U.S. patent application number 14/838531 was filed with the patent office on 2016-02-11 for methods and systems for treating ischemic tissues.
The applicant listed for this patent is MERCATOR MEDSYSTEMS, INC.. Invention is credited to Lynn Mateel BARR, Robert CAFFERATA, Kirk Patrick SEWARD.
Application Number | 20160038716 14/838531 |
Document ID | / |
Family ID | 33303195 |
Filed Date | 2016-02-11 |
United States Patent
Application |
20160038716 |
Kind Code |
A1 |
SEWARD; Kirk Patrick ; et
al. |
February 11, 2016 |
METHODS AND SYSTEMS FOR TREATING ISCHEMIC TISSUES
Abstract
Methods and systems for regenerating damaged tissue rely on
direct injection of selected therapeutic cells into a tissue at or
near the site of tissue damage. Direct injection is accomplished
using an intravascular catheter having a deployable needle, and
injection is usually targeted into the adventitial and
peri-adventitial tissues surrounding the blood vessel from which
the needle is deployed.
Inventors: |
SEWARD; Kirk Patrick; (San
Francisco, CA) ; BARR; Lynn Mateel; (Lafayette,
CA) ; CAFFERATA; Robert; (Santa Rosa, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MERCATOR MEDSYSTEMS, INC. |
San Leandro |
CA |
US |
|
|
Family ID: |
33303195 |
Appl. No.: |
14/838531 |
Filed: |
August 28, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12239589 |
Sep 26, 2008 |
9149497 |
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14838531 |
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10829905 |
Apr 21, 2004 |
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12239589 |
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60465013 |
Apr 22, 2003 |
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Current U.S.
Class: |
604/96.01 ;
604/272 |
Current CPC
Class: |
A61M 2025/0057 20130101;
A61K 35/54 20130101; A61M 25/0043 20130101; A61K 35/28 20130101;
A61M 25/10 20130101; A61K 35/545 20130101; A61P 9/10 20180101 |
International
Class: |
A61M 25/00 20060101
A61M025/00; A61K 35/28 20060101 A61K035/28; A61M 25/10 20060101
A61M025/10; A61K 35/545 20060101 A61K035/545 |
Claims
1-24. (canceled)
25. A system for treating ischemic tissue, said system comprising:
an amount of therapeutic cells selected to revascularize the
ischemic tissue; and an intravascular catheter advancable into a
lumen of a blood vessel, the intravascular catheter having a needle
advancable beyond the external elastic lamina of the blood vessel
to inject the therapeutic cells into a location in the perivascular
space surrounding the blood vessel adjacent the ischemic
tissue.
26. The system of claim 1, wherein the ischemic tissue comprises
ischemic cardiac tissue, neurological tissue damaged by stroke, or
other tissue damaged by inadequate blood circulation.
27. The system of claim 2, wherein the ischemic tissue comprises
ischemic cardiac tissue, and the ischemic cardiac tissue is cardiac
tissue which has been damaged by a myocardial infarction or by
inadequate blood circulation.
28. The system of claim 1, wherein the therapeutic cells are
selected from a group comprising stem cells, cardiomyocytes,
fibroblasts, endothelial cells, skeletal myoblasts, mesenchymal
stem cells, cells from unprocessed or minimally processed bone
marrow, peripheral blood stem cells, and mobilized peripheral blood
stem cells.
29. The system of claim 1, wherein the therapeutic cells are
pluripotent stem cells.
30. The system of claim 5, wherein the pluripotent stem cells are
mesenchymal adult progenitor cells.
31. The system of claim 1, wherein the blood vessel comprises a
coronary blood vessel.
32. The system of claim 1, wherein the blood vessel is a vein.
33. The system of claim 1, wherein the blood vessel is an
artery.
34. The system of claim 1, wherein the needle is advancable in a
radial direction relative to a longitudinal axis of the
intravascular catheter.
35. The system of claim 10, wherein the needle is advancable to a
radial direction to a depth beyond a endothelium of the blood
vessel equal to at least 10% of the mean luminal diameter of the
blood vessel at a location of the needle.
36. The system of claim 11, wherein the depth is a distance in the
range from 10% to 50% of the mean luminal diameter of the blood
vessel at the location.
37. The system of claim 1, wherein the intravascular catheter
comprises an expandable section, wherein the needle is disposed on
the expandable section and the expandable section is expandable to
advance the needle.
38. The system of claim 13, wherein the needle extends
approximately perpendicularly from a surface of the expandable
section.
39. The system of claim 1, wherein the intravascular catheter
comprises a plurality of the needles.
40. The system of claim 1, wherein the needle is 30-gauge or
smaller.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 10/829,905 (Attorney Docket No.
021621-001810US), which claims priority of U.S. Patent Application
Ser. No. 60/465,013 (Attorney Docket No. 021621-001800US), filed
Apr. 22, 2003, the full disclosures of which are incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to medical methods
and devices. More particularly, the present invention relates to
methods and systems for treating ischemic cardiac and other tissue
damaged by myocardial infarction and other causes by
intravascularly injecting therapeutic cells at or near the damaged
tissue.
[0004] Cardiac tissue can be damaged by a variety of causes,
including myocardial infarction, cardiac tissue infections,
diseases such as rheumatic fever, trauma, and the like. Extensive
damage to myocardial or valve tissues can cause heart failure and
death. Present treatments include heart transplantation, valve
repair surgery, and drug therapies. None of these treatments,
however, is effective for all patients, and heart failure remains a
leading cause of death world wide.
