2 were measured for PNNA
and other hydrophobic polymers evaluated for implants,
i.e., silicone, polypropylene, etc. The improved
hydrophilic gamma graft surface~, prepared under
preferred process conditions, exhibit much lower
adhesion; below 150 mg/cm2 and often less than 100
- mg/cm2. This is accompanied by a major reduction in
endothelium cell damage as measured by ~EM; from about
50-80% damage for PMNA or silicone to 20% or less for
surface-~ gamma grafted under preferred proces~
conditions of this invention.
The gamma graft surface modifications of thi
invention also show a major reduction in cell adhesion
as demonstrated by exposure to live cell culture~ of
chick embryo fibroblast cells ~CEF) or rabbit lens
epithelial cells (LE). Experiments indicate that 2-4
times more CEF or LE cells adhere to PMMA as compared
to PVP graft modified PMMA. Grafts prepared at 0.1
Nrad and using 15% NVP, for example, showed adherence
of only 35% of the number of CEF cell~ which adhere to
PMMA. Similarly, PHEMA grafts on PMMA exhibited only
38% cell adhesion and 15:1 NVP: HEMA (at 16% total
monomer) exhibited only 20% CEF cell adhesion compared
to PMMA. Under optimal conditions of the method of the
invention for PVP surface modified PMMA, PC or PSi,
les~ than 1-2 LB cells per sq. mm. adhere as compared
to about 10 LB cells or more to unmodified PMMA, PC or
PSi.
2 1 ) 5 ~ 8 3 ~
- 41 -
EXAMPLE 6
This example demonstrates the graft polymerizat~on
of HENA and mixtures of NVP and HEMA on PMMA.
The method of Example 1 wa~ repeated utilizing a
16% NVP/HEMA (15:1) aqueous solution at about 1300
rads/min and 0.10 Mrad dose. The PVP-PHEMA surface
modified PMNA had a C.A. of 17-. Under similar
condition~, a 7% NVP/HEMA solution (5:2) gave a surface
with C.A. 23-, and a 2.5% HENA solution gave a surface
with C.A. 18-.
EXAMPLE 7
- - This example demonstrates the graft copolymeriza-
tion of anionic or cationic monomers with the hydro-
philic monomers of this invention using ionic monomers
with NVP.
a. The method of Example 1 was used with PNNA
substrate and 15% NVP plus 1-5 wt% of acrylic acid (AA)
or crotonic acid (CA) as comonomers at 0.1 Nrad and
1235 rads/min. Contact angles were 18-22~ and
endothelium adhesion waq about one half or less that of
unmodified PMMA indicating formation of a good
hydrophilic graft coating. 8imilar results can be
obtained using dimethylaminoethylacrylate to produce
cationic graft coatings. 8tyrene sulfonic acid (88A)
was also used to produce anionic grafts with NVP on
PNMA according to the method of Example 1. Using an
8SA:NVP ratio of 1:2 (33% SSA) and total monomer
concentration of 30% at 0.15 Mrad and about 700
rads/min. dose rate, hydrophilic grafts with 30-40-
C.A. were prepared.
b. 8tyrene sulfonic acid sodium salt (NaSSA) was
used to prepare highly hydrophilic anionic copolymer
grafts with NVP on silicones (PD~8). PDM8 samples were
cleaned by sonication in ethanol and vacuum dried prior
~,5~8'~3
to irradiation in agueous monomer solution~. Table 16
li~ts grafting conditions, monomer concentrations and
contact angles for graft surfaces prepared at a doso
rate of about 700 rads/min.
TABLB 16
Dose
(Mrad) % NaSSA % NVP C.A.
0.05 20 20 17-
0.10 20 20 15-
O.lS 20 20 13-
- - A~ shown in Table 16, under condition~ of even a
relatively low total dose of 0.05 Mrad, using 40% total
monomer and 50% anionic NaSSA comonomer with NVP, very
hydrophilic (C.A. 17-l anionic grafts were achieved.
EXAMPLE 8
Thi~ example demonstrate~ the hydrophilic monomer
surface grafting of polypropylene ~PP) and the
importance of oxygen degassing for effective surface
modification.
~ydrophilic surface grafts on polypropylene are not
readily prepared by gamma irradiation of aqueou~ NVP in
the presence of oxygen. Under conditions of Example 1,
even at gamma doses ~0.1 Mrad and monomer concentra-
tion~ ~10%, little surface hydrophilicity and little
reduction in C.A. occurs. However, in oxygen degas~ed
media, at 157 rad/min, and doses as low as 0.01-0.05
Mrad with 10% NVP, contact angles were about 15-. Very
hydrophilic PP graft~ which are also mechanically
~table by a mechanical abrasion test are thereby
readily prepared using oxygen degassed proces~
condition~. Thi~ i~ especially important for gamma
2~52~
graft surface modification of IOLs with PMMA optic~ and
PP haptics.
