U.S. patent application number 14/496965 was filed with the patent office on 2015-01-08 for endoluminal medical access device.
The applicant listed for this patent is Karolinska Institutet Innovations AB. Invention is credited to Staffan Holmin, Stefan Jonsson, Johan Lundberg.
Application Number | 20150011909 14/496965 |
Document ID | / |
Family ID | 40677800 |
Filed Date | 2015-01-08 |
United States Patent
Application |
20150011909 |
Kind Code |
A1 |
Holmin; Staffan ; et
al. |
January 8, 2015 |
ENDOLUMINAL MEDICAL ACCESS DEVICE
Abstract
An endoluminal medical access device (1) is disclosed that is
devised for endoluminal delivery to an extravascular target site
(5) at a vasculature site of a human or animal body vasculature,
such as the microvasculature. The device (1) comprises a hollow
body (112) arranged around a continuous channel (113) that ends in
a distal end (100) and comprises a distal penetration portion (102)
that is devised to extend across a tissue wall of said
microvasculature said microvasculature site (4) at an extravascular
target site in said body to provide communication with said
extravascular target site through said channel (113) and devised
for at least partly apposition to said tissue wall, and a proximal
connection section (101), which proximally adjoins said penetration
portion (102), and optionally comprises an intrusion depth limit
unit (116, 118) and/or a hollow separation section (115) devised to
provide a controllable separation of the penetration portion (102)
from a connected proximal portion (110) of the hollow body.
Inventors: |
Holmin; Staffan; (Bromma,
SE) ; Jonsson; Stefan; (Sollentuna, SE) ;
Lundberg; Johan; (Taby, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Karolinska Institutet Innovations AB |
Solna |
|
SE |
|
|
Family ID: |
40677800 |
Appl. No.: |
14/496965 |
Filed: |
September 25, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12936825 |
Oct 7, 2010 |
8876792 |
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PCT/EP2009/054273 |
Apr 8, 2009 |
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14496965 |
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61043337 |
Apr 8, 2008 |
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Current U.S.
Class: |
600/562 ;
604/117; 604/507 |
Current CPC
Class: |
A61M 25/0082 20130101;
A61B 2017/3425 20130101; A61B 2018/1892 20130101; A61B 17/3423
20130101; A61B 17/3494 20130101; A61M 25/0069 20130101; A61N 1/05
20130101; A61M 25/06 20130101; A61B 2017/3492 20130101; A61M
25/0084 20130101; A61M 25/0068 20130101; A61B 10/04 20130101; A61M
2025/0042 20130101 |
Class at
Publication: |
600/562 ;
604/507; 604/117 |
International
Class: |
A61B 17/34 20060101
A61B017/34; A61B 10/04 20060101 A61B010/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 8, 2008 |
SE |
0800787-4 |
Claims
1-25. (canceled)
26. A method of endoluminal access to an extravascular target site
in a heart, said method comprising: perforating a vessel wall of a
coronary artery or coronary vein at an extravascular target site in
said heart with a distal portion of an endoluminal access device,
positioning said distal portion of said endoluminal access device
extending across said vessel wall at least partly in apposition to
said vessel wall, limiting an intrusion distance of said distal
portion through said vascular wall, and providing communication
with an extravascular space at said target site through a
communication channel in said endoluminal access device.
27. The method of claim 26, further comprising withdrawing said
endoluminal access device.
28. The method of claim 26, wherein said endoluminal access device
comprises: a hollow body that is arranged around a continuous
channel that ends in an opening at a distal end of said device; a
distal portion that is configured to perforate a tissue wall of
said coronary artery or coronary vein at said target site to
provide communication with said extravascular target site through
said channel while said distal portion is at least partly in
apposition to said tissue wall; and an intrusion distance
limitation unit that prevents perforation of said distal portion
beyond an intrusion distance through said vascular wall.
29. The method of claim 28, wherein said intrusion distance
limitation unit comprises a flange configured to limit an intrusion
distance of said endoluminal medical access device into said tissue
wall.
30. The method of claim 29, wherein said flange is foldable towards
said hollow body.
31. The method of claim 28, wherein said intrusion distance
limitation unit is a recess in an outer wall of said hollow
body.
32. The method of claim 26, wherein said distal portion has an
inner diameter to length ratio such that the flow of blood through
said channel is zero at physiological pressures, whereby said
endoluminal access device is adapted for delivery either in an
arterial or a venous side of the vasculature.
33. The method of claim 26, comprising navigating said endoluminal
access into a vessel having a luminal diameter of 1 mm or less.
34. The method of claim 26, wherein said perforating is performed
with a sharp tip at a distal end of said distal portion.
35. A method of communicating with a target site in a heart, said
method comprising establishing communication with said target site
by performing the method according to claim 26, and wherein said
procedure is delivery of a substance to said target site or taking
of a sample from said target site through said communication
channel, wherein said delivery or taking of sample is made at a
pressure higher than a physiological pressure in said vessel.
36. The method of claim 35, wherein said substance comprises cells,
thus endovascularly transplanting said cells into said target
site.
37. The method of claim 35, wherein said delivery or taking of
sample is to or from heart muscle or to or from a vessel wall.
38. The method of claim 35, wherein said delivery of a substance
comprises local administration of said substance.
39. The method of claim 37, wherein said substance comprises a stem
cell, a fluid, a pharmaceutical agent, a cytostatic substance, a
growth factor, a contrast agent, a radioactive agent, or
radioactive isotope particle, or any combination of these.
40. The method of claim 35, wherein said taking of said sample
comprises a puncture of a cyst.
41. The method of claim 36, further comprising subintimally passing
an occlusion or stenosis of a vessel with said device.
42. An endoluminal medical access device for endoluminal delivery
to an extravascular target site at a vasculature site of a human or
animal body vasculature, said device comprising: a hollow body that
is arranged around a continuous channel that ends in an opening at
a distal end of said device; wherein: said hollow body comprises an
elongate distal penetration portion that is configured to perforate
a tissue wall of said vasculature at said vasculature site and to
provide communication with said extravascular target site through
said channel while at least partly in apposition to said tissue
wall; said device comprises an intrusion depth limitation unit
configured to prevent introduction of said distal penetration
portion beyond a desired insertion depth through said vascular wall
into the extravascular target site; said distal portion has an
inner diameter to length ratio such that the flow of blood through
said channel is zero at physiological pressures, whereby said
endoluminal access device is adapted for delivery via coronary
arteries or veins or via coronary sinus.
43. The device of claim 42, wherein said hollow body comprises a
fiducial marker.
44. The device of claim 42, wherein said device is sized to access
a coronary vessel having a luminal diameter of 1 mm or less.
45. The device of claim 42, wherein said intrusion depth limitation
unit comprises a flange configured to limit an intrusion depth of
said device into said tissue wall or wherein said depth limitation
unit comprises a flange that is foldable towards said hollow body.
Description
FIELD OF THE INVENTION
[0001] This invention pertains to the field of catheter based
medical devices. More particularly, the invention relates to hollow
probes having a piercing tip. Even more particularly, the invention
relates to an endoluminal vascular medical access device for
endoluminal delivery of substances to and/or from a vasculature
site of a human or animal body and access to an extravascular
target site located outside of the lumen of the vasculature at said
site. The vascular site may be a microvasculature site.
BACKGROUND OF THE INVENTION
[0002] There is today a trend towards minimally invasive techniques
for administration or sampling of substances or cells to or from
various organ systems. Most organs and tissues in the body can be
reached by needles with or without ultrasonic or computerized
tomography guidance and if this is not possible, open surgery is an
option. Stereotactic delivery, assisted by modern imaging
techniques, are also existing alternatives.
[0003] However, these techniques are not applicable for all organ
systems, e.g. due to the limited resolution of the imaging
modalities and sub-sequential planning of safe route at justifiable
patient risk and radiation doses.
[0004] Moreover, there are some target areas in the body that are
not accessible by known minimally invasive techniques and devices
via safe routes. For such organs with less accessible anatomical
location, parenchymal access can be associated with significant
surgical risks.
[0005] The development of endovascular microcatheter techniques
during the last years has opened a possibility to reach parts of
the body that have been difficult to reach previously by
conventional means by using arteries and veins as via the "internal
routes" that they constitute. The potential of these techniques was
recognized due to the possibility to do minimally invasive
transplantations, such as disclosed in Bliss, T., R. Guzman, et al.
(2007). "Cell transplantation therapy for stroke." Stroke 38(2
Suppl): 817-26.
[0006] U.S. Pat. No. 6,602,241 of Transvascular Inc. discloses
methods and apparatus for delivery of substances or apparatus to
target sites located outside blood vessels. A vessel wall
penetrating catheter is disclosed that is inserted into the
vasculature, positioned and oriented within a blood vessel near a
target extravascular site and a penetrator is advanced from the
catheter so as to perform an outward penetration through the wall
of the blood vessel in the direction of the target site.
Thereafter, a delivery catheter is passed through a lumen of the
penetrator to the target site. A desired substance or apparatus is
then delivered to or obtained from the target site. In some
applications, the penetrator may be retracted into the vessel wall
penetrating catheter and the vessel wall penetrating catheter may
be removed, leaving the delivery catheter in place for chronic or
continuous delivery of substance(s) to and/or obtaining of
information or samples from the target site. Alternatively, a
delivery catheter having an occlusion member or balloon may be
advanced into a vein or venule and the occlusion member or balloon
may be used to occlude the lumen of the vein or venule during and
after injection of a substance through the catheter, such that the
substance will not be carried away by normal venous blood flow and
will remain in the vein or venule for a sufficient period of time
to have its intended effect, e.g. to enter adjacent tissues through
capillary beds drained by that vein or venule.
[0007] However, the disclosure of U.S. Pat. No. 6,602,241 describes
a system providing penetration of a vein, i.e. the low pressure
side of the vasculature, leaving a catheter in position at the
penetration site of the vein. The catheter is connected all the way
through the vasculature to the entry point into the body or
vasculature.
[0008] In addition, it appears that the system disclosed in U.S.
Pat. No. 6,602,241 does not provide a satisfactory solution to
avoid bleeding at the penetration side inside the body after
completed treatment when the catheter is retracted. It is mentioned
that a backflow of injected fluid may be prevented by injecting a
suitable adhesive or embolizing material such as a cyanoacrylate,
polyethylene glycol, hydrogel or fibrin glue through the catheter
lumen as the catheter is being pulled back through the tissue
tract, through which it was initially inserted.
[0009] However, this solution to avoid bleeding at the penetration
site is not satisfactory from a clinical point of view as it is
difficult to perform and to monitor the success thereof. In
addition, the injection of adhesive or embolization material may
induce thrombotic embolies or unintentionally occlude the delivery
vessel completely. Furthermore, the use of adhesives is not
feasible in arterial vessels due to the existing higher blood
pressure pushing the adhesive material out of the penetration site
into the surrounding tissue before the penetration site is
closed.
