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This invention relates to new hydrogel forms of natural animal and
vegetable proteins which have superior properties compared with present
known forms of the same materials. It more specifically relates to such
compositions as soft contact lenses (disposable, fugitive, and dressing
forms), and cosmetic, pharmaceutical, and surgical preparations containing
these new forms of natural animal and vegetable proteins when used in
contact with aqueous liquids. The invention also relates to methods of
producing superior and more widely useful products from such natural
proteins than has been heretofore possible.
By natural hydrogel (hydrocolloidal) animal or vegetable protein polymers
is meant throughout the specification and claims a crosslinked protein
polymer of natural origin having an average molecular weight of about
100,000 or less, capable of being swollen by water over a wide range of
water contents ranging from as low as 30 percent to 1000 percent and
higher while possessing useful rheological control properties for specific
end product uses.
Specifically, one object of this invention is to provide soft contact
lenses capable of being colored completely or at least partly if desired
using effective protein dyes, lenses that will correct optical defects of
the wearer's eye.
Another object of this invention is to produce contact lenses that may be
worn continuously until they become cloudy--and can be thrown away
(disposable), and replaced by a fresh lens or a pair of lenses.
Still another ofject of the invention is to control the properties of
contact lenses--using the same raw materials--so that such lenses may have
their properties so engineered in advance that they may be used as corneal
dressings, fugitive lenses, or in the form of rigid rheologically-tailored
hydrogels, capable of serving as a replacement for vitreous fluids.
Still another object of this invention is to control the composition and
chemistry of the natural protein hydrogels to provide burn and wound
dressings having superior properties in the wet state.
A further object of the invention is to adapt this new technology to
produce novel fibers for textile and medical uses.
A still further object of the invention is to provide a hydrogel base from
which bone-like structures, arteries, and similar prostheses possessing
outstanding properties in an aqueous fluid saturated state never before
available.
The art has long worked with low molecular weight proteins (such as animal
gelatins) and vegetable proteins (such as soybean proteins)--using them
with and without varying degrees and types of crosslinking. However, great
limitations, especially in wet physical properties, of such prior products
limited their use, especially in the structural forms described by the
present invention. For example, prior art has clearly concluded that
gelatin or agar never were found suitable to produce contact lenses (Soft
Contact Lens, by Montague Ruben, John Wiley & Sons, p. 25, 1978).
The present invention provides new forms of treated protein polymers that
possess unique physical properties, especially in the wet state,
properties that are critically dependent upon the specific sequence of
controlling pH, crosslinking agent concentration, and most critically on
drying the structures to critical levels in accordance with specific
stepwise chemical and solvent dehydration sequences. Products prepared
using previously reported conditions of crosslinking and dyring did not
possess the outstanding wet physical integrity of products prepared in
accordance with the findings of this invention. They were deficient in
physical integrity to sustain the performance in the wet state provided by
the products of the present invention.
In producing my products, it is essential to begin with natural protein raw
materials that form clear solutions in water at concentrations up to 30
percent or higher. Ordinary household unflavored gelatin is a typical
starting natural animal protein as one starting raw material for this
invention and edible soybean protein is a typical starting vegetable
protein example.
Depending on the desired end-product form, I have found that controlling
such variables as pH, crosslinking agent, temperature, solids
concentration, and solvent dehydration sequences are critical variables. A
further critical variable is to air dry at temperatures not exceeding
about 35.degree. C. to a moisture content in the dried form of not more
than 10 percent, preferably 7 percent or less. I have found that if these
critical steps are not carried out, e.g. if the products are heated to
40.degree. C. or higher at any time prior to the final air drying to not
more than 10 percent moisture and do not receive appropriate organic
solvent dehydration treatments, unsatisfactory water instability in the
final products results. Instead of possessing extremely pliable, bendable,
and good physical integrity including superior tear strength properties in
the wet state, products that are dried in any manner before initially
being air dried to not more than 10 percent moisture, and preferably below
7 percent moisture, in sequence with organic solvent dehydration
treatments give products having a cheese texture, extremely brittle and
friable physcial state when saturated with water. Of course, loss of wet
physical integrity such as above described (and clearly characteristic of
the prior art) makes the resulting products essentially useless for the
products produced by this invention: e.g. soft contact lenses,
ophthalmological dressings, artificial corneas, vitreous fluid, novel
protein fibers for textile and surgical uses, prostheses such as
artificial cartilage and artificial bone, capsules, sutures, burn and
wound dressings, etc. The importance of this invention lies in making
possible a wide range of products having such a wide line of useful
properties from inexpensive and abundant relatively low molecular weight
natural protein raw materials.
