Note: Descriptions are shown in the official language in which they were submitted.
~IOCOl~PATIBIE MA~ERIAI ~OR '~R~A~E~
o~ ~TS~ulAR OR O~GANIC D~EC~S
~ he present invention relat~s to ~edicine and has par-
ticular reference to a bioco:ilpatible material for treat~ent
of tissular or orGanic defects that can be applied for co-
vering the pancreas botn in normal state and in case o~ pan-
creatitis, for closin~ up the resected surface of the paren-
ch~ atous orga~s, for reparation of the dural defects, or
of extensive defects of the anterior abodiminal wall, for
reparative surgery of the rectal cphincter, as well as for
treat~ent of suppurative skin lesions a~d operative wounds.
~ nown in the present state of the art is a co~position
for connective e~e~ents of soft tissues and organs based on
resorbable poly~ers and co~prisin~ a copoly~er of i~-vinyl-
pyrrolidone and al~yl acrylates and/or al~yl methacr~lates
which contain 2 to 8 carbon atoms in their alkyl group (cf.
Belgian patent No. 899.078 issued September 6, 1984). The
connective elements are in fact sheets and films of preset
configuration and are employed mos-tly in reuni-ting and
hermetically sealing incised or resected portions of the
parenchymatous organs. The film is resorbed in the organism
within 35 to 250 days, its tensile strength ranging within 6.7
and 18.8 kgf/cm2 and percentage elongation after a 30-minute
holding in physiological saline which is a measure of its
elasticity in a swollen state varying from 21 to 880~
~ owever, the compositions mentioned abov~ are charac-
terized by the ~act that when in the ~orm o~ dry films,
a
they are brittle; therefore, the Eilms should be
placed in physiological saline within 10 to 15
minutes before use in order to impart adequate
elasticity thereto.
On the other hand, higher elasticity of the
films (characterized by their percentage elongation)
results in a reduced strength of the material. Since
the resorption period of the films exceeds the
regeneration period of the soft tissues, the latter
have no time enough to grow into the connec~ive
elements.
Besides, since the material of the connective
elements does not allow one to adjust its absorbality
characterized by the degree of swelling, it cannot be
used for treatment of suppurative skin lesions and
operative wounds.
Known to be used commonly is also the
material Debrisan (available from Pharmacea Co.,
Sweden) which is applicable for treatment of suppur-
ative wounds (cf. the journal "Surgery", Meditsina
Publishers, Moscow, No. 8, 1982, pp. 88-91 (in
Russian). Debrisan appears as a white powder
consisting of dextran polymers; it features high
degree of absorbability, i.e., 4 ml per gram of the
agent. Debrisan is poured into the wound, then a
moistened towelette is placed thereon and a piece a
wax paper is put atop. Dressings are to be changed
lV~
. 3
daily, the powder belng removed by gauze balls and
washed oEf with any suitable solution. Application
of Debrisan contributes to debridement and drying of
the wound and reduces the degree of edema. However,
application of DEBRISAN is inneffective when the
wound is invaded with blue pus bacillus, as well as
in cases of acute suppuration of -the wound. In such
a case administration of antibacterial drugs within
the initial 2 or 3 days is more effective.
In addition, application of Debrisan to and
its removal from deep wounds or fistular cavities.
It is an object of the present invention to
provide a biocompatible material for treatment of
tissular or organic defects that would possess
adjustable absorbability and resorption rate
coordinated with tissue regeneration rate, and would
feature higher elasticity in combination with
adequately high s-trength.
The a:Eoresaid object is accomp~ished due to
the fact -that a biocompatible material for treatment
of tissular or organic defects based on a resorbable
polymer, according to the invention, comprises a
graft copolymer of alpha-cyanacrylate and polyacrylic
acid having a molecular mass of 200,000 to 600,000
and obtained due to intereaction of alpha-cyan-
* Trade mark
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. ~
acrylate with polyacrylic acid in the presence of a
cross-linking agent, the weight percentage ratio of
the aforesaid components being as follows:
alpha-cyanacrylate 14 to 34
polyacrylic acid having a
molecular mass of 200,000
to 600,000 15 to 43
cross- linking agent 71 to 23.
