Note: Descriptions are shown in the official language in which they were submitted.
CA 02308146 2000-O1-27
WO 99105180 PCTIUS98/15382 _
COLLAGEN TYPE I AND TYPE III ADHESIVE COMPOSITIONS
This application relates to and claims priority to U.S. Provisional Patent
Application Serial No: 601053,872 filed July 28, 1997.
1. FIELD OF THE INVENTION
The present invention is directed to polymerized recombinant type I and/or
type III collagen based compositions and combinations thereof for medical use
as
adhesives and sealants and the preparation of such compositions. The
recombinant
type I and type III collagen compositions are useful as medical adhesives for
bonding soft tissues or in a sealant film for a variety of medical uses,
including in
wound closure devices and tendon wraps for preventing the formation of
adhesion
following surgical procedures. In a further aspect of the present invention,
the
polymerized type I and type III collagen composition includes agents which
induce
wound healing or provide for additional beneficial characteristics desired in
a tissue
adhesive and sealant.
2. BACKGROUND OF THE INVENTION
Mechanical, Chemical, Synthetic and Autologous Adhesion Techniques.
The ability to bond biological tissues is a goal of biomedical researchers.
Attempts
to provide desired adhesion through mechanical bonding have proven to be
neither
convenient nor permanent (Buonocore, M., Adhesion in Biological Systems, R. S.
Manly, ed., Academic Press, New York, 1970, Chap. 15). For example, the
conventional methods of choice to close incisions in soft tissue following
surgery,
injury and the like have been sutures and staples. These techniques and
methods,
however are limited by, for example, tissue incompatibility with sutures or
staples
which may cause painful and difficult to treat fistulas granulomas and
neuromas.
Sutures and staples may also tend to cut through weak parenchymatous or poorly
vascularized tissue. Sutures also leave behind a tract which can allow for
leakage of
fluids and organisms. The needle for any suture is larger than the thread
attached to
CA 02308146 2000-O1-27
WO 99105180 PCTIC1S98/15382 -
2
it. This causes a problem as the needle tract is larger than can be filled by
the
thread.
In addition, limits are imposed by the required manual dexterity and eyesight
of the surgeon and the excessive amount of time that is required for the use
of
sutures or staples in microsurgeries. Finally, even when properly applied, the
joints
in the gaps between the staples or sutures may be inherently weak or may
structurally weaken over time and will leak.
Several investigators have worked on laser closure of wounds (White et al.,
1986; White, J. V., 1989; Oz and Bass et al., 1989; White et al., 1987). Early
contributions concentrated on welding tissues using lasers of different
wavelengths
applied directly to wound edges. Investigating the microstructural basis of
the tissue
fusion thus produced, Schober and coworkers proposed that there occurred a
"homogenizing change in collagen with interdigitation of altered individual
fibrils"
(Schober et al., 1986). These investigators, as well as others, proposed that
the
concentrated heating of the collagen fibrils above a threshold level allowed
for their
cross-linking (Goasey et al., 1980; Chacon et al., 1988; Tanner, M. L., 1973).
Unfortunately, the heat necessary to allow this reaction to occur causes
collateral
thermal damage. Even a slight distortion, in ocular tissue for example, may
have
functional consequences. Also, in the event of laser weld failure, the edges
of the
tissues may be damaged by the original treatment and cannot be re-exposed to
laser
energy (Oz, 1990).
Further work attempted to enhance heat-activated cross-linking by placing a
dye in the wound. It was reported that matching the absorbance of the dye with
the
laser wavelength, allowed an adhesive effect to be achieved with less laser
power
output and collateral thermal injury (Chuck et al., 1989; Foote, C. S., 1976;
Oz M.
C. and Chuck et al, 1989). Coupling the dye with a protein to create a tissue
"solder" was also investigated. The protein of choice has been fibrinogen, and
in
particular autologous fibrinogen in order to avoid problems of the transfer of
viral
diseases through the use of blood components from pool donors. In previous
applications, fibrinogen has been obtained as a fraction of whole blood. It is
not
pure fibrinogen, but also contains other blood elements, such as clotting
factors.
Application of such a protein-dye mixture in various animal models proved to
be an
CA 02308146 2000-O1-27
WO 99105180 PCT/US98/15382 -
3
improvement to dye alone (Oz et al. , 1990; Moazami et al. , 1990).
