U.S. patent application number 12/114717 was filed with the patent office on 2008-08-28 for methods and compositions to treat myocardial conditions.
Invention is credited to Eugene T. Michal, John Stankus.
Application Number | 20080208167 12/114717 |
Document ID | / |
Family ID | 33302789 |
Filed Date | 2008-08-28 |
United States Patent
Application |
20080208167 |
Kind Code |
A1 |
Stankus; John ; et
al. |
August 28, 2008 |
METHODS AND COMPOSITIONS TO TREAT MYOCARDIAL CONDITIONS
Abstract
Methods, devices, kits and compositions to treat a myocardial
infarction. In one embodiment, the method includes the prevention
of remodeling of the infarct zone of the ventricle. In other
embodiments, the method includes the introduction of structural
reinforcing agents such as those agents containing aloe-derived
pectin. In other embodiments, the structural reinforcing agent may
be accompanied by other therapeutic agents. These agents may
include, but are not, limited to pro-fibroblastic and angiogenic
agents.
Inventors: |
Stankus; John; (Campbell,
CA) ; Michal; Eugene T.; (San Francisco, CA) |
Correspondence
Address: |
GUIDANT CORPORATION, INC./BLAKELY
1279 OAKMEAD PARKWAY
SUNNYVALE
CA
94085-4040
US
|
Family ID: |
33302789 |
Appl. No.: |
12/114717 |
Filed: |
May 2, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10414602 |
Apr 15, 2003 |
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12114717 |
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Current U.S.
Class: |
604/511 ;
128/898; 604/48; 604/500; 604/522 |
Current CPC
Class: |
A61K 41/0042 20130101;
A61L 2430/20 20130101; A61K 31/00 20130101; A61K 31/79 20130101;
A61P 9/10 20180101; A61P 43/00 20180101; A61K 31/728 20130101; A61P
7/02 20180101; A61K 38/1891 20130101; A61P 7/04 20180101; A61K
38/1858 20130101; A61L 24/043 20130101; A61K 38/1825 20130101; A61L
27/20 20130101; A61K 31/732 20130101; A61K 45/06 20130101; A61L
27/54 20130101; A61K 47/60 20170801; A61K 35/34 20130101; A61K
31/734 20130101; A61K 38/18 20130101; A61K 36/886 20130101; A61K
47/34 20130101; A61K 49/0404 20130101; A61K 38/40 20130101; A61K
47/62 20170801; A61L 27/50 20130101; A61P 9/04 20180101; A61K
9/0024 20130101; A61K 31/728 20130101; A61K 31/79 20130101; A61K
2300/00 20130101; A61N 1/3625 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 31/78 20130101; A61K 38/1866 20130101; A61K
38/1841 20130101; A61K 38/40 20130101; A61N 1/36521 20130101; A61P
9/14 20180101 |
Class at
Publication: |
604/511 ;
604/522; 604/500; 604/48; 128/898 |
International
Class: |
A61M 31/00 20060101
A61M031/00 |
Claims
1. A method comprising identifying an infarct region within the
ventricle of a subject; and delivering near or in the infarct
region material comprising aloe-derived pectin.
2. A method comprising identifying an infarct region within the
ventricle of a subject; and delivering to the infarct region
material comprising aloe-derived pectin.
3. The method of claim 1 wherein delivering aloe-derived pectin
prevents thinning of the ventricle.
4. The method of claim 1 wherein delivery of the aloe-derived
pectin occurs within 2 weeks of a myocardial infarction (MI).
5. The method of claim 1 wherein delivery of the aloe-derived
pectin occurs within 5, 10, 15, or 20 weeks of a myocardial
infarction (MI).
6. The method of claim 1 wherein the aloe-derived pectin material
further comprises at least one of cells, proteins, peptides, growth
factors or microparticles containing at least one of cells,
proteins, peptides, or growth factors or nanoparticles containing
at least one of cells, proteins, peptides or growth factors.
7. The method of claim 6 wherein the aloe-derived pectin material
comprises cells and proteins, cells and growth factors, or proteins
and growth factors.
8. The method of claim 1 wherein said subject with the MI displays
at least 20 percent ventricular damage.
9. The method of claim 1 wherein the aloe-derived pectin displays a
pseudoplastic characteristic.
10. The method of claim 1 wherein delivering aloe-derived pectin
comprises: delivering the aloe-derived pectin material to the
infarct region in a liquid phase and once delivered the
aloe-derived pectin material is capable of transitioning to a solid
phase in the presence of an endogenous material.
11. The method of claim 1 further comprising delivering at least
one matrix metalloproteinase inhibitor (MMPIs) to the
ventricle.