Although Formalin (37% Formaldehyde solution) is the crosslinking agent
used in illustrating the examples, other suitable crosslinking agents may
be used, such as glyoxal, glutaraldehyde, ethylene glycoldimethacrylate,
diethylene glycoldimethacrylate or methylene-bis-methacrylamide, together
with an aqueous solution, for example, a 4% by weight solution of ammonium
persulphate or potassium persulphate, or another peroxidic initiator or
polymerisation and an activator, such as for example
2-dimethylenaminomethyl-acetate, or a p-toluene sulphonic acids. A small
amount of cuprous salts or bivalent iron salts may be added.
The products of the present invention are prepared from solutions of the
natural protein containing from about 0.5 percent to about 15 percent, by
weight, preferably from 0.5 percent to 10 percent, of the protein or
mixtures of the proteins. The solution is heated to
60.degree..+-.5.degree. C. so as to aid in dissolving the protein and
produce a clear solution. Following the dissolution of the protein, the pH
of the solution is adjusted to about pH 3.5 to about pH 5.5 and thereby
form an aqueous acidic solution of the protein. While maintaining the
acidic solution within this temperature range, the crosslinking agent is
added to and incorporated in the solution with vigorous mixing. Commercial
Formalin containing 37% formaldehyde is particularly convenient and
satisfactory as the crosslinking agent. Formalin is added to the solution
in an amount sufficient to provide from about 0.5 percent to about 15
percent, preferably from 0.5 percent to 10 percent formaldehyde, based
upon the weight of the protein. Equivalent amounts of other crosslinking
agents may be substituted for Formalin.
The solution is cast or formed into a desired dimensional configuration or
structure followed by air drying at temperatures not exceeding 35.degree.
C. to a moisture content of not more than 10 percent, preferably less than
7 percent. In instances where a clear, water white product is desired, the
dried structure is bleached by the use of an oxidizing agent, such as, for
example, hydrogen peroxide, sodium hypochlorite, and the like. Where the
characteristic tan color of low molecular weight proteins is not
objectionable, this treatment may be omitted. The bleached or unbleached
structure is thoroughly washed with water followed by a dehydration
treatment by immersion in a water-miscible organic solvent, such as, for
example, ethanol, denatured ethanol, isopropanol, acetone, and the like.
After the organic solvent treatment, the structure is thoroughly washed
with water and air dried at temperatures not exceeding 35.degree. C. to
reduce the moisture content to not more than 10 percent, preferably less
than 7 percent.
Because the base raw material is proteinaceous, products made in accordance
with this invention lend themselves to being permanently dyed in single or
multiple colored forms and designs using dyeing procedures commonly
applied to polymer materials containing NH, NH.sub.2, and COOH groups.
Accordingly, any desired color either for functional or cosmetic purposes
may be imparted to these products by the addition of suitable dyes or
pigments.
A few of the preferred examples of carrying out the invention are given
below.
EXAMPLE 1
A 400 ml clean gel mixture comprising 400 ml of a 10 percent gelatin
solution (approximately 50,000 molecular weight and a bloom of 225) was
heated to 60.degree. C. To this clear mixture is added with smooth, steady
stirring 4 drops of 10N HCl bringing the pH to 4.30. Immediately
thereafter, 8 ml of Formalin, approximately 7.5 percent formaldehyde based
on the gelatin, is added to the mixture with vigorous mixing, maintaining
the temperature at 60.degree..+-.5.degree. C.
The initial casting of the natural hydrogel, preconditioned as above, to
produce a water-stable product must be carried out promptly after the
addition of the crosslinking agent. The casting may be done either by
stationary air drying in a mold or by spin casting and drying in a mold.
Disposable Soft Contact Lens
From a burette or measuring pipette, 4 drops of the above mixture are
carefully added to standard polymethacrylate (11 mm) diameter molds under
ambient temperature conditions. The thickness of the contact lens--as well
as its refractory properties--are predetermined both by concavity
specifications of these molds and the number of drops added to them at a
given concentration level, respectively. The hydrogel is allowed to dry
slowly at about 25.degree. C. (R.T.) for at least 24 hours, during which
the crosslinking reaction proceeds essentially to completion.