Unfortunately,
human application was forestalled owing to the need to isolate the needed
protein
(fibrinogen) from the patient prior to the procedure to avoid the risks of
infection
from donor plasma. Work with albumin found it to be an unsatisfactory
substitute as
it did not yield welds of comparable strength.
Comparisons of protein-dye versus sutured closures have found the protein-
dye group to produce less of an inflammatory response, result in greater
collagen
production, greater mean peak stress at rupture and better cosmesis (Wider et
al.,
1991). Ophthalmologic application of such a tissue solder has included the
sealing of
conjunctival blebs (Weisz, et al., 1989), sclerostomy (Odrich et al., 1989),
closure
of retinectomies (Wolf et al., 1989), and thermokeratoplasty (Wapner et al.,
1990)
using similar mixtures.
Due to the deficiencies and limitations of these mechanical means, whether
sutures, staples or more recently applied laser techniques, much attention was
devoted to developing synthetic polymers, e.g., cyanoacrylates, as biomedical
adhesives. These plastic materials, however, have been observed to induce
inflammatory tissue reaction. Moreover, the ability of these materials to
establish
permanent bonding under physiological conditions has yet to be fully realized.
The known toxicity associated with synthetic adhesives has led to
investigations towards the development of biologically derived adhesives as
bonding
materials. Among such adhesives, fibrin based glues have commanded
considerable
attention. (See, e.g., Epstein, G. H. et al. Ann. Otol. Rhinol. Laryngol. 95:
40-45
(1986); Kram, H. B et al. Arch. Surg. 119: 1309-1311 (1984); Scheele, J. et
al.
Surgery 95: 6-12 (January 1984); and Siedentop, K. H. et al. Laryngoscooe 93:
1310-1313 (1983) for general discussion of fibrin adhesives). Commercial
fibrin
tissue adhesives are derived from human plasma and hence pose potential health
risks such as adverse immunogenic reactions and transmission of infectious
agents,
e.g., Hepatitis B virus. Moreover, the bond strength imparted by such
adhesives are
relatively weak compared to collagen adhesives (see De Toledo, A. R. et al.
Assoc.
for Res. in Vision and Ophthalmology, Annual Meeting Abstract, Vol. 31, 317
(1990). Accordingly, there is a need for safe, effective biologically
compatible
tissue adhesives for biomedical applications.
CA 02308146 2000-O1-27
WO 99/05180 PCTlUS98115382 -
4
More recently, combination products have been devised for use as a tissue
adhesive. For example, Staindl (Ann. Otol (1979) 88:413-418) describes the use
of
a combination of three separately prepared substances, human fibrinogen
cryoprecipitate, thrombin in the presence of calcium ion, and Factor XIII
concentrate, to obtain a glue that was applied in skin graft applications,
myringoplasty, repair of ducal defects, hemeostatis after tonsillectomy, and
tracheoplasty. In this same time frame, Immuno-AG, Vienna, Austria, began
producing and commercializing a two-component. "fibrin seal" system, wherein
one
component contains highly concentrated human fibrinogen, Factor XIII, and
other
human plasma proteins, prepared from pooled blood, and the other component
supplies thrombin and calcium ion. The two components are added together in
the
presence of a fibrinolysis inhibitor. After application, the processes of
coagulation
and fibrin cross-linking occur. Eventually, the seal may lyse in the process
of
healing of the wound or trauma which accompanies the reconstruction of the
tissue.
Redl, H., et al., "Biomaterials 1980," Winter, G. D., et al., eds. (1982),
John
Wiley & Sons, Ltd., at page 669-675, describe the development of an applicator
device for this system which mixes and applies the two components of the
system
simultaneously. These combination systems and their uses have been described
widely: Seelich, T., J Head and Neck Pathol (1982) 3:65-69; O'Connor, A. F.,
et
al., Otolaryngol Head Neck Surg (1982) 90:347-348; Marquet, J., J Head and
Neck
Pathol ( 1982) 3:71-72; Thorson, G. K. , et al. , J Surg Oncol ( 1983) 24:221-
223.
McCarthy, P. M., et al., Mayo Clin Pros (1987) 62:317-319, reported the
addition
of barium ion to this fibrin glue system in the treatment of a bleeding
duodenal sinus
in order to facilitate fallow-up surveillance. See also Portrnann M., J Head
and
Neck Pathol ( 1982) 3:96; Panic, R. , ibid. , 94-95 .
