Note: Descriptions are shown in the official language in which they were submitted.
CA 02704971 2010-05-20
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TITLE OF THE INVENTION
Embolizing sclerosing hydrogel
FIELD OF THE INVENTION
[0001] The present invention relates to the art of medical treatments. More
specifically, the present invention is concerned with an embolizing sclerosing
hydrogel and its applications in medical treatments.
BACKGROUND
[0002] Endovascular aneurysm repair is an interesting alternative to surgical
repair of abdominal aortic aneurysm which enables to reduce patient operating
risks and time of recovery. However, this treatment is presently limited by
the
persistence of blood leaks (called endoleaks). Some of these endoleaks (type
11
endoleaks) can be treated by injecting an embolizing agent to block blood
flow.
[0003] Several embolizing agents (mainly N-butyl-2- cyanoacrylate (NBCA) [1-
4],
Ethylenevinyl alcohol copolymer (EVOH, Onyx [5, 6], polyurethane fragments
and fibrin glue [7], combined or not with coils [4, 8]) have been tested
recently for
the treatment of endoleaks or for their prophylactic prevention by injection
into the
aneurismal sac. Although these studies showed that sac embolization has
potential to minimize endoleak occurrence, they also show that materials
existing
presently are limited. Recurrence of endoleaks are frequent. It is believed to
be
due to recanalisation process through or around the injected materials. The
same
limitation occurs when prophylactic injection of embolizing agent around the
implant is performed in order to prevent endoleak formation [3, 9, 10]. It is
believed
that combining embolizing and sclerosing properties would improve clinical
results
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by inducing endothelial denudation and thus preventing recanalisation
processes
and promoting fibrosis and healing. The only commercialized embolizing agent
that may present sclerosing properties to date is cyanoacrylate. However this
agent is not biodegradable and such embolizing agent do not exist presently or
they do not present adequate mechanical and biodegradation properties.
[0004] In the case of arteriovenous malformation, sclerosing agents (ethanol,
STS
foam...) are already used to permanently occlude the vessels. However, these
agents are far from ideal since their poor mechanical properties make
injection
difficult to control and do not enable to efficiently occlude blood flow.
[0005] Accordingly, there is a need in the industry to provide a gel for
repairing
aneurysms and other defects. An object of the present invention is therefore
to
provide such a gel.
SUMMARY OF THE INVENTION
[0006] In a broad aspect, the invention provides a sclerosing embolizing gel
comprising from about 0.1% by weight to about 4.0% by weight of chitosan; from
about 0.01M to about 1M of hydrochloric acid; from 0% by volume to about 40%
by volume of iopamidol; from 0.5% by weight to about 25% by weight of p-
glycerophosphate disodium salt; and from about 0.01% by weight to about 4% by
weight of sodium tetradecyl sulphate.
[0007] In a specific embodiment of the invention, the gel includes: about 0.1M
of
hydrochloric acid; about 2% by weight of chitosan, about 20% by volume of
iopamidol, about 12% by weight of 13-glycerophosphate disodium salt and about
1% by weight of sodium tetradecyl sulphate, the formed hydrogel having a pH of
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from about 7.0 to about 7.4.
[0008] The present invention relates to a new injectable embolizing material
with
sclerosing properties. This unique material could be used (but not
exclusively) for
the treatment of abdominal aortic aneurysms and vascular anomalies. More
particularly for:
[0009] - The treatment of endoleaks after endovascular aneurysm repair (EVAR).
[0010] - The prophylactic embolization of abdominal aortic aneurysm during
EVAR.
[0011] - The treatment of vascular anomalies (arteriovenous malformation,
venous malformation, lymphatic malformation, hemangioma, varicocele, pelvic
congestion syndrome)
[0012] Such material could also be used to treat other pathologies such as the
treatment of cancer.
[0013] These pathologies require embolizing treatments but materials existing
presently do not lead to satisfactory results. We developed a new embolizing
material based on a new paradigm and which unique properties enable a safe,
efficient and durable embolization.
