U.S. patent application number 10/913304 was filed with the patent office on 2005-05-05 for cell seeded expandable body.
Invention is credited to Looi, Kareen, Owens, Gary K..
Application Number | 20050096731 10/913304 |
Document ID | / |
Family ID | 34557880 |
Filed Date | 2005-05-05 |
United States Patent
Application |
20050096731 |
Kind Code |
A1 |
Looi, Kareen ; et
al. |
May 5, 2005 |
Cell seeded expandable body
Abstract
Devices, systems and methods for treating medical conditions
using cell therapy via body lumens. Localized delivery is achieved
with the use of a stent-like expandable body seeded with cells. The
expandable body is expanded to contact at least a portion of the
inner walls of the body lumen and the cells, cellular products
and/or other therapeutic agents are delivered to the surrounding
tissue. The therapeutic benefit provided is dependent on the type
of cells used and the features of the expandable body.
Inventors: |
Looi, Kareen;
(Charlottesville, VA) ; Owens, Gary K.;
(Earlysville, VA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Family ID: |
34557880 |
Appl. No.: |
10/913304 |
Filed: |
August 6, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10913304 |
Aug 6, 2004 |
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PCT/US03/21754 |
Jul 11, 2003 |
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10913304 |
Aug 6, 2004 |
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PCT/US03/21611 |
Jul 11, 2003 |
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60494045 |
Aug 7, 2003 |
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60395180 |
Jul 11, 2002 |
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60421404 |
Oct 24, 2002 |
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60395180 |
Jul 11, 2002 |
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60421404 |
Oct 24, 2002 |
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60421350 |
Oct 24, 2002 |
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60428803 |
Nov 25, 2002 |
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Current U.S.
Class: |
623/1.16 ;
435/402; 623/1.36; 623/1.41; 623/1.42 |
Current CPC
Class: |
A61F 2220/0016 20130101;
A61F 2/90 20130101; A61F 2/915 20130101; A61F 2/07 20130101; A61L
31/005 20130101; A61F 2/0077 20130101; A61F 2002/075 20130101; A61F
2230/0013 20130101; A61L 31/146 20130101; A61F 2002/91533 20130101;
A61L 31/088 20130101; A61F 2220/0033 20130101; A61F 2/848 20130101;
A61F 2/91 20130101; A61L 2400/12 20130101; A61F 2002/91575
20130101 |
Class at
Publication: |
623/001.16 ;
623/001.36; 623/001.41; 623/001.42; 435/402 |
International
Class: |
A61F 002/06; C12N
005/08; A61F 002/04 |
Goverment Interests
[0004] This invention was made with government support under grant
number R21 HL071976-01 (G. K. Owens, PI) entitled "Derivation of
Smooth Muscle Lineages from Stem Cells," awarded by the National
Institutes of Health. The government may have certain rights in the
invention.
Claims
What is claimed is:
1. A system for treating a patient comprising: an expandable body
having a proximal end, a distal end, a longitudinal axis
therebetween, and at least one microstructure having an attached
end attached to the body and a free end which is projectable
radially outwardly from the expandable body; and a plurality of
cells disposed on at least one surface of the expandable body.
2. A system as in claim 1, wherein the at least one surface is
located on an outer surface of the expandable body.
3. A system as in claim 1, wherein the surface includes pores.
4. A system as in claim 3, wherein the pores are sized to allow
positioning of the cells within the pores.
5. A system as in claim 3, wherein the surface provides controlled
time dependent release of a substance over time.
6. A system as in claim 2, wherein the surface comprises a
nanoporous metallic coating wherein the coating has a morphology
that provides controlled time dependent release of a substance over
time.
7. A system as in claim 6, wherein the substance promotes cell
adherence and/or cell growth.
8. A system as in claim 7, wherein the substance comprises a member
of the TGF.sub..beta. family.
9. A system as in claim 8, wherein the substance comprises
TGF.sub..beta.1.
10. A system as in claim 6, wherein the substance augments growth
of endothelial cells and/or smooth muscle cells.
11. A system as in claim 10, wherein the substance comprises VEGF,
bFGF, PLGF, PDGF, or a combination of these.
12. A system as in claims 5 or 6, wherein at least some of the
plurality of cells contain a therapeutic gene and wherein the
substance comprises an agent that controls the activity of the
therapeutic gene contained with the cells.
13. A system as in claim 1, further comprising a substance on the
surface which improves adhesion of the plurality of cells to the
surface.
14. A system as in claim 13, wherein the substance comprises
polymer substrates, biocompatible proteins, growth factors,
extracellular matrix components or a combination of any of
these.
15. A system as in claim 1, wherein the at least one surface is
located on an internal lumen within the at least one
microstructure.
16. A system as in claim 15, wherein the plurality of cells
comprise cells which are non-autologous to the patient, and wherein
the non-autologous cells are disposed within the at least one
microstructure so that the non-autologous cells are immunologically
isolated from the patient's immune system.
17. A system as in claim 1, wherein expansion of the body creates
forces which deploy the at least one microstructure from an
undeployed position wherein the free end is substantially aligned
with an outer surface of the expandable body to a deployed position
wherein the free end projects radially outwardly from the
expandable body.
18. A system as in claim 1, wherein the plurality of cells comprise
smooth muscle cells, autologous smooth muscle cells, non-autologous
smooth muscle cells, stem cell derived smooth muscle cells, or
smooth muscle progenitor cells.
19. A system as in claim 1, wherein the plurality of cells comprise
endothelial cells.
20. A system as in claim 1, wherein the plurality of cells comprise
epithelial cells.
21. A system as in claim 1, wherein the plurality of cells comprise
stem cell derived cell populations.
22. A system as in claim 1, wherein the plurality of cells comprise
embryonic stem cells and/or derivatives of embryonic stem
cells.
23. A system as in claim 1, wherein the plurality of cells comprise
pancreatic beta cells, myofibroblasts, cardiac myocytes, skeletal
muscle satellite cells, dendritic cells, multi-potential somatic
stem cells, derivatives of multi-potential somatic stem cells,
neuronal cells, glial cells, hepatocytes, or endocrine cells.
24. A system as in claim 1, wherein the plurality of cells are
genetically modified.
25. A system as in claim 24, wherein the plurality of cells are
genetically modified to over-express endothelial nitric oxide
synthase, inducible nitric oxide synthase, TGF.sub..beta.1, IL-4,
IL-10, IL-13, PDGF, PLGF, VEGF, or a combination of these.
26. A system as in claim 1, wherein the expandable body is sized
for positioning within a body lumen having a wall.
27. A system as in claim 26, wherein the free end is projectable
radially outwardly from the expandable body a distance sufficient
to penetrate the wall of the body lumen.
28. A system as in claim 26, wherein the body lumen comprises a
blood vessel.
29. A system as in claim 26, wherein the body lumen is disposed
within the gastro-intestinal tract, the pulmonary system, the
urinary system or the reproductive system.
30. A system for treating a patient comprising: an expandable body
having a proximal end, a distal end, a longitudinal axis
therebetween, and at least one microstructure having an attached
end attached to the body and a free end in an undeployed position
along the expandable body, expansion of the body creating forces
which deploy the at least one microstructure from the undeployed
position to a deployed position wherein the free end projects
radially outwardly from the expandable body; and a plurality of
genetically modified cells disposed on at least one surface of the
expandable body.
31. A system as in claim 30, wherein the plurality of genetically
modified cells are genetically modified to over-express a
therapeutic gene.
32. A system as in claim 31, wherein the therapeutic gene comprises
endothelial nitric oxide synthase, inducible nitric oxide synthase,
TGF.sub..beta.1, IL-4, IL-10, IL-13, PDGF, PLGF, VEGF or a
combination of these.
33. A system as in claim 30, wherein the plurality of genetically
modified cells comprises genetically modified autologous smooth
muscle cells, stem cell derived smooth muscle cells, smooth muscle
progenitor cells or a combination of any of these.
34. A system as in claim 30, wherein the plurality of cells
comprise endothelial cells.
35. A system as in claim 30, wherein the plurality of cells
comprise epithelial cells.
36. A system as in claim 30, wherein the plurality of cells
comprise embryonic stem cells and/or derivatives of embryonic stem
cells.
37. A system as in claim 30, wherein the plurality of cells
comprise pancreatic beta cells, myofibroblasts, cardiac myocytes,
skeletal muscle satellite cells, dendritic cells, multi-potential
somatic stem cells, derivatives of multi-potential somatic stem
cells, neuronal cells, glial cells, hepatocytes, or endocrine
cells.
38. A system as in claim 30, wherein the at least one
microstructure has a directional axis between the free end and the
attached end, and wherein the directional axis extends along the
longitudinal axis while the at least one microstructure is in the
undeployed position.
39. A system as in claim 30, wherein the at least one
microstructure has a directional axis between the free end and the
attached end, and wherein the directional axis extends across the
longitudinal axis while the at least one microstructure is in the
undeployed position.
40. A system as in claim 30, wherein the free end has a pointed
shape.
41. A system as in claim 40, wherein the at least one
microstructure has an internal lumen therein and wherein the at
least one surface is located on the internal lumen.
42. A system as in claim 41, wherein the expandable body comprises
an endoluminal stent sized for positioning within a vascular lumen
having a vascular lumen wall.
43. A system as in claim 42, wherein the vascular lumen wall
includes a medial layer and the at least one microstructure are
sized to dissect the vascular lumen wall during expansion of the
expandable body for delivery of the plurality of genetically
modified cells to at least the medial layer.