Efforts have also recently focused on methods which seek to avoid the health
issues raised by the use of blood plasma derived products in commercially
available
tissue adhesive products and systems. To this end, attempts have been made to
varying degrees of success to isolate an autologous counterpart of the
fibrinogen-
containing component. For example, see Feldman, M. C., et al., Arch
Otolaryngol-Head and Neck Surg (1988) 114:182-185; Feldman, M. C., et al.,
Arch Ophthalmol ( 1987) 105 : 963-967; Feldman, M . C . , et. al . , M J
Otolog ( 1988)
CA 02308146 2000-O1-27
WO 99/05180 PCT/US98/15382
9:302-305; Silberstein, L. E., et al., Transfusion (1988) 28:319-321. Use of
autologous fibrinogen preparations also have obvious limitations.
Collagen As A Biomaterdal. Collagen, the major connective tissue
protein in animals, possesses numerous characteristics not seen in synthetic
polymers. Characteristics of collagen often cited include good compatibility
with
living tissue, promotion of cell growth, and absorption and assimilation of
implantations (Shimizu, R. et al. Biomat. Med. Dev. Art. Org., 5(1): 49-66
(1977)). Various applications of this material are being tested, for example,
as
dialysis membranes of artificial kidney (Sterzel, K. H. et al. Ameri. Soc.
Artif. Int.
Organs 17: 293 (1971)), artificial cornea (Rubin, A. L. et al. Nature 230: 120
(1971} and U.S. Pat. No. 4,581,030), vitreous body (Dune, M. et al. Amer. Soc.
Artif. Int. Organs 17: 421 (1971)), artificial skin and blood vessels
(Krajicek, M. et
al. J. Surg. Res. 4, 290 (1964)), as hemostatic agents (U.S. Pat. No.
4,215,200),
soft contact lens (U.S. Pat. Nos. 4,264,155; 4,264,493; 4,349,470; 4,388,428;
4,452,925 and 4,650,616) and in surgery (Chvapil, M. et al. Int. Rev. Conn.
Tiss.
Res. 6: 1-61 (1973)}.
Natural collagen fibers, however, are basically insoluble in mature tissues
because of covalent intermolecular cross-links that convert collagen into an
infinite
cross-linked network. Dispersal and solubilization of native collagen can be
achieved by treatment with various proteolytic enzymes which disrupt the
intermolecular bonds and removes immunogenic non-helical end regions without
affecting the basic, rigid triple-helical structure which imparts the desired
characteristics of collagen (see also, U.S. Pat. Nos. 3,934,852; 3,121,049;
3,131,130; 3,314,861; 3,530,037; 3,949,073; 4,233,360 and 4,488,911 for
general
methods for preparing purified soluble collagen).
Various methods and materials have been proposed for modifying collagen to
render it more suitable as biomedical adhesives. (See, e.g., De Toledo, A. R.
et al.
Assoc. for Res. in Vision and Ophthalmology, Annual Meeting Abstract, Vol. 31,
317 (1990); Lloyd et al., "Covalent Bonding of Collagen and Acrylic Polymers,"
American Chemical Society Symposium on Biomedical and Dental Applications of
Polymers, Polymer Science and Technology, Vol. 14, Plenum Press (Gebelein and
Koblitz eds.), New York, 1980, pp. 59-84; Shimizu et al., Biomat. Med. Dev.
Art.
CA 02308146 2000-O1-27
WO 99105180 PCTIUS98115382 -
6
Org., 5(1): 49-66 (1977); and Shimizu et al., Biomat. Med. Dev. Art. Org.,
6(4):
375-391 (1978), for general discussion on collagen and synthetic polymers.).
In
many instances, the prior modified collagen-based adhesives suffer from
various
deficiencies which include (1) cross-linking/polymerization reactions that
generate
exothermic heat, (2) long reaction times, and (3) reactions that are
inoperative in the
presence of oxygen and physiological pH ranges (Lee M. L. et al. Adhesion in
Biological Systems, R. S. Manly, ed., Academic Press, New York, 1970, Chap.
17). Moreover, many of the prior modified collagen-based adhesives contain
toxic
materials, rendering it unsuitable for biomedical use (see, for example,
Buonocore,
M. G. (1970) and U.S. Pat. No. 3,453,222).
Additionally, the use of collagen-based adhesives also presents
immunological concerns as such adhesives have been derived from animal sources
and typically bovine sources. Studies with respect to the use of such
collagens as
injectible devices have reported minor inflammatory responses. More recently,
potential issues regarding the transmission of disorders to humans related to
bovine
spongiform encephalopathy ("mad cow disease") have focused attention,
especially
in Europe, to limiting bovine sourced materials.