The biocompatible material as herein claimed
comprises as alpha-cyanacrylate preferably ethyl-
alpha-cyanacrylate, ethoxyethyl-alpha-cyanacrylate,
butyl-alpha-cyanacrylate, or mixtures thereof.
The biocompatible material herein claimed
comprises as a cross-linking agent polyvinyl alcohol
having a molecular mass of 50,000 to 60,000,
glycerol, or a mixture thereof. The biocompatible
material of the invention can be obtained in the form
of dia. 0.5 to 1.5 mm granules, or dia. 0.8 to 2.5 mm
strings, films 100 to 1000 ~m thick, sheets 10 to 50
mm thick, sheets with a developed surface providing a
a maximum area of contact with the wound.
The density IP) of the material ranges within
0.16 and 0.8 g/cm , the absorbability characterized
by the daily swelling weight percent increment (A)
varying from 500 to 15000, percentage elongation (E)
at tension characterizing elasticity, ranging within
10 to 150 percent, and ultimate tensile strength,
':, '' :' ''' `
~L;27~8~
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within 40 to 55 kgf/cm . The material is amenable to
fragmentation and biodegradation under the effect of
the biological fluids of human organism.
The degree of swelling of the biocompatible
material may amount to 10000 or 15000 percent which
renders the material promising for treatment of
supperative skin lesions and operative wounds.
Whenever necessary the biocompatible material
may be doped with some medicinal substances, e.g.,
antiseptics, and hence it is applicable in surgery
and traumatology for prevention or stopping of infec-
tion. According to the invention, the biocompatible
material contains preferably an antiseptic in an
amount of 9 to 50 weight percent.
The biocompatible material of the invention
is featured by such a resorption time that provides
for its permanent replacemen-t by the regenerating
organism's tlssue. A biocompatible material can be
established within the limi-ts of the aforestated
formulation, said material being featured by
comparatively high strength and elasticity when both
dry and swollen, which renders it easily mouldable on
intricately shaped surfaces. The degree of swelling
of the biocompatible material that characterizes its
absorbability may amount to 15000 percent within a 24
..
_~ 6
hour period, which makes the ma-terial promising for
treatment of suppurative skin lesions and operative
wounds.
The biocompatible material resulting from
formulations that come beyond the limits specified
above, fails to meet, as for its characteristics, the
requirements imposed thereon. Thus, the material
resulting from the reaction of aqueous solutions of
polyacrylic acid and polyvinyl alcohol with alpha-
cyanacrylate taken in an amount below 14 percent, is
liable to undergo fragmentation and biodegradation as
early as in six hours after preparation and cannot
therefore be used for closure and treatment of soft-
tissue and organic defects. The biocompatible
material resulting from the use of alpha-cyana-
crylates taken in an amoun-t exceeding 34 percent,
features the resorption period in -the organism
exceeding two months, thus precluding its permanent
replace~ent by the regenerating tissue, and cannot
therefore be applied for closure and treatment of
soft-tissue and oryanic defects.
The biocompa-tible material being claimed has
been studied experimentally on 20 male rats of the
Vis-tar race, weighing 200 to 240 g. Experiments were
conducted on the test animals under inhalation ether
narcosis. Once a 1.2 to 2.0 cm long incision had
been made in the skin of the anterior abdominal wall,
the skin was separated by the blun-t technique from
the subjacent muscles, whereupon a film measuring 1.0
to 1.5 cm in length was placed in the thus formed
pocket. The experiment results have demonstrated
that vast proliferation of the granulation tissue
occurs round the film and between the muscular fibres
of the adjacent muscle on the seventh day after the
implantation, and the tissue becomes collagenated on
the side of the implant. A tendency is observed for
a connective-tissue capsule to form round the film,
which capsule is finally established on the twenty-
first day after surgery, and is closely adhered to
the subjacent muscles, and somewhere to the skin.
The film biodestruction process which begins
in step with the start of the connective-tissue
capsule formation, is practically terminated on the
twenty-first or twenty-third day after surgery.