[0014] Other objects, advantages and features of the present invention will
become more apparent upon reading of the following non-restrictive description
of
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preferred embodiments thereof, given by way of example only with reference to
the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Fig. 1. Time dependence of elastic modulus (G') of radio-opaque
chitosan
hydrogel as a function of STS concentration (0, 1, 2 and 3% w/v) at 37 C. The
addition of STS provides more appropriate rheological and mechanical
properties
for embolization.
[0016] Fig. 2. Time dependence of elastic (G') and viscous (G") moduli of
radio-
opaque STS solution (20% v/v 10P, 3% w/v STS, without chitosan hydrogel) at
37 C. A viscous liquid behavior is observed without any mechanical properties.
[0017] Fig. 3. Elastic modulus (G') of radio-opaque chitosan hydrogel (2% w/v
CH, 20% v/v 10P, 12% w/v 3GP) obtained after 1 week of gelation at 37 C as a
function of STS concentration (0, 1, 2 and 3% w/v). The elastic modulus is
increased after 1 week as a function of STS concentration, thus enabling
better
embolisation properties. The present invention solves many problems inherent
in
the art. The chitosan/STS hydrogel is much stronger than the STS (3%) foam and
can displace the blood into aneurysm more effectively.
[0018] Fig. 4. Porous structure of the chitosan/STS hydrogel (2% w/v CH, 20%
v/v 10P, 12% w/v 13GP, 3% w/v STS), as observed by scanning electron
microscopy after gold sputtering.
CA 02704971 2010-05-20
DETAILED DESCRIPTION
[0019] The present invention relates to the development of an embolizing agent
with sclerosis properties which combines appropriate mechanical,
biocompatibility,
biodegradation and gelation properties for such applications. The hydrogel
created
is based on chitosan, a biocompatible biodegradable biomaterial and sodium
tetradecyl sulfate (STS) a well known sclerosing agent. Methods were developed
to create an embolic sclerosing gel which does not precipitate, has superior
mechanical properties and enables controlled injection.
[0020] The present invention relates to an embolic hydrogel with sclerosing
properties. The composition of this hydrogel is:
[0021] 0 Chitosan (CH).
[0022] o 13-glycerophosphate ( I3GP).
[0023] o Sodium tetradecyl sulfate (STS).
[0024] 0 Depending on the desired application, the hydrogel can be created
radioopaque or not, by addition of a contrast agent such as lopamidol (or
others).
Radioopacity is important in some treatments of abdominal aortic aneurysms. It
is
sometimes not required for some vascular malformations.
[0025] The unique combination of chitosan, 13GP and STS enables to create an
embolic sclerosing hydrogel with good mechanical properties, that can be
injected
easily and has immediate mechanical properties adequate for embolisation (Fig.
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1). The addition of a contrast agent such as lopamidol does not prevent
gelation
and only slightly increases its final mechanical properties.
[0026] The unique association of chitosan, 13GP
and STS provides more
appropriate rheological and mechanical properties compared to chitosan+ pGP
(Fig. 1) or to STS alone, which is liquid (Fig. 2):
[0027] 0 Creates a gel with physiological pH.
[0028] o The addition of p GP enables to add STS to chitosan without inducing
its precipitation. The procedure of fabrication itself (pH of each component
before
mixing and the order of addition) is important to avoid precipitation or phase
separation of chitosan at physiological pH (Table 1).
[0029] 0 Enables to create an elastic material (G'>1000Pa) compared to STS
foam (viscous material) that is presently used in the treatment of
arteriovenous
malformations (Fig. 2).
[0030] 0 Increases the elastic modulus of chitosan+ pGP gels, thus enabling
better embolisation properties (Table 2). For example, just after mixing, G'
of
chitosan+ pGP is around 10 Pa compared with chitosan/STS (1357Pa). After 1
week of gelation at 37 C, G' of chitosan+ p GP is 1213Pa compared with
chitosan/STS (3297Pa) (Fig. 3).
[0031] 0 Gives sclerosing properties to chitosan, which allow preventing
recanalisation processes and promoting fibrosis (healing).
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[0032] 0 The gel is a porous matrix appropriate for cell invasion during
healing
process (Fig. 4).