Notwithstanding these deficiencies, certain collagen-based adhesives,
reportedly having appropriate adhesive strength and utility in many medical
applications, particularly involving soft tissues, have been described. U.S.
Pat. No.
5,219,895). These reports identify the use of type I and type II in collagen-
based
adhesives; wherein purified collagen types I and II are chemically modified to
form
monomers which are soluble at physiological conditions and then polymerized to
form a composition having adhesive and sealant properties. The reports are
limited
to collagen-based adhesives which are composed of collagens derived from
natural
sources; and consequently, represent a collagen mixture. For example, type I
collagen, as isolated from natural sources are typically comprised of
approximately
10-20 % type III and other collagens, depending upon the tissue source used,
and 90-
80 % type I collagen.
The reports further do not refer to collagen type III, the unexpected
hemostatic characteristics of type III collagen or the use of recombinant
collagens so
that the first chemical modification step may be avoided.
CA 02308146 2000-O1-27
WO 99105180 PCTIUS98/15382 -
7
3. SUMMARY OF THE INVENTION
A biologically compatible, collagen type III and/or type I product with
sealant and adhesive properties can be formed using soluble recombinantly
derived
collagen type III and/or type I monomers; wherein said monomers are
polymerized
to form a collagen type III andlor type I composition having adhesive and
sealant
properties. Preferably, the collagen is human and derived using recombinant
technology. Collagen type III was selected for its unexpectedly superior
hemostatic
characteristics, as compared to other collagen types. Collagen type I was
selected
for its structural characetristics. The polymerization reaction may be
initiated with
an appropriate polymerization initiator such as a chemical oxidant,
ultraviolet
irradiation, a suitable oxidative enzyme or atmospheric oxygen.
For purposes of optimizing the sealant and adhesive properties of the
recombinant collagen product by optimizing the structural stability of the
product as
well as the hemostatic characteristics or the product, the product is
comprised
preferably of a combination of pure recombinant type I and type III collagen
The
ratio of pure recombinant collagen type III to pure recombinant type I is
about 30
and greater type III collagen to about 70 % or less type I collagen. More
preferably,
the ratio of pure recombinant type III collagen to pure recombinant type I
collagen is
about 30 % to about 50 % type III collagen to about 70 %to about 50 % type I
collagen. Most preferably, the ratio of pure recombinant type III collagen to
pure
recombinant type I collagen is about 30 % to about 40 % type III collagen to
about
70 % to about 60 % type I collagen.
It is the object of this invention to provide for a pure recombinant collagen
type III tissue sealant, a pure recombinant type I tissue sealant or a pure
recombinant collagen type I and type III tissue sealant, free from other
collagen
types I, having the following characteristics and capabilities:
(i) Hemostasis. The sealant acts as a hemostatic barrier and
reduces the risk of serum, lymph and liquor leakage. As collagen type III
possesses
inherently hemostatic properties, its use in a hemostatic device provides an
improvement over known fibrin sealants. Collagen type I also possesses some
hemostatic properties.
CA 02308146 2000-O1-27
WO 99!05180 PCT/US98I15382 -
8
(ii) Glueing. Due to its adhesive properties, the sealant
atraumatically connects tissues by forming a strong joint between them and
adapts
uneven wound surfaces. This glueing effect is increased by a combination of
agents,
as described below, and collagen type III andlor collagen type I.
(iii) Wound healing. The sealant promotes the growth of
fibroblasts which in combination with efficient hemostasis and adhesion
between the
wound surfaces provides for an improved healing process. The use of the
compositions according to the invention as an anti-adherencelwound healing
composition is expected to result in a normal (regenerative) tissue rather
than scar
tissue, i.e. optimal wound healing. Furthermore, such compositions also reduce
the
inflammatory response.
Accordingly, it is an object of the present invention to provide polymerized
collagen type III andlor type I compositions as a safe, effective biological
adhesives
with appropriate adhesive strength for biomedical applications, particularly
involving soft tissues. More specifically, the present invention is directed
to
compositions useful in sealing punctures and incisions in internal organs, the
dermis
and large blood vessels. The polymerized materials may assume a number of
sizes
and shapes consistent with their intended biomedical applications, which
include use
in ophthalmology, plastic surgery, orthopedics and cardiology.