[0005] Neurologic tissue can also become ischemic due to a number
of causes, including blocked arteries, stroke, trauma, and the
like.
[0006] Chronic limb ischemia is a condition that arises from the
inability of diseased arteries to conduct sufficient blood flow to
the lower leg, ankle and toes. It can cause persistent, recurring
rest pain, ulceration and gangrene. If blood flow cannot be
restored by surgical or interventional procedures, patients will
eventually require amputation of the affected limb. Recently, a
study reported positive results of autologous bone marrow cell
transplantation into patients with limb ischemia due to peripheral
artery disease.
[0007] Such cell therapy apparently provided re-vascularization by
promoting development of collateral arteries flowing to the
ischemic muscle. Cells were injected intramuscularly requiring the
harvest of 500 ml of bone marrow. Such marrow harvest is very
traumatic. If cells could be delivered more precisely to the
affected muscles and placed in a non-ischemic depot where there
viability was maintained, it should be possible to achieve patient
benefit with fewer cells. This would reduce patient discomfort
associated with the bone marrow procedure and improve dose
response.
[0008] Much research is focused on developing therapies for
inducing or enhancing the repair of damaged cardiac tissues in
patients suffering from or at risk of heart failure. Some, such as
transmyocardial revascularization, rely on inducing controlled
injury to damaged heart tissue in the hope of causing
revascularization and tissue regeneration. Other therapies intended
to regenerate tissue include systemic and local administration of
growth factors, angiogenic factors, and the like, to promote tissue
repair.
[0009] Of particular interest to the present invention, the
introduction of therapeutic cells into damaged cardiac tissues has
been proposed. For example, of the injection of pluripotent stem
cells, such as embryonic stem cells or mesenchymal adult progenitor
cells (MAPC's), has been shown to have therapeutic benefit when
introduced into damaged cardiac tissues. Other cells and cell lines
which are the subject of current research for cardiac tissue
regeneration include cardiomyocytes, fibroblasts, endothelial
cells, and skeletal myoblasts.
[0010] Despite this promise, the injection of therapeutic stem and
other cells presents a number of challenges. Direct injection of
the cells to the myocardium through an epicardial surface is
difficult, requiring either an open chest or a transthoracic
procedure. Open chest procedures are very traumatic, and
transthoracic procedures are complicated and limit the ability to
precisely locate the site into which the cells are to be
injected.
[0011] Intracardiac protocols where the therapeutic cells are
injected through the endocardial surface have also been proposed.
Such inside-the-heart procedures are also complex and require
sophisticated intracardial catheters with complicated positioning
systems. Even with such advanced systems, the precise delivery of
the therapeutic cells to a particular target location can be
difficult.
[0012] A third alternative which has recently been proposed is to
use an arterial infusion catheter to deliver cells within a blood
vessel near the site of the damaged tissue. This catheter-based
technique relies on blocking blood flow with a balloon and infusing
cells distally into the artery. The need for the cells to migrate
through the endothelium, however, may be problematic and ultimately
limit the success of this approach. Recent studies have also shown
that intraluminal delivery of cells results in micro-infarctions
due to the extended balloon occlusion of the artery or the embolism
of cellular material blocking capillary flow.
[0013] For these reasons, it would be desirable to provide improved
methods and systems for delivering therapeutic cells to damaged
coronary and other tissues. Such methods and systems will
preferably be catheter-based and permit introduction of the cells
into cardiac and other tissue via the coronary and peripheral
vasculature, including both arteries and veins. The methods and
systems should further provide for delivering the therapeutic cells
to precisely controlled locations within or adjacent to the damaged
tissues, and should also provide for direct delivery into the
tissue without dilution in the systemic circulation. Preferably,
the methods and systems will allow for injection of the therapeutic
cells into the space between a blocked artery and an adjacent
collateral vessel to promote enlargement of the collateral vessel.
Additionally, the cells which are injected and those which
proliferate in situ should be able to migrate and distribute from
the site of injection into adjacent regions of damaged tissue in
order to provide effective therapy. At least some of these
objectives will be met by the inventions described hereinafter.
[0014] 2. Description of the Background Art
[0015] The endocardial and epicardial injection of stem and other
cells are described in U.S. Pat. Nos. 6,387,369; 6,099,832;
5,602,301; and 5,591,625, and U.S. Patent Publication No. US
2002/0182186. Isolation, purification and culturing of human
mesenchymal stem cells are described in U.S. Pat. No. 5,486,359.
The full disclosures of each of these patents and patent
publication are incorporated herein by reference.
[0016] Publications of interest include: [0017] 1. Penn M S,
Francis G S, Ellis S G, Young J B, McCarthy P M, Topol E J;
"Autologous Cell Transplantation for the Treatment of Damaged
Myocardium". Progress in Cardiovascular Diseases, Vol. 45, No. 1,
July/August 2002: pp 21-32. [0018] 2. Assmus B, MD; Schachinger V,
MD; Teupe C, MD; Britten M, MD; Lehmann R, MD; Dobert N, MD;
Grunwald F, MD; Aicher A, MD; Urbich C, PhD; Martin H, MD; Hoelzer
D, MD; Dimmeler S, PhD; Zeiher A M, MD; "Transplantation of
Progenitor Cells and Regeneration Enhancement in Acute Myocardial
Infarction (TOPCARE-AMI)". Circulation. 2002; 106: 3009-3017.