44. A system as in claim 41, wherein the expandable body comprises
an endoluminal stent sized for positioning within a body lumen
disposed within the gastro-intestinal tract, the pulmonary system,
the urinary system or the reproductive system.
45. A system for treating a patient comprising: a stent having a
proximal end, a distal end, a longitudinal axis therebetween, the
stent sized for positioning within a body lumen; and a plurality of
progenitor cells of a desired cell type disposed on at least one
surface of the stent for delivery to the body lumen, the progenitor
cells derived by a method comprising the steps of providing a
population of cells comprising totipotent or pluripotent cells,
transfecting the population of cells with a nucleic acid sequence
comprising a desired cell type specific promoter/enhancer operably
linked to a marker, inducing the population of cells to become
cells of the desired cell type, and identifying the progenitor
cells based on the expression of the marker.
46. A system as in claim 45, wherein the desired cell type
comprises epithelial cells.
47. A system as in claim 45, wherein the desired cell type
comprises endothelial cells.
48. A system as in claim 45, wherein the desired cell type
comprises smooth muscle cells.
49. A system as in claim 45, wherein the surface comprises a
nanoporous metallic coating.
50. A system as in claim 49, wherein the coating has a morphology
that provides controlled time dependent release of a substance.
51. A system as in claim 50, wherein the substance promotes cell
adherence and/or cell growth.
52. A system as in claim 51, wherein the substance comprises a
substrate in the TGF.sub..beta. family.
53. A system as in claim 50, wherein the substance augments growth
of endothelial cells and/or smooth muscle cells.
54. A system as in claim 53, wherein the substance comprises VEGF,
bFGF, PLGF, PDGF, or a combination of these.
55. A system for treating a patient comprising: a stent having a
proximal end, a distal end, a longitudinal axis therebetween, the
stent sized for positioning within a body lumen; and a plurality of
smooth muscle progenitor cells disposed on at least one surface of
the stent for delivery to the body lumen, the progenitor cells
derived by a method comprising the steps of providing a population
of cells comprising totipotent or pluripotent cells, transfecting
the population of cells with a nucleic acid sequence comprising a
smooth muscle cell specific promoter/enhancer operably linked to a
marker, inducing the population of cells to become smooth muscle
cells and identifying the smooth muscle progenitor cells based on
the expression of the marker.
56. A system as in claim 55, wherein the at least one surface is
located on an outer surface of the stent.
57. A system as in claim 55, wherein the at least one surface
includes pores.
58. A system as in claim 55, further comprising a substance on the
surface to improve adhesion of the plurality of cells to the
surface.
59. A system as in claim 58, wherein the substance comprises
polymer substrates, biocompatible proteins, growth factors,
extracellular matrix components or a combination of any of
these.
60. A system as in claim 58, wherein the at least one surface
comprises a nanoporous metallic coating.
61. A system as in claim 60, wherein the coating has a morphology
that provides controlled time dependent release of the
substance.
62. A system as in claim 61, wherein the substance promotes cell
adherence and/or cell growth.
63. A system as in claim 62, wherein the substance comprises a
substrate in the TGF.sub..beta. family.
64. A system as in claim 61, wherein the substance augments growth
of endothelial cells and/or smooth muscle cells.
65. A system as in claim 64, wherein the substance comprises VEGF,
bFGF, PLGF, PDGF, or a combination of these.
66. A system for repair of an aneurysm in a blood vessel of a
patient comprising: a tube having a first end, a second end and a
wall extending between the first and second ends, the tube shaped
to be disposed at least partially within the aneurysm; at least one
expandable body attached to the tube wall including at least one
microstructure having an attached end attached to the body and a
free end in an undeployed position, wherein expansion of the at
least one expandable body creates forces which deploy the at least
one microstructure from the undeployed position to a deployed
position wherein the free end of the at least one microstructure
projects radially outwardly from the tube; and a plurality of cells
disposed on at least one surface of the at least one expandable
body.
67. A system as in claim 66, wherein the at least one surface is
located on an internal lumen within the at least one
microstructure.
68. A system as in claim 66, wherein the at least one surface is
located on an outer surface of the expandable body.
69. A system as in claim 66, wherein the surface includes
pores.
70. A system as in claim 66, wherein the plurality of cells are
selected from the group consisting of smooth muscle cells,
autologous smooth muscle cells, stem cell derived smooth muscle
cells, and smooth muscle progenitor cells.
71. A system as in claim 66, further comprising a coating on the
surface to improve adhesion of the plurality of cells to the
surface.
72. A system as in claim 71, wherein the coating includes a
nanoporous metallic coating.
73. A system as in claim 74, wherein the substance comprises
polymer substrates, biocompatible proteins, growth factors or a
combination of any of these.
74. An apparatus as in claim 66, wherein the at least one
expandable body is attached to an exterior surface of the tube
wall.
75. An apparatus as in claim 66, wherein the at least one
expandable body is embedded within the tube wall.
76. An apparatus as in claim 66, wherein the at least one
expandable body is attached to an interior surface of the tube
wall.
77. An apparatus as in claim 66, wherein the at least one
microstructure projects radially outwardly from the tube a distance
sufficient to penetrate the blood vessel to deliver the plurality
of cells to the blood vessel.
78. An apparatus as in claim 66, wherein the blood vessel comprises
a segment of an aorta having two iliac arteries therewith at an
aortic bifurcation, and wherein the tube further comprises an
opening between the first end and the second end to align with one
of the iliac arteries.
79. A system for treating a patient comprising: an expandable body
having a proximal end, a distal end, a longitudinal axis
therebetween; and a plurality of cells disposed on at least one
surface of the expandable body.
80. A system as in claim 79, wherein the expandable body includes
at least one surface having a coating which augments cell
attachment, augments cell growth and/or releases a therapeutic
substance.
81. A system as in claim 80, wherein the coating comprises a
nanoporous metallic coating.
82. A system as in claim 81, wherein the nanoporous metalling
coating has a morphology that provides controlled time dependent
release of the therapeutic substance.
83. A system as in claim 82, wherein the substance comprises a
member of the TGF.sub..beta. family.
84. A system as in claim 82, wherein the substance comprises VEGF,
bFGF, PLGF, or a combination of these.
85. A system as in claim 79, wherein the plurality of cells
comprise smooth muscle cells, autologous muscle cells, stem cell
derived smooth muscle cells, or smooth muscle progenitor cells.
86. A system as in claim 85, wherein the plurality of cells are
genetically modified.
87. A system for treating a patient comprising: an expandable body
having a proximal end, a distal end, a longitudinal axis
therebetween, and at least one microstructure having an attached
end attached to the body and a free end which is projectable
radially outwardly from the expandable body to penetrate a body
lumen of the patient; and a plurality of cells disposed on at least
one surface of the expandable body so that the cells are
immunoisolated from the body lumen of the patient.
88. A system as in claim 87, wherein the at least one surface is
located on an internal lumen within the at least one
microstructure.
89. A system as in claim 88, wherein the cells produce a
therapeutic agent, and wherein the microstructures are configured
to deliver the therapeutic agent to the body lumen without the
cells contacting the body lumen.
90. A system as in claim 87, further comprising a nanoporous
membrane incorporated into the microstructures.
91. A system as in claim 90, wherein the cells produce a cellular
products, and wherein the membrane permits transport of the
cellular products out of the microstructures and into the body
lumen.
92. A system as in claim 90, wherein the membrane permits in-flow
of nutrients to the cells.
93. A system as in claim 87, wherein the cells comprise embryonic
stem cells.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit and priority of U.S.
Provisional Patent Application No. 60/494,045 (Attorney Docket
021258-001700US), filed Aug. 7, 2003, the full disclosure of which
is hereby incorporated by reference for all purposes.
[0002] This application is also a continuation in part of PCT
Patent Application No. PCT/US03/21754 (Attorney Docket
021764-000920PC) filed on Jul. 11, 2003 which claims the benefit
and priority of U.S. Provisional Patent Application No. 60/395,180
(Attorney Docket 021258-000900US) filed Jul. 11, 2002, and U.S.
Provisional Patent Application No. 60/421,404 (Attorney Docket
021258-000910US) filed Oct. 24, 2002, the full disclosures of which
are hereby incorporated by reference for all purposes.
[0003] This application is also a continuation in part of PCT
Patent Application No. PCT/US03/21611 (Attorney Docket
021764-000720PC) filed on Jul. 11, 2003 which claims the benefit
and priority of U.S. Provisional Patent Application No. 60/395,180
(Attorney Docket 021258-000900US) filed Jul. 11, 2002, U.S.
Provisional Patent Application No. 60/421,404 (Attorney Docket
021258-000910US) filed Oct. 24, 2002, U.S. Provisional Patent
Application No. 60/421,350 (Attorney Docket 021258-000700US) filed
Oct. 24, 2002, and U.S. Provisional Patent Application No.
60/428,803 filed Nov. 25, 2002, the full disclosures of which are
hereby incorporated by reference for all purposes.
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISK.
[0005] NOT APPLICABLE
BACKGROUND OF THE INVENTION
[0006] The present invention relates to apparatuses, systems and
methods of treating a patient. Particularly, the present invention
relates to treating medical conditions using cell therapy via body
lumens. In some instances, the present invention relates to
treating a blood vessel, such as in the treatment of heart disease
and aneurysms.