[0033] 0 It can be become radioopaque by addition of non-ionic contrast agent
(20% v/v) which does not significantly modify its gelation or mechanical
properties.
The contrast agent is simply entrapped in the gel, is rapidly eliminated and
thus
not to interfere with further imaging follow-up.
[0034] The two solutions required to create the chitosan/STS hydrogel can be
sterilized before mixing.
[0035] The chitosan/STS hydrogel is considered as a ready-to-use biomaterial.
[0036] - The chitosan/STS hydrogel is considered as an easy-to-use
biomaterial:
The two solutions can be mixed in the operating room and then injected via
catheter without significant damage on its mechanical properties.
[0037] - Finally, it is the first product with sclerosing properties proposed
to treat
endoleaks or do prophylactic prevention of endoleaks in abdominal aortic
aneurysms. The two principle roles of the chitosan/STS hydrogel are:
[0038] 0 The embolisation of aneurysm sac (to block any blood flow entering
the
aneurysms).
[0039] 0 To cause irreversible endothelial injury in the aneurysm sac and
prevent
recanalisation process by endothelial cells that could lead to recurrence of
blood
flow after a while (this process is thought to be a cause of failure of
presently used
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embolic treatments.
[0040] Such an embolic sclerotic agent has a large commercial potential for
the
treatment of endoleak or for their prophylatic prevention by injection just
after
stent-graft (SG) deployment.
[0041] This embolization agent has many advantages compared to presently
used agents (mainly Histoacryl T" (cyanoacrylate) and Onyx TM (polyvinyalcool
mixed with DMSO), Embogel TM (Alginate mixed with calcium chloride).
[0042] 1) Its sclerosing effect is well controlled. STS is an anionic
surfactant that
has been demonstrated to destroy endothelial lining in vivo. It is commonly
used in
sclerotherapy. Its combination with the cationic chitosan limits its diffusion
during
the EVAR procedure and thus decreases safety risks. It can be added at any
concentrations (preferably between 0.5 to 3%, based on clinical data). In
Onyx,
DMSO can also have a sclerosing effect. Yet DMSO is liquid and can be easily
release in surrounding tissues.
[0043] 2) Gelation of chitosan/STS was found to be adequate to allow easy
clinical handling, positioning and injection while limiting risks of migration
in vivo.
The rapid increase of elastic modulus avoids risks of migration but does not
require to be mixed in vivo as other products, nor create risk of catheter
adhesion
in vivo. In contrast, rapid polymerisation of cyanoacrylate can lead to
catheter
obstruction and sticking into the treated arteries.
[0044] 3) Its mechanical properties (above 1000Pa after gelation) are
sufficient for
flow occlusion in the aneurismal sac but its viscosity allows it to easily
fill and mold
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to any shape or defect in vivo (in contrast to cyanacrylate that often lead to
empty
spaces).
[0045] 4) Chitosan is biocompatible and biodegradable. It forms a porous
matrix
which can be infiltrated and progressively replaced by tissue, thus not
impairing
the healing process after EVAR [11] in contrast to permanent Onyx and
cyanoacrylate that are permanent.
[0046] 5) Chitosan/STS is also biodegradable. After injection in the rabbit
auricular artery, chitosan/STS prepared with chitosan 83% DDA was shown to be
replaced by fibrous tissue within 1 month. The DDA of chitosan can be modified
to
modify the degradation rate.
[0047] 6) Chitosan is hemostatic and may thus favour thrombosis in the
aneurismal sac [11]. It is muco-adhesive, and by binding with surrounding
tissues,
should allow good flow occlusion and limit migration.
