Note: Descriptions are shown in the official language in which they were submitted.
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The invention relates to a biologic absorbable implant
material for filling and closing soft-tissue cavities and
for replacing soft-tissue parts, as well as to a method of
its preparation.
In the field of orthopedics, implant materials for
filling bone cavities are known, which are produced by
partial deproteinisation and denaturation of the residual
protein from spongiosa bone tissue (German Patent No.
961,654). This material, which is known as "Kieler
spongiosa", basically has the same calcium content as
native spongiosa. Consequently, it is hard and totally
inelastic, thus being unsuited for application in soft-
tissue parts.
In bone surgery, a material produced from cortical
bones, i.e., tubular bones, by decalcification is known
(Journal of Surgical Research 37, 487-496 (1984)), which
has an osteoinductive effect supposed to be due to its
content of bone morphogenetic protein. On account of this
osteoinductive property, its use outside bones is contra-
indicated.
In EP-A No. 0,171,176, a composition for repairing
bone defects is described, which is prepared from bone
collagen by decalcification and lyophilization, forming a
gel upon reconstitution. On account of the desired
osteoinductive effect of this material, care is taken that
no cross-link formation of the collagen occurs during
preparation.
Furthermore, a collagen-based bone substitute material
is known from German Auslegeschrlft No. 28 54 490. It is
prepared from bones by removing the blood pigment and other
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water-soluble proteins, degreasing and eliminating the
mineral portions by means of complexing agents or ion
.-exchangers and finally freeze-drying. Upon reconstitution,
the material is insufficiently elastic and not suited for
application in soft tissue parts.
So far, only collagen fleeces have become known as
coverage and implant materials for the application at or in
soft tissue parts. However, such fleeces have no
dimensional stability and no elasticity in the moist state;
they are suited for firm bonding to mobile tissue, e.g.,
to the lung, to a limited extent only. Synthetic materials,
such as acrylates, which likewisely have been proposed,
still have other disadvantages, among which massive
stimulus caused by a foreign body, encapsulation,
insufficient healing and the possible release of toxic
decomposition and side products are particularly
emphasized.
Further known prior art prosthetic implant materials
are produced from body tissues by treatment with protein
cross-linking agents. Such materials are used in order to
increase the stability of certain organs, e.g., of cardiac
valves or vascular prostheses. Such implants are described,
for instance, in EP-B No. 0,174,737 and in U.S. Patent No.
4,120,649.
The invention has as its object to provide a well
tolerated implant material that may be used to close tissue
cavities, on the one hand, and to substitute certain tissue
parts, on the other hand, and which does not have the
disadvantageous properties of the known products, which
limit their therapeutic utilization.
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After lung resections and also after other diseases ofthe lung, bronchopleural fistulas may occur. These are
septic openings or cavities forming between the bronchial
tree and the pleura and filled with secretions and pus.
They are constantly passed by air and secretions during
breathing and coughing, their sizes ranging from a few
millimeters to several centimeters in terms of diameter.
Therefore, it is a still unsolved problem in thorax surgery
how to seal such bronchial fistulas and how to enhance
curing of the same, in particular, if the introduction of
the implant is to be effected by way of endoscopy, which
were the quickest and mildest way. Special demands are set
on an implant material to be introduced and fixed
endoscopically. On the one hand, mechanical spreading must
be feasible, on the other hand, introduction through the
bronchial tree to the fistula must be possible.
The implant must be deformable and compressible. It
must be able to reassume its original shape in the presence
of moisture, i.e., it must have a high memory effect. In
addition, the material must offer a considerable strength,
yet remain absorbable, because germs may adhere to non-
absorbable materials, thus causing abscesses and new
fistulas again and again. Besides, according to a further
aspect of the invention, it is to be possible to obtain a
gas- and liquid-tight closure immediately upon introduction
of the implant. Finally, it is to be possible to
incorporate into the material bactericidal and/or other
pharmaceutical substances or such stimulating wound
healing.
The invention by which these objects are achieved with
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a biologic absorbable implant material for filling and closing
soft-tissue cavities and for replacing soft-tissue parts
consists in that
- the implant material consists essentially of
spongiosa bone tissue of human or animal origin
molded into shaped products,
- which is decalcified,
- vhose native proteins are cross-linked with a protein
cross-linking agent in order to avoid osteoinductive
activity,
- the shaped products exhibiting a high elasticity at a
lov hysteresis between loaded and unloaded
conditions.
Thus, according to the invention, the initial protein
content of the decalcified osseous hard substance remains
almost unchanged and the high elasticity and stability are
brought about by the cross-link formation of the native
proteins.
The shaped products formed of bone tissue may, for
instance, have block, conical or spherical shapes.
To fill and close tissue cavities, the implant
material may have spongy consistency, the pore volume of the
material belng 55 to 95%. The material is compressible in the
dry state; however, it reassumes its original shape in the
presence of moi~ture, which means that it has a marked memory
effect.
Decalcification is continued until the residual
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content of calcium amounts to 80 mMol/g wet weight at the
most.
~ According to a preferred embodiment, the implant
material may contain a tissue adhesive on fibrinogen or
collagen base.
The invention, furthermore, relates to a method of
preparing the implant material, which is characterized in
that native protein-containing bone material is decalcified
by a decalcifying agent, is washed free from the
decalcification agent, then is treated with a protein
cross-linking agent, is repeatedly washed to remove the
protein cross-linking agent, if desired, is combined with
pharmaceutical solutions, such as tissue adhesive solutions
on fibrinogen or collagen base, and finally is dried and
sterilized.
As the cross-linking agents, aldehydes, in particular
glutaraldehyde, polyepoxide compounds, diisocyanate
compounds or carbodiimides may be used.