[0010] Moreover, the vessel wall penetrating catheter disclosed in
U.S. Pat. No. 6,602,241 is of such large size that it cannot
navigate into the microvasculature, e.g. into the central nervous
system (CNS). Furthermore, the vessel wall penetrating catheter
body includes a rigid proximal section and an elongated flexible
distal section joined to the proximal section, wherein the distal
section is sized to be received within the coronary sinus (venous
system). The catheter body also has a penetrator lumen
accommodating a vessel wall penetrator, such as a hollow Nitinol
(NiTi--an alloy of Nickel and Titanium) needle, advanceable out of
a side exit port. The catheter body also has a guidewire lumen
which extends to the distal end of the catheter body. In summary,
the catheter comprises many components and is therefore of the
aforementioned large size.
[0011] Hence, the vessel penetrating catheter disclosed in U.S.
Pat. No. 6,602,241 is not suited for vascular navigation into the
CNS or other similar small vessels in the body. The vessel wall
penetrator body is, amongst other things due to the multi lumen
design, so large that it would occlude such small vessels, which is
highly undesired, and may be fatal to the CNS parenchyma supported
by such an artery.
[0012] Other known techniques using stent connections between
vessels comprise transjugular intrahepatic portosystemic shunts
(TIPS), which is a technique to provide a permanent stent
connection between large veins of the liver, e.g. the v. porta and
the v. hepatic. This is an endovascular technique, using a
radiologic procedure to place a stent in the middle of the liver to
reroute the blood flow. The TIPS procedure is done using
intravenous sedation or general anesthesia. During the procedure,
an interventional radiologist makes a tunnel through the liver with
a needle, connecting the portal vein, i.e. the vein that carries
blood from the digestive organs to the liver, to one of the hepatic
veins, i.e. the three veins that carry blood from the liver. A
metal stent is placed in this tunnel to keep the track open.
However, this endovascular technique is not suited for the arterial
part of the body vascular system. Furthermore, it is not suited for
use in microvessels, but in large vessels. In addition, a stent is
left in place for keeping a permanent communication between
vessels. Moreover, in practice the radiologist usually pushes and
retracts the needle several times until the second vein is hit,
which implies a risk for bleedings. The amount of bleeding that can
occur can sometimes be life threatening needing costly patient
monitoring in intensive care.
[0013] Similar unwanted multi penetration of a vessel wall with
potential patient bleeding is potential while using an apparatus as
disclosed in U.S. Pat. No. 6,302,870. The apparatus comprises a
plurality of laterally flexible needles for reaching body cavities.
The configuration of the apparatus is such that the wall of the
blood vessel juxtaposed to the site of delivery is potentially
circumferential penetrated by the several needle points. As the
blood vessel wall becomes perforated a rupture in the wall may
occur, in particular at the arterial side of the vascular
system.
[0014] A further issue is when vascular walls are penetrated, e.g.
by a needle, upon retraction of the needle, a compression of the
exit site is needed in order to avoid bleeding. However, often it
is not possible to provide a compression of such an exit site at
conventionally difficult accessible target sites in a human or
animal body.
[0015] Various needle tips may be found for example as disclosed in
WO00/13728 or U.S. Pat. No. 5,092,848. Commonly these have in
common the ability to penetrate into soft tissue and are disclosed
to be permanently secured to the distal end of a delivery catheter.
As the catheter is retracted the tip follows back with the
catheter, leaving a transmural hole which hopefully will collapse
sealing the channel in the vessel wall to the extravascular space.
However, the ability to seal properly depends on e.g. the
compliance of the tissue and the blood pressure in the vessel. A
self sealing ability is not sufficient on the arterial side of the
vascular system especially in areas where no bleeding is tolerated,
e.g. in connection with CNS interventions.
[0016] Conventionally difficult accessible target sites in the body
may not be reached with the aforementioned devices.
[0017] Hence, it is difficult to deliver substances to and/or from
conventionally difficult accessible target sites in a human or
animal body.
[0018] Microcatheters are for instance disclosed in WO03080167A2.
However, a penetration of vessel walls is not anticipated or
implementable with this type of microcatheter as the distal tip of
the disclosed microcatheter is blunt, and the distal end portion is
in addition flexible and has spiral cuts. This provides for a
vascular navigation to target sites which are located far more
remote in the vascular system than accessible with catheter based
techniques aimed for transvascular access such as the technique
disclosed in U.S. Pat. No. 6,602,241. Thus, extravascular target
sites are not accessible for this kind of microcatheters.
[0019] Another microcatheter device disclosed in WO2007121143 has a
tissue penetrating tip member. This device appears to be not suited
for use in the microvasculature. The tip is constructed with
electrodes to heat the tip facilitating advancement in the tissue.
Potentially necrosis may occur. Moreover, a transluminal channel is
created, which when the microcatheter is retracted, leaves a hole
trough the vessel wall to the extravascular space. An undesired
effect as e.g. hemorrhage, at least on the arterial side of the
vascular system is likely to occur.
[0020] An issue needing a novel and inventive solution is thus
delivery of substances to and/or from conventionally difficult
accessible target sites in a human or animal body, such as the
microvasculature, e.g. in the CNS or pancreas.
[0021] In addition, or alternatively, there is a need to provide a
solution that prevents or avoids bleeding from a penetration site
of a vessel wall at the target site upon completed delivery or
extraction of the substances.
[0022] Furthermore, a device suitable to be used on both the venous
and arterial side of the vascular system would be beneficial in the
operating theater as less equipment systems would be necessary.
SUMMARY OF THE INVENTION
[0023] Accordingly, embodiments of the present invention preferably
seek to mitigate, alleviate or eliminate one or more deficiencies,
disadvantages or issues in the art, such as the aboveidentified,
singly or in any combination by providing an endoluminal medical
access device, a kit, and methods according to the appended patent
claims.
[0024] The invention relates to an endoluminal medical access
device for endoluminal delivery of substances to and/or from a
vasculature site of a human or animal body and access to an
extravascular target site located outside of the lumen of the
vasculature at said site.
[0025] The vasculature site may be a microvasculature site, wherein
microvasculature is defined as the portion of the circulatory
system that is composed of the smallest vessels, such as the
capillaries, arterioles, and venules.
[0026] According to a first aspect of the invention, a device is
provided. The device is an endoluminal medical access device,
devised for endoluminal delivery to a microvasculature site, or a
vasculature site, of a human or animal body vasculature, and access
to an extravascular target site at said site located outside of the
lumen of the vasculature at said site. The device comprises a
hollow body that is arranged around a continuous channel that ends
in an opening at a distal end of the device. The hollow body
comprises a distal portion that is devised to extend across a
tissue wall of the microvasculature, or vasculature, at an
extravascular target site in the body and devised to provide
communication with the target site through the channel and devised
for at least partly apposition to the tissue wall, and a proximal
section, which proximally adjoins the distal portion. The distal
portion is detachable or seperable from the proximal portion to be
left in place at the vasculature site. The device optionally
comprises an intrusion depth limiting unit.
[0027] According to a second aspect of the invention, a kit is
provided. The kit comprises an endoluminal medical access device
according to the first aspect of the invention, and an elongated
tubular delivery device.
[0028] According to a third aspect of the invention, a method is
provided. The method is a method of endoluminal access to a target
site in a human or animal body, and comprises of using a device
according to the first aspect of the invention. The method
comprises perforating a vessel wall of the microvasculature, or
vasculature, with the distal portion at an extravascular target
site in the body, and positioning the distal portion for extending
across the vessel wall at least partly in apposition to the tissue
wall, providing communication with the target site through the
channel, and detaching said distal portion from a proximal portion
when a procedure is finished.
[0029] According to a further aspect of the invention, another
method is provided. The method is a method of communicating with a
target site in an animal or human body, comprising of establishing
communication with the target site by performing the method
according to the third aspect of the invention, and providing
parenchymal injection of a substance, cells, fluids or other
materials possible to deliver through said intervention to the
target site or taking of samples from the target site through the
channel.
[0030] The aspects of the invention provide for targeted substance
delivery and/or sampling.
[0031] Further embodiments of the invention are defined in the
dependent claims, wherein features for the second and subsequent
aspects of the invention are as for the first aspect mutatis
mutandis.
[0032] The medical access device is an endoluminal medical access
device, herein named "extraducer" or extroducer device. The term
"extroducer" is, in contrast to an "introducer", a device that is
advanced from the inside of a vessel, i.e. from the inner lumen
formed by the vessel, to the outside thereof. The extroducer device
is advanced into the tissue of the vessel wall. The extroducer
device is devised to penetrate the tissue, or alternatively or in
addition, penetration may be assisted. When delivered into position
through the tissue of the vessel wall, the extroducer device is
providing a communication path, by an inner hollow, from the inner
lumen across the tissue of the vessel wall to the extravascular
space. Further, the extroducer device is distally extending into
the extravascular space with a distal end thereof arranged at a
target site in the extravascular space. This type of endoluminal
outward delivery is described by the term "extroduced", which is an
"inverted introduction" from the inside to the outside of the
vessel, all inside the body. The term "extraducer" is based on this
understanding. The extroducer device provides in such manner a
communication channel between the inner lumen and the extravascular
space. In particular embodiments, the extroducer device is devised
for exiting the microvasculature from the inner lumen thereof to an
extravascular target site by perforation of the lumen. The vessel
for endoluminally inserting the extroducer may be any vessel
throughout the body in both the arterial and the venous side. The
term "extroducer" or "extroducer device" used throughout this
description is contemplated being such a vascular extroducer or an
`endoluminal medical access device`.
[0033] The extroducer device provides for safely penetrating
arterial or venous blood vessels with a luminal diameter, in
current practical implementations down to a size of approximately
0.7 mm, to be able to administrate or sample cells and substances
to/from the extravascular space at such vessels. This provides for
combining minimal invasiveness of an endoluminal approach with an
accurate administration in a desired anatomical target
location.
[0034] For transplantation purposes, this also further provides for
increasing the ratio between engrafted and transplanted cells.
[0035] Previously, in works with intravascular transplantation of
cells, a control over cellular engraftment location, or a favorable
ratio between transplanted and engrafted cells has not been
thoroughly considered. Embodiments of the extroducer device provide
for delivery of an increased ratio between engrafted and
transplanted cells in a minimally invasive way. The endovascular
technique provides, at least in certain instances, such as for the
CNS, the pancreas, and the heart, the merit of less invasiveness
than open surgical procedures of percutaneous transplantation.
[0036] Certain embodiments of the extroducer are believed to
combine favorable properties of minimal invasiveness with accurate
and efficient engraftment of stem cells. The extroducer provides
for local administration of any substances, such as pharmaceutical
agents, including cytostatics; growth factors or contrast.