[0007] 1. Heart Disease
[0008] Heart disease continues to be a leading cause of death in
the United States. The mechanism of this disease is often
progressive narrowing of coronary arteries by atherosclerotic
plaque which can lead to acute myocardial infarction and disabling
angina. Techniques to treat coronary atherosclerosis include
percutaneous transluminal coronary angioplasty, (or PTCA, commonly
referred to as balloon angioplasty), atherectomy, and coronary
stenting. In each of these treatments, compression of the plaque
and expansion of the coronary artery, or removal of the
atherosclerotic plaque, often restores lumen patency. In stenting,
a stent, such as a metal or wire cage-like structure, is expanded
and deployed against the plaque.
[0009] Despite the overall initial success of these procedures,
many patients undergoing these therapeutic procedures to clear
blocked coronary arteries will suffer restenosis (re-blockage) at
some point after the initial procedure. Such restenosis may be a
manifestation of the general wound healing response or may be due
to a variety of other factors.
[0010] Thus, it would be desired to provide devices, systems and
methods which would provide therapeutic benefits to injured or
diseased tissue. Such benefits may include reduction of the
incidence of restenosis, particularly in blood vessels treated for
atherosclerosis. However such benefits may be applicable to any
body lumen which suffers from occlusion and possible restenosis. In
addition, such benefits may include a reduction in any initial
injury induced by intervention, such as by stenting. At least some
of these objectives will be met by the embodiments of the present
invention.
[0011] 2. Aneurysms
[0012] An aneurysm is the focal abnormal dilation of a blood
vessel. The complications which arise from aneurysms can include
rupture, embolization, fistularisation and symptoms related to
pressure on surrounding structures. Aneurysms are commonly found in
the abdominal aorta, being that part of the aorta which extends
from the diaphragm to the point at which the aorta bifurcates into
the common iliac arteries. These abdominal aortic aneurysms
typically occur between the point at which the renal arteries
branch from the aorta and the bifurcation of the aorta. When left
untreated, an abdominal aortic aneurysm may eventually cause
rupture of the aorta with ensuing fatal hemorrhaging in a very
short time. High mortality associated with the rupture has led to
the development of transabdominal surgical repair of abdominal
aortic aneurysms.
[0013] A clinical approach to aneurysm repair which is less
invasive than conventional transabdominal surgery is known as
endovascular grafting. Endovascular grafting typically involves the
transluminal placement of a prosthetic arterial graft within the
lumen of the artery. The graft may be attached to the internal
surface of an arterial wall by means of attachment devices (often
similar to expandable stents), one above the aneurysm and a second
below the aneurysm. Such attachment devices permit fixation of a
graft to the internal surface of an arterial wall without
sewing.
[0014] It would be desirable, to provide devices, systems and
methods that improve the treatment of aneurysms, such as improving
fixation of the graft, increased resistance to graft migration and
leakage and/or improvements in the characteristics of the
surrounding tissue once in place. At least some of these objectives
will be met by the embodiments of the present invention.
[0015] 3. Use of Cell-Based Therapies
[0016] Methods have been developed for using pluripotent stem cells
for therapeutic applications, including the delivery of therapeutic
genes. Pluripotent stem cells appear to have the ability to
differentiate into a number of different cell types, including
neurons, cardiomyocytes, skeletal muscle, smooth muscle and
pancreatic beta cells, to name a few, that are involved in the
pathogenesis of many human diseases, such as atherosclerosis,
diabetes, hypertension and various others. However, current methods
have limitations which preclude the successful use of such
pluripotent stem cells in treating various medical conditions.
[0017] To begin, a stem cell per se exhibits almost no target
tissue selectivity. As such, if stem cells are simply introduced to
target tissues by current methods, such as intravenously or by
direct injection, a safety concern is the risk that the cells will
differentiate into a non-target cell type and disrupt the normal
functions in the target tissues. At worst, this may result in
tumorigenesis and/or patient mortality. A possible solution is to
use stem cells which have been triggered to becoming the target
cell type, i.e. progenitor cell types such as smooth muscle
progenitor cells. Since these stem-cell derived progenitor cells
have started onto the differentiation pathway sufficiently to be
"committed" to becoming the desired cell type, there is reduced
risk of tumorigenesis or differentiation into an undesired cell
type. The drawback to this approach (i.e. the use of progenitor
cells) is that the engraftment efficiency is usually inversely
related to the extent of cell differentiation. Thus, while the use
of stem-cell-derived progenitor cells may reduce or eliminate
safety concerns, the fact that the progenitor cells are further
down the differentiation pathway as compared to pluripotent stem
cells means that their engraftment efficiency is reduced, and this
will in turn reduce the likelihood of a clinical benefit.
[0018] Alternatively, differentiated somatic cells have been used
for cell-based therapies. However, these applications have also
been limited by the lack of methods to provide efficient
engraftment as described above.
[0019] Thus, it would be desirable to provide devices, systems and
methods that will deliver therapeutic cells directly to the target
site, such that regardless of the extent to which these cells have
differentiated, their engraftment into the target site will be
significantly improved. At least some of these objectives will be
met by the embodiments of the present invention.
[0020] 4. Immune Issues Related to Use of Non-Autologous Cells
[0021] Interest has developed in using non-autologous cells for
cell-based therapies, particularly non-autologous embryonic stem
cells. Embryonic stem cells may have properties, such as
pluripotentiality and infinite replicative life span, that are not
obtainable with autologous somatic stem cells. In addition, various
non-human cells may be used in the treatment of human diseases, for
example, porcine pancreatic beta cells for treatment of diabetes.
However, non-autologous and non-human cells are attacked by the
patient's immune system, thus limiting their long term efficacy and
viability.
[0022] Thus, it would be desirable to provide devices, systems and
methods that allow the delivery of non-autologous cells to a
desired tissue site while simultaneously isolating them from the
patient's immune system. This would reduce or prevent any
immunologic rejection of the cells. At least some of these
objectives will be met by the embodiments of the present
invention.
BRIEF SUMMARY OF THE INVENTION
[0023] The present invention provides devices, systems and methods
for the localized delivery of cells which provide a therapeutic
benefit. The cells may include but are not limited to autologous
stem cells. Localized delivery is achieved with the use of a
stent-like expandable body seeded with cells which is positioned
within a body lumen. The expandable body is expanded to contact at
least a portion of the inner walls of the body lumen and the cells
and/or cellular products are delivered to the surrounding tissue.
The therapeutic benefit provided is dependent on the type of cells
used and the features of the expandable body, to name a few.
[0024] In a first aspect of the present invention, the expandable
body may take the form of any of a variety of stents used for
placement within body lumens, such as blood vessels. For example,
the expandable body may comprise a conventional stent used to treat
coronary occlusions, such as described by U.S. Pat. Nos. 6,540,775,
6,113,621, and 4,776,337, each of which is incorporated by
reference herein for all purposes. Or, the expandable body may
comprise a conventional stent graft used to treat aneurysms,
particularly abdominal aortic aneurysms, such as described by U.S.
Pat. Nos. 5,824,039 and 5,693,084, each of which is incorporated by
reference herein for all purposes.
[0025] In other embodiments, the expandable body comprises a device
such as provided by Reed et al. (U.S. Pat. No. 6,197,013),
incorporated by reference herein for all purposes. The Reed et al.
devices include arrays of micromechanical probes present on the
surface of the devices which penetrate the body lumen wall and
allow for efficient transport of therapeutic agents, such as cells,
into the wall. In the specific example of blood vessels, delivery
can be effected directly to at least the medial layer of the vessel
wall.
[0026] In still other embodiments, the expandable body comprises a
device having deployable microstructures, such as provided by U.S.
Provisional Patent Application No. 60/395,180 (Attorney Docket
021258-000900US), U.S. Provisional Patent Application No.
60/421,404 (Attorney Docket 021258-000910US), and PCT Application
No. PCT/US03/21754 (Attorney Docket 021764-000920PC), the full
disclosures of which are hereby incorporated by reference for all
purposes. The microstructures are formed in or attached to the
expandable body in a low profile fashion suitable for atraumatic
introduction to the body lumen with the use of a catheter or other
suitable device. Each microstructure has an end which is attached
to the expandable body and a free end. Once the apparatus is
positioned within the body lumen in a desired location, the body is
expanded and the microstructures deployed to a position wherein the
free ends project radially outwardly. The free ends of the deployed
microstructures then penetrate the lumen wall by continued
expansion of the body. Additionally, a therapeutic agent, such as
cells, may be delivered to the lumen wall by the microstructures.
When the expandable body comprises a stent, the mechanism may be
left in place, the microstructures providing anchoring and sealing
against the lumen wall.
[0027] In yet other embodiments, the expandable body comprises any
of the devices for treating aneurysms described in U.S. Provisional
Patent Application No. 60/421,350 (Attorney Docket
021258-000700US), U.S. Provisional Patent Application No.
60/428,803 and PCT Application No. PCT/US03/21611 (Attorney Docket
021764-000720PC), the full disclosures of which are hereby
incorporated by reference for all purposes. These devices include a
tube which is held in place within the vasculature by at least one
expandable body having at least one microstructure. The
microstructures are attached to the expandable body in a low
profile fashion suitable for atraumatic introduction to the
vasculature with the use of a catheter or other suitable device.
Each microstructure has an end which is attached to the expandable
body and a free end. Once the apparatus is positioned within the
vasculature in the desired location, the microstructures are
deployed so that the free ends project radially outwardly. The free
ends of the deployed microstructures then penetrate the blood
vessel wall by continued expansion of the body, holding the tube in
place.
[0028] It may be appreciated that the expandable body may take the
form of any device which is expandable within a body lumen to
provide localized delivery of cells and/or cellular products to the
body lumen. Various body lumens are found in but are not limited to
the vascular system, the pulmonary system, the gastro-intestinal
tract, the urinary tract and the reproductive system.