[0048] The addition of f3 -glycerophosphate salt allows to avoid precipitation
of
chitosan before its gelation in a viscoelastic gel. Addition of sodium
tetradecyl
sulphate (3%) at one particular phase of the mixture increase the gelation
rate and
lead to higher mechanical properties compared to chitosan alone, as
characterized
by rheometry (Fig. 3). This allowed good embolisation properties in vivo, as
assessed on efficient embolisation of renal artery
[0049] Materials & methods
[0050] 0 Materials
CA 02704971 2010-05-20
[0051] Medium molecular weight chitosan (Mw 4.2x105Da) with a high degree
of deacetylation (DDA - 83%) and p-glycerophosphate disodium salt hydrate (
8GP) were used in this study. Chitosan with other DDA could be used
alternatively
to modify the degradation rate. The contrast agent used in this study was
iopamidol (10P) from Bracco Diagnostics Inc. (Canada) but other liquid
iodinated
contrast agents can also be used. Sodium tetradecyl sulphate (STS), dibasic
sodium phosphate, monobasic sodium phosphate and hydrochloric acid were
acquired from Sigma-Aldrich (Canada).
[0052] 0 Preparation of ST S solution at physiological pH
[0053] Different STS solutions were prepared at different concentrations by
diluting STS solution (27% w/v) until an appropriate volume of dibasic sodium
phosphate/monobasic sodium phosphate.
[0054] 0 Preparation of radio-opaque chitosan hydrogel with sclerosing
properties: chitosan/STS
[0055] A chitosan solution was prepared by dissolving chitosan powder in 0.1M
HCI with an appropriate amount of iopamidol at room temperature under constant
magnetic stirring. The sample was sterilized at 121 C for 20min and stoked at
4 C
for 24h. 8GP-STS solutions were prepared by dissolving an appropriate amount
of
I3GP powder in STS solution. The 8GP-STS solution was then sterilized using a
0.2pm filter. The 8GP/STS solution was mixed with chitosan solution to form
the
radio-opaque chitosan hydrogel at 37 C with sclerosing properties
(chitosan/STS).
[0056] O Rheological measurements
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[0057] Rheological measurements were performed using the Bohlin CVO
rheometre (Malvern Instruments Inc., USA) equipped with co-axial cylinder or
parallel-plate geometry and a circulating water bath to control the
temperature.
Rheological data were collected using the Bohlin software. Small-amplitude
oscillatory shear experiments were performed at 37 C. The time evolution of
storage (or elastic) modulus G' and loss (or viscous) modulus G" was
determined
within the linear viscoelasetic region, at fixed frequency (1Hz) and stress
amplitude (1Pa). The time dependence of G' and G" of chitosan hydrogels were
measured as a function of STS concentration. The gelation time (tgei) was then
determined as the time at which G' = G" in accordance with the approach
proposed in the literature [12, 13].
[0058] 0 Morphology of chitosan/STS hydrogels
[0059] The morphology of chitosan/STS hydrogels was observed by scanning
electron microscopy (SEM). After 1 week of gelation at 37 C, the prepared
specimens were freeze-dried under vacuum during 24h and sputter-coated with
gold, and their morphology was observed. As chitosan gels, chitosan-STS gels
were shown to exhibit a porous structure (Fig. 4).
[0060] 0 In vivo testing of chitosan/ST S hydrogels
[0061] Chitosan/STS hydrogels were tested in vivo in various studies.
[0062] - Rabbit artery model: The objective of this experiment was to
investigate if
embolization with chitosan/STS can prevent endothelial recanalization in a
rabbit
auricular artery (AA) model. Each AA was canulated and injected with 0.6 ml of
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chitosan (0Ch; n=14) on one side and either saline (0Sal; n=2), chitosan/STS
1%
(OCS1; n=6), or chitosan/STS 3% (OCS3; n=6) in the controlateral side
(randomly
assigned). AA patency and percentage of recanalisation was assessed by visual
inspection and Laser Doppler after embolization and at 1, 7, 14, and 30 days.
The
rabbits were sacrificed at 30 days to assessed endothelial ablation and
inflammatory response by histological analyses. All AA's were catheterized and
embolized with success. After 30 days, all the OSal were patent. Percentage of
recanalization in comparison with initial embolization length were 25.6+/-34.4
% in
OCS1 (6+/-7 mm), and 22.5+/-15.9 % in OCS3 (12+/-8 mm) without statistical
difference with student test (p 0.05). At histology, chitosan/STS was shown to
generate inflammatory response and was then replaced by fibrous tissue.