In another object of the invention, the collagen type III andlor type I
composition is further comprised of agents which will confer additional
desirable
characteristics for a sealant or adhesive. For example, fibrin, fibrinogen,
thrombin,
calcium ion, Factor XIII may be included in the composition to better effect
the
formation of a three-dimensional network of polymerized collagen. In yet
another
object of the invention, the recombinant collagen type III composition
incorporates a
drug having wound healing capabilities. In one embodiment, the drug is
connective
tissue growth factor and is incorporated in the composition to effect slow-
release of
the drug to the wound.
4. DETAILED DESCRIPTION OF THE INVENTION
4.1 Definitions
CA 02308146 2000-O1-27
WO 99105180 9 PCT/U598/15382 -
As employed herein, the term "biologically compatible" refers to
recombinant collagen type III and/or type I modified in accordance with the
present
invention (i.e., a polymerized collagen type III recombinant product) which is
incorporated or implanted into or placed adjacent to the biological tissue of
a subject
and more particularly, does not deteriorate appreciably over time or induce an
immune response or deleterious tissue reaction after such incorporation or
implantation or placement.
As employed herein, the term "pure recombinant collagen type I"
refers to human collagen type I manufactured by recombinant techniques which
is
substantially free from other collagen types. The term excludes collagen type
I
isolated from natural sources.
As employed herein, the term "pure recombinant collagen type III"
refers to human collagen type I manufactured by recombinant techniques which
is
substantially free from other collagen types. The term excludes collagen type
III
isolated from natural sources.
4.2 Preparation of Polymerized Recombinant Collagen Type I and III
Production of Collagen Type 1 and III Monomers. The type of
collagen useful to form the biologically compatible collagen product with
adhesive
and hemostatic properties of this invention is recombinant collagen type I and
III.
Monomeric soluble collagen type I and III is obtained by recombinant
processes,
including processes involving the production of collagen type III in
transgenic
animals. Said recombinant processes are set forth at U.S. Patent No.
5,593,859,
which is incorporated herein by reference. Preferably, collagen type I or III
will be
recombinantly manufactured by culturing a cell which has been transfected with
at
least one gene encoding the polypeptide comprising collagen type I or III and
genes
encoding the a and ~i subunits of the post-translational enzyme prolyl 4-
hydroxylase
and purifying the resultant collagen monomer therefrom. Preferably, the
monomeric soluble collagen type I and III material exhibits a viscous
consistency
and varying degrees of transparency and clarity.
Polymerization Of Collagen Type 1 and Ill Monomers. The
recombinant collagen type I and III solution may be subsequently subjected to
CA 02308146 2000-O1-27
WO 99/05180 PCTIUS98/15382
polymerization or cross-linking conditions to produce the polymerized collagen
composition of the present invention. Polymerization may be carried out using
irradiation, e.g., UV, gamma, or fluorescent light. UV irradiation may be
accomplished in the short wave length range using a standard 254 nm source or
using UV laser sources. With a standard 254 nm source, 4-12 watts,
polymerization
occurs from 10 to 40 minutes, preferably 20 to 30 minutes, at an exposure
distance
of from 2.5-10 cm, preferably from 2.5 to 5 cm distance. Excess UV exposure
will
begin to depolymerize the collagen polymers. Polymerization using gamma
irradiation can be done using from 0.5 to 2.5 Mrads. Excess Gamma exposure
will
also depolymerize collage polymers. Polymerization in the presence of oxygen
can
be done by adding an initiator to the fluid prior to exposure. Non-limiting
examples
of initiators include sodium persulfate, sodium thiosulfate, ferrous chloride
tetrahydrate, sodium bisulfate and oxidative enzymes such as peroxidase or
catechol
oxidase. When initiators are employed, polymerization occurs in 30 seconds to
5
minutes, usually from 1 to 3 minutes.
The polymerizing agent is preferably UV irradiation. However, the
polymerization or cross-linking of the monomeric substituents can be carried
out by
simply exposing the material to atmospheric oxygen, although the rate of
polymerization is appreciably slower than in the case of UV irradiation or
chemical
agents .
Other agents may also be useful in the polymerization process. For
example. to improve the cohesive strength of adhesives formed from the
compositions of this invention, difunctional monomeric cross-linking agents
may be
added to the monomer compositions of this invention to effect polymerization.
Such
cross-linking agents are known in the art, for example, to U.S. Pat. No.
3,940,362
(Overhults), which is hereby incorporated by reference herein.