At the end of this drying cycle, the lenses still in their molds are given
a further drying in an air circulating oven for a minimum of 4 hours at
30.degree.-35.degree. C. maximum to insure that the moisture content at
this point of production is reduced to not more than 10 percent,
preferably less than 7 percent.
The lenses are now easily removed from the molds and immediately immersed
in a dilute aqueous solution of standard household hydrogen peroxide (3%
by volume) for a minimum of 1 hour at R.T. (25.degree. C.). This step is
especially effective in substantially removing the natural tan or light
brown coloration characteristic of relatively low molecular weight,
natural proteins--whether crosslinked or not.
The lenses now receive a vigorous and thorough washing using distilled
water, preferably, to insure removal of all residual minute amounts of
crosslinking reagent and any residual hydrogen peroxide.
After this thorough washing treatment the water-swollen lenses are added to
commercial (either undenatured or denatured) ethyl alcohol (95% by
volume), and allowed to remain immersed therein for a minimum of two
hours.
At the end of the ethyl alcohol dehydration soaking treatment, the lenses
are once again washed thoroughly with distilled water to remove all traces
of residual ethyl alcohol and related denaturation components if denatured
ethyl alcohol is used. Repeated extensive washings in distilled water,
preferably, is important at this step.
The thoroughly rewashed clear lenses are now slowly air dried once again
using the precise sequence described above--namely--air dired for 25 hours
at about R.T. (25.degree. C.), followed by a minimum of 4 hours in an air
circulating oven at 30.degree.-35.degree. C. maximum, until the residual
moisture content is reduced to not more than 10 percent, preferably below
7 percent. If desired, the final water-washed lenses may be dried in their
respective molds in which they were originally cast, although this is
purely an option. Sterilization, if desired, is effected by dry heating at
temperatures up to 120.degree. C.
This completes the manufacturing sequence (subject to subsequent
inspection, edge-bevelling if desired, packaging, and sterilization, etc.)
to obtain water-white soft contact lenses having superior physical
properties and gaseous transmission properties both in the wet and dry
states, respectively. Among these advantages are almost immediate water
hydration (2-3 minutes versus 1-2 hours or longer for conventional
HEMA-type synthetic polymer soft contact lenses) along with high levels of
oxygen gas permeability.
EXAMPLE 2
A 400 ml clear gel mixture comprising 300 ml of a 10 percent gelatin
solution and 100 ml of a 1 percent partially hydrolyzed bovine edible
collagen (molecular weight of about 100,000) is heated to 60.degree. C. To
this mixture is added with smooth, steady stirring 4 drops of 10N HCl,
bringing the pH to 4.65. Immediately thereafter, 8 ml of Formalin,
approximately 9.5 percent formaldehyde based on the protein, is added to
the mixture with vigorous mixing, maintaining the temperature at
60.degree. C..+-.5.degree. C.
The initial casting of the natural hydrogel preconditioned as above to
produce a water-stable product must be carried out promptly after the
addition of the crosslinking agent.
Conventional Soft Contact Lenses
From a burette or measuring pipette, 4 drops of the above mixture are
carefully added to standard polymethacrylate (11 mm) diameter molds under
ambient temperature conditions. The thickness of the contact lens--as well
as its refractory properties are predetermined both by the concavity
specifications of these molds and the number of drops added to them at a
given concentration level, respectively.
The air drying, bleaching, washing, dehydration, washing, and final air
drying steps are identical to those described in detail in Example 1.
The resulting water-white contact lenses are suitable for continuous wear
as soft contact lenses. They lend themselves to economical mass production
as that they may also be used as disposable lenses--capable of being
discarded once they develop excessive clouding due to coating deposits,
etc. If so desired, these contact lenses may provide a route to the
elimination of repeated use of costly cleaning solutions and the infection
hazards related to repeated removal handling of the lenses for daily
cleaning.