[0063] - Canine model of aneurysms reproducing endoleaks after endovascular
aneurysm repair with a stent-graft were created in 3 dogs. One endoleak was
treated by chitosan/STS and its controlateral control by chitosan.
Chitosan/STS
led to good control during embolisation while chitosan gel showed some
migration
into the collaterals. No migration into the stent-graft lumen was observed.
One
small leak was visible by angiography just after embolisation but diseapeared
during the first week. At three months, no endoleak was detected while
endoleak
was present in 1/3 aneurysm treated with chitosan alone. In this challenging
animal model, untreated endoleak persist in all aneurysms when left untreated.
[0064] Problems related to endovascular aneurysms repair - EVAR clinical
outcome is severely limited by the persistence of blood flow perfusing the
aneurysm, called endoleaks, observed in 10% to 36% of cases [14-17]. The most
frequent type of endoleak is type II endoleak, which corresponds to retrograde
flow
from collateral arteries [18, 19]. Persistent type II endoleaks with sac size
progression require interventions as they can lead to aneurysm rupture [14,
15,
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17, 18, 20-26]. Several attempts have been recently made to treat or prevent
type
II endoleaks using coils or polymeric embolising agents (mainly N-butyl-2-
cyanoacrylate (NBCA) [1-4], Ethylenevinyl alcohol copolymer (EVOH, Onyx [5,
6],
polyurethane fragments [27] and fibrin glue [7], combined or not with coils
[4, 8].
These studies showed that sac embolisation has potential to minimize endoleak
occurrence. However, embolisation failure (recurrence, recanalisation) was
reported with all tested agents. Prophylactic embolisation of the inferior
mesenteric
and/or lumbar arteries or of the entire aneurismal sac during EVAR has also
been
proposed in patients to prevent endoleak formation, once again with limited
success [3, 9, 10]. Uflacker et al. reported a high proportion of residual
leaks in an
animal model despite deacetylated glucosamine injection into the aneurysm
[28].
In a human study, injection of fibrin glue decreased the rate but did not
completely
prevent type II endoleaks (2.4%) [7]. Injectable agents developed to date are
not
only unable to treat or prevent all endoleaks. They are also far from ideal
for such
clinical use. Cyanoacrylate and Onyx are difficult to control during
injection, are
non-biodegradable and non porous, thus preventing tissue healing in the cast.
Their long-term biocompatibility is questionable. Moreover they are also very
radio-opaque and could create a diagnostic challenge in surveillance imaging
studies. The two components of fibrin glue must be injected separately and
cannot
easily fill up the cavity, since they immediately form a blood clot.
[0065] While only some examples of gels in accordance with the invention are
provided, it is believed that a gel according to the claims will have similar
beneficial
properties.
[0066] Business potential: In industrialized countries, abdominal aortic
aneurysms (AAA) are found in approximately 8% of men above 65 years, and this
prevalence is expected to increase with aging of the population in the coming
CA 02704971 2010-05-20
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years [29, 30]. Surgical treatment of AAA is increasingly being replaced by
EVAR
using stent-grafts (SGs). EVAR reduces peri-operative mortality and morbidity
as
well as time for hospitalisation and convalescence compared to open surgical
repair with a vascular graft [31, 32]. However there are more complications
associated with EVAR, and there is an increase in reintervention needs after
EVAR compared with open repair" [33]. This represents higher costs for the
health
care system along with obvious inconvenience for the patient. Main
complications
are endoleaks, observed in 10% to 36% of cases [14-17]. Current solutions to
treat
these endoleaks are only partially efficient. Such a new embolisation agent
may
overcome this limitation. Moreover, this therapeutic approach may also be used
for
the prophylactic prevention of complications. One can imagine the important
impact of marketable improvements of EVAR considering that the market for
EVAR is expected to reach US $1.3 billion by 2012 (Abdominal Aortic Aneurysm:
Endovascular Technology & Market Forecasts, Medtech Reports, July 1, 2007).
Moreover, the invention could also be used for the treatment of vascular
malformations which also constitute a large market.