[0029] It may be further appreciated that the surface of the
expandable body may be porous to allow for a greater retention of
therapeutic agents, cells or other substances that may have direct
or indirect therapeutic benefits, such as matrix components, growth
factors and/or combinations thereof. These substances may promote
wound healing or tissue/organ regeneration or repair by augmenting
the function of the patient's existing cells or tissues. Some
embodiments of such a porous surface are obtained by means of a
de-alloying method, preferred embodiments of which have been
described in U.S. Provisional Patent Application No. 60/426,106
filed on Nov. 30, 2002, incorporated herein by reference for all
purposes. In other embodiments, the porous surface provides
controlled release over time of substances that regulate the
activity or properties of the cells contained on the device or in
proximity to the device. For example, the porous surface may
provide controlled release of TGF.sub..beta.1, a substance known to
increase matrix production by smooth muscle cells as well as many
other cell types. Such controlled release may be useful in the
repair of aneurysms where it is desirable to have cells produce
large quantities of extracellular matrix components. In still other
embodiments, the porous surface is used to deliver agents that
control the activity of a therapeutic gene contained with cells
seeded thereon. Such control is achieved by influencing the
activity of the therapeutic gene (e.g. through an activation
mechanism) or the activity of a promoter-enhancer used to drive
expression of the therapeutic gene (e.g. by inclusion of
tetracycline or similar responsive elements within the promoter
driving the therapeutic gene and inclusion of the inducing agent
for that response element in the porous surface).
[0030] In a second aspect of the present invention, the cells
seeded on the expandable body may be comprised of any cells which
provide a therapeutic benefit to the body lumen. Examples of such
cells include endothelial cells, pancreatic beta cells,
myofibroblasts, cardiac myocytes, skeletal muscle satellite cells,
smooth muscle cells, dendritic cells, epithelial cells,
multi-potential somatic stem cells and derivatives thereof,
embryonic stem cells and derivatives thereof, neuronal cells, glial
cells, hepatocytes, and various endocrine cells (e.g. thyroid,
parathyroid, adrenal cortex), to name a few.
[0031] In some embodiments, genetically modified cells are used to
over-express a therapeutic gene. In preferred embodiments,
genetically modified smooth muscle cells (SMC) are used. This is
because a large number of major human diseases, including coronary
artery disease, hypertension, and asthma are associated with
abnormal function of SMCs. In addition, SMC dysfunction also
contributes to numerous other human health problems including
vascular aneurysms, and reproductive, bladder and gastrointestinal
disorders. Therefore, a therapeutic effect can be achieved by
delivering SMCs which have been genetically modified to over
express a therapeutic agent, thereby reducing or eliminating the
physiological consequences caused by SMC dysfunction.
[0032] Although the present invention relates to the use of a
plurality of cell types and sources, one preferred embodiment uses
genetically modified stem cells or cells derived therefrom. Stem
cells exhibit a virtually infinite replicative lifespan which is
beneficial for carrying out genetic engineering methods. Such a
lifespan is also beneficial for being able to generate sufficient
numbers of cells for clinical applications. This is particularly
useful since a patient's own stem cells may often be available in
very limited supply, at least without major surgery or patient
risk. In contrast, use of somatic differentiated cell populations
are limited in that these cells can only undergo a relatively small
number of population doublings before senescing.
[0033] One preferred embodiment of the present invention is to
employ stem cell derived smooth muscle progenitor cells produced
using methods described in WO 02/074925, incorporated herein by
reference for all purposes. These smooth muscle progenitor cells
have been isolated and purified by transforming a population of
pluripotent somatic or embryonic stem cells with a DNA construct
comprising a smooth muscle specific promoter operably linked to a
selectable marker gene.
[0034] A major limitation in using these stem cell derived smooth
muscle progenitor cells with conventional delivery methods is that
the conventional delivery methods do not provide effective
engraftment of the cells into the desired tissue site while at the
same time reducing or eliminating the risks of delivery to
non-target sites. As mentioned, the engraftment potential is
highest for undifferentiated cells, however undifferentiated cells
pose the greatest risk for tumorigenesis or other undesired side
effects. Therefore, a balance between these risks and benefits is
desired. Such a balance may be achieved by the use of expandable
bodies having micromechanical probes, such as provided by Reed et
al. (U.S. Pat. No. 6,197,013), or expandable bodies having
deployable microstructures as described above. In this preferred
embodiment, the cells are seeded onto the expandable body and
delivered directly to specific locations, particularly within the
wall of a body lumen. The cells are mechanically embedded into
and/or held against the wall of the body lumen which improves
engraftment of the cells into the target tissue. This process may
be further aided by use of the porous coating to deliver agents
that promote engraftment as well as other desired properties of the
cells.
[0035] In preferred embodiments, genetically modified autologous
SMC, adult or embryonic stem cell derived SMC or SMC progenitor
cells isolated from the patient's own somatic stem cells are used.
In some embodiments, SMC progenitor cells as described in
PCT/US02/08402, incorporated herein for all purposes, may be used.
Any of these cells may be modified to over-express a possible
therapeutic gene, such as endothelial nitric oxide synthase (eNOS)
or inducible nitric oxide synthase (iNOS). Nitric oxide (NO) has
many actions that could be beneficial to the vascular system,
particularly following vascular injury. These include inhibition of
platelet deposition and leukocyte adherence, inhibition of vascular
smooth muscle cell proliferation and migration, inhibition of
endothelial cell apoptosis, stimulation of endothelial cell growth,
and vasodilation. Furthermore, inadequate NO production at sites of
injury has been shown to contribute to vascular occlusive diseases
including atherosclerosis and restenosis following angioplasty,
endarterectomy, cardiac bypass surgery, or peripheral vascular
bypass surgery. Local delivery of NO to a particular site may be
achieved through transfer of an NOS gene, such as eNOS, iNOS, or
NNOS, to the site by incorporation into the cells of the
cell-seeded expandable body of the present invention. By delivering
NOS gene expressing cells to a specific site, NO will be produced
at that site without systemic effects. In addition, a porous
surface on the expandable body, as described previously, may be
used to release co-factors that are known to enhance the biological
activity of NOS/NO.
[0036] Alternative genes that might be expressed to confer a
therapeutic benefit include TGF.sub..beta.1, which has
anti-inflammatory properties and which also has been shown to
inhibit SMC growth, promote differentiation, and enhance production
of extracellular matrix components. Other possibilities include
cytokines IL-4, IL-10 or IL-13 whose anti-inflammatory properties
may promote wound repair or regeneration and/or reduced
restenosis.
[0037] It may be appreciated that genetic modification such as
described above may be applied to cells other than SMCs, and these
cells may also be used with the cell-seeded expandable body of the
present invention. In addition, the methods provided in WO
02/074925, exemplified for the isolation of SMC and smooth muscle
progenitor cells, are readily adaptable to the production of any
desired cell type by replacing the SMC specific/selective
promoter/enhancer of the reporter gene construct with an
appropriate promoter regulatory element that is selective/specific
for the cell type of interest. Examples include the use of
promoter/enhancers specific for cardiac myocytes, endothelial cells
and neurons. As an example, cells used in the present invention may
be comprised of progenitor cells derived by a method comprising the
steps of providing a population of cells comprising totipotent or
pluripotent cells, transfecting the population of cells with a
nucleic acid sequence comprising a smooth muscle cell specific
promoter/enhancer operably linked to a marker, inducing the
population of cells to become smooth muscle cells and identifying
the smooth muscle progenitor cells based on the expression of the
marker.
[0038] In other embodiments, cells which have not been genetically
modified to over-express a possible therapeutic gene, referred to
herein as "unmodified cells", are used. Such cells may be used to
augment tissue repair and regeneration. For example, when
unmodified autologous SMC, stem cell derived SMC or SMC progenitor
cells are used, proliferation of the SMCs and/or associated
production of extracellular matrix components including collagen
and elastin can rebuild blood vessels. The blood vessels may have
been damaged due to traumatic injury, such as by an accident, major
reconstructive surgery, or repair of a congenital vascular defect.
The SMCs can also be used to rebuild blood vessels which suffer
from aneurysms, a progressive vascular abnormality associated with
degeneration and dissection of the blood vessel wall and SMC
hypocellularity. They may be caused by many factors including
extensive atherosclerotic disease, a congenital vascular defect, or
mutations in genes important for determining the tensile strength
of blood vessels, such as in the case of Marfan's Syndrome which is
the result of mutations in the fibrillin gene. In addition, a
porous surface on the expandable body may be employed to deliver
agents that enhance the desired properties of the unmodified cells.
For example, TGF.sub..beta.1 may be used since it is known to
dramatically enhance matrix production, and/or PDGF BB may be used
to promote proliferation of progenitor cells provided on the device
as well as recruitment of resident cells that could aid in the
repair process.
[0039] When the cell-seeded expandable bodies of the present
invention are used to treat an aneurysm, the expandable bodies
anchor a tube or graft to the vessel walls surrounding an aneurysm.
SMCs may be delivered to the vessel walls to increase anchorage of
the tube and reduce migration of the tube along the blood vessel.