EXAMPLE 3
A 400 ml. clean gel mixture comprising 400 ml of a 10 percent gelatin
solution (approximately 50,000 molecular weight and a bloom of 225) was
heated to 60.degree. C. To this clear mixture is added with smooth, steady
stirring 4 drops of 10N HCl, bringing the pH to 4.76. Immediately
thereafter, 80 drops (4 ml) of Formalin, approximately 3.7% formaldehyde
based on the gelatin, is added to the mixture with vigorous mixing,
maintaining the temperature at 60.degree. C..+-.5.degree. C.
The initial casting of the natural hydrogel preconditioned as above to
produce a water-soluble product must be carried out promptly after the
addition of the crosslinking agent.
Fugitive Soft Contact Lens Dressings
From a burette or measuring pipette, 4 drops of the above mixture are
carefully added to special 14-15 mm diameter glass molds under ambient
temperature conditions. The thickness of the contact lens--as well as its
refractory properties are predetermined both by the concavity
specifications of these molds and the number of drops added to them at a
given concentration level, respectively.
The air drying, bleaching, washing, dehydration, washing, and final air
drying steps are identical to those described in detail in Example 1.
This completes the manufacturing sequence (subject to subsequent
inspection, edge-bevelling if desired, packaging, and sterilization, etc.)
to obtain water-white soft contact lenses whose properties in the wet
state make them ideal for use as fugitive dressings for ophthalmological
use. For example, lenses prepared in this way possess low wet abrasion
properties; when placed in the eye along with medication, the movement of
the eyelids over the dressing progressively erodes the dressing so that it
is washed away over a period of 10-16 hours by the tear flow. Furthermore,
such hydrogel lenses or film strips when saturated with glaucoma treatment
drugs such as pilocarpine or timoptic (formulated from timolol maleate)
proffer use in lieu of high viscosity drops when mechanically dispensed
into the eye.
EXAMPLE 4
A 400 ml clean gel mixture comprising 200 ml of a 10 percent gelatin
solution (approximately 50,000 molecular weight and a bloom of 275) and
200 ml of a 2 percent partially hydrolyzed bovine edible collagen
(molecular weight of about 100,000) is heated to 60.degree. C. To this
mixture is added with smooth, steady stirring 4 drops of 10N HCl, bringing
the pH to 5.10. Immediately thereafter, 8 ml (160 drops) of Formalin,
approximately 12.3% formaldehyde based on the protein, is added to the
mixture with vigorous mixing, maintaining the temperature at 60.degree.
C..+-.5.degree. C.
The initial casting of the natural hydrogel preconditioned to produce a
water-stable product must be carried out promptly after the addition of
the crosslinking agent, e.g. before the crosslinking reaction proceeds
irreversibly to a solid, non-pourable gel.
Durable Ophthalmological Films and Corneal Transplants
From a burette or measuring pipette, 3 drops of the above mixture are
carefully added to standard polymethacrylate (11 mm) diameter molds under
ambient temperature conditions. The thickness of the contact lens--as well
as its refractory properties--are predetermined both by the concavity
specifications of these molds and the number of drops added to them at a
given concentration level, respectively.
The air drying, bleaching, washing, dehydration, washing, and final air
drying steps are identical to those described in detail in Example 1.
EXAMPLE 5
A 400 ml clean gel mixture comprising 400 ml of a 10 percent gelatin
solution (approximately 50,000 molecular weight and a bloom of 225) was
heated to 60.degree. C. To this clear mixture is added with smooth, steady
stirring 4 drops of 10N HCl, bringing the pH to 4.35. Immediately
thereafter, 40 drops (2 ml) of Formalin, approximately 1.85% formaldehyde
based on the gelatin, are added to the mixture with vigorous mixing,
maintaining the temperature at 60.degree. C..+-.5.degree. C.
Viscosity-Control Hydrogels
This product is allowed to stand at room temperature (25.degree. C.) for at
least 15 minutes with continuous stirring to insure maximum homogenization
of the crosslinking process.
The hydrogel is then dried preferably by flash spray drying, thereby
converting it into a find particulate form. Or the hydrogel may be spread
out in trays to be slowly air dried.
No matter what drying procedure is used, it is necessary that the moisture
content be reduced at the drying step, using maximum temperatures at
atmospheric pressure of 30.degree.-35.degree. C., to a residual moisture
content of not more than 10 percent, preferably less than 7 percent.