Alternatively, or in addition, the extroducer device provides for a
puncture, of for example cysts, in difficult accessible anatomical
locations.
[0037] The extroducer device according to some embodiments provides
for a high degree of flexibility. The system is devised for
delivery inside micro catheters. In embodiments the system is
adapted for navigation into vessels down to 1 mm and smaller. Other
embodiments are not restricted to such small vasculature
dimensions. This provides for a vascular navigation to target sites
which are located far more remote in the vascular system than
accessible with catheter based techniques aimed for transvascular
access such as the technique disclosed in U.S. Pat. No. 6,602,241.
The access provided by embodiments, provides for instance for
delivering of substances, cells or taking cytological preparations
according to previously mentioned techniques.
[0038] The extroducer device according to some embodiments provides
for arterial navigation. Some embodiments provide for venous
navigation.
[0039] The extroducer device according to some embodiments provides
for usability during interventions, where it is not necessary or
desired to leave a catheter or fluid communication line in the
vasculature, e.g. after substance delivery or finished treatment.
Bleeding is avoided after finished treatment.
[0040] The extroducer device according to some embodiments
comprises a communication channel devised for injection and/or
aspiration purposes integrally formed with a perforation device
devised for perforation of a vessel wall. This, amongst others,
makes the miniaturization of the extroducer possible.
[0041] The extroducer device may provide parenchymal injection of a
substance, cells, fluids or other materials, or taking of samples,
even in difficult accessible anatomical locations.
[0042] The extroducer device according to some embodiments provides
for a perforation of a vessel wall, wherein the perforation site in
the vessel wall does not need to be plugged up upon withdrawal of
the extroducer device.
[0043] Some embodiments of the extroducer device provide for
devices which may be left in place in a punctured vessel wall over
a period of time.
[0044] Some embodiments of the extroducer device provide for
devices that are devised to seal off communication thereto at
physiological pressure levels, whereby the extroducer device may be
left in place in a punctured vessel wall over a period of time,
wherein no leakage to or from the vessel occurs, or wherein
substantially no leakage flow occurs.
[0045] Some embodiments of the extroducer device provide for
devices which may be left in place in a punctured vessel wall over
a period of time, wherein no or substantially no leakage or
bleeding to or from the vessel occurs, and wherein the device
degrades over time at the site of puncture.
[0046] A detachable distal elongate portion of the device of some
embodiments may be left in place in the vessel wall at the
perforation site and inherently thanks to its advantageous design
prevents a flow therethrough at physiological pressures. There is
no need for using an adhesive or embolization agent to close the
puncture channel.
[0047] Some embodiments of the extroducer device comprise an
automatic sealing. The extroducer device has such dimensions that
is uses physical principles according to which a flow through the
communication channel of the device does not occur at physiological
blood pressure levels. This has also been demonstrated by means of
in vivo experiments. Higher pressures to provide a fluid flow
through the communication channel have to be provided through the
connected microcatheter. The driving pressure are chosen that cells
in suspension are not killed. Positive pressures provide a delivery
of fluid to the target site through the communication channel of
the hollow body. Negative pressures provide an aspiration from the
target site through the communication channel of the hollow
body.
[0048] Some embodiments of the extroducer device comprise an
element for limiting the entry depth of the perforation device in
tissue, e.g. a vessel wall. The limitation element may be a rigid
or foldable stop element, or a recess in the outer wall of the
hollow body.
[0049] Some embodiments of the extroducer device provide for a
separation from the perforation device from the microcatheter. A
distal portion of the hollow body is detachable and may be left in
place at the target site after treatment. Thus the proximal part of
the hollow body, and the microcatheter, may be retracted from the
target site through the vasculature. As mentioned above, the
extroducer device is devised to seal off or prevent a flow through
the communication channel and may be left in the tissue. In vivo
experiments has shown that the device does not return into the
vessel due to positive driving pressure from the inside of the
vessel vis-a-vis the extra vascular space and does not
substantially travel further into tissue, ensuring patient
safety.
[0050] Some embodiments of the extroducer device provide for a
bioresorption or biodegradation of the device in the body when
manufactured in a biodegradable material.
[0051] Some embodiments of the extroducer device provide for a
clinically well acceptable and useful system.
[0052] Some embodiments of the extroducer device provide for a safe
way of reaching a target site at or adjacent to a small vessel,
wherein a retraction of at least a part of the device is achievable
without causing bleedings or thrombotic embolies in the small
vessel and without leaving behind a catheter system in the
patient.
[0053] Some embodiments of the extroducer device, specifically with
larger diameters, provide for devices which are sealed by advancing
a sealing plug through the hollow part of the system to the distal
detachable penetration device that is left in the vessel wall.
[0054] Some embodiments of the extroducer device also provide for
advantageous endovascular intervention that may provide both
transplantation of cells, delivering drugs, radioactive substances
and other substances and sampling body fluids and cytological
preparations.
[0055] Some embodiments of the extroducer device also provide for a
system that in its entirety fits into current standard
microcatheter systems that provide navigation capabilities and
integration with currently used equipment. Embodiments of the
extroducer device thus provide for quick treatment in emergency
cases.
[0056] It should be emphasized that the term "comprises/comprising"
when used in this specification is taken to specify the presence of
stated features, integers, steps or components but does not
preclude the presence or addition of one or more other features,
integers, steps, components or groups thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0057] These and other aspects, features and advantages of which
embodiments of the invention are capable of will be apparent and
elucidated from the following description of embodiments of the
present invention, reference being made to the accompanying
drawings, in which
[0058] FIG. 1 is a schematic illustration of a device according to
an embodiment in a side view from above;
[0059] FIG. 2 is a schematic illustration of the device of FIG. 1
in a lateral view;
[0060] FIG. 3A is a schematic illustration of delivery of the
device of FIG. 1 through the microvasculature to a target site;
[0061] FIG. 3B is a schematic illustration of the device of FIG. 1
in penetration of a vascular wall;
[0062] FIG. 4a is a graph illustrating a circular Poiseuille flow
through a practical implementation of an extroducer device; and
[0063] FIG. 4b is a graph illustrating velocity fields of circular
Poiseuille flows through a practical implementation of an
extroducer device;
[0064] FIGS. 5A, 5B and 6A, 6B are graphs illustrating the velocity
fields of flows of whole blood in two different communication
channels;
[0065] FIGS. 7A, 7B, 7C are a perspective view, a side view from
above, and a lateral view of a practical implementation of an
extroducer device;
[0066] FIGS. 8A, 8B, 8C are a perspective view, a side view from
above, and a lateral view of another practical implementation of an
extroducer device;
[0067] FIGS. 9A, 9B, 9C are a perspective view, a side view from
above, and a lateral view of a further practical implementation of
an extroducer device;
[0068] FIGS. 10A, 10B, 10C are a perspective view, a side view from
above, and a lateral view of yet another practical implementation
of an extroducer device;
[0069] FIGS. 11A, 11B, 11C, 12A, 12B, 13A, 13B, 14A, 14B, 15A, 15B,
16A, and 16B illustrate different configurations of intrusion depth
limitation units; and
[0070] FIGS. 17A, and 17B are schematic illustrations of an
extroducer device and a polymer tube 2 with a proximal intrusion
depth limitation unit.
DESCRIPTION OF EMBODIMENTS
[0071] Specific embodiments of the invention will now be described
with reference to the accompanying drawings. This invention may,
however, be embodied in many different forms and should not be
construed as limited to the embodiments set forth herein; rather,
these embodiments are provided so that this disclosure will be
thorough and complete, and will fully convey the scope of the
invention to those skilled in the art. The terminology used in the
detailed description of the embodiments illustrated in the
accompanying drawings is not intended to be limiting of the
invention. In the drawings, like numbers refer to like
elements.
[0072] Advancements in stem cell techniques have created a
potential for regenerative treatments to a vast spectrum of
diseases, e.g. diabetes mellitus, morbus Parkinson, ischemic heart
disease, traumatic brain injury, and stroke.
[0073] Therefore there is a need for efficient and minimally
invasive techniques for delivering the cells to a desired target
organ and/or pathological system. Such delivery is provided by the
extroducer device.
[0074] A comparison of different techniques for administration to
the central nervous system (CNS) following stroke with emphasis on
the sheer number of cells engrafted shows that the most efficient
way of administration is intracerebral (ic) followed by
intracerebroventricular (icy) and then intravenous (iv)
delivery.
[0075] To make a successful transplantation of stem cells, a few
considerations must be made, e.g. accessibility to a target organ,
number of cells and volume of cell suspension and the engraftment
success-rate. It has been argued that some cells possess an
internal homing feature mediated through receptor-ligand
interactions. For cells with such properties an iv route would
probably be favorable giving better distribution throughout the
transplantation target volume.
[0076] In situations where the cellular engraftment rate after
endovascular administration is low and when a high anatomical
specificity for the engraftment is required, direct puncture of the
parenchyma is preferable. This was hitherto done with a
percutaneous guided needle puncture or in a combination with open
surgery.
[0077] However, as mentioned above, with percutaneous guided needle
puncture or in a combination with open surgery, some target regions
of the body, such as the CNS or the pancreas, are difficult or not
at all accessible without jeopardizing patient safety, including an
increased risk of e.g. morbidity, expense, trauma, patient
mortality, and other complications. Hence, a system with improved
patient safety would be desirable and is provided in form of the
extroducer device.
[0078] The design and concept of the device of embodiments is
adapted to be clinically applied according to the clinically well
proven Seldinger technique, as disclosed in Seldingers original
work describing the introducer, Seldinger, S. I. (1953) "Catheter
replacement of the needle in percutaneous arteriography; a new
technique." Acta radiol 39(5): 368-76, which is incorporated herein
in its entirety for all purposes. However, there are differences
between the Seldinger introducer and devices according to
embodiments.
[0079] The design of the extroducer device facilitates to provide
the small dimensions necessitated by the required microvasculature
access to specific target sites. However, the design is also
compatible and adaptable for larger dimension catheter systems,
when required in specific embodiments or applications.
[0080] The extroducer devices comprise an integrated communication
channel in a hollow body and a distal perforating unit in a single
lumen system. Navigation through the vascular system down into
microvessels, for instance of a diameter of 1 mm or smaller, is
facilitated by the devices. Some embodiments are not such limited
and are scaled up to use in larger vessel systems.
[0081] Some embodiments have a stop element for the perforation
unit. The stop element limits intrusion depth., Intrusion depth is
thus advantageously controllable without the need of high
resolution (and dosage) imaging modalities. The stop element may be
a protruding flange. The flange may be foldable or fixed. The stop
element may also be a recess in the outer wall of the hollow body
at a defined distance from the distal tip of the perforation unit.