Such migration could lead to leakage, exposure of the aneurysm and
damage to the blood vessel, to name a few. In addition, the
improved anchorage may also prevent apparent migration of the
apparatus which occurs when the aneurysmal sac grows in size and as
such encroaches upon the ends of the apparatus. This results in a
reduction of the distance between the terminus of the apparatus and
the aneurysm which is the same effect as migration. Thus, the SMCs
help maintain intimate contact between the apparatus and the vessel
wall and prevent aneurysmal sac growth. The SMCs can also be
delivered to the blood vessel lumen, the blood vessel walls and/or
the outer surface of the blood vessel to encourage tissue regrowth
or extra-cellular matrix formation. The SMCs may also be delivered
to the aneurysmal sac. This may allow for tissue regrowth within
the sac, strengthening the tissue within the aneurysmal walls. In
addition, as noted above, a porous surface on the device may be
employed to deliver agents to enhance the repair or regenerative
process.
[0040] SMCs may also be employed in reconstructive surgery of the
gastrointestinal tract, urinary tract, or other tissues in which
SMC are a predominant cell type. Other cell types may also be used
to rebuild other types of tissues. For example, autologous stem
cell derived cell types may be used to enhance wound healing, bone
repair, musculo-skeletal repair following traumatic injury or
disease, tissue engineering, and replacement of degenerative or
senescent cells, to name a few.
BRIEF DESCRIPTION OF THE DRAWINGS
[0041] FIG. 1 is a perspective view of an embodiment of an
apparatus of the present invention comprising an expandable body
and at least one microstructure.
[0042] FIGS. 2A-2B provide cross-sectional views of the apparatus
of FIG. 1 in the unexpanded and expanded states, respectively.
[0043] FIGS. 3A-3B provide a schematic illustration of the
embodiments of FIGS. 2A-2B with cells seeded thereon.
[0044] FIG. 4 illustrates a microstructure having cells seeded
within an internal lumen of a microstructure.
[0045] FIGS. 5A-5B, 6A-6B illustrate possible relationships of the
directional axis of the microstructure to the longitudinal axis of
the body.
[0046] FIG. 7 illustrates an embodiment of the apparatus wherein
the microstructures are aligned as in FIGS. 5A-5B, and FIG. 7A
provides an exploded view of a microstructure of FIG. 7.
[0047] FIGS. 8A-8B shows the microstructure of FIG. 7A in an
undeployed and deployed position, respectively.
[0048] FIGS. 9A-9C illustrate embodiments of the free ends of the
microstructures of FIG. 7A.
[0049] FIGS. 10A-10C illustrate an additional embodiment of the
microstructures.
[0050] FIG. 11 illustrates an embodiment of the apparatus wherein
the microstructures are aligned as in FIGS. 6A-6B, and FIG. 11A
provides an exploded view of a microstructure of FIG. 11.
[0051] FIG. 12A illustrates a representative portion of the
radially expandable body having a cylindrical shape and FIGS.
12B-12C illustrate the movement of the expandable body,
particularly the movement of the free ends of the microstructures
as the expandable member radially expands the body.
[0052] FIGS. 13A-13C illustrate embodiments of the free ends of the
microstructures of FIG. 11A.
[0053] FIGS. 13D-13G illustrate embodiments of the apparatus having
various designs.
[0054] FIG. 13H illustrates the embodiment depicted in FIG. 13G
having the microstructures in a deployed position.
[0055] FIGS. 14A-14B illustrate an embodiment of the expandable
body 12 shown in FIGS. 13G and 13H having cells 5 seeded
thereon.
[0056] FIG. 15A illustrates an embodiment of an apparatus of the
present invention in a low profile, unexpanded state wherein the
microstructures are in an undeployed position, and FIG. 15B
illustrates the apparatus of FIG. 15A in the expanded state wherein
the microstructures are in a deployed position, extending radially
outwardly from the tube.
[0057] FIG. 16 depicts an embodiment including a tube and two
removable expandable bodies which are sized for positioning within
the tube.
[0058] FIG. 17 is a cross-sectional view of the embodiment of FIG.
16 illustrating the penetration of the microstructures through the
tube and into the surrounding vessel wall.
[0059] FIG. 18 illustrates an aneurysm within a blood vessel and an
apparatus of the present invention positioned across the aneurysmal
sac.
[0060] FIG. 19 illustrates an apparatus of the present invention
positioned across the aneurysmal sac and the delivery of cells to
this sac through microstructures.
[0061] FIG. 20 illustrates the embodiment of a bifurcated apparatus
of the present invention positioned within an abdominal aortic
aneurysm.
[0062] FIG. 21 illustrates a cross-sectional view of the expandable
body expanded inside a blood vessel lumen, and FIG. 21A provides an
exploded view of a microstructure penetrating the wall of the
vessel lumen.
DETAILED DESCRIPTION OF THE INVENTION
[0063] It may be appreciated that any combination of the above
described cell types and expandable body types may be used.
However, for clarity of description, cells will mainly be described
and illustrated as generic "cells" representing any of the
described cell types. In addition, the expandable bodies will
mainly be described and illustrated as comprising a device having
deployable microstructures. However, this is not intended to limit
the scope of the invention as the features provided may apply to
any of the expandable body types.
[0064] Overview
[0065] Referring to FIG. 1, an embodiment of an apparatus 10 of the
present invention is illustrated, the apparatus 10 comprises an
expandable body 12 and at least one microstructure 14. The
expandable body 12 has a proximal end 16, a distal end 18, a
longitudinal axis 20 therebetween. A cross-sectional diameter 24 is
also shown. In this embodiment, the expandable body 12 comprises a
cylindrical structure surrounding the longitudinal axis 20.
However, it may be appreciated that the expandable body 12 can
comprise any shaped structure, including oval, hemispherical,
ellipsoidal, spherical, square, rectangular, or polygonal, to name
a few, and may be symmetrical or non-symmetrical. Further, the
expandable body 12 may be sized and shaped for delivery from a
catheter or other suitable device for positioning within a body
lumen. The embodiment of FIG. 1 is suitable for permanent placement
within the body lumen, such as to resemble a conventional vascular
stent.
[0066] Together, the microstructures 14 and the expandable body 12
form the cylindrical structure surrounding the longitudinal axis
20. FIG. 1 illustrates the apparatus 10 in an unexpanded state
wherein the microstructures 14 are in an undeployed position. Here,
the microstructures 14 are preferably aligned or flush with an
outer surface 22 of body 12 so that the surface 22 does not include
substantial protrusions. Alternatively, the microstructures 14 may
be positioned below the surface 22.
[0067] FIGS. 2A-2B provide cross-sectional views of the apparatus
10 of FIG. 1 in the unexpanded and expanded states, respectively.
FIG. 2A shows the wall of the body 12 within which lie
microstructures 14, highlighted by shading. Thus, when the
expandable body 12 is in the unexpanded state, the microstructures
14 are in an undeployed position which is aligned with the surface
22. FIG. 2B illustrates the expandable body 12 in an expanded state
wherein the cross-sectional diameter 24 is increased. Here, the
microstructures 14 are in a deployed position wherein a free end 32
of each microstructure 14 projects radially outward from the
longitudinal axis 20 while an attached end 30 remains attached to
the body 12. In some embodiments the mechanical act of expansion of
the body 12 creates forces which deploy the microstructures 14. It
may be appreciated that the deployed microstructures 14 may form
any angle with the surface 22, including a substantially 90 degree
angle as shown. Further, different microstructures 14 may form
different angles, angles may vary randomly or in a pattern, angles
may be selectable particularly based on amount of expansion, and
some microstructures may not deploy while others deploy. Any
spacing between the microstructures 14 may also be used, preferably
between 5 microns and 10,000 microns. Deployed microstructures have
heights which may vary but are typically sufficient to penetrate
the lumen wall to a desired depth. In a blood vessel, this may
include traversal of the thickness of any atherosclerotic plaque
lining the vessel wall. Thus, the deployed microstructures may have
heights which vary from less than 25 .mu.m to over 5000 .mu.m.
[0068] As illustrated in FIG. 1, the expandable body 12 may
comprise a series of interconnected solid sections 36 having spaces
35 therebetween. In preferred embodiments, the expandable body 12
comprises an endoluminal stent. Although such stents may be
introduced into various body lumens, such as within the pulmonary
system, the gastrointestinal tract, the urinary tract and the
reproductive system, to name a few, conventional stents are
commonly used in the vascular system, particularly the coronary
arteries. Conventional vascular stents are typically formed from
wires bent or woven to define a series of relatively tightly spaced
convolutions or bends or from a solid metal structure from which
portions are removed in a selected pattern. The expandable body 12
of the present invention may resemble conventional stents and may
be similarly manufactured. For example, the expandable body 12 can
be laser machined from annealed 316 L tubing; electric discharge
machining (EDM) or electrochemical etching can also be used to
fabricate the devices, to name a few. The particular design of the
structure is dependent upon the microstructures and the way that
they deploy upon expansion of the body 12. Examples of such designs
will be provided in later sections.
[0069] Cell Seeding of Expandable Body
[0070] The expandable body 12 is seeded with the desired cells by
any suitable method. Typically the cells are mixed with whole blood
or tissue culture media and incubated with the expandable body 12.
The incubation time will be sufficient to provide desired cell
retention upon the body 12. In some embodiments, the incubation
time will be sufficient to generate a confluent monolayer of cells
on the surfaces of the expandable body 12. Various methods of
cellular application may be used, including rotating the expandable
body 12 about cell-rich seeding suspensions, application of an
external vacuum or use of surface electrocharging to improve
seeding efficiency, adhesion strength and uniformity. In addition,
the expandable body 12 may be coated with a substance or substrate
prior to seeding to improve ultimate seeding efficiency. The
substances may comprise polymer substrates, biocompatible proteins,
growth factors, extracellular matrix components, or a combination
of these.