EXANPLB 9
Polycarbonate i8 a useful engineering plastic for
ocular implants. Surface modification of polycarbonate
is most readily accomplished u~ing gamma radiation of
oxygen degassed aqueous monomer NVP solutions, e.g.,
grafting conditions of oxygen degassed 10% NVP at 93
rad/min and 0.05 Nrad dose yield C.A. 19-.
EXAMPLE 10
- Although silicone ~PSi) doe~ not gamma graft with
NVP as readily as PMMA, PSi surfaces were modified
using oxygen degassed 10% NVP solutions. Irradiation
to 0.05 Mrad at 93 rad/min yield~ C.A. of about 45-
indicating significant surface hydrophilicity. Higher
dose~, swelling solvents, higher monomer concentration~
~ and different hydrophilic monomers can produce improved
hydrophilicity. For example, gamma grafting of
NVP/HEMA (10:1) at 0.10 Mrad and 157 rad/min even
without oxygen degassing yields grafts with 30~ C.A.
8~
EXAMPLB 11
Polyvinylidene fluoride (PVDF) is an example of a
fluorocarbon polymer which can be surface modified by
gamma irradiation of agueous NVP, NVP/water-methanol
solutions or BtOAc-water systems. Hydrophilic grafts,
with C.A. about 30-, are prepared at 326 rad/min and
0.20 Mrad. However, PVDF is preferably grafted using
oxygen degassed process conditions. Conditions of 157
rad/min, 0.05 Mrad and 10% agueous NV produce PVP
grafts with C.A. 17-. ~ince NVP monomer is also an
effective swelling solvent for PVDF, allowing pre-
radiation swelling time is favorable for producing
- - improved grafts. For example, C.A. as low as 14- is
obtained using 5 hrs. swelling time with 7% NVP, 0.10
Mrad and 94 rads/min.
EXAMPLE 12
Grafting Conditions for Combinations of Materials:
,...
Lenses with Haptics of Different Polymers
One of the important aspects of this invention is
the discovery that certain specific grafting process
conditions make it feasible to surface modify combina-
tions of materials to be used as lens/haptic pairs in
ocular implants. Surface grafting of an assembled IOL
can then take place in a one-step simultaneous grafting
procedure yielding improved more biocompatible
surfaces. Lens materials such as PMMA, PC and P~i can
thereby be grafted under specific conditions of this
invention which also achieve good grafting of haptic
fiber materials such as PVDF or PP. Table 16 sum-
marizes some lens/haptic combinations with preferredmutual grafting conditions for obtaining improved PVP
grafts.
;~05~
- 45 -
PMMA/PP and PMMA/PVDF
It has been demonstrated that PMMA and PP gamma
graft under degassed condition~ at 157 rad/min, 0.05
Nrad, 10% NVP. These conditions yield contact angle~
of 20- and 15- for PMMA and PP, respectively, and are
mechanically stable. Non-degassed PP does not graft
efficiently under conditions similar to PMMA because of
the adverse effect oxygen has on PP surface grafting.
PVDF surface graft studies also indicate the
importance of oxygen degassing. A 10% degassed aqueous
NVP solution, irradiated at 157 rad/min to 0.05 Mrad,
gives good hydrophilic grafts on both PMMA and PVDF.
- - 8ee Table 16.
PC/PP and PC/PVDF
PC and PP graft under similar gamma irradiation
conditions when NVP solutions are degassed. Using 157
rad/min, 0.05 Mrad and 10% aqueou~ NVP solutions,
efficient hydrophilic grafting occurs on both polymer~
yielding contact angles of 19- and 15-, respectively.
PVDF and PC are both grafted under the same
conditions which graft PC/PP and PMM~/PP combinations;
e.g., 157 rad/min, 0.05 Mrad, 10% degassed NVP. 8ince
PVDF swells in NVP, gamma grafting with prior swelling
time can result in improved binding of PVP to the PVDF.
Conditions are thereby afforded for simultaneous
hydrophilic polymer grafting to IOLs or other ocular
implant~ which are made of two or more polymer~ a~
indicated above. 8ee Table 16.