The dry natural protein polymer hydrogel particles are next immersed in a
dilute aqueous solution of standard household hydrogen peroxide (3% by
volume) for a minimum of 1 hour at R.T. (25.degree. C.). This step is
especially effective in substantially removing the natural tan or light
brown coloration characteristic of relatively low molecular weight,
natural proteins--whether crosslinked or not.
The swollen hydrogel particles now receive a vigorous and thorough washing
using distilled water, preferably, to insure removal of all residual
minute amounts of crosslinking reagent and any residual hydrogen peroxide.
After the above thorough washing treatment, the water-swollen hydrogel
particles are added to commercial (either undenatured or denatured) ethyl
alcohol (95% by volume), and allowed to remain immersed therein for a
minimum of two hours.
At the end of the ethyl alcohol dehydration soaking treatment, the hydrogel
particles are once again washed thoroughly with distilled water to remove
all traces of residual ethyl alcohol and related denaturation components
if denatured ethyl alcohol is used. Repeated extensive washings in
distilled water, preferably, is important at this step.
The thoroughly rewashed clear, highly swollen hydrogel clusters are now
slowly air dried once again using the precise drying sequence described
above--namely--either spray dried or air dried until the residual moisture
content does not exceed 10 percent, preferably below 7 percent.
The resulting product is especially suitable when swollen in aqueous
ophthalmological solutions (e.g. pilocarpine hydrochloride solutions for
treating glaucoma) for controlling the viscosity and flow properties. More
importantly, the high swollen network internal structure of the hydrogel
particles provides a means of prolonging the action of drug components of
which they are an ingredient.
EXAMPLE 6
A 800 ml clear gel mixture comprising 600 ml of a 10 percent gelatin
solution and 200 ml of a 1 percent partially hydrolyzed bovine edible
collagen (molecular weight of about 100,000) is heated to 60.degree. C. To
this mixture is added with smooth, steady stirring 10 drops of 10N HCl,
bringing the pH to 4.80. Immediately thereafter 18 ml of Formalin,
approximately 10.7% formaldehyde based on the protein, is added to the
mixture with vigorous mixing, maintaining the temperature at 60.degree.
C..+-.5.degree. C.
Films, Burns and Wounds Dressings
Immediately after thoroughly mixing the above composition, it is deaerated
in a vacuum desiccator at 28-29 inches of vacuum to help deaerate bubbles.
The mixture is next cast into flat Pyrex dishes the dimensions of which
are chosen to reflect the final dimensions desired for the film. For
example, a circular film or dressing may be made by using a Petri dish, a
rectangular film by using a rectangular glass dish.
The hydrogel is allowed to dry slowly at about 20.degree. C. (R.T.) for at
least 24 hours, during which the crosslinking reaction proceeds
essentially to completion. Depending on the thickness of the film desired,
slow air drying may continue for a period of a week or more until all of
the hydrogel has been dried to not more than 10 percent moisture,
preferably less than 7 percent residual moisture. In order to reduce the
drying time, after 24 hours the mold containing the shaped structure may
be further dried in an air circulating oven.
Should it be desired to produce a film which is fabric laminated within or
fabric laminated to such hydrogel products, the fine mesh fabric is placed
smoothly in the casting chamber before the fluid hydrogel is cast.
Subsequent handling of such cast films follows the sequence of treatments
involving whitening with an oxidizing (H.sub.2 O.sub.2) agent, followed by
a treatment using organic solvent dehydration steps, etc., all as
described for producing contact lenses having unique physical and chemical
properties (Example 1).
EXAMPLE 7
Tubes, Arteries, and Other Structural Forms
Using the same formulation described in Example 6, the deaerated hydrogel
is poured into a concentric mold in order to cast a tube (or artery), with
or without a fabric matrix within the mold.
The crosslinking reaction is allowed to proceed at R.T. (25.degree. C.) and
58 percent R.H. for at least 24 hours and to bring the moisture content to
not more than 10 percent. The solid hydrogel is slipped out of its
concentric mold to form a tubular structure suitable for use as an
artery-like prosthesis.
The tubes are then subjected to bleaching, washing, dehydration, washing,
and final air drying steps identical to those described in detail in
Example 1.