The bone material, suitably, may be degreased by means
of an organic solvent, such as chloroform-methanol, before
or after decalcification.
There may also be provided to treat the bone material
with agents that reduce possibly present contents of
undesired antigens, e.g., detergents or enzymes, before or
after protein cross-linking.
The implant material according to the invention and
the method of its preparation may be modified in various
aspects to impart additional pharmaceutical effects and
properties. Thus, when using a detergent, e.g.,
octylphenoxy-polyethoxyethano] Triton* X-100 in a one-
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percent concentration, in the washing solutions, it is not
only possible to reduce the content of undesired antigens,
but the danger of a subsequent calcification of the implant
may be lowered, too. Moreover, a low content (about 0.5 M)
of ethylenediaminetetraacid sodium may be provided in the
washing solutions, whereby decalcification is improved. i,
The intermediate treatment of the implant material
with a buffer solution containing enzymatically effective
substances, for instance, ficin and/or neuraiminidase, may
be provided, which likewisely reduce the antigen content
in the finished product.
In order to make sure that the finished product will
not contain any traces of glutaraldehyde, the material may
be rinsed with a glycine or lysine solution (content about
5 mg/ml) after the cross-linking treatment.
If the implant material according to the invention has
been produced from spongiosa, it is suitable if the implant
material is compressed, approximately to half its volume,
prior to being filled into final containers.
20A special field of application of the material
according to the invention is the substitution for tubular
tissue parts, such as trachea parts. As the starting
material for such an implant, femur bones are used, which
are tubularly reduced to a wall thickness of about 2 mm by
mechanical surface abrasion on a lathe, before being
subjected to the combined treatment by decalcification and
protein cross-linking according to the invention.
The end product according to the invention, if
destined to fill tissue cavities, suitably is brought into
block shape.
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The material may be sterilized by gamma rays and may
be stored in containers, which, for instance, contain a 70
-% ethanol solution. The blocks are rinsed with a Ringer
solution prior to being applied into patients.
It is also possible to store the blocks in a dry state
after sterilization with gamma rays, wherein, according to
a particularly preferred embodiment of the invention, the
blocks are soaked with a fibrin sealant under sterile
conditions and subsequently are lyophilized in the final
container.
Naturally, the product according to the invention, in
addition to the block or tubular shape already described,
may be made available also in disk or sheet form.
The method according to the invention and the product
produced thereby will be explained in more detail in the
following example.
1 kg of spongiosa bone material from the calf was
obtained by cutting the head of a femur into cubes.
These spongiosa cubes were rinsed with hot water
(50C) and subsequently were decalcified at room tempera-
ture in 0.6N hydrochloric acid (10 1) under continuous
motion and by repeatedly changing, pressing and washing the
spongiosa blocks (24 to 72 hours). Subsequently, the blocks
were washed free of acid and incubated with 1 % glutaralde-
hyde in a 0.05 M phosphate buffer solution (1 1) at a pH of
7.4 at room temperature for one hour so as to effect cross-
linking.
By at least five times of washing with a sterile
washing solution and pressing of the spongiosa, the
residual glutaraldehyde was removed from the spongiosa. The
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bloeks were freeze-dried, filled into final containers and
sterilized within the same by means of 2.5 Mrad gamma rays.
.- A thus produced implant material in block form was
inserted into patients as a fistula closure by way of
endoscopy: The patient was intubated with a rigid
bronehoseope and respiration in the open system was
performed by means of jet ventilation. After inspection of
the fistula, a suitable spongiosa piece was cut and
eompressed so as to be able to be guided through the
bronehus with the bronchoseope. The implant was placed into
the fistula by biopsy forceps, where it got moistened upon
eontaet with the bronehial wall, expanding very rapidly and
spreading. Immediately upon setting of the implant, 1 to 2
ml of a fibrin sealant were dropped about the implant by a
three-lumen spraying eatheter, the implant, thus, swelling
further and bonding with the bronehial wall. An immediate
air-tight elosure of the fistula was obtained.
The implant material aeeording to the invention does
not exert any osteoinductive effect, which can be proved by
measuring alkaline phosphatase and by histologic
investigations. Consequently, the material can safely be
used for application in soft tissue regions.
The implant material produced according to the
invention has excellent elasticity properties. For the
purpose of eomparison with known preparations, spongiosa
bloeks having an edge length of 1.5 cm were produced, once
without treatment with a protein cross-linking agent and
once with the treatment according to the invention by
eombined deealeification and protein cross-linking as
described in the above embodiment. The blocks were dried
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and then were moistened with a 0.9 % NaCl solution. All the
blocks were checked in a loading apparatus (transducer 0 -
.1000 pond at a loading speed of 1 cm/min), with load andrelief curves resulting, which are illustrated in the
drawing.
The load curve and the relief curve (power - distance)
of the spongiosa blocks that have not been subjected to
cross-linking are denoted by 1 and 2; 1' and 2' represent
the respective curves of the preparations according to the
invention. It is apparent that, with the prior art
preparations, which have not been cross-linked, a
relatively low strength and an intense hysteresis occur,
whereas the spongiosa blocks according to the invention do
not develop any signs of hysteresis and exhibit high
strength values.
The tissue tolerance of spongiosa blocks according to
the invention, having the dimensions of 0.5 x 0.5 x 1 cm
and produced according to the exemplary embodiment, was
tested in rat experiments. The blocks were implanted
subcutaneously into the backs of the rats, were taken at
various time intervals, were fixed and processed
histologically.
It appeared that noncross-linked spongiosa blocks
showed more intensive inflammatory reactions, more foreign-
body giant cells, more fibrosis and the tendency to
absorption already after a fortnight, clear signs of dis-
integration occurring after 4 weeks. In contrast, no such
side effects could be observed with the samples treated
according to the invention.