The stop element provides a defined maximum penetration depth and
position in tissue upon insertion. The stop element may be
integrated with an anchoring element.
[0082] Some embodiments of the devices are devised to provide an
absence of fluid communication in the communication channel under
physical blood pressure levels thanks to its physical dimensions.
In larger vessels some embodiments might have to be sealed by
advancing some form of plug through the working channel. This
facilitates the use of the device even on the high pressure side of
the vascular system. Bleeding at the perforation site is
efficiently avoided, in small vessels without the need of a plug or
other measures.
[0083] The arterial system is anatomically substantially more
homogenous than the venous system and therefore it is easier to
reach target sites via arteries. Conventionally, however, the
arterial access path is regarded as more problematic due to the
existing higher blood pressure, potentially more difficult stopped
bleeding, etc.
[0084] Thanks to the extroducer devices having in embodiments an
inert property to allow fluid flow through a channel in the hollow
body only at driving pressures well exceeding physiological
systolic blood pressures, this issue is overcome and more
convenient access paths are accessible than previously feasible.
Alternatively, or in addition, a stopper element, such as a stop
plug may suitable be provided, e.g. in situ by delivery through the
working channel or hollow body of the system in order to provide a
closing off of the communication channel, e.g. in larger
embodiments of the extroducer device. The stop plug may be made of
a bio-compatible material like gold or silicone or tissue glue.
[0085] Some embodiments comprise a hollow separation or detachment
section that provides a controllable separation of the distal
portion of the hollow tube including the perforation unit from the
proximal part of the device and/or the microcatheter. Thus, the
proximal part and the microcatheter may be retracted from the
target site through the vasculature, leaving a distal part
perforated in the vessel wall. Fluid communication of the distal
part may be shut off due to the dimensions of the distal part or by
using a plug unit.
[0086] Applicable separation mechanisms are disclosed in
WO2006/024040 which is incorporated herein by reference in its
entirety for all purposes. However, the present invention differs
from the disclosure of WO2006/024040 in many aspects. WO2006/024040
applies to delivery of implants, such as occlusion devices or
stents in the vasculature. Applicants refer to the detachment
mechanisms, which may be applied to embodiments of the extroducer
device. Detachment of the proximal part of the device from the
distal, penetration part may thus be implemented according to the
detachment principles described in WO2006/024040. These and further
embodiments of detachment units are described in more detail
below.
[0087] The extroducer device may be used according to at least two
alternative procedures.
[0088] In the first alternative procedure, a vessel wall, such as a
microvessel wall, is perforated with a sharp tip of distal end of
the extroducer device, namely the hollow penetration portion. Then
the penetration portion is further inserted, through the vessel
wall, such that access to the extravascular space is provided
through the inner lumen of the extroducer device. An intrusion
depth limiting unit may provide controlled intrusion depth of the
penetration portion into the vessel tissue and extravascular space.
A fluid communication through the microcatheter and through the
extroducer device is thus provided with the extravascular space at
the puncture site, e.g. of the microvessel. After the procedure is
completed, i.e. a delivery or sampling of material to or from the
extravascular space of the target site at the puncture site, the
distal penetration device is then separated or detached from the
proximal hollow body of the system and left in place in the tissue
at the penetration site or left in place for future use. The
detached distal part is then sealed off. This sealing may be
provided automatically at physiological pressures, or by plugging
of the inner hollow of the device, depending on the applied
diameter of the inner hollow of the extroducer device.
[0089] In the second alternative procedure, penetration is made
with a separate, solid or hollow elongated puncture device located
inside the hollow extroducer system (not illustrated). The distal
end of the extroducer device is slid over the solid or hollow
elongated puncture device until it is in position. A stop element
may provide an advantageous positioning in the vessel wall. Then
the solid or hollow elongated puncture device is retracted, leaving
the distal portion of the extroducer device punctured in position
and arranged for fluid or tissue or cell-suspension communication
to or from the extravascular space of the target site at the
puncture site. The solid or hollow penetrating device may have a
sharp tip or be compromised of an eximer laser or other cutting
devices. After the procedure is completed, i.e. a delivery or
sampling of material to or from extravascular space of the target
site at the puncture site, the penetration device is sealed,
automatically or by plugging as described in the first alternative
procedure. Then the distal portion of the extroducer device is
separated from the proximal portion thereof or the microcatheter.
The distal portion is left in place in the tissue at the
penetration site.
[0090] The extroducer device may be made of a bioresorbable or
biodegradable material, such that the extroducer device is resorbed
or degraded and thus eliminated from the target site over time.
[0091] Now turning to the Figures, an embodiment of the extroducer
device is illustrated in FIGS. 1 and 2.
[0092] The extroducer device is an endoluminal medical access
device 1, devised for endoluminal delivery to a target site, e.g.
to a microvasculature 4 of a human or animal body vasculature.
[0093] The device 1 comprises a hollow body 112 that is arranged
around a continuous channel 113 that ends in an opening at a distal
end 100 of said device. The hollow body 112 has a wall thickness
defining an outer wall having a cross-section or diameter and an
inner wall around the lumen or channel 113. The hollow body 112
comprises a distal elongate portion or penetration portion 102 that
is devised to extend across a tissue wall 200 (see FIGS. 3A and
3B), e.g. of said microvasculature 4, at an extravascular target
site 5 in said body. The distal elongate portion 102 (herein in
short "distal portion") may have a sharp tip 114. The distal
portion 102 may be conically tapering, as shown in the Figs., to
allow for improved seating and sealing in the tissue wall 200. The
conical tapering is present either along a substantial portion or
the entire length of the distal portion 102, as illustrated in some
of the Figs., in addition to the pointed tip portion (when present
in embodiments not using an external penetrator unit) at the very
distal end of the device.
[0094] The hollow body 112 has a longitudinal axis 105, and is
devised to provide communication with said target site 5 through
said channel 113 and devised for at least partly apposition to said
tissue wall 200. A proximal connection section 101 proximally
adjoins said penetration portion 102. The embodiment of device 1
comprises an intrusion depth limitation unit 116. Alternative
intrusion depth limitation units are described below. In addition,
the intrusion depth limitation unit 116 may be integrated with an
anchoring unit, such as a barb, prong, spike, hook, etc. The latter
may advantageously support later detachment, as the distal portion
102 is kept safely inserted in the vessel wall, preventing a
withdrawal of the distal portion at e.g. partial detachment.
[0095] The proximal portion 110, extending from the proximal end of
the endoluminal medical access device, may have a larger
cross-sectional outer wall dimension (diameter in circular cross
sections) and corresponding inner lumen diameter than a distal
portion, extending from the distal end thereof. A transition from
the larger diameter to the smaller diameter may be stepwise or
continuously tapering. In this manner the distal end may navigate
more flexibly to the target site, such as the microvascular site 4.
For instance when navigating towards a target site in the CNS, it
is sufficient that a distal portion of approximately 30 cm has a
very small cross-sectional dimension, while the remaining proximal
part can have a larger cross-sectional dimension/diameter. A
stepwise or continuously narrowing or tapering endoluminal medical
access device has an advantageous stability and torsional rigidity
providing for good maneuverability of the endoluminal medical
access device intravascularly.
[0096] The endoluminal medical access device 1 comprises a
transition section from said distal penetration portion 102 to said
proximal connection section 101, which comprises a hollow
separation section 115 that is devised to provide a controllable
separation of said distal (penetration) portion 102 from a
connected proximal portion 110 of said hollow body.
[0097] The hollow body 112 may be made as a monolithic, integral
part including the proximal portion 110 and the distal portion 102.
The hollow separation section 115 may be positioned close to a stop
flange 118, or at the flange 118, such that the flange 118 bears
against the vessel wall 200 upon insertion, as illustrated in FIG.
3B. In this manner no portion, or only a minor portion, of the
endoluminal medical access device 1 protrudes into the
microvasculature 4 upon separation, detachment or release of said
distal penetration portion 102 from the proximal portion 110 of the
hollow body. Flange 118 may also be detached from the proximal
portion 110, as in the present embodiment. In other embodiments,
the flange portion may be detached from the distal penetration
portion 102. The proximal portion 110 may thus be withdrawn from
the punctured delivery site upon finished communication with the
extravascular space of the target site at the puncture site.
[0098] The separation, detachment or release is made in a
controlled manner and may be done in several ways. Releasing the
distal penetration portion 102 from the proximal portion 110, at
the hollow separation section 115 may be done in several ways.
Separation is for instance achieved by means of electrolytic,
magnetic, induction or thermal detachment. Some detachment
mechanisms may for instance be thermal, as disclosed in
WO2006/024040, which is fully incorporated by reference herein. The
disclosure of WO2006/024040 has to be suitably modified to adapt to
the present invention for hollow tube distal portion
detachment.
[0099] The change in mechanical material properties of the
structure of the hollow tube at the separation section 115 results
in detaching the distal penetration portion 102 from the proximal
portion 110.
[0100] Thermal activation, may e.g. initiated by an electrical
current heating a portion of the hollow separation section 115
until separation is achieved and the proximal portion 110 can be
withdrawn. An electrical current may be provided via suitable
conduction along the hollow body. Conduction of electricity may be
made along the hollow body, either by integrated wires or the
hollow body itself. When the hollow body is made of a conductive
material, it may be provided with an isolating layer along the
length of the hollow body which ends at the non-isolated separation
section 115. One conductor along the hollow body from the proximal
end may be sufficient, in case a counter electrode is provided e.g.
outside the body. Alternatively, two conductors may be provided,
e.g. in the same layer of separate isolated layers that extend
along the hollow body from the proximal end to the hollow
separation section 115. Applying the electrical current for a
pre-determined time activates the separation. Monitoring the
current allows for a feedback when separation has occurred when the
current drops. Alternatively, or in addition, an external power
source may be used, e.g. outside the body or inside the body but
remote from the penetration site. Such external power source may
transmit energy by magnetic induction. Alternatively, or in
addition, catheter based or endoscopic delivery of external power
sources may be provided within the body to the separation section
115. Separation or detachment is provided upon delivery of energy
from the external power source.
[0101] An electrolytic detachment mechanism may for some
embodiments utilize reconfiguration of chemical properties in the
separation section 115. By causing e.g. a locally elevated
temperature, or initiating a chemical reaction which locally
changes the chemical properties of the hollow separation section
115, detaching the distal penetration portion 102 may be achieved.
Disintegration of a portion of the hollow separation section 115
may be initiated by removing disintegration or removing of a cover
layer and exposing the separation section 115 to body fluids.