EXAMPLE 8
Bone-Like Prostheses
The starting raw material for producing both cancellous-like and
cortical-like prosthesis from the stabilized natural protein polymer
hydrogels of this invention is identical to or closely similar to the
formulation described on Example 6. One of the major differences involves
the use of phosphoric acid in preference to hydrochloric acid to adjust
the acidity of the hydrogel prior to the addition of the crosslinking
reagent.
The initial water-soluble non-crystalline natural protein solution has
intimately dispersed within it calcium phosphate particles or crystals
with or without inclusion of other ions such as are found in naturally
occurring bone and cartilage. The product consists primarily of an
intimate and homogenous physical mixture of the various ingredients and
various ions may be included to increase the hardness of the product prior
to the addition of the protein crosslinking agents described in prior
examples.
The calcium phosphate may be formed by mixing solutions of a soluble
calcium salt, such as calcium acetate, and of a soluble phosphate, such as
sodium phosphate. In the event other salts and/or ions are to be included,
such as the fluoride or carbonate ions, soluble salts, such as calcium
fluoride or sodium carbonate, may be incorporated in the salt solutions
during the formation of the calcium phosphate. The precise structure of
the calcium phosphate compounds formed are complex and the term "calcium
phosphate" is used to include dicalcium phosphate, tricalcium phosphate,
octacalcium phosphate, hydroxyapatite, carbonate-apatite, chlorapatite,
fluorapatite, and mixtures thereof.
A modification of Example 6 found to be desirable in producing extremely
porous, cancellous-type prostheses is the replacement of water as the
protein solvent with a dilute aqueous solution of hydrogen peroxide, for
example, a 1 percent by volume aqueous solution. Following dissolution of
the protein in the dilute solution of hydrogen peroxide, a sufficient
amount of a 25 percent (by weight) aqueous slurry of calcium phosphate was
incorporated into the protein solution to provide approximately equal
amounts of protein and calcium phosphate. The pH was then adjusted with
phosphoric acid and the crosslinking agent added and the mixture
vigorously agitated while maintaining the temperature at 60.degree.
C..+-.5.degree. C. The use of the hydrogen peroxide solution as the
protein solvent results in the formation of small uniformly dispersed
bubbles during the adjustment of the pH addition of the crosslinking agent
and thus forms a uniformly porous structure during crosslinking and
drying.
In some instances, it may be preferred to freeze-dry the resulting
hydrogel-calcium phosphate compositions in lieu of the usual air drying
sequences described in prior examples. In any case, the requisite sequence
drying initially to a moisture content of not more than 10 percent,
preferably 7 percent or less, followed by further soaking in hydrogen
peroxide (3% by volume) and organic solvent dehydration as described in
Examples 1, 2, and 3, remains desirable in order to obtain bone-like
structure having durable wet-strength properties. For example, when placed
in water they exhibit a swelling but remain as coherent and do not
disintegrate.
These products are new compositions of matter from which useful structures
resembling cartilage, bone, and ivory may be produced.
EXAMPLE 9
Fibers, Textile Products, and Sutures
The same composition of water soluble protein hydrogel described for
Example 6 is a suitable starting raw material for producing novel fibers
capable of being fashioned into many conventional textile forms--webs,
fabrics, mats, etc.
The gel, prior to the addition of the crosslinking additive, is pumped into
a chamber in sequence with a mechanism capable of extruding the hydrogel
through spinnerets to form ultrafine fibers or even monofils; such
equipment is commonly used in producing viscose rayons.
The temperature of the gel is kept at 60.degree. C..+-.5.degree. C. in the
antichamber, prior to being passed through a mixing pump into which the
appropriate amount of crosslinking agent is metered. The filaments are
continuously extruded into long vertical cylindrical drying chambers in
which they are dried to a moisture content of not more than 10 percent,
preferably 7 percent or less, so that they can be collected on reels or in
the form of skeins. Following the initial drying step described above, the
yarns are next treated with the same oxidizing treatment (e.g. H.sub.2
O.sub.2), organic solvent dehydration, extensive final washing, and final
drying following the sequence of process steps similar to that described
in prior examples.
Such fibers are suitable for a variety of medical and apparel uses. When
extruded in the form of small diameter filaments, they may be used as
sutures for surgery.
As many apparently widely different embodiments of this invention may be
made without departing from the spirit and scope thereof, it is to be
understood that I do not limit myself to the specific embodiments thereof
except as defined in the following claims:
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