4.3 Collagen Type I and III Compositions
The compositions of the present invention are comprised of
polymerized type I and III collagen wherein said composition is manufactured
by a
process comprising the steps: (1) production of collagen type I and III
monomers
by the recombinant methods described above; and (2) polymerization of such
monomers .
CA 02308146 2000-O1-27
WO 99105180 PCT/US98115382 -
11
For purposes of optimizing the sealant and adhesive praperties of the
recombinant collagen product by optimizing the structural stability of the
product as
well as the hemostatic characteristics or the product, the product is
comprised
preferably of a combination of pure recombinant type I and type III collagen
The
ratio of pure recombinant collagen type III to pure recombinant type I is
about 30
and greater type III collagen to about 70% or less type I collagen. More
preferably,
the ratio of pure recombinant type III collagen to pure recombinant type I
collagen is
about 30 % to about SO % type III collagen to about 70 % to about 50 % type I
collagen. Most preferably, the ratio of pure recombinant type III collagen to
pure
recombinant type I collagen is about 30 % to about 40 % type III collagen to
about
70 % to about 60 % type I collagen.
The compositions of the present invention may be further comprised of other
agents which are useful to glueing or sealing tissues. For example, in
addition to
recombinant collagen type I and/or type III protein, the composition will
preferably
comprise Factor XIII and/or fibrin/fibrinogen/fibronectin andlor plasminogen.
Advantageously, the composition will also include clotting enzyme, i.e.
thrombin,
especially in combination with bivalent calcium, such as calcium chloride. The
concentration of calcium chloride will then vary, e.g. between 40 mM to 0.2M
depending on the specific purpose of the tissue adhesive composition, high
concentrations of calcium chloride inhibiting fibroblast growth and therefore
being
preferred for anti-adherence applications (along with absence of fibronectin
which
stimulates the growth of fibroblasts). It may further be valuable to include a
fibrinolysis inhibitor, such as a plasmin inhibitor, e.g. aprotinin,
aprilotinin, alpha-
2-antiplasmin, alpha-2-macroglobulin, alpha-1-antitrypsin, epsilon-
aminocaproic add
or tranexamic acid, or a plasmin activator inhibitor, e.g. PAI-1 or PAI-2.
While the proportions of the previously known ingredients in the tissue
adhesive compositions of the invention may be selected with guidance of prior
art
compositions, the necessary amount of the viscosity enhancing polymer: can
readily
be determined by a person skilled in the art depending on the particular
polymer and
the intended use form. Thus, if the concentration and/or molecular weight of
the
viscosity enhancing polymer is too low, the viscosity increase will be
insufficient,
CA 02308146 2000-O1-27
WO 99/05180 PCT/US98115382 -
12
and a too high concentration andlor molecular weight will inhibit the fibrin
polymerization and the adhesion to the tissue.
By increasing the thrombin concentration, the polymerization of composition
of the present invention may be speeded up with a consequential influence on
the
time until the glue sets. At low thrombin concentrations, for example, the
fibrin of
the composition will remain more or less fluid for several minutes after
application.
A further beneficial effect of increasing the viscosity with a viscosity
enhancing
polymer in accordance with the invention is therefore the possibility to use
lower
concentrations of thrombin, which is required in situations where the parts to
be
sealed require subsequent adaptation even on non-horizontal surfaces.
Likewise, the compositions of the present invention may, rather than
including a combination of the agents described herein, be a fusion protein
wherein
the collagen type I and/or type III and, for example, fibrin, are combined to
form
one molecule. Such fusion proteins may be manufactured according to the
recombinant techniques described herein.
In a further embodiment of the invention, the composition of the present
invention includes agents useful in wound healing, either by inducing or
promoting
the formation of tissue, or alternatively, limiting the formation of fibrotic
adhesions.
Such agents include antibiotics, or growth factors, such as connective tissue
growth
factor, which is described at, for example, U.S. Patent No. 5,408,040 and
5,585,270, said references are incorporated herein by reference.
4.4 Fields Of Use
The polymerized collagen type III and/or type I product may be
useful to produce mechanical sealants and adhesive systems.
Tissue Adhesive Systems. Fields of application include among
others: ear, nose and throat surgery, general surgery, dentistry,
neurosurgery,
plastic surgery, thorax and vascular surgery, abdominal surgery, orthopaedics,
accident surgery, gynaecology, urology, and opthalmology. The collagen
sealants
of the present invention have also been used for local application of drugs,
such as
antibiotics, growth factors and cytostatics.