[0102] Alternatively, or in addition, spring force release may be
used two provide the separation. A spring unit is thus provided at
the hollow separation section 115. The spring force, when
initiated, acts upon the hollow separation section 115 to achieve
the separation. The spring force may for instance act upon a
pre-determined breaking point or weakening in the hollow body. The
weakening may be an indentation or notch in the hollow body that is
chosen to be sufficient strong for normal handling during insertion
and use of the channel 113. Release of the spring force may done in
several ways, e.g. by a tether when drawn from the proximal end,
removing a restriction unit that keeps a spring in tension until
removed, dissolving a restriction unit after a predetermined time
in the body, etc. The spring action may be provided axially pushing
the distal penetration portion 102 away from the proximal portion
110 with a sufficient force, e.g. to disrupt the two portions from
each other at the hollow separation section 115.
[0103] Alternatively, or in addition a predetermined breaking point
may be provided at the hollow separation section 115. The
predetermined breaking point may be activated by a sufficient high
pressure from inside the hollow tube, provided from the proximal
end thereof. When applying such a high pressure for a short time
only, the separation is achieved by breaking the connection at the
hollow separation section 115 without causing a flow or otherwise
harming tissue at the target site. Separation is achieved by
mechanically breaking open the hollow separation section 115.
[0104] Alternatively, or in addition, a threaded detachment may be
used two provide the separation. The distal penetration portion 102
may be threaded to the proximal portion 110. Upon suitable rotation
of the proximal portion 110 the two may be unscrewed from each
other for separation.
[0105] Alternatively, or in addition, a cutting rotational movement
of a cutter element at the hollow separation section 115 may
provide for the separation, similar like a pipe cutter.
[0106] A sheath around the hollow separation section 115 may avoid
damage to surrounding tissue during separation.
[0107] In summary, the hollow separation section 115 allows to
withdraw the proximal portion of the hollow tube, leaving behind
the distal portion inserted in the tissue through the vascular
wall.
[0108] In embodiments, the endoluminal medical access device 1
comprises an intrusion depth limitation unit 116.
[0109] The intrusion depth limitation unit 116 may be an abutment
unit. The abutment unit is for instance comprising the flange 118
devised to limit an intrusion depth of said endoluminal medical
access device into said tissue wall upon insertion thereof.
[0110] In an embodiment the flange 118 may be foldable towards said
hollow body 112.
[0111] The hollow body 112 may be tapered towards said distal end
100. This ensures that the device 1 securely is held in position in
the vessel wall tissue.
[0112] Alternatively, or in addition, the intrusion depth
limitation unit 116 may be a recess in the outer wall of the hollow
body, such as shown in FIGS. 11A and 11B. The recess is received in
the surrounding tissue, which resiliently enters the recess and
provides for an increased intrusion force holding the distal
portion 102 in place when inserted into the tissue of the vessel
wall. Alternatively, or in addition, an intrusion depth limitation
unit 116 may be placed at the proximal end of the elongated tubular
delivery device 2 (polymer tube) enclosing the extroducer device.
During advancement to the target site, the extroducer device is
encapsulated by the polymer tube 2, see FIG. 17A. At the target
site, the extroducer device is slid inside the polymer tube 2 until
stopped by the proximal intrusion depth limitation unit 116, see
FIG. 17B. The vessel wall is then penetrated by the distal portion
of the extroducer device until contact is established between the
vessel wall and the distal end of the polymer tube. The distal end
of the polymer tube acts as shoulder element. As the length of the
distal portion 102 outside the distal end of the polymer tube is
determined by the intrusion depth limitation unit 116, the
intrusion depth of the extroducer device through the vessel wall
into the extravascular space to the target site is well defined.
The distal end 2a of the polymer tube 2 will then act as an
intrusion depth limiting device. An advantage of the proximal
position of the intrusion depth limitation unit is that the
intrusion depth can be adjusted with appropriate design of the
stopping mechanism, allowing for adjustments of the fixation point
to the extroducer device. In case the proximal portion of the
extroducer device is a microcatheter, the depth limitation unit 116
is attached to the microcatheter as illustrated in FIG. 17A. The
depth limitation unit 116 is provided as a radial protruding
element, such as a flange. Attachment of the depth limitation unit
116 may be accomplished in various ways, such as adhesive
attachment, friction engagement, clamping, crimping, welding,
soldering, etc. When the procedure is completed, the distal portion
102 may be detached from the proximal portion of the extroducer
device as described above, and the polymer tube 2a and the proximal
portion of the extroducer device are retracted from the vessel and
the body.
[0113] The channel 113 has such physical dimensions that it is auto
sealing at physiological pressures, such that the device 1 is
adapted for delivery either in an arterial or a venous side of said
vasculature. Auto-sealing refers to a zero flow, or substantially
zero flow, through the hollow channel 113. As for instance can be
seen in the practical implementations shown in FIGS. 7-10, an inner
diameter of such auto-sealing devices is approximately 0.1 mm at a
channel length of approx. 1 mm. If larger dimensions of the system
are used, the channel 113 may be sealed by a plug that is advanced
through the hollow body 112 to the distal penetration portion 102.
Sealing is advantageous to prevent bleeding when the distal portion
102 is left in place in the vessel wall after treatment.
[0114] The hollow body 112 may be a hollow tube, and a material of
said hollow body 112 may be metal, such as NiTinol. Alternatively,
the hollow body 112 may be made of a polymeric material. In
addition, the hollow body may comprise fiducial markers, such as of
a radiopaque material, such as gold, tantalum, wolfram. Such
fiducial markers may for instance be positioned on the oblique tip
of the penetration portion 102. In this manner a position and
orientation of the device 1 is determinable by imaging units known
in the art.
[0115] A material of said extroducer device or only the distal
penetration portion 102 may also be a bioresorbable or
biodegradable material.
[0116] Now turning to FIG. 3A, the device 1 of FIG. 1 is
illustrated in a position delivered through the microvasculature to
a target site 5. FIG. 3B gives a more detailed view of the
penetration site of the vascular wall 200. It should be noted that
the wall thickness of the vessel wall 200 is not shown to scale for
illustrative purposes. The vessel wall 200 has a thickness that is
substantially smaller than the length of the hollow body 112.
[0117] In a kit an endoluminal medical access device 1 is
comprised, as well as an elongated tubular delivery device 2. The
elongated tubular delivery device 2 may be provided in form of a
tubing of polymeric material arranged coaxially around said
endoluminal medical access device 1, thus providing a first
assembly. The medical access device 1 is arranged for sliding
motion in said elongated tubular delivery device 2.
[0118] The first assembly is coaxially and arranged for sliding
motion in a microcatheter 3, providing a second assembly. The
microcatheter 3 may for instance be a microcatheter as disclosed in
WO03080167A2. The microcatheter may be of standard types with or
without a distal balloon mounted on the outside of the working
channel.
[0119] The second assembly may be coaxially and arranged for
sliding motion in a conventional catheter, for delivery in vessels
of a diameter down to approximately 1 mm. When the conventional
catheter is at the target site, the microcatheter is advanced
towards the microvasculature or the vessel wall, and the extroducer
device 1 is advanced in the tube of the first assembly towards the
target site 5. The microcatheter 3 (and/or the conventional
catheter) may comprise an inflatable balloon 31 mounted on the
outside of the working channel for fixation of the microcatheter or
conventional catheter to the surrounding vessel, as shown in FIG.
3A. The distal tip of the microcatheter 3 may be angled to point
radially outwards, towards the interior of vessel wall 200. At the
target site, the extroducer device 1 is pushed out of the elongated
tubular delivery device 2 and thus penetrates the vessel wall 200.
Alternatively, a separate penetrator device may be used, as
mentioned above.
[0120] Thus endoluminal access is provided to an extravascular
target site 5 in a human or animal body by using an extroducer
device 1 from inside the vasculature through the vessel wall. In
more detail, the extroducer device 1 perforates and/or bridges the
vessel wall 200 of said microvasculature 4 with said penetration
portion 102 at the extravascular target site 5 in said body. The
penetration portion 102 is positioned such that it is extending
across said vessel wall 200 at least partly in apposition to said
tissue wall 200. Thus communication with said target site 5 is
provided through said channel 113. Fluid flow may be provided
through the channel from the proximal section 110 to or from the
distal end 100 of the device 1 through the channel 113.
[0121] Communicating with the target site 5 may thus be provided by
establishing communication with said target site 5 by performing
the above described endoluminal access method. Delivery of a
substance to said target site 5 or taking of a sample from said
target site 5 may thus be provided or performed through said
channel 113. The substance may comprise cells, such as stem cells,
thus providing endovascularly transplanting said cells into said
target site 5.
[0122] The delivery of said substance may comprise local
administration of said substances, such as cytostatics, contrast or
growth factors. The substances may also include radioactive agents,
such as radioactive isotope particles.
[0123] The substances may be delivered to a target site by means of
the present device upon puncture. The puncture may comprise, except
puncturing a vessel wall, a puncturing of a cyst for delivery of
substances to the interior of said cyst for treatment thereof.
[0124] The taking of said sample comprises a puncture, of for
example a cyst and providing communication to the interior of said
cyst by the present device.
[0125] The method may further comprise subintimally passing an
occlusion or stenosis of a vessel. The intima is the inner layer of
the wall of an artery or vein. The hollow body 112 may be at least
partly passed within the intima along the vessel wall 200, at an
oblique angle, in contrast to the illustration of FIG. 3B, where
the vessel wall 200 is penetrated perpendicularly.
[0126] The target site 5 may be located and accessed in difficult
accessible organs or areas of the body, such as for instance the
Central Nervous System (CNS), the pancreas, the heart, or the like,
but is not restricted to these organs.
[0127] One possible application of the endoluminal medical access
device is in connection with cardiac indications, such as
myocardial infarction or cardiomyopathy, or the like. The
endoluminal medical access device may be delivered via the coronary
arteries or veins, which supply a diseased portion of the heart, to
a vascular site at the diseased portion of the heart. The
endoluminal medical access device is then used to penetrate the
vessel wall at the vascular site in order to gain access to the
treatment site of the diseased portion of the heart. In this manner
substances like cells, growth factors, or other agents may be
delivered in order to ameliorate cardiac function.