[0019] 3. Stamm C, Westphal B, Kleine H- D, Petzsch M, Kittner C,
Klinge H, Schumichen C, Nienaber C A, Freund M, Steinhoff G;
"Autologous bone-marrow stem-cell transplantation for myocardial
regeneration". The Lancet Vol. 361 Jan. 4, 2003. [0020] 4. Zhong H,
Zhu H, Zhang Z; "Affects of different access routes on autologous
satellite cell implantation stimulating myocardial regeneration".
Chin Med J (Engl) 2002 October; 115(10): 1521-4. [0021] 5. Strauer
B E, MD; Brehm M, MD; Zeus T, MD; Kostering M, MD; Hernandez A,
PhD; Sorg R V, PhD; Kogler G, PhD; Wernet P, MD; "Repair of
Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone
Marrow Cell Transplantation in Humans". Circulation. 2002; 106:
1913-1918. [0022] 6. Tse H- F, Kwong Y- L, Chan J K F, Lo G, Ho C-
L, Lau C- P; "Angiogenesis in ischaemic myocardium by
intramyocardial autologous bone marrow mononuclear cell
implantation". The Lancet 2003; 361: 47-49. [0023] 7. Hagege A A,
Carrion C, Menasche P, Vilquin J- T, Duboc D, Marolleau J- P,
Desnos M, Bruneval P; "Viability and differentiation of autologous
skeletal myoblast grafts in ischaemic cardiomyopathy". The Lancet
2003; 361: 91-92. [0024] 8. Yateishi-Yuyama E, Matsubara H,
Murohara T, Ikeda U, Shintani S, Masaki H, Amano K, Kishimoto Y,
Yoshimoto K, Akashi H, Shimada K, Iwasaka T, Imaizumi T for the
Therapeutic Angiogenesis using Cell Transplantation (TACT) Study
Investigators; "Therapeutic angiogenesis for patients with limb
ischaemia by autologous transplantation of bone-marrow cells: a
pilot study and a randomized controlled trial". The Lancet 2002;
360: 427-35. [0025] 9. Kawamoto A, MD; Tkebuchava T, MD; Yamaguchi
J- I, MD; Nishimura H, MD; Yoon Y- S, MD; Milliken C, BS; Uchida S,
MD; Masuo O, MD; Iwaguro H, MD; Ma H, BS; Hanley A, BS; Silver M,
BS; Kearney M, BS; Losordo D W, MD; Isner J M, MD; Asahara T, MD;
"Intramyocardial Transplantation of Autologous Endothelial
Progenitor Cells for Therapeutic Neovascularization of Myocardial
Ischemia". Circulation. 2003; 107: 461-468. [0026] 10. Min J. Y.,
Sullivan M F, Yang Y, Zhang J P, Converso K L, Morgan J P, Xia Y F;
"Significant improvement of heart function by cotransplantation of
human mesenchymal stem cells and fetal cardiomyocytes in
postinfarcted pigs". Ann Thorac Surg 2002 November; 74(5): 1568-75.
[0027] 11. Shake J G, Gruber P J, Baumgartner W A, Senechal G,
Meyers J, Redmond J M, Pittenger M F, Martin B J; "Mesenchymal stem
cell implantation in a swine myocardial infarct model: engraftment
and functional effects". Ann Thorac Surg 2002 June; 73(6): 1919-25;
discussion 1926. [0028] 12. Fuchs S, MD; Baffour R, PhD; Zhou Y F,
MD; Shou M, MD; Pierre A, BSc; Tio F O, M D; Weissman N J, MD; Leon
M B, MD; Epstein S E, MD; Kornowski R, MD; "Transendocardial
Delivery of Autologous Bone Marrow Enhances Collateral Perfusion
and Regional Function in Pigs With Chronic Experimental Myocardial
Ischemia". Journal of the American College of Cardiology 2001; Vol.
37, No. 6: 1726-1732. [0029] 13. Tomita S, MD, PhD; Mickle D A G,
MD; Weisel R D, MD; Jia Z- Q, MD; Tumiati L C, BSc; Allidina Y,
RTNM; Liu P, MD; Li R- K, MD, PhD; "Improved heart function with
myogenesis and angiogenesis after autologous porcine bone marrow
stromal cell transplantation". Journal of Thoracic and
Cardiovascular Surgery; June 2002: 1132-1140. [0030] 14. Li R- K,
MD, PhD; Weisel R D, MD; Mickle D A G, MD; Jia Z- Q, MD; Kim E- J,
MD; Sakai T, MD; Tomita S, MD; Schwartz L, MD; Iwanochko M, MD;
Husain M, MD; Cusimano R J, MD, MSc; Burns R J, MD; Yau T M, MD,
MSc; "Autologous Porcine Heart Cell Transplantation Improved Heart
Function After A Myocardial Infarction". Journal of Thoracic and
Cardiovascular Surgery; January 2000: 62-68. [0031] 15. Yau T M,
MD, MS; Tomita S, MD; Weisel R D, MD; Jia Z- Q, MD; Tumiati L C,
MS; Mickle D A G, MD; Li R- K, MD, PhD; "Beneficial Effect of
Autologous Cell Transplantation on Infarcted Heart Function:
Comparison Between Bone Marrow Stromal Cells and Heart Cells". Ann
Thorac Surg 2003; 75: 169-77. [0032] 16. Orlic D, Kajstura J,
Chimenti S, Jakoniuk I, Anderson S M, Li B, Pickel J, McKay R,
Nadal-Ginard B, Bodine D M, Leri A, Anversa P; "Bone marrow cells
regenerate infracted myocardium". Nature 2001 Apr. 5; 410 (6829):
701-5. [0033] 17. Orlic D, Kajstura J, Chimenti S, Limana F,
Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine D M, Leri A, Anversa
P; "Mobilized bone marrow cells repair the infracted heart,
improving function and survival". PNAS Aug. 28, 2001. [0034] 18.