Histologic examination reveals accretion of
some individual elements of the capsule between the
muscular fibres at the spots where the capsule
adheres to the muscle. Implantation of the material
is accompanied by the development of neither drastic
dystrophic nor necrobiotic changes in the subjacent
muscular tissue.
The biocompatible material of the infection
has been tested experimentally for closure of the
pancreas on 10 sexually mature rats weighing 200 to
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250 g each. The experiment was carried out with the
test animals under inhalation ether narcosis. The
supramedian laparotomy was made, the duodenum was
brought through the operative wound together with the
stomach, pancreas and spleen. A film measuring
2X3cm2 was placed on the pancreas, whereupon the
gland was reinvaginated in the abdominal cavity and
the operative wound was stitched up in layers. The
test rats were withdrawn from the experiment within
various periods after the surgery for being subjected
to macroscopic and histologic examinations. In three
weeks after surgery the film was found to be no
longer in the abdominal cavity. Macroscopically the
pancreas developed no perceptible change, no
adhesions being observed in the abdominal cavi-ty.
Histologic examina-tion demonstrated the norma]
structure of the organ without any symptoms of
inflammatory al-terations.
There has been studied also a possibili-ty of
application of the present biocompatible material
reinforced with lavsan net-ting to restore the lost
colic sphincter in children developing neurogenic
disturbances of the pelvic organs. The experiment
was carried out on 10 test cats using the following
procedure. The distal segment of the rectum was
exposed and embraced with a strip of the bio
compatible material which was then stitched to the
~7
pubic bones. Thus, the rectum was drawn forward to
establish the rectal sphinc-ter. Morphologic examin-
ations at terms from one to three months after
surgery has shown that the biocompatible material is
replaced by the cicatricial connective tissue which
will subsequently serve as -the sphincter of the
rectum. Such a surgical procedure has been applied
clinically in eight patients with complete rectal
incontinence, a positive result being obtained in
every case.
The present biocompatible material featuring
high absorbabili-ty (the daily swelling percent
ranging within 5000 and 15000) has been tested on
liquid media to show that there occurs uniform
absorbing of the microorganisms situated throughout
the entire thickness of the materials. The evidence
obtained served as the grounds for application of the
biocompatible material clinically for drainage oE
suppurative flat skin lesions in patients.
With such purpose in view the present bio-
compatible material has been used, comprising anti-
septics, e.g., chlorophyllitum (an extract of
eucalyptus leaves, containing a mixture of chloro-
phylls). The biocompatible material containing anti-
septics has been applied to 15 patients clinically~
In every case a markedly pronounced positive clinical
effect has been observed, i.e., rapid depuration of
,, - 10 ~
the wound from purulent debris, change in -the
microbial coun-t, quick appearance of granulations and
marginal epithelialization, reduced healing period of
the wound as compared with traditional treatment
methods.
Plastic reparation of extensive defects of
the anterior abdominal wall using the present bio-
compatible material in the form of sheets reinforced
with lavsan netting has been studied experimentally
on 50 test rats aged 2 to 2.5 months and weighing 150
g each. Four kinds of defects of the anterior
abdominal wall were established by excisions arranged
longitudinally and transversely and occupying 20 and
~0 percent of the total abdominal wall area. Then
the defect was covered with an oval piece of the
reinforced biocompatible material, and the skin above
it was stitched up. The results of the experimen-t
have demonstrated the healing of the operative skin
wound to occur by firs-t intention. Morphologic exam-
ination of excised preparations of the anterior
abdominal wall of the test rats carried out one, two,
and three months after surgery has demonstrated good
replacement of the present biocompatible materlal by
connective tissue without any symptoms of an inElam-
matory process. On the part of the abdominal cavity,
there were exhibited no manifestations of adhesion of
the intestinal loops to the anterior abdominal wall,
the inner surface of the repaired defect had ap-
eritoneum-like lining provided with a developed net-
work of small vessels. Similar surgical procedure
was carried out clinically in 6 patients suffering
from embryonal hernias and gastroschisis. In all
cases the defect of the anterior abdominal wall was
managed to be closed completely, while the operating
time was cut down considerably.