[0067] The above suggest an embolisation procedure to treat aneurisms, other
vascular defects and other pathologies and defects. The embolization procedure
is
similar to that of other polymeric embolization agents such as Onyx and
Histoacryl.
For the prevention of endoleaks after EVAR, the agent could be easily injected
at
the time of the endovascular treatment by an angiographic catheter which would
be placed into the aneurysm before stent-graft deployment. Once the stent-
graft is
deployed, the aneurysm is excluded from blood flow and the agent can be safely
injected into the aneurysmal sac.
[0068] To minimize risks of migration in collateral vessel, an occlusive
balloon
catheter can be deployed proximally in the vessel to avoid blood flow. The
volume
CA 02704971 2016-05-16
of the agent to be injected could be evaluated before based on imaging data.
Injection through a Glicath 4 French (Terumo, Tokyo, Japan) have been tested
with success both in vitro and in vivo.
[0069] When an endoleak has been observed during stent-graft imaging follow-
up, the agent can be used to treat the endoleak. In this case, the agent could
be
injected by a microcatheter (for example a 3 French catheter) positioned in
the
collateral vessel involved in the leak. It could also be injected by direct
punction
into the aneurysm (under CT scan or fluoroscopy). In this case, the agent is
injected with a needle (for example 21 or 22 gage) then replaced by a
micropunction system and a catheter or microcatheter. In this circumstances,
only
a small volume would be injected into the endoleak area,
[0070] For arteriovenous malformations or other treatments, the agent can be
injected directly in the nidus by a needle, or using a catheter when
necessary.
[0071] The proposed hydrogel is also usable in many other treatments, for
example to treat varicose veins and cancer, the later, for example, by serving
as a
vehicle for a therapeutic agent. In addition, STS can act on blood irrigation
of a
tumor though its sclerosing properties, as well as acting on the tumor through
these same properties. In these applications, the proposed gel is used in
replacement to gels used in similar methods in the prior art.
[0072] Although the present invention has been described hereinabove by way of
preferred embodiments thereof, it can be modified, without departing from the
nature of the subject invention as defined in the appended claims.
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References
1. Raymond J, Berthelet F, Desfaits AC, Salazkin I, Roy D. Cyanoacrylate
embolization of experimental aneurysms. AJNR Am J Neuroradiol 2002;23:129-
138.
2. Stavropoulos SW, Kim H, Clark TW, Fairman RM, Velazquez 0, Carpenter JP.
Embolization of type 2 endoleaks after endovascular repair of abdominal aortic
aneurysms with use of cyanoacrylate with or without coils. J Vasc Interv
Radiol
2005;16:857-861.
3. Stavropoulos SW, Park J, Fairman R, Carpenter J. Type 2 endoleak
embolization comparison: translumbar embolization versus modified
transarterial
embolization. J Vasc Interv Radio! 2009 Oct;20(10):1299-1302.
4. Maldonado TS, Rosen RJ, Rockman CB, Adelman MA, Bajakian D, Jacobowitz
GR, et al. Initial successful management of type I endoleak after endovascular
aortic aneurysm repair with n-butyl cyanoacrylate adhesive. J Vasc Surg
2003;38:664-670.
5. Martin ML, Dolmatch BL, Fry PD, Machan LS. Treatment of type II endoleaks
with onyx. J Vasc Interv Radio! 2001;12:629-632.
6. Ling AJ, Pathak R, Garbowski M, Nadkarni S. Treatment of a large type II
endoleak via extraperitoneal dissection and embolization of a collateral
vessel
using ethylene vinyl alcohol copolymer (onyx). J Vasc Interv Radiol
2007;18:659-
662.
7. Zanchetta M, Faresin F, Pedon L, Ronsivalle S. Intraoperative intrasac
thrombin
injection to prevent type II endoleak after endovascular abdominal aortic
aneurysm
repair. J Endovasc Ther 2007;14:176-183.
8. Raymond J, Leblanc P, Desfaits AC, Salazkin I, Morel F, Janicki C, et at.
In situ
CA 02704971 2010-05-20
17
beta radiation to prevent recanalization after coil embolization of cerebral
aneurysms. Stroke 2002;33:421-427.