Kocher A A, Schuster M D, Szabolcs M J, Takuma S, Burkhoff D, Wang
J, Homma S, Edwards N M, Itescu S; "Neovascularization of ischemic
myocardium by human bone-marrow-derived angioblasts prevents
cardiomyocyte apoptosis, reduces remodeling and improves cardiac
function". Nature Medicine; Vol. 1, No. 4, April 2001: 430-36.
[0035] 19. Jackson K A, Majka S M, Wang H, Pocius J, Hartley C J,
Majesky M W, Entman M L, Michael L H, Hirschi K K, Goodell M A;
"Regeneration of ischemic cardiac muscle and vascular endothelium
by adult stem cells". Journal of Clinical Investigation, June 2001,
Vol. 107, Number 11: 1395-1402. [0036] 20. Kawamoto A, MD; Gwon H-
C, MD; Iwaguro H, MD; Yamaguchi J- I, MD; Uchida S, MD; Masuda H,
MD; Silver M, BS; Ma H, BS; Kearney M, BS; Isner J M, MD; Asahara
T, MD; "Therapeutic Potential of Ex Vivo Expanded Endothelial
Progenitor Cells for Myocardial Ischemia". Circulation. 2001; 103:
634-637.
BRIEF SUMMARY OF THE INVENTION
[0037] The present invention provides improved methods and systems
for treating patients at risk of or suffering from conditions
related to ischemic and other damaged tissue, particularly from
congestive heart failure, myocardial infarction, stroke, peripheral
vascular disease, and other conditions of compromised circulation.
The methods and systems of the present invention provide for the
direct and local delivery of therapeutic cells at or near the
location(s), typically ischemic cardiac or other tissue damage.
Such direct and local administration is achieved using a catheter
or other intravascular access device which is capable of injecting
or otherwise introducing the therapeutic cells through the
endothelium of an artery or vein into the target site within the
cardiac and other tissue within or adjacent to the location of the
damaged tissue to be treated. The therapeutic cells are thus
delivered into the perivascular space, preferably within the
adventitial regions where the cells may find a particularly
conducive location for growth and proliferation. A presently
preferred location is into a space in tissue between a blocked
artery and an adjacent collateral vessel. By introducing the
therapeutic cells at a location midway down the length of the
blocked artery, enlargement of a nearby segment of a collateral
blood vessel is achieved. Shear stress of arterial flow in the
collateral vessel will then cause enlargement of the entire
collateral vessel to revascularize the ischemic tissue. Moreover,
it is believed that the cells may rapidly migrate from the adventia
into the damaged regions of the myocardium or other target tissue
where they will promote tissue regeneration and repair.
[0038] Suitable therapeutic cells include any known or presently
unknown human or animal cell or cell line which can provide a
therapeutic benefit when introduced into the perivascular or
adventitial regions according to the methods described herein.
Exemplary cells and cell lines include both autologous and
heterologous cells, including stem cells, cardiomyocytes,
fibroblasts, endothelial cells, skeletal myoblasts, and the like.
Preferred are pluripotent stem cells, particularly mesenchymal
adult progenitor cells, embryonic stem cells and mobilized
peripheral blood stem cells. Efficient peri-adventitial or
perivascular injection will allow use of autologous bone marrow
and/or mobilized peripheral blood stem cells with little or no
enrichment, isolation, or manipulation.
[0039] The methods and systems of the present invention rely on
injection of the therapeutic stem cells into the adventitial or
perivascular tissue surrounding the impaired blood vessels in the
coronary and peripheral vasculature. Delivery of the therapeutic
cells into these ischemic tissues results in rapid migration and
distribution of the cells throughout the adventitial pericardial
space and into the myocardium, particularly to regions of the
myocardium which are damaged and in need of regeneration.
Optionally, injection of the therapeutic cells may be made at
multiple sites and/or at different times in order to further
enhance even and rapid distribution and persistence of the
therapeutic cells over wide regions and/or prolonged periods.
[0040] Preferably, injecting the therapeutic cells into the
adventitial and perivascular tissues comprises advancing a needle
from a lumen of the blood vessel to the location beyond the
endothelium. The therapeutic cells are then delivered through the
needle to the target tissues. Typically, the needle is advanced
into a perivascular space beyond the outside of the endothelium of
the blood vessel, more typically being advanced into the adventitia
surrounding the blood vessel. The needle may be advanced in a
radial direction to a depth in the adventitia equal to at least 10%
of the mean luminal diameter of the blood vessel at the site of
injection. More typically being in the range from 10% to 50% of the
mean luminal diameter.
[0041] Systems according to the present invention for damaged
cardiac tissues comprise an amount of therapeutic cells selected to
treat the tissue damage and an intravascular catheter having a
needle for injecting the substance into a location beyond the
endothelium of the blood vessel.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1A is a schematic, perspective view of an intravascular
injection catheter suitable for use in the methods and systems of
the present invention.
[0043] FIG. 1B is a cross-sectional view along line 1B-1B of FIG.
1A.
[0044] FIG. 1C is a cross-sectional view along line 1C-1C of FIG.