The biocompatible material conslsting of a
graft copolymer of alpha-cyanacrylate with poly-
acrylic acid, is prepared by mixing a solution of
alpha-cyanacrylate in an organic solvent that does
not polymerize alpha-cyanacrylate and is immiscible
with water, with an aqueous solution of polyacrylic
acid having a molecular mass of 200,000 to 600,000,
and a cross-linking agent, preferably polyvinyl
alcohol having a molecular mass of 50,000 to 60,000,
or glycerol, or a mixture of both, until an emulsion
is obtained. The biocompatible material in the form
of films or sheets is obtained by casting the emul~
sions, in the form of granules, by pouring the
emulsion dropwise into a settling ba-th (an
electrolyte solution), and in the form of strin~s, by
extruding through a profiled die or spinneret into a
settling bath. The solvents are then removed by one
of the known methods, e.g., by holding the fi~ished
product within a definite tempexature interval.
- ~2 -
After having been dried the finished product from the
biocompatible material in the form of films, sheets,
granules, or strings may be additionally subjected to
heat treatment to produce cross-linked polymers.
Characteristic curves of the differential-
thermal analysis of the films produced by the afore-
said method, confirm the presence of an interaction
between alpha-cyanacrylates and polyacrylic acid,
thus differing from the characteristic curves
obtained with homopolymers (such as polyethyl-alpha-
cyanacrylate, polyacrylic acid, and mechanical
mixtures of both). The nitrogen content of the
speeimens of the biocompatible material being claimed
ranges within 1.10 and 3.84 weight percent.
For a better understanding of the present
inven-tion, the following examples of the bio-
compatible material as therein claimed are given
below by way of illustration.
Example 1
_
The biocompatible material, comprising a
graft copolymer of alpha-eyanacrylate and polyacrylic
acid having a molecular mass of 200,000 to 600,000,
is prepared due to interaction of alpha-cyanacrylate
with polyacrylic acid in the presence of a cross-
linking agent, viz., a mixture of polyvinyl alcohol
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having a molecular mass of 50,000 to 60,000, with
glycerol, the weight percentage ra-tio of the afore-
said components being as follows:
mixture of e-thyl-alpha-cyanacrylate and
ethoxyethyl-alpha-cyanacrylate (1:1) 19
polyacrylic acid having a molecular
mass of 200,000 to 600,000 35
polyvinyl alcohol having a molecular
mass of 50,000 to 60,000 35
glycerol 11
The aforementioned material is prepared by
adding 0.790 g (19 weight percent) of a mixture of
ethyl-alpha-cyanacrylate and ethoxyethyl-alpha-cyan-
acrylate taken in a ratio of 1:1, dissolved in
chloroform, to 1.41 g (35 weight percent) of poly-
acrylic acid having a molecular mass of 200,000 to
600,000 in the presence of 1.41 (35 weight percent)
of polyvinyl alcohol having a molecular mass of
50,000 to 60,000 and 0.46 g (11 weight percent) of
glycerol.
Then a fllm is formed by -the casting method
with the use of an extrusion die or spinneret, where-
upon the solvent is eliminated at 37 to 39 C. Next
the thus-obtained film is subjected to heat treatment
at 100C within 60 min. The biocompatible material
which is in effect a cross-linked graft copolymer of
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alpha-cyanaerylate and polyaerylle aeid, is prepared
as a foamed film having the following character-
stles:
-thickness 400 ~m
absorbability (in terms of daily
swelling pereentage) 1250
pereentage elongation at tension 125
density 0.36g/cm3
ultimate tensile strength54 kgf/cm2
0 Example 2
The bioeompatible material, comprising a
graft copolymer of ethyl-alpha-cyanacrylate and
polyaerylic acid having a molecular mass of 200,000
to 600,000, is prepared by interaetion of ethyl-
alpha-cyanacrylate ~ith polyacrylic acid in the
presence of a mixture of polyvinyl alcohol and
glycerol, the weigh-t percentage ratio of the afore-
said original components being as follows:
ethyl-alpha-eyanaerylate 34
polyacrylic acid haviny a molecular
mass of 200,000 to 600,000 43
polyvinyl alcohol having a molecular
mass of 50,000 to 60,000 21
glycerol 2
The aforesaid material is prepared by inter-
aetion of 3.25 g (34 weight percent) of ethyl-alpha-
cyanaerylate with 4.1 g (43 weight percent) of poly-
~ .