[0071] To increase the ability of the cells 5 to be seeded on the
microstructures 14, the structural material of the expandable body
12 may have a porous surface. This may allow any substances which
are used to more highly bond with the expandable body 12. This may
in turn increase the retention of the cells 5. In one embodiment
pores are created by anodizing the metal forming the apparatus or
coating the metal with a material which is then anodized.
Anodization produces a high density of small, vertically oriented
pores, of which the size and configuration can be controlled by
varying the anodization current, temperature and solution
concentration. If the pores are of sufficient size in relation to
the cells 5, the cells 5 may seed within the pores themselves
allowing even greater retention. In other embodiments, a porous
coating is created by depositing a precursor alloy onto the
expandable body followed by a de-alloying procedure. The
de-alloying procedure chemically or electrochemically removes one
or more components of the precursor alloy leaving behind a
nanoporous matrix. Embodiments of such a method have been described
in U.S. Provisional Patent Application No. 60/426,106 filed on Nov.
30, 2002, incorporated herein by reference for all purposes.
[0072] In these and other embodiments, the porous surface may
comprise a controlled release porous coating which provides time
dependent release of various substances. When the coating comprises
a nanoporous metallic coating, the coating may have a morphology
that provides the controlled time dependent release of various
substances. One or more substances may be used to regulate the
activity or properties of the cells on the expandable body or in
proximity to the expandable body. For example, the substances may
promote cell adherence and/or cell growth. An example of such a
substance is a member of the TGF.sub..beta. family, such as
TGF.sub..beta.1 which is known to dramatically increase matrix
production by smooth muscle cells as well as other cell types.
Release of TGF.sub..beta.1 in a controlled manner is useful in the
repair of aneurysms where it is desirable to have cells produce
large quantities of extracellular matrix components. Other
substances may augment growth of endothelial cells and/or smooth
muscle cells. Example substances include VEGF, bFGF, PLGF, and
PDGF. Or, one or more substances may be used to control the
activity of a therapeutic gene (e.g. through an activation
mechanism) or the activity of a promoter-enhancer used to drive
expression of the therapeutic gene (e.g. by inclusion of
tetracycline or similar responsive elements within the promoter
driving the therapeutic gene and inclusion of the inducing
substance for that response element in the porous coating).
[0073] FIGS. 3A-3B provide cross-sectional views of the apparatus
10 of FIG. 1 in the unexpanded and expanded states, respectively,
wherein the apparatus is seeded with cells 5. The size, shape and
deposition of the cells 5 have been exaggerated and simplified for
clarity of illustration. FIG. 3A shows the wall of the body 12
within which lie microstructures 14, highlighted by shading. Thus,
when the expandable body 12 is in the unexpanded state, the
microstructures 14 are in an undeployed position which is aligned
with the surface 22. The expandable body 12 is shown having cells 5
deposited along an interior lumen 52 and along the outer surface
22, however it may be appreciated that the cells 5 may be deposited
on select surfaces, such as the outer surface 22 only or particular
portions of the outer surface 22. Since the microstructures 14 are
formed in the wall of the body 12, the microstructures 14 are also
seeded with cells 5. FIG. 3B illustrates the expandable body 12 in
an expanded state wherein the cross-sectional diameter 24 is
increased. Here, the microstructures 14 are in a deployed position
wherein a free end 32 of each microstructure 14 projects radially
outward from the longitudinal axis 20 while an attached end 30
remains attached to the body 12. As shown, the cells 5 are located
on various surfaces of the microstructures 14, ready for delivery
to the tissue upon penetration by the microstructures 14.
[0074] Alternatively, as illustrated in FIG. 4, the cells 5 may be
held in one or more internal lumens 70 within the microstructures
14. Here, the free end 32 has a pointed shape. It may be
appreciated that the internal lumen 70 may be of any size or shape
within the microstructure 14, and may be an isolated lumen or a
lumen which extends continuously from microstructure to
microstructure. The cells 5 may be in suspension or grown on a
surface of the internal lumen 70, such as forming a monolayer,
ready for delivery to the tissue upon penetration by the
microstructures 14. Positioning of the cells within the
microstructures provides a variety of benefits. To begin, the
microstructures protect the cells within from dislodgement during
handling of the device, during delivery of the device and during
deployment of the microstructures 16. Penetration of the tissue by
the microstructures 16 positions the free ends 32 of the
microstructures 16 within the tissue, allowing direct delivery of
the cells 5 to a location within the tissue. In addition, the
microstructures 16 may serve to immunoisolate the cells 5 from the
surrounding tissue. For example, embryonic stem cells may be
positioned within the internal lumens 70 of the microstructures 16
so as to avoid any potential immune reaction from the tissue. The
stem cells may then produce a therapeutic agent for delivery from
the microstructures 16 without the cells themselves contacting the
tissue. Or, a nanoporous membrane may be incorporated into the
microstructures to provide immunoisolation of the cells therein.
The nanoporous membrane may function similarly to the nanoporous
membranes described in T. A. Desai, et al.: Nanopore Technology for
Biomedical Applications. J. of Biomedical Microdevices, 1999, 2 (1)
11-4, incorporated herein by reference for all purposes. The
nanoporous membranes may be incorporated into the microstructures
in a manner similar to the incorporation of dialysis membranes into
microfabricated needles as described in J. D. Zahn, et al.: An
Integrated Microfluidic Device for the Continuous Sampling and
Analysis of Biological Fluids. Proceedings of 2001 ASME
International Mechanical Engineering, Congress and Exposition, Nov.
11-16, 2001, New York N.Y., pp.1-6, incorporated herein by
reference for all purposes. Thus, the nanoporous membranes permit
the transport of cellular products out of the microstructures and
into the penetrated vessel wall, also allowing the in-flow of
nutrients to the embedded cells while effectively screening these
cells from the patient's immune system. This allows, for example,
the use of xenografts and embryonic stem cells while reducing risk
of immunorejection by the patient.
[0075] Microstructures
[0076] As mentioned, each microstructure 14 has an attached end 30,
attached to the body 12, and a free end 32, both in the deployed
and undeployed positions. In preferred embodiments, each
microstructure has a directional axis 40, such as shown in FIG. 5A,
between the free end 32 and the attached end 30. In some
embodiments of the apparatus 10, the directional axis 40 extends
across the longitudinal axis 20 at an angle while the
microstructure 14 is in the undeployed position. Here, the
directional axis 40 is shown to form an angle of approximately 90
degrees with the longitudinal axis 20. Deployment of the
microstructure 14 projects the free end 32 radially outwardly from
the longitudinal axis 20, as shown in FIG. 5B, so that the
microstructure 14 extends beyond the surface 22. Alternatively, in
some embodiments, the directional axis 40 extends along the
longitudinal axis 20 while the microstructure 14 is in the
undeployed position, as illustrated in FIG. 6A. In this case,
deployment of the microstructure 14 also projects the free end 32
radially outward from the longitudinal axis 20, as shown in FIG.
6B, so that the microstructure 14 extends beyond the surface
22.
[0077] Generally, the expandable body 12 comprises a series of
interconnected solid sections having spaces therebetween. The solid
sections form the structure of the expandable body 12 and form the
microstructures 14. In most embodiments, each microstructure has at
least a first support and a second support and a free end, the
first and second supports being affixed to associate first and
second adjacent portions of the radially expandable body. Expansion
of the expandable body effects relative movement between the
associated first and second portions of the expandable body. For
example, the relative movement of the associated first and second
portions of the expandable body may comprise circumferential
movement of the first portion relative to the second portion when
the expandable body expands radially. Although this relative
movement may be in any direction, typically the relative movement
comprises moving the associated first and second portions apart.
Often the circumferential movement pulls the affixed ends of the
first and second supports apart, which in turn moves the free end.
Thus, such relative movement deploys the microstructures from an
undeployed position along the expandable body to a deployed
position with the free end projecting radially outwardly from the
longitudinal axis. A variety of embodiments are provided to
illustrate these aspects of the present invention.
[0078] FIG. 7 illustrates an embodiment of the apparatus 10 wherein
the microstructures 14 are oriented as in FIGS. 6A-6B. Thus,
although the apparatus 10 is illustrated in a flat plane, it is
formed cylindrically around longitudinal axis 20 in this
embodiment. As shown, the body 12 comprises a series of
interconnected solid sections 36 having spaces 35 therebetween. A
portion of the apparatus 10 including a microstructure 14 is
illustrated in exploded view in FIG. 7A. Here, a first support 37a,
a second support 37b and a third support 37c are shown, each
comprising elongate shafts, wherein the second support 37b is
disposed longitudinally between the first support 37a and third
support 37c. The first, second, and third supports 37a, 37b, 37c
are attached to the free end 32 and to first, second and third
adjacent portions 38a, 38b, 38c, respectively, of the expandable
body, as shown. FIG. 8A shows the microstructure 14 of FIG. 7A
wherein the supports 37a, 37b, 37c are adjacent to each other and
aligned with a circumference 39 of the expandable body 12 in the
undeployed position. Here, the body 12 is in the unexpanded state,
wherein the cross-sectional diameter has a radius R.sub.1. FIG. 8B
shows the body 12 is in the expanded state, wherein the
cross-sectional diameter has a larger radius R.sub.2. Such
expansion draws the first and second associated portions 38a, 38b,
apart while the associated third portion 38c moves in unison with
the associated first portion 38a. Thus, the supports 37a, 37b, 37c
pull the free end in opposite directions forming a tripod structure
which causes the free end to project radially outwardly, as
shown.