1A.
[0045] FIG. 2A is a schematic, perspective view of the catheter of
FIGS. 1A-1C shown with the injection needle deployed.
[0046] FIG. 2B is a cross-sectional view along line 2B-2B of FIG.
2A.
[0047] FIG. 3 is a schematic, perspective view of the intravascular
catheter of FIGS. 1A-1C injecting therapeutic cells into an
adventitial space surrounding a coronary blood vessel in accordance
with the methods of the present invention.
[0048] FIG. 4 is a schematic, perspective view of another
embodiment of an intravascular injection catheter useful in the
methods of the present invention.
[0049] FIG. 5 is a schematic, perspective view of still another
embodiment of an intravascular injection catheter useful in the
methods of the present invention, as inserted into a patient's
vasculature.
[0050] FIGS. 6A and 6B are schematic views of other embodiments of
an intravascular injection catheter useful in the methods of the
present invention (in an unactuated condition) including multiple
needles.
[0051] FIG. 7 is a schematic view of yet another embodiment of an
intravascular injection catheter useful in the methods of the
present invention (in an unactuated condition).
[0052] FIG. 8 is a perspective view of a needle injection catheter
useful in the methods and systems of the present invention.
[0053] FIG. 9 is a cross-sectional view of the catheter FIG. 8
shown with the injection needle in a retracted configuration.
[0054] FIG. 10 is a cross-sectional view similar to FIG. 9, shown
with the injection needle laterally advanced into luminal tissue
for the delivery of therapeutic cells according to the present
invention.
[0055] FIG. 11 is a chart comparing the viability of cells injected
through a 25 G needle and through a microsyringe in accordance with
the principles of the present invention.
[0056] FIGS. 12A and 12B compare the formation of ectopic cell
clusters in response to the injection of porcine mononuclear cells
(FIG. 12A) and saline (FIG. 12B).
DETAILED DESCRIPTION OF THE INVENTION
[0057] The present invention provides methods and systems for
treating patients at risk of or suffering conditions associated
with damaged or ischemic tissue. In particular, these patients will
have been diagnosed to have region(s) of damaged tissues such as
ischemic tissues, particularly ischemic cardiac tissue, neurologic
tissue, and tissue in the legs at risk of peripheral vascular
disease by conventional techniques. Ischemic cardiac tissue may be
located by angiogram, while compromised circulation in the
peripheral vasculature can be identified by other conventional
techniques.
[0058] The present invention will preferably utilize
microfabricated devices and methods for intravascular injection of
the therapeutic cells. The following description provides several
representative embodiments of microfabricated needles
(microneedles) and macroneedles suitable for the delivery of the
therapeutic cells into a perivascular space or adventitial tissue.
The perivascular space is the potential space between the outer
surface and the endothelium or "vascular wall" of either an artery
or vein. The microneedle is usually inserted substantially normal
to the wall of a vessel (artery or vein) to eliminate as much
trauma to the patient as possible. Until the microneedle is at the
site of an injection, it is positioned out of the way so that it
does not scrape against arterial or venous walls with its tip.
Specifically, the microneedle remains enclosed in the walls of an
actuator or sheath attached to a catheter so that it will not
injure the patient during intervention or the physician during
handling. When the injection site is reached, movement of the
actuator along the vessel is terminated, and the actuator is
operated to cause the microneedle to be thrust outwardly,
substantially perpendicular to the central axis of a vessel, for
instance, in which the catheter has been inserted.
[0059] As shown in FIGS. 1A-2B, a microfabricated intravascular
catheter 10 includes an actuator 12 having an actuator body 12a and
central longitudinal axis 12 b. The actuator body more or less
forms a C-shaped outline having an opening or slit 12d extending
substantially along its length. A microneedle 14 is located within
the actuator body, as discussed in more detail below, when the
actuator is in its unactuated condition (furled state) (FIG. 1B).
The microneedle is moved outside the actuator body when the
actuator is operated to be in its actuated condition (unfurled
state) (FIG. 2B).
[0060] The actuator may be capped at its proximal end 12e and
distal end 12f by a lead end 16 and a tip end 18, respectively, of
a therapeutic catheter 20. The catheter tip end serves as a means
of locating the actuator inside a blood vessel by use of a radio
opaque coatings or markers. The catheter tip also forms a seal at
the distal end 12f of the actuator. The lead end of the catheter
provides the necessary interconnects (fluidic, mechanical,
electrical or optical) at the proximal end 12e of the actuator.
[0061] Retaining rings 22a and 22b are located at the distal and
proximal ends, respectively, of the actuator. The catheter tip is
joined to the retaining ring 22a, while the catheter lead is joined
to retaining ring 22b. The retaining rings are made of a thin, on
the order of 10 to 100 microns (.mu.m), substantially rigid
material, such as Parylene (types C, D or N), or a metal, for
example, aluminum, stainless steel, gold, titanium or tungsten. The
retaining rings form a rigid substantially "C"-shaped structure at
each end of the actuator. The catheter may be joined to the
retaining rings by, for example, a butt-weld, an ultra sonic weld,
integral polymer encapsulation or an adhesive such as an epoxy.
[0062] The actuator body further comprises a central, expandable
section 24 located between retaining rings 22a and 22b. The
expandable section 24 includes an interior open area 26 for rapid
expansion when an activating fluid is supplied to that area. The
central section 24 is made of a thin, semi-rigid or rigid,
expandable material, such as a polymer, for instance, Parylene
(types C, D or N), silicone, polyurethane or polyimide. The central
section 24, upon actuation, is expandable somewhat like a
balloon-device.