7~
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acrylic acid having the aforesaid moleeular mass, in
the presence of 2.0 g (21 weight percent) of poly-
vinyl alcohol and 0.19 g (2 weight percent) of
glycerol. The resultant emulsion is poured onto a
back-up pla-te that provides for formation of a sheet
with developed surface. Then the back-up plate along
with the material in question is placed in a bath
containing an aqueous sodium chloride solution and
kept there for two hours. The biocompatible material
obtained after drying and heat treatment is in fact a
cross-linked graft copolymer of ethyl-alpha-cyanacry-
late with polyacrylic acid and appears as a sheet
havi.ng developed surface and featured by the
following eharacteristics:
thickness 30 to 50 mm
absorbability (in terms of
daily swelling percentage) 5000
density 0.17 g/em
Example 3
__ .
I'he biocompatible material composed of a
graft copolymer of butyl-alpha-cyanacrylate and poly-
acrylic acid having a molecular weight of 200,000 to
600,000, is prepared by interaction of butyl-alpha-
cyanacrylate with polyacrylic acid in the presence of
polyvinyl alcohol, the weight percent ratio of the
aforementioned components being as follows:
butyl-alpha-cyanacrylate 24
'
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polyacrylic acid having a molecular
mass of 200,000 to 600,000 38
polyvinyl alcohol having a molecular
mass of 50,000 to 60,000 38
The aforesaid material is prepared by inter-
action of l.lg (24 weight percent) of butyl-alpha-
cyanacrylate with 1.7g (38 weight percent) of poly-
acrylic acid having the aforesaid molecular mass, in
the presence of 1.7 g (38 weight percent) of poly-
vinyl alcohol having a molecular mass of S0,000 to
60,000. The thus-obtained emulsion is poured, while
stirring, dropwise into a settling bath, containing a
sodium chloride solution. In three hours after
completing the pouring of the emulsion the resultant
granules are filtered out and dried by any of the
heretofore known methods.
The biocompatible material appearing as
granules is in fact a graft copolymer of butyl-
alpha-cyanacrylate and polyacrylic acid cross-lin}ced
with polyvinyl alcohol and features the following
characteristics:
average granule diameter1 to 2 mm
absorbability (in terms of
daily swelling percentage) 15000
density 0.4 g/cm3
Example 4
The biocompatible material, composed of a
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graft copolymer of ethoxyethyl-alpha-cyanacrylate and
polyacrylic acid is obtained by interaction of
ethoxyethyl-alpha-cyanacrylate with polyacrylic acid
in the presence of a mixture of polyvinyl alcohol
with glycerol, the weight percentage ratio of the
aforesaid components being as follows:
ethyl-alpha-cyanacrylate 14
polyacrylic acid having a molecular
. mass of 200,000 to 600,000 15
polyvinyl alcohol having a molecular
mass of 50,000 to 60,000 60
glycerol 11
The aforesaid material is prepared by inter-
action of 1.3 g (14 weight percent) of ethoxyethyl~
alpha-cyanacrylate with 1.4 g (15 weight percen-t) of
polyacrylic acid having a molecular mass of 200,000
to 600,000 in the presence of 5.6 g (60 weight
percent) of polyvinyl alcohol having a molecular mass
of 50,000 to 60,000 and 1.0 g (11 weight percent) of
glycerol. One half of the thus-obtained emulsion (by
volume) is applied, through an extrusion dle or
spinneret, to a backing-up plate, then a poly-
ethyleneterephthalate (lavsan) net of a required size
is placed on the spread layer of the emulsion, and
the other half (by volume) of the emulsion is applied
~7~
thereto. Then the solvents are removed at 37 to
40C, and the material is subjected to heat treatment
at 90C within 90 min.