12. The method of claim 1 wherein delivering the aloe-derived
pectin comprises introducing the aloe-derived pectin to the
ventricle through a procedure.
13. The method of claim 12 wherein the procedure to the ventricle
region is selected from at least one of minimally invasive such as
sub-xiphoid, percutaneous, or surgical approach such as open-chest
procedure in conjunction with Coronary Bypass Graft (CABG).
14. The method of claim 13 wherein the percutaneous introduction of
the aloe-derived pectin into the ventricle comprises at least one
of the following modes consisting of intracoronary infusion,
intraventricular catheter, intravenous pressure perfusion,
transvascular needle catheter, and retrograde venous perfusion.
15. The method of claim 1 wherein delivering the aloe-derived
pectin comprises delivering a composition suspended in a
solution.
16. The method of claim 1 wherein delivering aloe-derived pectin
near the infarct region is capable of increasing the compliance of
the ventricle.
17. A kit comprising a delivery lumen; agents delivered from the
delivery lumen; and at least one agent comprising a structural
reinforcing agent wherein said structural reinforcing agent is
capable of forming a matrix product within a ventricle wherein the
structural re-inforcing agent comprises a material comprising
aloe-derived pectin.
18. The kit of claim 17 further comprising forming a matrix product
within or near an infarct region of a ventricle.
19. The kit of 17 further comprising a delivery device.
20. The kit of 17 wherein the structural reinforcing agent
comprises a material in a liquid phase and once delivered the
material is capable of transitioning to a solid phase in the
presence of an endogenous material in or near an infarct
region.
21. A kit comprising a delivery lumen and agents comprising
aloe-derived pectin, wherein the agents are capable of increasing
the compliance of a ventricle.
22. The kit of claim 21 further comprising a delivery device.
23. A method comprising delivering a liquid phase of a structural
reinforcing agent to a ventricle wherein the structural reinforcing
agent is capable of transitioning to a solid when an environmental
temperature is approximately a body temperature of a mammalian
subject and wherein the structural reinforcing agent comprises a
material comprising aloe-derived pectin.
24. The method of claim 23 wherein delivering a liquid phase of a
structural reinforcing agent to a ventricle comprises delivering a
liquid phase of a structural reinforcing agent to or near an
infarct region of a ventricle.
25. A method comprising delivering a first material and a second
different material to a ventricle wherein a first material and a
second different material are components of a final product and
wherein the first or second material comprises aloe-derived
pectin.
26. The method of claim 25 wherein the final product prevents
thinning of the ventricle.
27. A kit comprising at least two delivery lumen; agents delivered
from each delivery lumen; and a first material and a second
different material wherein the first material and the second
different material are components of a final product and are
capable of forming the final product within a ventricle and wherein
the first or second material comprises aloe-derived pectin.
28. The kit of claim 27 wherein the first material and the second
material are housed in separate lumen.
29. The kit of claim 27 wherein a final product is formed within or
near an infarct region of a ventricle from the first material and
the second material.
30. The kit of claim 27 further comprising a delivery device.
31. The kit of claim 30 wherein the delivery device comprises a
dual chamber delivery device comprising separate chambers for the
first material and the second different material.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of application
10/414,602, filed on Apr. 15, 2003, and fully incorporates the
contents of that application.
FIELD
[0002] The treatment of myocardial infarction, and more
particularly, in one embodiment, to the reinforcement of the
infarct regional wall of a heart chamber and/or the inhibition of
the thinning of the infarct regional wall of a heart chamber.
BACKGROUND
[0003] Ischemic heart disease typically results from an imbalance
between the myocardial blood flow and the metabolic demand of the
myocardium. Progressive atherosclerosis with increasing occlusion
of coronary arteries leads to a reduction in coronary blood flow.
Blood flow can be further decreased by additional events such as
changes in circulation that lead to hypoperfusion, vasospasm or
thrombosis.
[0004] Myocardial infarction accounts for approximately 20% of all
deaths. It is a major cause of sudden death in adults.
[0005] Myocardial Infarction (MI) is one form of heart disease that
often results from the sudden lack of supply of oxygen and other
nutrients. The lack of blood supply is a result of closure of the
coronary artery that nourishes the particular part of the heart
muscle. The cause of this event is generally caused by
arteriosclerosis "hardening of the arteries" in coronary
vessels.
[0006] Formerly, it was believed that an MI was caused from a slow
procession of closure from for example 95% then to 100% but an MI
can also be a result of minor blockages where, for example, there
is a rupture of the cholesterol plaque resulting in blood clotting
within the artery. Thus, the flow of blood is blocked and
downstream cellular damage occurs. This damage can cause irregular
rhythms that can be fatal, even though the remaining muscle is
strong enough to pump a sufficient amount of blood. As a result of
this insult to the heart tissue, scar tissue tends to naturally
form.