[0063] The central section is capable of withstanding pressures of
up to about 100 psi upon application of the activating fluid to the
open area 26. The material from which the central section is made
of is rigid or semi-rigid in that the central section returns
substantially to its original configuration and orientation (the
unactuated condition) when the activating fluid is removed from the
open area 26. Thus, in this sense, the central section is very much
unlike a balloon which has no inherently stable structure.
[0064] The open area 26 of the actuator is connected to a delivery
conduit, tube or fluid pathway 28 that extends from the catheter's
lead end to the actuator's proximal end. The activating fluid is
supplied to the open area via the delivery tube. The delivery tube
may be constructed of Teflon.COPYRGT. or other inert plastics. The
activating fluid may be a saline solution or a radio-opaque
dye.
[0065] The microneedle 14 may be located approximately in the
middle of the central section 24. However, as discussed below, this
is not necessary, especially when multiple microneedles are used.
The microneedle is affixed to an exterior surface 24a of the
central section. The microneedle is affixed to the surface 24a by
an adhesive, such as cyanoacrylate. Alternatively, the microneedle
maybe joined to the surface 24a by a metallic or polymer mesh-like
structure 30 (See FIG. 4F), which is itself affixed to the surface
24a by an adhesive. The mesh-like structure may be-made of, for
instance, steel or nylon.
[0066] The microneedle includes a sharp tip 14a and a shaft 14b.
The microneedle tip can provide an insertion edge or point. The
shaft 14b can be hollow and the tip can have an outlet port 14c,
permitting the injection of a pharmaceutical or drug into a
patient. The microneedle, however, does not need to be hollow, as
it may be configured like a neural probe to accomplish other
tasks.
[0067] As shown, the microneedle extends approximately
perpendicularly from surface 24a. Thus, as described, the
microneedle will move substantially perpendicularly to an axis of a
vessel or artery into which has been inserted, to allow direct
puncture or breach of vascular walls.
[0068] The microneedle further includes a pharmaceutical or drug
supply conduit, tube or fluid pathway 14d which places the
microneedle in fluid communication with the appropriate fluid
interconnect at the catheter lead end. This supply tube may be
formed integrally with the shaft 14b, or it may be formed as a
separate piece that is later joined to the shaft by, for example,
an adhesive such as an epoxy.
[0069] The needle 14 may be a 30-gauge, or smaller, steel needle.
Alternatively, the microneedle may be microfabricated from
polymers, other metals, metal alloys or semiconductor materials.
The needle, for example, may be made of Parylene, silicon or glass.
Microneedles and methods of fabrication are described in U.S.
application Ser. No. 09/877,653, filed Jun. 8, 2001, entitled
"Microfabricated Surgical Device", having a common inventor with
the subject application, the entire disclosure of which is
incorporated herein by reference.
[0070] The catheter 20, in use, is inserted through an artery or
vein and moved within a patient's vasculature, for instance, a vein
32, until a specific, targeted region 34 is reaches (see FIG. 3).
The targeted region 34 may be the site of tissue damage or more
usually will be adjacent the sites typically being within 100 mm or
less to allow migration of the cells. As is well known in
catheter-based interventional procedures, the catheter 20 may
follow a guide wire 36 that has previously been inserted into the
patient. Optionally, the catheter 20 may also follow the path of a
previously-inserted guide catheter (not shown) that encompasses the
guide wire.
[0071] During maneuvering of the catheter 20, well-known methods of
fluoroscopy or magnetic resonance imaging (MRI) can be used to
image the catheter and assist in positioning the actuator 12 and
the microneedle 14 at the target region. As the catheter is guided
inside the patient's body, the microneedle remains furled or held
inside the actuator body so that no trauma is caused to the
vascular walls.
[0072] After being positioned at the target region 34, movement of
the catheter is terminated and the activating fluid is supplied to
the open area 26 of the actuator, causing the expandable section 24
to rapidly unfurl, moving the microneedle 14 in a substantially
perpendicular direction, relative to the longitudinal central axis
12b of the actuator body 12a, to puncture a vascular wall 32a. It
may take only between approximately 100 milliseconds and two
seconds for the microneedle to move from its furled state to its
unfurled state.
[0073] The ends of the actuator at the retaining rings 22a and 22b
remain rigidly fixed to the catheter 20. Thus, they do not deform
during actuation. Since the actuator begins as a furled structure,
its so-called pregnant shape exists as an unstable buckling mode.
This instability, upon actuation, produces a large-scale motion of
the microneedle approximately perpendicular to the central axis of
the actuator body, causing a rapid puncture of the vascular wall
without a large momentum transfer. As a result, a microscale
opening is produced with very minimal damage to the surrounding
tissue. Also, since the momentum transfer is relatively small, only
a negligible bias force is required to hold the catheter and
actuator in place during actuation and puncture.
[0074] The microneedle, in fact, travels so quickly and with such
force that it can enter perivascular tissue 32b as well as vascular
tissue. Additionally, since the actuator is "parked" or stopped
prior to actuation, more precise placement and control over
penetration of the vascular wall are obtained.
[0075] After actuation of the microneedle and delivery of the cells
to the target region via the microneedle, the activating fluid is
exhausted from the open area 26 of the actuator, causing the
expandable section 24 to return to its original, furled state. This
also causes the microneedle to be withdrawn from the vascular wall.
The microneedle, being withdrawn, is once again sheathed by the
actuator.