EXAMPLB 13
Intraocular lenses (IOLs) were surface modified
using several conditions described in the above
examples and implanted in rabbit eyes for periods of up
to one year to demonstrate the good bioacceptance of
hydrophilic gamma polymerization surface modified IOL
~5~
- 46 -
ocular implants prepared by the process condition~ of
thi invention. For example, 8inskey-style-037 J-loop
lenses (PMMA optic/PP haptics) were surface modified
with PVP, ethylene oxide sterilized and implanted in
the anterior chambers, and one-piece flexible haptic
PMMA IOLs wer~ implanted in the po~terior chambers of
New Zealand white rabbits. Process conditions for IOL
surface modifications include: -
(a) 15% NVP, 0.10 Mrad, 30 and 12 rads/min,
C.A. 20--25-;
(b) Conditions of Example 4, Table 15, a, b, d.
Periodic slit lamp examinations of eyes, histo-
- - pathology after one year and microscopic examination of
explanted lenses (compared to ungrafted PMMA control
IOLs), indicated good biocompatibility and normal
behavior for the hydrophilic polymer surface graft
modifications of this invention.
_,~
T~BLE 17
8urface Nodification of Lens/Haptic
Combination with PVP
Typical Preferred Gamma
Polymerization Grafting
Lens/Haptic Conditions*
PMMA/PP a. 10% degassed NVP, low
dose rate tLDR)**,
0.05 Mrad.
b. 2.5% EtOAC, 6 hr
swell, 10% NVP,
degassed LDR, 0.05
Mrad.
PMMA/PVDF a. 10% degassed NVP, LDR,
0.05 Mrad.
b. 10% NVP, 5 hr swell,
LDR, degassed, 0.15
Nrad.
2~ }?~.'t
- 47 -
c. 2.5% EtOAc, 6 hr
swell, 10% NVP,
degassed, LDR, 0.05
Nrad.
PC/PP a. 10% degassed NVP, LDR,
0.05 Nrad.
b. 2.5%, EtOAc, 6 hr
swell, 10% NVP, LDR,
degassed.
PC/PVDF a. 10% degassed NVP, LDR,
0.05 Mrad.
b. 10% NVP, 5 hr swell,
LDR, degassed, 0.05
Mrad.
c. 2.5% EtOAc, 6 hr
swell, 10% NVP,
degassed, LDR, 0.05
Mrad.
* To produce C.A. less than about 25-.
_ 20 ~* LDR: 30-300 rads/min.
EXAMPLB 14
This example illustrates the efficient grafting
which can be achieved by the process of thi~ invention
at extremely low gamma doses (0.005 Mrad or less1 even
at very low aqueous monomer concentrations (0.5 wt% or
less).
PVDF surfaces were surface modified using condi-
tions described in the above examples at the extremely
low gamma-radiation dose~ ~0.01 and 0.005 Mrad) and low
HEMA monomer concentrations (0.5-2.0%) summarized in
Table 18. PVDF sample~ were cleaned, gamma irradiated
in aqueous HBMA solutions and washed according to the
general method of Bxample 1. Highly hydrophilic
surface graft modifications are achieved as indicated
by the low contact angles listed in Table 18. Good
graft efficiency for PHEMA on PVDF under these
2~ P~
- 48 -
extremely low dose and monomer concentration conditions
is further confirmed by the XPS analyses given in Table
19 which shows little surface fluorine and a corre-
sponding increase in carbon for the P~EMA-g-PVDF; a
surface analysis which closely approximates the
composition of P~BMA.
2~ 6
TABLB 18
Gamma Radiation Graft Polymerization of Argon
Degassed Aqueous HEMA on PVDF at 88 rads/min
Total DoQe % HBNA Contact Angle
(Nrads) ~-)
0.5 24
0.005 1.0 24
2.0 12
0.5 21
. 0.01 1.0 19
2.0 16
Even at doses as low a~ 0.005 Mrad or les~ and
monomer concentration~ a3 low as 0.5 wt% or less,
extremely hydrophilic PHEMA graft~ are obtained. For
~ 15 comparison PVDF itself i~ very hydrophobic and haQ a
contact angle greater than 85-.
TABLE 19
XP8 Analysis of PVDF and PHEMA-g-PVDF
C(ls) F(ls)
Carbon Fluorine
Unmodified PVDF 50.5 45.3
PHEMA-g-PVDF
2% HEMA 69.0 0.9
0.005 Mrad
PVDF (theoretical) 50.0 50.0
PHEMA (theoretical) 66.7
~S~8
~ 50 ~
The XP8 surfaee analysis elearly shows that
effieient surfaee grafting of PHEMA oeeurred at O.005
Mrad. The surface carbon coneentration for the graft
was about that expected for a P~EMA surface and very
little surfaee fluorine for PVDF was detected.