Sealant Films. In one aspect of the invention, the polymerized
collagen products can be made in the form of a sealant film. A collagen based
film
CA 02308146 2000-O1-27
WO 99/05180 PCTIUS98/15382 -
13
will be flexible and elastic with the consistency and feel of plastic film,
and yet the
film should exhibit high biological compatibility. Uses of sealant films
include:
Prevention of adhesion formation following tendon surgery (i.e., use as a wrap
around tendons), use as a synthetic tympanic membrane, substitute facial
tissue and
wound dressing component. Additional examples of potential usage of sealant
films
include: treatment of corneal abrasions, wound closure, coating of catheters
and
instruments, use as a material to prevent adhesion formation in tissues than
tendons
(e.g., peritoneal cavity).
Further embodiments of the present invention include sealant and adhesive
formulations which can be used as systems specific for delivery of numerous
drugs
and pharmaceutical compositions, including growth factors, antibiotics, and
other
biologically beneficial compounds. Such materials can be added to the collagen
adhesive or sealant to promote cell migration, cell adhesion, and wound
healing.
Angioplasty and Angiography. Angiography is a diagnostic
procedure whereby dye is injected into an artery, preferably the femoral
artery, to
detect the presence or absence of coronary disease. Angioplasty, also known as
PCTA, is a therapeutic procedure which involves the inflation of a balloon in
an
artery, such as the coronary artery, for the purpose of relieving arterial
blockages.
After puncturing the femoral artery, a balloon-catheter is introduced through
the
femoral artery and navigated through to the coronary artery blocked by
atherosclerosis (plaque). Once in position, the balloon is inflated and
deflated
several times in an effort to open the artery by pushing the fatty material
against the
vessel walls, allowing for blood to circulate to the affected regions of the
heart
muscle. Various types of balloon catheters are commonly used in angioplasty
and
angiography including over-the-wire catheters which ride over an independent
guidewire to the site of the disease; 2) fixed-wire catheters, which combine a
balloon catheter with a guidewire into one device; 3) rapid-exchange or single-
operator exchange catheters, which are over-the-wire catheters that can be
exchanged more conveniently than standard over-the-wire catheters; and 4)
perfusion catheters, which allow blood flow during the procedure. A rotational
tip
catheter removes plaque buildup on arterial walls. These devices utilize a
technique
CA 02308146 2000-O1-27
WO 99/05180 PCTICTS98115382 -
14
called differential cutting. Calcified material is rendered into microscopic
particles
without damaging the artery due to the elastic nature of the arterial walls.
Angioplasty is a more invasive and complicated procedure than angiography,
since it requires the insertion of a larger sheath than that used in
angiography. The
sheath is used as a vehicle for introducing the catheter into the artery.
Additionally,
angioplasty also requires the use of blood thinners, such as heparin, to
prevent
clotting during and after the surgical procedure. The anti-clotting agent
prevents the
body's natural sealinglclotting mechanism and, thus, sealing punctures
requires a
significant length of time.
According to the present invention, after withdrawing the catheter and other
invasive devices from the artery, an adhesive applicator may optionally be
inserted
into the sheath and is placed into a position near to or contacting the
puncture in the
artery. During the procedure, manual or mechanical pressure is applied to the
artery to reduce the flow of blood at the puncture site. If possible, excess
bloodlfluid is removed from the puncture site. Subsequently, recombinant
collagen
type III and/or type I monomer of the present invention may be applied to the
puncture on the external surface of the artery and/or within the puncture
track. The
monomer then is polymerized andlor cross-linked by the techniques described
herein, for example, UV irradiation, such that polymerization takes place
within 0
to 300 seconds, preferably 0 to 120 seconds, more preferably 0 to 30 seconds,
and
even more preferably 3 to 10 seconds. By applying the collagen monomer
composition on the outside of the artery, the incidence of embolism (blockage
of the
artery or circulatory system) is virtually eliminated. Alternatively, a
polymerized
collagen type III and/or type I may be used and the polymerization step may be
avoided. Because of the bonding strength of the adhesive of the present
invention,
only small amounts of the adhesive are required to seal a punctured artery.
Moreover, because the surgical adhesive according to the present invention can
polymerize almost immediately, the adhesive can polymerize on the surface
andlor
along the puncture track of the artery without penetrating the interior of the
artery.
Accordingly, large pieces or particles of material will not enter the
circulatory
system, thereby substantially reducing risk of embolism. Due to the fast and
strong
CA 02308146 2000-O1-27
WO 99105180 PCTIITS98/15382 -
bonding of preferred adhesives of the invention, the patient will need to be
immobilized for only a minimal period of time.