[0076] Various microfabricated devices can be integrated into the
needle, actuator and catheter for metering flows, capturing samples
of biological tissue, and measuring pH. The device 10, for
instance, could include electrical sensors for measuring the flow
through the microneedle as well as the pH of the pharmaceutical
being deployed. The device 10 could also include an intravascular
ultrasonic sensor (IVUS) for locating vessel walls, and fiber
optics, as is well known in the art, for viewing the target region.
For such complete systems, high integrity electrical, mechanical
and fluid connections are provided to transfer power, energy, and
pharmaceuticals or biological agents with reliability.
[0077] By way of example, the microneedle may have an overall
length of between about 200 and 3,000 microns (.mu.m). The interior
cross-sectional dimension of the shaft 14b and supply tube 14d may
be on the order of 20 to 250 urn, while the tube's and shaft's
exterior cross-sectional dimension may be between about 100 and 500
.mu.m. The overall length of the actuator body may be between about
5 and 50 millimeters (mm), while the exterior and interior
cross-sectional dimensions of the actuator body can be between
about 0.4 and 4 mm, and 0.5 and 5 mm, respectively. The gap or slit
through which the central section of the actuator unfurls may have
a length of about 4-40 mm, and a cross-sectional dimension of about
50-500 .mu.m. The diameter of the delivery tube for the activating
fluid may be about 100 .mu.m. The catheter size may be between 1.5
and 15 French (Fr).
[0078] Variations of the invention include a multiple-buckling
actuator with a single supply tube for the activating fluid. The
multiple-buckling actuator includes multiple needles that can be
inserted into or through a vessel wall for providing injection at
different locations or times.
[0079] For instance, as shown in FIG. 4, the actuator 120 includes
microneedles 140 and 142 located at different points along a length
or longitudinal dimension of the central, expandable section 240.
The operating pressure of the activating fluid is selected so that
the microneedles move at the same time. Alternatively, the pressure
of the activating fluid may be selected so that the microneedle 140
moves before the microneedle 142.
[0080] Specifically, the microneedle 140 is located at a portion of
the expandable section 240 (lower activation pressure) that, for
the same activating fluid pressure, will buckle outwardly before
that portion of the expandable section (higher activation pressure)
where the microneedle 142 is located. Thus, for example, if the
operating pressure of the activating fluid within the open area of
the expandable section 240 is two pounds per square inch (psi), the
microneedle 140 will move before the microneedle 142. It is only
when the operating pressure is increased to four psi, for instance,
that the microneedle 142 will move. Thus, this mode of operation
provides staged buckling with the microneedle 140 moving at time
t.sub.1, and pressure p.sub.1, and the microneedle 142 moving at
time t.sub.2 and p.sub.2, with t.sub.1, and p.sub.1, being less
than t.sub.2 and p.sub.2, respectively.
[0081] This sort of staged buckling can also be provided with
different pneumatic or hydraulic connections at different parts of
the central section 240 in which each part includes an individual
microneedle.
[0082] Also, as shown in FIG. 5, an actuator 220 could be
constructed such that its needles 222 and 224A move in different
directions. As shown, upon actuation, the needles move at angle of
approximately 90.degree. to each other to puncture different parts
of a vessel wall. A needle 224B (as shown in phantom) could
alternatively be arranged to move at angle of about 180.degree. to
the needle 224A.
[0083] Moreover, as shown in FIG. 6A, in another embodiment, an
actuator 230 comprises actuator bodies 232 and 234 including
needles 236 and 238, respectively, that move approximately
horizontally at an angle of about 180.degree. to each other. Also,
as shown in FIG. 7B, an actuator 240 comprises actuator bodies 242
and 244 including needles 242 and 244, respectively, that are
configured to move at some angle relative to each other than
90.degree. or 180.degree.. The central expandable section of the
actuator 230 is provided by central expandable sections 237 and 239
of the actuator bodies 232 and 234, respectively. Similarly, the
central expandable section of the actuator 240 is provided by
central expandable sections 247 and 249 of the actuator bodies 242
and 244, respectively.
[0084] Additionally, as shown in FIG. 7, an actuator 250 may be
constructed that includes multiple needles 252 and 254 that move in
different directions when the actuator is caused to change from the
unactuated to the actuated condition. The needles 252 and 254, upon
activation, do not move in a substantially perpendicular direction
relative to the longitudinal axis of the actuator body 256.
[0085] The above catheter designs and variations thereon, are
described in published U.S. Patent Application Nos. 2003/005546 and
2003/0055400, the full disclosures of which are incorporated herein
by reference. Co-pending application Ser. No. 10/350,314, assigned
to the assignee of the present application, describes the ability
of substances delivered by direct injection into the adventitial
and pericardial tissues of the heart to rapidly and evenly
distribute within the heart tissues, even to locations remote from
the site of injection. The full disclosure of that co-pending
application is also incorporated herein by reference. An
alternative needle catheter design suitable for delivering the
therapeutic cells of the present invention will be described below.
That particular catheter design is described and claimed in
co-pending application Ser. No. 10/397,700 (Attorney Docket No.
021621-001500 U.S.), filed on Mar. 19, 2003, the full disclosure of
which is incorporated herein by reference.