9. Conrad MF, Adams AB, Guest JM, Paruchuri V, Brewster DC, LaMuraglia GM,
et al. Secondary intervention after endovascular abdominal aortic aneurysm
repair.
Ann Surg 2009 Sep;250(3):383-389.
10. Nevala T, Biancari F, Manninen H, Aho PS, Matsi P, Makinen K, et al. Type
11
Endoleak After Endovascular Repair of Abdominal Aortic Aneurysm: Effectiveness
of Embolization. Cardiovasc Intervent Radiol 2009 Aug 18.
11. Hoemann CD, Hurtig M, Rossomacha E, Sun J, Chevrier A, Shive MS, et al.
Chitosan-glycerol phosphate/blood implants improve hyaline cartilage repair in
ovine microfracture defects. J Bone Joint Surg Am 2005 Dec;87(12):2671-2686.
12. Fuchs T, Richtering W, Burchard W, Kajiwara K, Kitamura S. Gel point in
physical gels: rheology and light scattering from thermoreversibly gelling
schizophyllan. Polym Gels networks 1997;5:541-559.
13. Winter HH. Can the gel point of a cross-linking polymer be detected by the
G¨
G crossover? Polym Eng Sci 1987;27:1698-1701.
14. Hiramoto JS, Reilly LM, Schneider DB, Sivamurthy N, Rapp JH, Chuter TA.
Long-term outcome and reintervention after endovascular abdominal aortic
aneurysm repair using the Zenith stent graft. J Vasc Surg 2007 Jan 23.
15. Seriki DM, Ashleigh RJ, Butterfield JS, England A, McCollum CN, Akhtar N,
et
al. Midterm follow-up of a single-center experience of endovascular repair of
abdominal aortic aneurysms with use of the talent stent-graft. J Vasc Interv
Radiol
2006 Jun;17(6):973-977.
16. Steingruber 1E, Neuhauser B, Seiler R, Greiner A, Chemelli A, Kopf H, et
al.
Technical and clinical success of infrarenal endovascular abdominal aortic
CA 02704971 2010-05-20
18
aneurysm repair: A 10-year single-center experience. Eur J Radio! 2006
Sep;59(3):384-392.
17. Thomas SM, Beard JD, Ireland M, Ayers S. Results from the prospective
registry of endovascular treatment of abdominal aortic aneurysms (RETA): mid
term results to five years. Eur J Vasc Endovasc Surg 2005 Jun;29(6):563-570.
18. Brewster DC, Jones JE, Chung TK, Lamuraglia GM, Kwolek CJ, Watkins MT,
et al. Long-term outcomes after endovascular abdominal aortic aneurysm repair:
the first decade. Ann Surg 2006 Sep;244(3):426-438.
19. Veith FJ, Baum RA, Ohki T, Amor M, Adiseshiah M, Blankensteijn JD, et al.
Nature and significance of endoleaks and endotension: summary of opinions
expressed at an international conference. J Vasc Surg 2002 May;35(5):1029-
1035.
20. Endovascular aneurysm repair and outcome in patients unfit for open repair
of
abdominal aortic aneurysm (EVAR trial 2): randomised controlled trial. Lancet
2005 Jun 25-Jul 1;365(9478):2187-2192.
21. Blankensteijn JD, de Jong SE, Prinssen M, van der Ham AC, Buth J, van
Sterkenburg SM, et al. Two-year outcomes after conventional or endovascular
repair of abdominal aortic aneurysms. N Engl J Med 2005 Jun 9;352(23):2398-
2405.
22. Fransen GA, Vallabhaneni SR, Sr., van Marrewijk CJ, Laheij RJ, Harris PL,
Buth J. Rupture of infra-renal aortic aneurysm after endovascular repair: a
series
from EUROSTAR registry. Eur J Vasc Endovasc Surg 2003 Nov;26(5):487-493.
23. Harris PL, Vallabhaneni SR, Desgranges P, Becquemin JP, van Marrewijk C,
Laheij RJ. Incidence and risk factors of late rupture, conversion, and death
after
endovascular repair of infrarenal aortic aneurysms: the EUROSTAR experience.