4.5 Administration
Formulations. The tissue treatment composition of the present
invention may be presented in the same type of preparations as the prior art
fibrin
sealants. The components may be provided in deep frozen solution form or as
lyophilized powders, to be diluted prior to use with appropriate aqueous
solutions,
e.g. containing aprotinin and calcium ions, respectively.
With respect to compositions of the present invention comprising
pharmaceutical agents, such as an antibiotic, a growth factor, etc, by
incorporating
said agent into the tissue adhesive so as to be enclosed in the collagen
network
formed upon application of the tissue adhesive. It will thereby be ensured
that the
drug is kept at the site of application while being controllably released from
the
composition, e.g. when used as ocular drops, a wound healing preparation, etc.
As
also mentioned above the pharmaceutically active substance to be released from
the
present tissue adhesive composition may be the viscosity enhancing polymer in
itself
or a substance coupled thereto. A specific example of such a viscosity
enhancing
polymer fulfilling the viscosity enhancing requirement as well as having
therapeutical and pharmaceutical utility, and for which it may be desired to
sustain
the bioavailability, is hyaluronic acid and salts and derivatives thereof
which are
easily soluble in water and, as mentioned previously, have an extremely short
biological half-life. The tissue treatment composition of this invention thus
constitutes an advantageous slow-release preparation for proteoglycans such as
hyaluronic acid and its salts and derivatives, and considerably increases the
bioavailability thereof.
Notably, the compositions of the present invention are not restricted to the
adhesive properties, but non-adhesive compositions are also included,
especially
when the compositions primarily are intended for wound healing. The latter
compositions may in particular include non-adhesive proteins such as albumin
and/or growth factors. Substantially non-adhesive compositions may also be
obtained when the polymer part of the composition inhibits the adhesive
properties
CA 02308146 2000-O1-27
WO 99105180 PCT/US98/15382 -
16
of the protein part. It should in this context be emphasized that the
invention
comprises both adhesive and substantially non-adhesive compositions, although
it
has for simplicity reasons often has been referred to as an "adhesive" in this
specification.
Application Of Compositions. The compositions of the present
invention may be applied using a variety of dispensing devices. For example,
the
surgical adhesive may be applied using the devices set forth in U.S. Pat. Nos.
4,900,303 (Lemelson) and 5,372,585 (Tiesenbrun) while monitoring the
application
process through an optical viewing system. The composition of the present
invention may also be applied by the devices set forth in U.S. Pat. No.
5,129,882
(Weldon et al.). The subject matter of these patents is incorporated herein by
reference.
The composition according to the present invention may also be applied in
conjunction with other sealing means. For example, the adhesive may be applied
to
puncture sites which have been closed using surgical suture or tape, such as
in the
sealing of a puncture or incision in internal organs, e.g., liver,
gallbladder,
intestines, stomach, kidney, heart, urinary bladder, ureter, lung, esophagus
and the
like. The adhesive in this instance will provide a complete seal, thereby
reducing
the risk of body fluid leakage from the organ or vessel, e.g., leakage from
liver
puncture sites. The surgical adhesive of the present invention may
additionally be
used in conjunction with other sealing means, such as plugs, and the like.
Such
techniques are set forth in U.S. Pat. Nos. 4,852,568 (Kensey), 4,890,612
{Kensey),
5,053,046 (Janese), 5,061,274 (Kensey), 5,108,421 (Fowler), 4,832,688 (Sagae
et
al), 5,192,300 (Fowler), 5,222,974 (Kensey et al.), 5,275,616 (Fowler),
5,282,827
{Kensey et al.), 5,292,332 (Lee), 5,324,306 (Makower et al.), 5,370,660
(Weinstein
et al.), and 5,021,059 (Kensey et al.). The subject matter of these patents is
incorporated herein by reference.
Notably, the compositions of this invention can be used to join together two
surfaces by applying the particular composition to at least one of said
surfaces.
Depending on the particular requirements of the user, the adhesive
compositions of
this invention can be applied by known means such as with a glass stirring
rod,
sterile brush or medicine dropper; however, in many situations a pressurized
aerosol
CA 02308146 2000-O1-27
WO 99105180 PCT/US98/15382
I7
dispensing package is preferred in which the adhesive composition is in
solution
with a compatible anhydrous propellant. Aerosol application of the monomers is
particularly advantageous for use in hemostasis.