[0079] The free ends 32 of the microstructures 14 depicted in FIG.
7 and FIG. 7A are each shown to have a flat-edged shape. However,
the free ends 32 may have any desired shape. For example, FIGS.
9A-9C illustrate additional embodiments of microstructures 14
having different shaped free ends 32. In each of these embodiments,
the free ends 32 have a pointed shape. When the apparatus 10 is
positioned in a body lumen, such as a blood vessel, the pointed
shapes of the free ends 32 may assist in penetration of the lumen
wall. The shape, size and tapering of each point may possibly guide
the free end 32 to a certain penetration depth, such as to a
specified tissue layer. In FIG. 9A, the free end 32 has a single
point 33 and in FIG. 9B the free end 32 has multiple points 135. In
FIG. 9C, the free end 32 has an arrow-shaped point 137. The
arrow-shaped point 137 includes a pointed tip 27 and at least one
undercut 29 to reduce the ability of the free end 32 from
withdrawing from a lumen wall once penetrated. This may be useful
when the microstructures are used for anchoring. It may be
appreciated that microstructures 14 throughout the apparatus 10 may
all have the same free end 32 shape or the shapes may vary randomly
or systematically.
[0080] FIG. 10A also illustrates an embodiment of the apparatus 10
wherein the microstructures 14 are oriented as in FIGS. 5A-5B. FIG.
10A provides a portion of the apparatus 10 including the
microstructure 14 in exploded view. In this embodiment, the
microstructure 14 has first and second supports 37a, 37b and a free
end 32, the supports 37a, 37b affixed to associate first and second
adjacent portions 38a, 38b of the radially expandable body 12. FIG.
10B shows the microstructure 14 of FIG. 10A wherein the supports
37a, 37b are adjacent to each other and aligned with a
circumference 39 of the expandable body 12 in the undeployed
position. Here, the body 12 is in the unexpanded state, wherein the
cross-sectional diameter has a radius R.sub.1. The first and second
supports 37a, 37b comprise elongate shafts extending between the
free end 32 and the associated first and second adjacent portions
38a, 38b of the radially expandable body 12. FIG. 10C shows the
body 12 is in the expanded state, wherein the cross-sectional
diameter has a larger radius R.sub.2. As shown, relative movement
of the associated first and second portions 38a, 38b of the
expandable body moves the associated first and second portions 38a,
38b apart so that the supports 37a, 37b pull the free end in
opposite directions causing the free end 32 to project radially
outwardly.
[0081] It may be appreciated that although the free end 32 is
illustrated to have a pointed shape, the free ends 32 may have any
desired shape, including the shapes illustrated in FIGS. 9A-9C.
And, it may also be appreciated that microstructures 14 throughout
the apparatus 10 may all have the same free end 32 shape or the
shapes may vary randomly or systematically.
[0082] FIG. 11 illustrates an embodiment of the apparatus 10
wherein the microstructures 14 are oriented as in FIGS. 6A-6B.
Thus, although the apparatus 10 is illustrated in a flat plane, it
is formed cylindrically around longitudinal axis 20 in this
embodiment. As shown, the expandable body 12 comprises a series of
interconnected solid sections 36 having spaces 35 therebetween. A
portion of the body 12 including a microstructure 14 is illustrated
in exploded view in FIG. 11A. Each microstructure has a first
support 37a, a second support 37b and a free end 32. The supports
37a, 37b are affixed to associate first and second adjacent
portions 38a, 38b of the radially expandable body.
[0083] FIG. 12A illustrates a representative portion of the
radially expandable body 12 having a cylindrical shape, the
remainder of the body illustrated by dashed body 12'. In this
embodiment the radially expandable body 12 further comprises an
interior lumen 52 along the longitudinal axis 20. The interior
lumen 52 may be configured for receiving an expandable member 54
which expands the expandable body 12, as illustrated. In this case,
the expandable member 54 is typically mounted on a catheter 56.
FIGS. 12B-12C illustrate the movement of the expandable body,
particularly the movement of the free ends 32 of the
microstructures 14 as the expandable member 54 radially expands the
body 12. FIG. 12B is a side view of a portion of the expandable
body 12, including a microstructure 14, mounted on expandable
member 54. Expansion of the expandable member 54 effects relative
movement between the associated first and second portions 38a, 38b,
in this case such expansion effects circumferential movement.
Circumferential movement is indicated by arrow 42. It may be
appreciated that the associated first portion 38a is not shown in
FIG. 12B since FIG. 12B is a side view and portion 38a would be
located symmetrically on the backside of the expandable member 54.
The circumferential movement pulls the affixed ends of the first
and second supports 37a, 37b apart which moves the free end 32,
indicated by arrow 48. As shown in FIG. 12C, such movement of the
free end 32 projects the free end 32 radially outwardly, as
indicated by arrow 60. Such projection may be due to friction
created between the free end 32 and the expandable member 54 as the
expandable member 54 expands the expandable body 12. Alternatively,
such projection may be due to other factors, such as the direction
of movement of the supports 37a, 37b, the shape of the supports
37a, 37b, or a combination of factors.
[0084] It may be appreciated that the expandable body 12 of FIGS.
12A-12C may alternatively be expanded by means other than expansion
by an expandable member 54. For example, the expandable body 12 may
be self-expanding, as previously mentioned. In this situation, the
expandable body 12 is pre-formed so that deployment of the body 12
allows the body 12 to self-expand toward a predetermined
configuration. Pre-forming may be achieved with the use of an
expandable member 54, wherein the body 12 is set while surrounding
an expandable member 54 so as to later form this configuration.
When the expandable body 12 expands within the body, projection of
the microstructures may be due to torqueing or movement of the
supports 37a, 37b, for example.
[0085] The free ends 32 of the microstructures 14 depicted in FIGS.
11, 11A, 12A-12C are each shown to have a flat-edged shape.
However, the free ends 32 may have any desired shape. For example,
FIGS. 13A-13C illustrate additional embodiments of microstructures
14 having different shaped free ends 32. In each of these
embodiments, the free ends 32 have a pointed shape. When the
apparatus 10 is positioned in a body lumen, such as a blood vessel,
the pointed shapes of the free ends 32 may assist in penetration of
the lumen wall. The shape, size and tapering of each point may
possibly guide the free end 32 to a certain penetration depth, such
as to a specified tissue layer. In FIG. 13A, the free end 32 has a
single point 33 and in FIG. 13B the free end 32 has multiple points
135. In FIG. 13C, the free end 32 has an arrow-shaped point 137.
The arrow-shaped point 137 includes a pointed tip 27 and at least
one undercut 29 to reduce the ability of the free end 32 from
withdrawing from a lumen wall once penetrated. This may be useful
when the microstructures are used for anchoring. It may be
appreciated that microstructures 14 throughout the apparatus 10 may
all have the same free end 32 shape or the shapes may vary randomly
or systematically. Likewise, the free end 32 may have a flat-shaped
inner edge 139, as illustrated in FIG. 13A, to maximize friction
against an expandable member 54 or the free end 32 may have various
other shaped inner edges 139, as illustrated in FIGS. 13B-13C.
[0086] FIGS. 13D-13F illustrate embodiments of the apparatus 10
having various designs. Again, although the apparatus 10 is
illustrated in a flat plane, it is formed cylindrically around
longitudinal axis 20 in each embodiment. In FIG. 13D, the
microstructures 14 have free ends 32 which are shaped as a single
point 33 and include a flat inner edge 139. Thus, the free ends 32
are similar to the embodiment illustrated in FIG. 13A. FIG. 13E
also illustrates an embodiment wherein the microstructures 14 have
free ends 32 which are shaped as a single point 33 and include a
flat inner edge 139. However, in this embodiment, the
microstructures 14 are positioned more closely together, in a
denser pattern. In FIG. 13F the microstructures 14 have free ends
32 which are shaped to have multiple points 135 and to include a
flat inner edge 139. In addition, the flat inner edge 139 is part
of a flange 43 which is directed opposite of the points 135. The
flange 43 provides a wide flat inner edge 139 to maximize friction
against an expandable member 54 and a narrow neck region 45 to
enhance flexibility and rotation of the multiple points 135
radially outwardly.
[0087] FIG. 13G illustrates an embodiment of the expandable body 12
wherein the free ends 32 of the microstructures 14 have a single
point 33 and curved inner edge 139. And, FIG. 13H illustrates the
microstructures of FIG. 13G in a deployed position. FIG. 13H
provides a view similar to FIG. 12C wherein circumferential
movement pulls the affixed ends of the first and second supports
37a, 37b apart which moves the free end 32. Such movement of the
free end 32 projects the free end 32 radially outwardly, as
indicated by arrow 60. As mentioned, such projection may be due to
friction created between the free end 32 and the expandable member
54 as the expandable member 54 expands the expandable body 12.
[0088] FIGS. 14A-14B illustrate an embodiment of the expandable
body 12 shown in FIGS. 13G and 13H having cells 5 seeded thereon.
FIG. 14A illustrates a portion of the expandable body 12 showing
one of the adjacent portions 38b and first and second supports 37a,
37b of a microstructure. Cells 5 are shown covering surfaces of the
expandable body 12, wherein the roundish shapes represent cell
nuclei and the cytoplasms of the cells extend therebetween. FIG.
14B provides an enlarged view of a portion of the expandable body
12 shown in FIG. 14A. Here, the adjacent portion 38b of the
expandable body 12 of FIG. 14A is shown enlarged and again the
roundish shapes represent cell nuclei and the cytoplasms of the
cells extend therebetween.