The biocompatible material appearing as a
sheet reinforced with lavsan netting is in fact a
graft copolymer of ethoxyethyl-alpha-cyanacryla-te and
polyacrylic acid cross-linked with polyvinyl alcohol
and glycerol and glycerol, its characteristics being
as follows:
thickness 1.2 mm
density 0.23 g/cm3
absorbability (in terms of
daily swelling percentage) 600
resorption period of polymeric
matrix in muscular tissue 30 to 40 days
Example 5
The biocompatible material, compose~ of a
graft copolymer o~ alpha-cyanacrylate and polyacrylic
acid is obtained by in-teracti.on of a mixture of
ethyl-alpha-cyanacrylate and ethoxyethyl-alpha-cyan-
acrylate (1:1) with polyacrylic acid in the presence
of glycerol and an antiseptic, viz~, chlorhexidine
gluconate(l,6-di(N-p-chlorophenyldiguanido) hexane
digluconate), the weight percentage ra-tio of the
aforesaid components being as follows:
mixture of ethyl-alpha--cyanacrylate
and ethoxyethyl-alpha-cyanacrylate 30
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., .~
polyacrylic acid having a
molecular mass of 200,000 to 600,000 43
glycerol 27
chlorhexidine gluconate 9 (of
a total weight
of the above
components)
The aforesaid material is prepared by inter-
action of 3.3 g t30 weight percent) of ethyl alpha-
cyanacrylate mixed with ethoxyethyl-alpha-cyan-
acrylate in a ratio of 1:1, and 4.7 g (43 weight
percent) of polyacrylic acid having a molecular mass
of 200,000 to 600,000 in the presence of 3.0 g (27
weight percent) of glycerol and 0.99 g chlorhexidine
gluconate (9 percent of a total weight of the afore-
said components). Then the resultant composition is
extruded through a profiled die or spinneret into a
settling bath containing a sodium chlor:Lde solu-tion
to shape the material as strings. Next the solvents
are removed a-t 37 to 40.
The biocompatible material which is in ~act a
graft copolymer of alpha-cyanacrylate and polyacrylic
acid, containing an antiseptic, i.e., chlorhexidine
gluconate, has the following characteristics:
absorbability (in terms of daily
swelling percentage) 700
antimicrobial activity against
7 ~
~ 20 ~
the strains of staphyloeoeei,
eolibacillus, and other gram-
positive baeteria
Example 6
The biocompatible material, eomposed of a
graft eopolymer of alpha-eyanaerylate and polyacrylic
acid having a molecular mass of 200,000 to 600,000 is
obtained by interaction of a mixture of ethyl-alpha-
cyanacrylate and ethoxyethyl-alpha-cyanacrylate (1:1)
with polyacrylic acid in the presence of polyvinyl
alcohol and an antiseptic, viz., gentamyein, the
weight percentage ratio of the original components
being as follows:
mixture of ethyl-alpha-eyanaerylate
and ethoxyethyl-alpha-cyanacrylate 26
polyacrylic acid havi.ng a moleeular
mass of 200,000 to 600,000 37
polyvinyl alcohol having a moleeular
mass of 50,000 to 60,000 37
gentamycin 2
(of a total
weight of the
above components)
The aforesaid material is obtained by inter-
action of 1.8 g (26 weight pereent) of ethyl-alpha-
cyanacrylate mixed with ethoxyethyl-alpha-cyana-
crylate taken in a ratio of 1:1, with 2.6 g (37
1~
~'7~#~L
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, . .
weight percent) of polyacrylic acid having a
molecular mass of 200,000 to 600,000 in the presence
of 2.6 g (37 weight percent) of the polyvinyl alcohol
having a molecular mass of 50,000 to 60,000 and 1.7 g
gentamycin (24 percent of a total weiyht of -the
aforesaid components).
Then a film is formed by the casting method
with the use of an extrusion die or spinneret, the
solvents are removed at 37 to 40C, the material is
heat-treated at lO0 C for 60 mln.
The biocompatible material which is in effect
a graft copolymer of alpha-cyanacrylate and poly-
acrylic acid containing an antibiotic gentamycin, its
characteristics being as follows: absorbability (in
terms of daily swelling percentage) antimicrobial
activity against many gram-positive and gram-negative
bacteria (colibacillus and staphylococci inclusive).