CA 02704971 2010-05-20
19
European Collaborators on Stent/graft techniques for aortic aneurysm repair. J
Vasc Surg 2000 Oct;32(4):739-749.
24. Tiesenhausen K, Hessinger M, Konstantiniuk P, Tomka M, Baumann A,
Thalhammer M, et al. Surgical conversion of abdominal aortic stent-grafts--
outcome and technical considerations. Eur J Vasc Endovasc Surg 2006
Jan;31(1):36-41.
25. Torsello G, Osada N, Florek HJ, Horsch S, Kortmann H, Luska G, et al.
Longterm outcome after Talent endograft implantation for aneurysms of the
abdominal aorta: a multicenter retrospective study. J Vasc Surg 2006
Feb;43(2):277-284; discussion 284.
26. van Marrewijk C, Buth J, Harris PL, Norgren L, Nevelsteen A, Wyatt MG.
Significance of endoleaks after endovascular repair of abdominal aortic
aneurysms: The EUROSTAR experience. J Vasc Surg 2002 Mar;35(3):461-473.
27. Rhee JY, Trocciola SM, Dayal R, Lin S, Chaer R, Kumar N, et al. Treatment
of
type II endoleaks with a novel polyurethane thrombogenic foam: induction of
endoleak thrombosis and elimination of intra-aneurysmal pressure in the canine
model. J Vasc Surg 2005;42:321- 328.
28. Uflacker R, Brothers T. Filling of the aneurysmal sac with deac-
glucosamine in
an
animal model of abdominal aortic aneurysm following stent-graft repair. J
Cardiovasc
Surg 2006;47:425-436.
29. Melton LI, Bickerstaff L, Hollier L. Changing incidence of abdominal
aortic
aneurysms : a population-based study. Am J Epidemiol 1984;120:379-386.
CA 02704971 2010-05-20
30. Newman AB, et al. Cardiovascular disease and mortality in older adults
with
small abdominal aortic aneurysms detected by ultrasonography: the
cardiovascular health study. Ann Intern Med 2001;134(3):182-190.
31. Prinssen M, Verhoeven EL, Buth J, Cuypers PW, van Sambeek MR, Balm R,
et al. A randomized trial comparing conventional and endovascular repair of
abdominal aortic aneurysms. N Engl J Med 2004;351:1607-1618.
32. Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG.
Comparison of endovascular aneurysm repair with open repair in patients with
abdominal aortic aneurysm (evar trial 1), 30-day operative mortality results:
randomised controlled trial. Lancet 2004;364:843-848.
33. Greenhalgh RM, Brown LC, Powell JT, Thompson SG. Current interpretation
of the UK EVAR Trials. Acta Chir Belg 2006 Mar-Apr;106(2):137-138.
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Table 1. Order of preparation to obtain a chitosan hydrogel with sclerosing
properties at physiological pH.
Order of preparation Hvdrociel formation Remarks
CH + STS N Precipitation and phase separation of
chitosan solution.
[CH + STS] + r3GP N Precipitation and phase separation of
chitosan solution.
The pGP addition didn't improve the
hydrogel formation.
[CH + 13GP] + STS N Phase separation of chitosan solution.
CH + I3GP Y Homogenous and injectable hydrogel
without sclerosing properties.
CH + [ r3GP + STS] Y Homogenous and injectable hydrogel with
sclerosing properties.
Table 2. Influence of STS concentration on rheological characteristics of
chitosan
hydrogel at 37 C (2% w/v CH, 20% v/v10P, 12% w/v i3GP).
Formulation STS (% w/v) pH at 23 C 6 (min) go f)(2p_y()_' go, (Pa
)+
CH/13GP-STS-0 0 7.24 897 121 10 1 1213 79
CH/ fiGP-STS-1 1 7.30 Immediate 40 23 1716 402
CH/13GP-STS-2 2 7.34 Immediate 444 21 2724 275
CH/13GP-STS-3 3 7.39 Immediate 1357 387 3297 351
* Initial storage modulus at time O.
+ Storage modulus after one week of gelation.