[0089] Embodiments for Repairing Aneurysms
[0090] As mentioned previously, the cell-seeded expandable bodies
of the present invention may be used to anchor a tube or graft to
the vessel walls surrounding an aneurysm. The cells are seeded on
the expandable bodies as described above. The cells may then be
delivered to the vessel walls to increase anchorage of the tube.
The cells can also be delivered to the blood vessel lumen, the
blood vessel walls and/or the outer surface of the blood vessel to
encourage tissue regrowth or extra-cellular matrix formation. Or
the cells may be delivered to the aneurysmal sac. This may allow
for tissue regrowth within the sac, strengthening the tissue within
the aneurysmal walls. Typically, smooth muscle cells will be used
for such application.
[0091] Referring to FIG. 15A, an embodiment of an apparatus 10 of
the present invention for treating an aneurysm is illustrated; the
apparatus 10 comprises a tube 2 having a first end 4, a second end
6 and a tube wall 8 extending between the first and second ends 4,
6. In addition, the apparatus 10 comprises an expandable body 12
attached to the tube wall 8 including at least one microstructure
14. Each microstructure 14 has an attached end 30 attached to the
body and a free end 32 in an undeployed position. FIG. 15A
illustrates the apparatus 10 in an unexpanded state wherein the
microstructures 14 are in the undeployed position. Here, the
microstructures 14 are preferably aligned or flush with an outer
surface of the apparatus 10 so that the surface does not include
substantial protrusions. Alternatively, the microstructures 14 may
be positioned below the surface of the apparatus 10. FIG. 15A also
shows cross-sectional diameter 24 and longitudinal axis 20. FIG.
15B illustrates the microstructures 14 in the deployed position
wherein the free ends 32 project radially outwardly from the tube
2.
[0092] It may be appreciated that any number of microstructures 14
may be present and may be arranged in a variety of patterns along
the entire length of the body 12 or along any subportion. For
example, FIGS. 15A-15B illustrate an embodiment wherein the
microstructures 14 are present along the entire length of the body
12 and the body 12 extends along the entire length of the tube 2.
Alternatively, the microstructures 14 may be present in select
locations, such as near the first end 4, near the second end 6, or
near both ends 4, 6 while the body 12 extends along the entire
length of the tube. These particular arrangements of
microstructures 14 may be useful in anchoring the apparatus 10
across an aneurysm.
[0093] Referring now to FIG. 16, an embodiment of a system of the
present invention is provided including a tube 2 having a first end
4, a second end 6 and a tube wall 8 extending between the first and
second ends 4, 6, and at least one expandable body 12 which is
sized for positioning within the tube 2. Here, two expandable
bodies 12a, 12b are shown, a first expandable body 12a partially in
place near the first end 4 to illustrate its moveability and a
second expandable body 12b in place near the second end 6. Thus,
the at least one expandable body 12 may be positioned at any
location along the length of the tube 2, including extending beyond
the ends 4, 6 of the tube.
[0094] When the expandable body 12 is positioned within the tube 2,
expansion of the body 12 and deployment of the microstructures 14
occurs within the tube 2 so that further expansion penetrates the
microstructures 14 through the tube wall 8, as illustrated in FIG.
17. FIG. 17 provides a cross-sectional view of the expandable body
12 within a tube 2 and illustrates a plurality of microstructures
14 penetrating the tube wall 8. FIG. 17 also illustrates the
microstructures 14 further penetrating a surrounding blood vessel
wall V. Thus, the microstructures 14 may be used to anchor the
apparatus 10 within the blood vessel and to deliver cells to the
blood vessel in a manner similar to that in which the expandable
body 12 is used alone.
[0095] FIG. 18 illustrates an aneurysm within a blood vessel V. An
aneurysm comprises a sac S caused by abnormal dilation of the wall
of the blood vessel V and may occur within any blood vessel in the
body. Life-threatening aneurysms can occur in cerebral blood
vessels and the aorta, to name a few. Repair of such aneurysms
typically involves bridging the sac S with a graft material,
wherein the graft is at least secured to the upper neck UN and
lower neck LN of the blood vessel V near the ends of the sac S.
This provides a conduit for blood flow through the blood vessel V,
preventing further collection of blood in the aneurysmal sac S and
reducing the progression of growth of the aneurysm and the risk of
sac rupture due to blood pressure. In addition, the micro
structures 14 can also be used to deliver cells 5. Cells 5, such as
unmodified smooth muscle cells may be delivered into the vessel
wall or deposited on the inner or outer surfaces of the vessel wall
to enhance sealing by cell proliferation and production of
extracellular matrix components. These cells 5 may also be
delivered to the aneurysmal sac S, as illustrated in FIG. 19. In
this embodiment, the expandable body 12 extends the length of the
tube wall 8 and has microstructures 14 near the first end 4 and
second end 6 to anchor the apparatus 10 in place and has
microstructures 14 between the ends 4, 6 for delivery of cells 5 to
the aneurysmal sac S.
[0096] The present invention may be particularly suitable for
repair of abdominal aortic aneurysms. An abdominal aortic aneurysm
is a sac caused by an abnormal dilation of the wall of the aorta, a
major artery of the body, as it passes through the abdomen. The
abdomen is that portion of the body which lies between the thorax
and the pelvis. It contains a cavity, known as the abdominal
cavity, separated by the diaphragm from the thoracic cavity and
lined with a serous membrane, the peritoneum. The aorta is the main
trunk, or artery, from which the systemic arterial system proceeds.
It arises from the left ventricle of the heart, passes upward,
bends over and passes down through the thorax and through the
abdomen to about the level of the fourth lumbar vertebra, where it
divides into the two common iliac arteries at a bifurcation.
[0097] To treat abdominal aortic aneurysms, the apparatus 10 is
shaped to be disposed at least partially within the aneurysm. In
particular, the tube 2 is shaped to fit the aortic geometry. For
example, FIG. 20 illustrates an embodiment of the apparatus 10 of
the present invention shaped to fit within the abdominal aorta,
traversing the bifurcation. Thus, the tube 2 includes a main shaft
61, a first leg 62, and a second leg 64. This embodiment further
includes three expandable bodies, a first expandable body 66
disposed near the end of the main shaft 61, a second expandable
body 68 disposed near the end of the first leg 62 and a third
expandable body 70 disposed near the end of the second leg 64, as
shown. Positioning of these expandable bodies 66, 68, 70 are
intended to provide anchoring for the apparatus within the aorta
and iliac arteries surrounding the abdominal aortic aneurysm.
Alternatively, one or more expandable bodies may extend over larger
portions of the tube wall 8, including over the entire tube 2.
Again, the microstructures 14 provide delivery of cells 5 to the
blood vessel V, areas within or surrounding the blood vessel,
and/or within the aneurysmal sac S.
[0098] Delivery of Cells from Expandable Body
[0099] Positioning of the apparatus of the present invention is
typically performed via standard catheterization techniques. These
methods are well known to cardiac physicians and are described in
detail in many standard references. Examples of such positioning
will be provided in relation to the vascular system, however, such
example is not intended to limit the scope of the invention. In
brief, percutaneous access of the femoral or brachial arteries is
obtained with standard needles, guide wires, sheaths, and
catheters. After engagement of the coronary arteries with a hollow
guiding catheter, a wire is passed across the coronary stenosis
where the apparatus is to be deployed. The apparatus is then passed
over this wire, using standard coronary interventional techniques,
to the site where therapy is to be delivered.
[0100] The apparatus is then delivered and expanded to force the
microstructures 14 through the tissue so the microstructure tips
reach within the vessel wall, as shown in FIGS. 21-21A. FIG. 21
shows a cross-sectional view of the expandable body 12 expanded
inside a blood vessel lumen L. Microstructures 14 pierce through a
layer of compressed plaque 3 and into the wall of the lumen L. FIG.
21 A provides an exploded view of a microstructure 14 penetrating
the wall of the lumen L. Here, an intimal layer I, medial layer M
and adventitial layer A are shown. The microstructure 14 may
penetrate any or all of the layers I, M, A, including penetrating
through the wall of the lumen L to the peri-adventitial space. FIG.
21A illustrates penetration to the adventitial layer A. Such
penetration provides controlled dissection of the vessel wall by
the microstructures and provides pathways for migration of the
cells into the blood vessel wall, and, when desired, into the
adventitial layer A. Cells seeded on the surfaces of the expandable
body migrate from the expandable body to the surrounding tissue
environment. In some cases it may be desired to penetrate the
microstructures through to the peri-adventitial space. The cells
which are held within the microstructures then enter the lumen wall
or are deposited peri-vascularly where they perform their desired
biological function. If the apparatus is intended to function in a
stent-like manner, the apparatus is then left behind in its
expanded state.
[0101] Applications
[0102] As mentioned previously, the present invention may be
utilized for any sort of treatment which involves delivery of a
therapeutic agent and/or anchoring of a device. The devices could
be introduced into various body lumens, such as those found in the
vascular system, the pulmonary system, the gastro-intestinal tract,
the urinary tract and the reproductive tract, to name a few. The
function of the microstructures includes but is not limited to
facilitating delivery of a therapeutic agent, such as cells,
securing the device in place and providing a mechanical seal to the
lumen wall.
[0103] Although the invention has been described in detail in the
foregoing embodiments for the purpose of illustration, it is to be
understood that such detail is solely for that purpose and that
variations can be made therein by those skilled in the art without
departing from the spirit and scope of the invention except as it
may be described by the following claims.
* * * * *