[0128] FIG. 4a is a graph illustrating a circular Poiseuille flow,
filled symbols, driven by a pressure of 200 mmHg through a
practical implementation of a device according to an embodiment of
2 mm lumen length and various lumen radii, wherein the flow rates
of water, plasma and whole blood at 37.degree. C. and a
physiological hematocrit of 45(Y-axis) are plotted against the
lumen radius (X-axis) in a logarithmical way. The calculations were
done in accordance with the detailed description in [James E. Fay,
Introduction to Fluid Mechanics, MIT Press, 1994, p288.]. The
viscosity of water at 37.degree. C., 6.17E-04 Pas was taken from
the same source (p. 17) whereas the viscosity of plasma, 1.5E-03
Pas and the viscosity of whole blood at 37.degree. C. and a
physiological hematocrit of 45, 3.2E03 Pas, were taken from
[http://ima.epfl.ch/.about.steiner/documents/Cours/Genie_Medical/VISCOSIT-
Y.pdf]. According to fluid mechanics, the flow rate out of the
lumen varies as the fourth power of the radius. Consequently, the
flow rate becomes very small very rapidly as the lumen radius is
reduced, which is clearly illustrated in FIG. 4. Calculations for
whole blood at 37.degree. C. and a physiological hematocrit of 45
were also performed using a commercial available product, COMSOL
Multiphysics, open symbols. At a radius of 50 micrometer, the
results of the two methods coincide but at higher radii, the open
symbols show lower flow rates because of turbulent flow, taken into
account in the calculations with COMSOL Multiphysics. The flow
velocity rates determinable from the graph correspond to those of
some embodiments of the extroducer device described herein. The
auto-sealing effect at physiological pressures of some embodiments
of the extroducer device becomes apparent from the graph in FIG. 4a
when taking into consideration the inert property of blood to
coagulate at low and/or turbulent flow. At least substantially no
leakage flow occurs.
[0129] FIG. 4b is a graph illustrating velocity fields of circular
Poiseuille flows, filled symbols, [James A. Fay, Introduction to
Fluid Mechanics, MIT Press, 1994, p288.] through a practical
implementation of an extroducer device according to an embodiment
having a 2 mm long lumen, wherein the velocity fields of whole
blood, at 37.degree. C. and a physiological hematocrit of 45,
driven by a pressure of 200 mmHg (Y-axis) are plotted against the
r-coordinate (X-axis) for different lumen radius. Open symbols show
calculations with a commercial programme, COMSOL Multiphysics,
taking turbulent flow into account which reduces the velocity in
the central part of the velocity fields when turbulent flow is
present. For a radius of 50 micrometer, the result by COMSOL
Multiphysics is identical to the circular Poiseuille flow,
indicating full laminar flow for this geometry whereas the result
by COMSOL Multiphysics is slightly reduced compared to the circular
Poiseulle flow at a radius of 100 micrometer and heavily reduced at
radii of 150 and 200 micrometer, respectively. The flow/lumen
ratios determinable from the graph correspond to those of some
embodiments of the extroducer device described herein.
[0130] FIGS. 5A, 5B and 6A, 6B are graphs illustrating the velocity
fields of flows of whole blood, at 37.degree. C. and a
physiological hematocrit of 45, driven by a pressure of 200 mmHg in
two different communication channels of embodied devices having 50
and 200 micrometer radii, respectively, and a lumen length of 2 mm,
simulated with a commercially available software product, COMSOL
Multiphysics. FIGS. 5B and 6B show the upper 0.5 mm parts of FIGS.
5A, 6A, respectively enlarged. The graphs are color coded, which in
a black and white reproduction corresponds to different grey values
in the figures. The figures show only half of the lumen, having
positive coordinates, due to geometrical symmetry. The left border
is a symmetry border, the bottom border is an inlet with an applied
pressure of 200 mmHg, the right border is a non slip wall, and the
upper border is an outlet with zero pressure. The lumen is filled
with a liquid given a dynamic viscosity of 0.0032 Pas representing
whole blood at 37.degree. C. and a physiological hematocrit of 45.
The velocity field is plotted and mapped by colour. As the graphs
are color coded, a black and white reproduction corresponds to
different grey values in the figures. The flow velocities
determinable from the graphs correspond to those of some
embodiments of the extroducer device described herein.
[0131] FIGS. 7A, 7B, 7C are a perspective view, a side view from
above, and a lateral view of a practical implementation of an
extroducer device 7 with an intrusion depth limitation unit and an
attached microcatheter 3. The extroducer has a tapered part 102
ending at a hollow depth limiting part with a sudden increase in
the radial dimension. The depth limiting part is attached to a
hollow separation unit 115 allowing the extroducer to be detached
from the micro catheter 3. The proximal portion 110 may comprise an
inner hollow tube inside the microcatheter in fluid connection with
the distal end 100. In an embodiment, the microcatheter 3 may act
as the proximal portion 110, wherein the distal portion is attached
to the microcatheter 3 by suitable means at the proximal connection
section 101, such as by adhesive attachment, friction engagement,
clamping, crimping, welding, soldering, etc. Preferably the
attachment is made at the hollow separation unit 115, allowing for
suitable detachment and separation of the distal portion 102 to be
left in situ.
[0132] If dimension units are shown in the drawings of exemplary
extroducer devices, the dimensions are given in mm. However, any
dimensions given are not to be regarded as limiting entities.
[0133] FIGS. 8A, 8B, 8C are a perspective view, a side view from
above, and a lateral view of another practical implementation of an
extroducer device 8. The extroducer device 8 has a tapered part 102
ending at a hollow depth limiting part 116 with a sudden increase
in the radial dimension (seen from the distal end). The depth
limiting part 116 provides thus a shoulder element. is attached to
a hollow separation unit 115 allowing the extroducer to be detached
from the micro catheter 3, which in the present embodiment
coincides with the proximal portion 110. Depth limiting part 116 is
integrated with the hollow separation unit 115. The hollow
separation unit 115 may be degradable, based on a spring effect,
thermal detachment, etc. as described above.
[0134] FIGS. 9A, 9B, 9C are a perspective view, a side view from
above, and a lateral view of a further practical implementation of
an extroducer device 9. The extroducer device 9 has a elongate,
tapered distal part 102 ending proximally at a hollow depth
limiting part 116 with a foldable flange 118. The depth limiting
part 116 is attached to the outside of the extroducer device 9. A
hollow separation unit 115 allows the distal part 102 of the
extroducer device 9 to be detached from the micro catheter 110.
[0135] FIGS. 10A, 10B, 10C are a perspective view, a side view from
above, and a lateral view of a yet another practical implementation
of an extroducer device 10 with an intrusion depth limitation
collar and a conical distal tip shape for easy accommodation in the
vascular wall. The extroducer device 10 has an elongate, tapered
part 102, proximally ending at a hollow depth limiting part 116
with a foldable flange 118. The depth limiting part 116 is attached
to the outside of the extroducer. A hollow separation unit 115
allows the distal part 102 of the extroducer to be detached from
the micro catheter 110. Compared to FIGS. 9A, 9B and 9C, the
tapered part 102 is longer. Extroducer device 10 has a particularly
advantageous dimension ratio to provide auto-sealing at
physiological pressures for blood.
[0136] FIGS. 11A, 11B and 11C show in close views alternative
configurations of an intrusion depth limiting unit. FIGS. 11A and
11B illustrates two configurations with circumferential
indentation, i.e. a waist appearance on the hollow body. FIG. 11C
illustrates a flange configuration of the intrusion depth limiting
unit where the adjacent structure of the unit is not tapered.
[0137] FIGS. 12A and 12B illustrate another intrusion depth
limitation unit as a wheel formed flange. The flange is produced
from a thin sheet of a highly flexible material as Nitinol by
etching techniques based on photo lithography but not limited to
these techniques. The flange 118 is attached to the exterior
surface of the extruducer's lumen by press fitting, welding such as
spot welding or laser welding or glued or by a combination of, but
not limited to these methods. During advancement of the micro
catheter system to the target site, the flange is folded forwards
or backwards, between the exterior lumen surface of the extroducer
or microcatheter and the interior surface of the polymer tube 2,
forming the first assembly. The flange 118 is unfolded when the
extroducer is advanced in the polymer tube 2 in order to perform a
punctuation of a vasculatory wall. The flange is noninvasive due to
lack of corners and is stress free in its unfolded position. The
stiffness of the flange can be suitable adjusted by the width and
thickness of the legs, blades, spokes, and the overall diameter of
the wheel in relation to the outside diameter of the distal portion
102. The curved, and/or radially inclined, spokes facilitate the
folding of the wheel when inserted into the polymer tube. It is
possible to further assist folding by rotating the extroducer and
micro catheter in the appropriate rotational direction, which can
be an appropriate procedure if the extroducer is advanced out of
the polymer tube at the target site and then, by any reason, the
punctuation is interrupted and the whole system is being retracted.
The illustrated flange has a thickness of 25 micrometer and a
diameter of 0.80 mm.
[0138] FIGS. 13A and 13B illustrate another intrusion depth
limitation unit as a loop formed flange. The flange 118 is in this
embodiment formed by attaching both ends of a highly flexible wire,
such as a Nitinol wire, to the same side of the outer surface of
the extroducer's outer body while the mid section of the wire is
attached to the opposite side of the outer surface of said body.
The attachment method can be one of the methods mentioned above or
a combination of them. The illustration shows the von Mises
stresses in a Nitinol wire of 44 micrometer circular cross
sectional diameter originally shaped as a stress free circular loop
of inner diameter 356 micrometer by first attaching the free wire
ends to the extroducer and then pressing the circular loop against
the extroducer on the opposite side, forming two wire loops
extending from the extroducer. The stresses are color coded giving
different grey levels in a black and white reproduction. The wire
ends are practically stress free, whereas the highest stresses are
found in the wire mid section pressed against the extroducer.
During advancement of the micro catheter system to the target site,
the flange is folded forwards or backwards, between the exterior
lumen surface of the extroducer or micro-catheter and the interior
surface of the polymer tube 2, forming the first assembly. The
flange is unfolded when the extroducer is advanced in the polymer
tube in order to perform a punctuation of a vasculatory wall. The
design is noninvasive due to lack of sharp corners. The stiffness
of the flanges can be adjusted by selecting different wire
thicknesses and/or lengths. The two loops can preferably be
oriented parallel to the blood vessel allowing a minimum
intervention with the blood stream after the extroducer is detached
from the micro catheter, being retracted, and left in position
through the vasculatory wall. Thus, a flush arrangement of the
detached proximal portion 102 is provided in a safe arrangement as
blood pressure in the vessel will prevent a backward movement of
the detached device into the vessel, and the flange 118 prevents a
forward movement.
[0139] FIGS. 14A and 14B illustrate another intrusion depth
limitation unit as a double loop formed flange of two loops 116a
and 116b. Each pair of loops has the same dimensions, is formed,
attached to the extroducer, folded during micro catheter
advancement to the target site and unfolded prior to punctuation of
the vasculatory wall, as described for FIGS. 13A and 13B. The
increased number of loops allows an increased stiffness without
selecting a thicker wire and hence allowing the use of finer micro
catheter systems.
[0140] FIGS. 15A, 15B, 16A, and 16B illustrate another intrusion
depth limitation unit as a triple loop formed flange in
respectively two different flange diameter versions. The loops are
formed, attached to the extroducer, folded during micro catheter
advancement to the target site and unfolded prior to punctuation of
the vasculatory wall, as described for FIGS. 13A and 13B. The
illustration shows an example constructed of three separate wires,
but as an alternative, a single wire can be used to form the three
loops of flange 118. The colors show the von Mises stresses in a
Nitinol wire of 44 micrometer circular cross sectional diameter
originally shaped as a stress free circular loop of inner diameter
300 micrometer simultaneously attaching the free wire ends to the
extroducer on its opposite sides, forming a wire loop extending
from the extroducer. The stresses are color coded giving different
grey levels in a black and white reproduction. The stresses are
more evenly distributed with the simultaneous deformation of the
free wire ends than the method previously described starting with
fixing only one wire end to the extroducer, then fixing the other
free end and finally, fixing the mid section of the wire to the
extroducer.