[0007] Even though relatively effective systemic drugs exist to
treat MI such as ACE-inhibitors and Beta-blockers, a significant
portion of the population that experiences a major MI ultimately
develops heart failure. An important component in the progression
to heart failure is remodeling of the heart due to mechanical
forces resulting in uneven stress and strain distribution in the
left ventricle. Once an MI occurs remodeling of the heart begins.
The principle components of the remodeling event include myocyte
death, edema and inflammation, followed by fibroblast infiltration
and collagen deposition, and finally scar formation. The principle
component of the scar is collagen. Since mature myocytes of an
adult are not regenerated the infarct region experiences
significant thinning. Myocyte loss is the major etiologic factor of
wall thinning and chamber dilation that may ultimately lead to
progression of cardiac myopathy. Myocyte death can and does occur.
In other areas, remote regions experience hypertrophy (thickening)
resulting in an overall enlargement of the left ventricle. This is
the end result of the remodeling cascade. These changes in the
heart result in changes in the patient's lifestyle and their
ability to walk and to exercise. These changes also correlate with
physiological changes that result in increase in blood pressure and
worsening systolic and diastolic performance.
[0008] FIGS. 1A-1C illustrate blood flow by longitudinal cross
sectioning of the artery. FIG. 1A illustrates a normal unobstructed
artery. FIG. 1B illustrates artery damage due to a tear or spasm.
This FIG. illustrates a minor insult to the interior wall. FIG. 1C
illustrates an artery with plaque build-up that reduces the blood
flow demonstrated by the blocked blood cell above the
atherosclerotic mass. Fat and cholesterol build up at the site of
damage. This mass can be detected by methods currently available,
such as an ECG, SPECT, MRI, angiogram.
[0009] FIGS. 2A-2B illustrate the progression of heart damage once
the build-up of plaque induces an infarct to occur. The most common
pathogenesis of this disease is occlusive intracoronary thrombus
where a thrombus is covering an ulcerated stenotic plaque. This
causes approximately 90% of transmural acute myocardial
infarctions. Other possible triggers of an MI are vasospasms with
or without coronary atherosclerosis and possible association with
platelet aggregation. Another possible trigger is embolisms from
left-sided mural thrombosis, vegetative endocarditis or a paradoxic
embolism from the right side of the heart through a patent foramen
ovale. FIG. 2A illustrates a site where blockage and restricted
blood flow can occur from any of the indicated causes. FIG. 2B
illustrates the extensive damage to the left ventricle that can be
a result of the lack of oxygen and nutrient flow carried by the
blood to the inferior region left ventricle of the heart. This area
will likely undergo remodeling and eventually a scar will form and
a non-functional (an area that does not contract) area will
exist.
[0010] Significant atherosclerotic build-up can reduce the arterial
lumen and reduce blood flow. Build-up is capable of rupturing
resulting in a total or partial occlusion of the artery. Complete
coronary occlusion will lead to an acute MI. Thus the T-cells,
platelets, fibrin and multiple other factors and cells are blocked
from progression through the blood stream and the result is an
inadequate vascular supply as seen. This leads to myocyte death.
Myocyte death, in addition to fibrosis in the form of collagen
deposition, can lead to a compromised left ventricle and overload
on the remaining myocytes. This process is further complicated by
compensation of the remaining myocytes that hypertrophy (enlarge).
This can cause the left ventricle to enlarge and if the cycle
continues can result in eventual heart failure.
[0011] The morphological appearance of the infarcted heart tissue
post MI can vary. A transmural infarct involves the entire
thickness of the left ventricular wall from the endocardium to the
epicardium. It may extend into the anterior free wall and the
posterior free wall. This damage may include extensions into the
right ventricular wall. A subendocardial infarct may have multiple
focal regions and necrosis area may be confined to the inner
one-third to one-half of the left ventricular wall. The
evolutionary changes in a subendocardial infarct do not evolve the
same as in a transmural MI.
[0012] Over time post-MI morphological changes occur. The gross
morphological changes that occur over approximately a 7-week period
are pallor of the myocardium that leads to some hyperemia then a
yellowing central to the damaged region. At approximately 15 days,
the area is mostly yellow with soft vascular margins. This area
eventually turns white from fibrosis. On a microscopic level, the
initial examination reveals wavy myocardial fibers. Coagulation and
necrosis with loss of cross striations occur followed by
contraction bands, edema, hemorrhage, and neutrophilic infiltrate.