[0086] Referring now to FIG. 8, a needle injection catheter 310
constructed in accordance with the principles of the present
invention comprises a catheter body 312 having a distal end 314 and
a proximal 316. Usually, a guide wire lumen 313 will be provided in
a distal nose 352 of the catheter, although over-the-wire and
embodiments which do not require guide wire placement will also be
within the scope of the present invention. A two-port hub 320 is
attached to the proximal end 316 of the catheter body 312 and
includes a first port 322 for delivery of a hydraulic fluid, e.g.,
using a syringe 324, and a second port 326 for delivering the
pharmaceutical agent, e.g., using a syringe 328. A reciprocatable,
deflectable needle 330 is mounted near the distal end of the
catheter body 312 and is shown in its laterally advanced
configuration in FIG. 8.
[0087] Referring now to FIG. 9, the proximal end 314 of the
catheter body 312 has a main lumen 336 which holds the needle 330,
a reciprocatable piston 338, and a hydraulic fluid delivery tube
340. The piston 338 is mounted to slide over a rail 342 and is
fixedly attached to the needle 330. Thus, by delivering a
pressurized hydraulic fluid through a lumen 341 tube 340 into a
bellows structure 344, the piston 338 may be advanced axially
toward the distal tip in order to cause the needle to pass through
a deflection path 350 formed in a catheter nose 352.
[0088] As can be seen in FIG. 10, the catheter 310 may be
positioned in a coronary blood vessel BV, over a guide wire GW in a
conventional manner. Distal advancement of the piston 338 causes
the needle 330 to advance into luminal tissue T adjacent to the
catheter when it is present in the blood vessel. The therapeutic
cells may then be introduced through the port 326 using syringe 328
in order to introduce a plume P of agent in the cardiac tissue, as
illustrated in FIG. 10. The plume P will be within or adjacent to
the region of tissue damage as described above.
[0089] The needle 330 may extend the entire length of the catheter
body 312 or, more usually, will extend only partially in
therapeutic cells delivery lumen 337 in the tube 340. A proximal
end of the needle can form a sliding seal with the lumen 337 to
permit pressurized delivery of the agent through the needle.
[0090] The needle 330 will be composed of an elastic material,
typically an elastic or super elastic metal, typically being
nitinol or other super elastic metal. Alternatively, the needle 330
could be formed from a non-elastically deformable or malleable
metal which is shaped as it passes through a deflection path. The
use of non-elastically deformable metals, however, is less
preferred since such metals will generally not retain their
straightened configuration after they pass through the deflection
path.
[0091] The bellows structure 344 may be made by depositing by
parylene or another conformal polymer layer onto a mandrel and then
dissolving the mandrel from within the polymer shell structure.
Alternatively, the bellows 344 could be made from an elastomeric
material to form a balloon structure. In a still further
alternative, a spring structure can be utilized in, on, or over the
bellows in order to drive the bellows to a closed position in the
absence of pressurized hydraulic fluid therein.
[0092] After the therapeutic cells are delivered through the needle
330, as shown in FIG. 10, the needle is retracted and the catheter
either repositioned for further agent delivery or withdrawn. In
some embodiments, the needle will be retracted simply by aspirating
the hydraulic fluid from the bellows 344. In other embodiments,
needle retraction may be assisted by a return spring, e.g., locked
between a distal face of the piston 338 and a proximal wall of the
distal tip 352 (not shown) and/or by a pull wire attached to the
piston and running through lumen 341.
EXPERIMENTAL
Comparison of Cell Recovery/Viability after Passage Through the
.mu.Syringe Versus a 25 G Needle
[0093] Methods.
[0094] Porcine bone marrow cells were aseptically harvested from a
needle-aspirate, washed in saline and centrifuged through Ficoll.
Triplicate 500 .mu.l aliquots (23.times.106 cells) of the resulting
mononuclear cells (MNCs) were injected into tubes containing
saline. Cell quantification and cell viability were determined
before and after injection by propidium iodide/flow cytometry.
Solid bars: % cells recovered; open bars: % viable cells recovered
(FIG. 11).
[0095] Results.
[0096] Injecting 500 ml post-Ficoll porcine bone marrow cells
(46.times.106/ml) through the .mu.Syringe or a tuberculin syringe
(25 gauge needle) resulted in identical recovery and viability of
cells in vitro.
[0097] Feasibility of Periadventitial Cell Delivery in Coronary
Arteries
[0098] Methods.
[0099] Porcine MNCs were harvested from peripheral blood with a B-D
Vacutainer.RTM. CPT and washed in saline. Each of the coronary
arteries received two 500 .mu.l injections 3.4.times.10.sup.6
cells, or 50:50 saline:contrast media spaced 1 cm apart. After
sacrifice at 3 days, cardiac tissues near injection sites were
H&E stained and prepared for histology. Photomicrography shows
ectopic cell clusters in the peri-vascular space between the LAD
and myocardium (FIG. 12A). In contrast, saline injection in the
right coronary artery (RCA) resulted in diffuse RBCs and
inflammatory infiltrates but no ectopic cell clusters (FIG.
12B).
[0100] Results.
[0101] Injecting autologous MNCs into the adventitia of distal
coronaries resulted in ectopic cell clusters (non-cardiomyocyte)
within the underlying myocardium. Ectopic cell clusters persisted
at 3 days after injecting into the left anterior descending artery.
In contrast, saline injections resulted in diffuse RBC and
inflammatory infiltrates in perivascular space but no ectopic cell
clusters.
[0102] While the above is a complete description of the preferred
embodiments of the invention, various alternatives, modifications,
and equivalents may be used. Therefore, the above description
should not be taken as limiting the scope of the invention which is
defined by the appended claims.
* * * * *