[0141] In alternative embodiments (not illustrated), the intrusion
depth limitation unit may be provided as partial loops, or
substantially straight radially extending protrusions, the distal
ends thereof not returning to the attachment point on the
extroducer device. Alternatively, or in addition, several of the
described intrusion depth limitation units may be advantageously
combined.
EXAMPLES
[0142] In Table 1, given below, typical dimensions of some
embodiments are given.
TABLE-US-00001 TABLE 1 Typical dimension ranges and ratios of some
embodiments of the extroducer dimensions in micrometers, Length of
approximal Length of Length of hollow measures distal penetration
detachment Lumen Flange only portion 102 limiter zone Outer
diameter diameter diameter Min Approx. 3x a few 0, if the 140 100
300 outer diameter micrometers catheter is of extroducer 10-20
dissolved 400-450 no zone is needed Max No limit if it Must not
Limited by Limited by polymer Limited by Limited by is made of a
affect blood time/energy tube and micro polymer dimensions highly
flexible stream. amount of catheter system, tube and of the vessel.
material, Approx 0.3 dissolved and intended micro The wheel such as
times vessel material. target site catheter design is nitinol. It
diameter, Process system and limited by must be typically must not
intended the vessel possible to 250 harm tissue. target site
diameter to advance it micrometer Smaller approx. through the is
better. 1.5x of vascular tree Approx. 0.3 vessel to the target of
vessel diameter site diameter, typically 250 micrometer Ratio lumen
dimensions in Ratio length of diameter/ micrometers, Ratio distal
portion 102/ length of approximal Total length of extroducer
length/diameter of total length before distal measures only device
before detachment distal portion 102 detachment portion 102 Min
100000 3 0.0042 Depending on above dimensions, example: Range
0.03-0.1 For advent. Auto seal Max 1.50E+08 undefined unlimited
Depending on above dimensions, example: 0.25
[0143] Several different practical implementations of the
extroducer device were used to test different aspects in procedures
designated for the extroducer device. The extroducer practical
implementations described below and all consecutive steps of
practical implementations were manufactured from a base of nitinol
alloy tubes superelastic with an outer diameter 0.193 mm.+-.0.0127
mm, inner diameter 0.104.+-.0.0127 mm (Tube NiTi SE 508, ground
surface, Euroflex GmbH, Pforzheim, Germany). However, these
dimensions are not to be understood to be limiting and represent
specific embodiments only.
[0144] The practical implementation A comprised a 29 cm long
nitinol tube with a sharply cut end for perforating a vessel wall
(FIG. 3B). Substances and cells were injected though the tube from
the introducer end of the tube to the extroducer part located
outside either the common carotid artery or the subclavian artery
of the rat.
[0145] A further practical implementation B comprised a 2.5 mm long
tube with a sharply cut end ground the same way as practical
implementation A, and with an open lumen. The practical
implementation B was advanced through a plastic microcatheter with
a 29 cm long nitinol tube acting as a "pusher" for the practical
implementation which was then inserted through the vascular
wall.
[0146] In practical implementation C, a mechanical stop was added
on the outer wall of the extraducer device. The mechanical stop was
calibrated in size to determine the optimal radius in relation to
the extroducer body to make an efficient stop for the extroducer
during vascular penetration. This was first performed ex vivo by
constructing a model of the human vasculature with its length and
curves. At the distal end of this model rat vessels with different
calibers were mounted and the practical implementation C, with
different stop radii, was tested to determine the optimal stop to
extroducer body ratio. The functionality of this stop radius was
then tested in vivo in the rat. Thereafter, an expandable design of
the chosen stop radius was developed and implemented to minimize
the outer diameter of the system.
[0147] A hollow detachment zone was added for the extroducer
practical implementation D, which was tested in vitro. During
vascular penetration with practical implementation D, optionally a
mandrel was inserted inside the extroducer to improve stability of
the detachment zone.
[0148] A practical implementation E comprised a 170 cm long nitinol
tube with a sharply cut end for perforating a vessel wall (compare
with implementation A). The implementation E was tested in a rabbit
model with full scale clinical routine guide- and micro-catheters
and with angiography- and fluoroscopy-directed endovascular
navigation.
[0149] As mentioned above, due to the small diameter of some
embodiments of extroducer devices, there is no need for a lumen
closure device before detachment. Physical principles prevent blood
from inside the vessel (arteries and veins) to flow through the
detached extroducer to the extravascular space. For larger diameter
extroducers, closure of the working channel may be made as
described and controlled with contrast injection before detachment.
A small deformation/a small metal point was welded inside the lumen
of the extroducer, to act as a stop for a metal (or silicon) plug
pushed in place by a mandrel through the hollow body of the
extroducer system.
[0150] The extroducer practical implementations A, B and C were
introduced in the rat vascular system within a PTFE-160 Sub-Lite
wall tubing with outer diameter of 0.41.+-.0.0254 mm and inner
diameter of 0.25.+-.0.0254 mm (AgnTho's, Sweden). Some of the
practical implementation C prototypes with a solid stop was tested
in an ex vivo model simulating the human vascular tree with
perforation of a vessel specimen mounted at the distal end of the
simulator model, introduced in the vascular system within a
Sub-Lite wall tubing with a comparatively slightly larger outer as
well as inner diameter, whereas the practical implementation C with
expandable stop fitted into the smaller Sub-Lite wall tubing for in
vivo testing. The practical implementation D was only tested in an
in vitro system. The practical implementation E was introduced in
the rabbit vascular system through a commercially available
introducer and guide catheter and navigated within the vascular
tree with a Prowler Plus microcatheter.
[0151] Extroducer--Design
[0152] When simulating water flow, with assistance of COMSOL
Multiphysics, through the detached Extroducer (Prototype B and D)
with an inner luminal diameter of such dimension that no laminar
flow was observed with a driving pressure of 200 mm Hg (26.7 kPa)
(FIG. 4a). This was also tested in vivo by rensing the
transvascularly positioned open design extroducer practical
implementations (B and D) with a nitinol mandrel. This was done to
reassure that no clotting inside the practical implementation
prevented bleeding from inside the vessel to the extravascular
space. The test was performed in rats and there was no bleeding in
any of the tested animals. However, when removing the entire
prototype a major bleeding took place, hence confirming flow inside
the vessel. This shows that, by providing that the distal portion
of the extroducer device is separable from the proximal part,
bleeding is effectively prevented when the distal portion is
separated and left in place after the procedure.
[0153] The development of practical implementation C included
testing of optimal stop to extroducer body ratio ex vivo. This
ratio was then tested in vivo in rats and in all cases, the chosen
stop radius made optimal positioning of the extroducer possible.
The expandable version of the stop mechanism was tested in an
identical fashion both ex vivo and in vivo.
[0154] Extroducer Device--Endovascular Testing
[0155] Small Animal Preparation
[0156] All animal experiments were conducted according to
guidelines from the regional ethics committee for animal research
at the Karolinska University Hospital, Stockholm, Sweden.
[0157] Male Sprague-Dawley rats (BW 240-350 g; B&K Universal
AB, Stockholm, Sweden) were included in the study. Rats were
divided into three groups to test the different practical
implementations of the extroducer.
[0158] In group 1 (280-330 g) intervention was performed with
practical implementation A. Directly following intervention,
vessels were sampled and animals euthanatized. Group 2 (220-260 g)
underwent intervention with practical implementation B, group 3
(220-240 g) with practical implementation C. Following intervention
in group 2-3, the animals were sutured and allowed to recover in
home cages. Animals in the groups 2-3 were sacrificed 14 days after
insertion of the extroducer. Non-successful navigation animals of
the subclavian or left common carotid artery were excluded from
their groups and euthanized via decapitation under the same
anesthesia session.
[0159] Surgical anesthesia was performed by an intramuscular (im)
injection of 0.2 ml HypnormDormikum (1:1:2; Hypnorm (fentanyl
citrate 0.315 mg/ml, fluanisone 10 mg/ml, Janssen Pharmaceutical,
Beerse, Belgium): Dormikum (midazolam 1 mg/ml, Roche AB, Stockholm,
Sweden)). Prior to skin incision, 0.1 ml Marcaine (5 mg/ml, Astra,
Sodertalje, Sweden) was injected subcutaneously in the area of
operation. Animals were anesthetized with 0.1 ml Hypnorm im before
decapitation.
[0160] Small Animal Surgical and Endovascular Procedures
[0161] All animal surgery was performed with a Leica M651 operating
microscope coupled to a Sony CCD DXC930P camera. For operational
video recording the CCD feed were streamed to a JVC SR-DVM70
DV/HDD/DVD recorder. Data was stored on DVD-R discs.
[0162] Introduction of catheters were performed via the medial tail
artery. A small longitudinal incision was cut on the ventral part
of the tail through the skin and the fascia overlying the artery. A
ligature was used to secure the PTFE-160 tube containing a blunt
nitinol tube and then the catheter system was blindly navigated up
through the aorta.
[0163] For observation and usages of the extroducer practical
implementations A-C, open surgical preparation of either the common
carotid artery via a small mid-line incision medially on the neck,
or the subclavian artery via an auxiliary exploration were
performed. To maximize navigational success-rates both the major
and the minor pectoral muscles were cut.
[0164] After navigation to exposed area with the blunted nitinol
tube inside the PTFE-160 tube, the nitinol was exchanged for an
extroducer practical implementation thereby protecting vessels from
unplanned damage. After reaching tip to tip, the extroducer
practical implementation was gently advanced through whatever
vessel wall was closest taking advantage of the vessels non-linear
anatomy. For all practical implementations, tests to exclude
vasospasm as a potential hemostatic cause, were performed by
soaking the perforated vessel with papaverin and observing for 90
minutes. Mechanical manipulation of the detached extroducer was
also performed to provoke possible hemorrhage.
[0165] To be able to perform the intervention with simultaneous
proximal balloon occlusion of the target vessel, the extroducer
system was tested in conjunction with standard navigable balloon
microcatheters. The diameter of the extroducer system made it
possible to pass the entire system, including the protecting
Sub-Lite tubing, inside standard balloon microcatheters.
[0166] Tissue Preparation
[0167] Following intervention animals in group 1, practical
implementation A was gently retracted, vessels were clamped, cut
and fixated in 4% buffered paraformaldehyde. Animals were then
euthanatized via decapitation. In groups 2-3, animals were
anesthetized 14 days after the first intervention and re-explored
to the site of vascular perforation. Vessels were clamped, cut and
fixated for 72 hours in 4% buffered paraformaldehyde at 4.degree.
C. Immediately following removal of vessels animals were
euthanatized via decapitation.
[0168] Histochemistry
[0169] Vessels were placed in 15% sucrose following the fixation
procedure for 24 hours at 4.degree. C. The tissue was then mounted
on a holder and frozen in a Leica cryostat (CM 3000, Leica
Instruments GmbH, Nussloch, Germany). After freezing vessels to
-24.degree. C. they were covered with mounting medium and cut in 10
.mu.m sections and then mounted onto Super Frost/Plus object
glasses (Menzel-Glazer, Braunschweig, Germany). Sections were
stained with Hematoxylin and Eosin. Slides were then viewed with a
Leica DM 4000 B and photographed with a coupled Leica DFC 320 CCD
camera. Quantification of perforations in vascular walls was
measured using ImageJ (Opensource software, NIH, Massachusetts,
USA).
[0170] Large Animal Preparation
[0171] All animal experiments were conducted according to
guidelines from the regional ethics committee for animal research
at the Karolinska University Hospital, Stockholm, Sweden. Two male
New Zealand White rabbits were included in the study. Surgical
anesthesia was induced by subcutaneous injection of Hypnorm
(fentanyl citrate 0.315 mg/ml, fluanisone 10 mg/ml, Janssen
Pharmaceutical, Beerse, Belgium) combined with diazepam. An
intravenous line was established in the ear veins bilaterally. A
bolus dose of Propofol was administered and thereafter, the rabbit
was intubated with a size 3 pediatric tube and connected to a
Siemens 900 servo ventilator. The animal was infused with propofol
according to standard rabbit doses. In addition, 0.1 ml of Hypnorm
was injected intravenously every 30 minutes.
[0172] Large Animal Surgical and Endovascular Procedures
[0173] The femoral artery of the anesthetized rabbit was exposed
surgically and a 5 French Introducer was inserted in the vessel
lumen (Terumo, USA). Under standard angiographic control, a 5
French Envoy guiding catheter (Cordis Corporation, USA) was
advanced to different parts of the vasculature of the rabbit. A
Prowler Plus microcatheter (Cordis Corporation, USA) was inserted
within the Envoy guiding catheter and together with a Transend
Platinum Tip guidewire (Boston Scientific, USA) navigated under
angiographic control to the microvasculature (0.5-1 mm in lumen
diameter) in different parts, including the central nervous system
of the rabbit. The guidewire was withdrawn from the Prowler Plus
microcatheter and the extroducer practical implementation E was
introduced in the Prowler Plus microcatheter within a PTFE-160
Sub-Lite wall tubing with outer diameter of 0.41.+-.0.0254 mm and
inner diameter of 0.25.+-.0.0254 mm (AgnTho's, Sweden).
[0174] Prototype A was tested on six animals with no case of
intra-operative bleeding or intraluminal thrombosis. Thus, the
vascular penetration procedure was uneventful and the vessel wall
completely sealed around the extroducer and prevented leakage of
blood. The vessel was exposed to papaverin to resolve potential
vasospasm due to the penetration procedure and no bleeding or other
complications were observed over a 90 minutes period. Histological
analyses of vessels showed an average penetration diameter of 70
.mu.m.
[0175] Prototype B was tested on seven animals again without any
bleeding or other complications. Fourteen days post intervention,
the group operated with practical implementation B followed their
designated weight charts, showed no signs of pain or discomfort
estimated by the Karolinska Institutet animal suffering template,
from day 2 and onwards. No signs of impairment of blood-flow distal
to intervention site were observed and histological analysis of the
organ supplied by the vessel, showed no infarcts. Examination of
vessels during re-exploration 14 days after the initial procedure,
showed that they were viable without vessel dissections, with
normal flow distal to the intervention site and with no signs of
delayed hemorrhage. The extroducer practical implementation B was
found associated to the outside vessel wall or in the
extra-vascular space adjacent to the penetration site.
[0176] Prototype C was first evaluated ex vivo by penetrating
vessel walls obtained from carcasses analyzing applied forces
through a loading cell connected to the vessels. Calculations of
force ratios between penetration with only the tip and perforation
with intrusion limiting devices were conducted. With suitable
diameters, the penetration of vessels in vivo was envisaged in all
cases and the stop radius made optimal positioning possible in all
cases. No complications such as bleeding, dissection or thrombosis
were encountered. The results of the testing of the expandable stop
design were identical to the results of the solid stop
mechanism.
[0177] Prototype D evaluated in vitro one possible mechanism of
dividing the distal penetrator end from the proximal access
catheter without complication. A 29 cm long nitinol tube was ground
at one end to produce a sharp tip, cleaned with alcohol and hung
vertically, with the sharp tip pointing down, on a twisteable
shaft. The whole tube was spray painted from four perpendicular
directions with a blanc white acrylic paint, CRC Pro Paint (Clas
Ohlsson, Sweden) and left to dry at room temperature for an hour. A
stainless steel tube with inner diameter 310 micrometer, outer
diameter 800 micrometer and length 10 mm was carefully threaded on
the painted catheter without damaging the paint. A circumferential
cut in the paint was made approximately 2 mm from the sharp tip and
adjacent to the stainless steel tube. An electrode was attached to
the stainless steel tube and about 5 cm of the catheter was
submerged into a physiological salt solution leaving only the
electrode and catheter sticking out of the solution. A voltage of
7V was applied by an external electrical source between the
electrode (cathode) and the catheter (anode) resulting in a
circumferential dissolution of the catheter where the cut in the
paint was made. The distal penetration end was then separated from
the proximal access portion of nitinol tube.
[0178] The extroducer practical implementation E was tested for its
ability to penetrate the vessel wall in different parts of the
microvasculature. Thus, these experiments were designed to fully
simulate the clinical situation and thereby make analysis of the
compatibility and behaviour of the extroducer system possible.
[0179] The extroducer practical implementations were constructed in
Nitinol and tested ex vivo in a simulator and in vivo in the rat
and rabbit. The extroducer consists of a single lumen long flexible
tube connected with a hollow detachment zone to a vascular
penetration device at the distal end. The device is protected
inside a microsilicon tubing during navigation to the desired
location. At the junction between the detachment zone and the
penetration device, there is an expandable stop which makes optimal
positioning of the system possible with fluoroscopy. The dimension
of the system can be varied according to the vascular dimensions in
the target organ. For small inner lumen diameters, physical laws
prevent blood from flowing from the inside to out through the
detached distal part. For larger inner lumen diameter, a plug of
suitable material, such as metal or silicon, is advanced through
the tube to the distal part to seal off the lumen before
detachment. Sealing is confirmed with contrast injection under
X-ray exposure. Catheterization of rat arteries was made via the
medial tail artery up to the left subclavian or common carotid
artery where exit of the vascular system was performed (n=40).
Catheterization of the veins was made via suitable access veins up
to vein were exit was performed. Surgical exposure was performed at
the site of vascular entry in the tail and at the site of exit in
the neck or in the axilla. The vessels and tissues were analyzed in
the acute phase and after 14 days.
[0180] To test the feasibility of one possible application, namely
a cell transplantation procedure, cell suspensions were injected
through the nitinol catheter and distal extroducer lumen. These
tests were performed in a system with the smallest lumen diameter
available (ID 0.104.+-.0.0127 mm).
[0181] Results
[0182] Interventions have been performed in the rat by introduction
of catheters through the medial tail artery and testing extroducer
practical implementations in either the subclavian artery or the
common carotid artery on the left side. Interventions have also
been performed in the rabbit by introduction of catheters through
the femoral artery using standard clinical introducers, guiding
catheters and microcatheters and wires.
[0183] Five different developmental steps of the extroducer were
tested, named practical implementations A-E. The implementations
A-C and E, all demonstrated absolute extravascular hemostasis and
absence of thromboembolic complications when exiting the artery or
vein from the inside to out, whereas implementation D was tested in
vitro.
[0184] Extroducer practical implementations B were placed in
vascular walls over a period of 14 days with no impairment on blood
flow upon re-exploration.
[0185] Practical implementation E further showed full compatibility
with the full clinical setting with fully preserved functionality
from small animal testing hence verifying the concept of a fully
operational kit, deployable for standard use. The penetration of
the vascular wall was easily performed in 100% of the attempts
(n=20). The two animals were sacrificed immediately after the
experiments. The rabbit experiments thereby demonstrated that the
extroducer system functions in a standard angiographic environment
and with standard, clinically available, introducers, guiding
catheters and microcatheters.
[0186] The evaluation of one possible application, i.e. cell
transplantation via the smallest available lumen diameter showed
that 10% of the cells died due to passage, but the remaining 90% of
the cells survived and were possible to passage in vitro again.
Injection of other substances with normal viscosity through the
catheter system and extroducer worked without any problem. This was
also demonstrated in vivo by deposition of Methylene Blue in the
extravascular space of the rat through the extroducer system.
[0187] Results of the Examples
[0188] Tests of the system was performed in an ex vivo system
simulating the size and tortuisity of human vasculature. The whole
system is easily placed within standard microcatheter systems. Rat
vessels of different sizes were mounted at the distal end of the
simulator to optimize the design of the distal part of the
extroducer. After exiting the artery or the vein from the inside to
out, cells or substances could be injected into the extravascular
space and thereafter the distal part was detached, leaving it
through the vessel wall with only the minute stop mechanism present
adjacent to the vessel wall on the separated distal end of the
extroducer. No complications such as bleeding, dissections or
thromboembolic complications were encountered, neither in the acute
phase, nor after 14 days.
[0189] Conclusion: A system for injection or sampling of cells or
substances in any organ throughout the body by using the
endovascular route is provided. The design of the system makes
navigation and exit of also the microvasculature possible on both
the arterial and venous side. The potential applications for the
system are numerous, for example stem cell transplantation to
organs difficult to reach by puncture or open surgery, such as the
central nervous system, the pancreas or the heart.
[0190] Extroducer practical implementations novel design has
sustained all testing without bleeding. It is a novel way of
applying endovascular intervention aimed at transplantation of cell
cultures, delivering drugs and possibly sampling body fluids and
cytological preparations. The entire system fits into current
standard catheter systems eliminating the need for navigation with
the extroducer system and easily integrating it with current
standard equipment.
[0191] The present invention has been described above with
reference to specific embodiments. However, other embodiments than
the above described are equally possible within the scope of the
invention. Different method steps than those described above,
performing the method by hardware or software, may be provided
within the scope of the invention. The different features and steps
of the invention may be combined in other combinations than those
described. The scope of the invention is only limited by the
appended patent claims.
* * * * *
References