Within 24-72 hours there is total loss of nuclei and striations and
heavy neutrophilic infiltrate. Then macrophage and mononuclear
infiltration begin resulting in a fibrovascular response. Once this
fibrovascular response occurs then prominent granulation of the
tissue follows. This ultimately leads to fibrosis and a scar is
formed by about 7 weeks post MI.
[0013] FIGS. 3A-3B illustrate the occlusion of an artery that may
lead to an MI. FIG. 3A illustrates the cross-section of a normal
coronary artery with unobstructed lumen 301. The normal arterial
wall 302 is made up of an intimal layer 303, a media layer 304, and
an adventitia layer 305. Within the arterial lumen, the intima is
in direct contact with the flow of blood. This region is mostly
made up of endothelial cells. The media layer is mostly smooth
muscle cells and extracellular matrix proteins. Finally, the
adventitia layer is primarily made up of collagen, nerves, blood
vessels and lymph vessels. FIG. 3B illustrates a coronary artery
with atherosclerosis. In this example, this artery is about 50
percent occluded (only 50 percent of the arterial lumen is free of
obstruction). Thus, the obstructed artery may lead to damage
observed in a ventricle of an MI subject.
[0014] After an MI has occurred, three layers of tissue can be
distinguished. The infarct region has (1) the region of significant
necrosis/apoptosis tissue (2) the border zone that consists of a
large concentration of apoptotic and necrotic tissue as well as
viable tissue and (3) the unaffected region that consists of mainly
viable tissue. In the border zone the cells exist in an
oxygen-deprived state due to the damage from the MI.
[0015] FIGS. 3C-3J illustrate the details of a post-MI remodeling
of the ventricle. The progression of heart failure after an MI is a
result of the remodeling of the heart after the infarct. The
remodeling process causes the infarcted region of the heart to
stretch and become thinner causing the left ventricular diameter to
increase. As the heart continues to remodel, the stresses on the
heart increase. FIG. 3C, on a cellular level, a normal myocardium
is illustrated. FIG. 3C illustrates the cross striations 306 and
central nuclei 307 of a healthy myocyte population.
[0016] FIGS. 3D-3J depict the progression of the remodeling of the
ventricle post MI. FIG. 3D illustrates an early acute MI. Here,
there are prominent pink contraction bands that are indicated by
reference number 308. FIG. 3E illustrates the increasing loss of
striations and some contraction bands. The nuclei in this
illustration are dying by a process called karyolysis 309.
Karyolysis is a stage of cell death that involves fragmentation of
the cell's nucleus; the nucleus breaks down into small dark beads
of damaged chromatin. In addition, the neutrophils are infiltrating
the damaged myocardial region. FIG. 3F illustrates an acute MI. The
loss of nuclei and loss of cross striations are evident. There is
extensive hemorrhaging on the infarct border 310. FIG. 3G
illustrates the prominent necrosis and hemorrhaging 310, as well as
the neutrophilic infiltrate 311. Subsequently, a yellowish center
is formed within the damaged area with necrosis and inflammation
surrounded by the hyperemic border. After 3-5 days post-MI, the
necrosis and inflammation are extensive. There is a possibility of
rupture at this point. FIG. 3H illustrates approximately one week
after the MI with capillaries, fibroblasts and macrophages filled
with haemosiderin 312. Haemosiderin is a long-term stored reserve
of iron in tissues. In two to three weeks, granulation is the most
prominent feature observed. FIG. 3I illustrates extensive collagen
deposition 313 seen after a couple of weeks. Collagenous scarring
occurs in subendocardial locations in remote myocardial infarct
regions. FIG. 3J illustrates the myocytes 314 after several weeks
of healing post MI. They are hypertrophied with large dark nuclei
315 and interstitial fibrosis 316. These enlarged cells contribute
to the enlarged left ventricle.
[0017] A complication of an MI is an aneurysm that looks like a
bulge in the left ventricular wall. The aneurysm is made up of
non-functional tissue that is unable to contract. Therefore, the
ejection and stroke volume of the heart are reduced. Additionally,
parts of this mass can form a mural thrombus that can break off and
embolize to the systemic circulation.
SUMMARY
[0018] Compositions and methods to treat myocardial infarction of
the ventricle are described. In one embodiment, a composition is
described that is capable of reinforcing the ventricular wall and
may be capable of releasing an agent to recruit the natural cell
population in order to stabilize the region. In another embodiment,
a method is described to increase the compliance of a ventricle. A
treatment agent is advanced through a delivery device to the
infarct zone. In some embodiments, a delivery device is described
to accurately deliver one or more treatment agents. In some
embodiments, the treatment agent is delivered via a multiple of
small volumes to the region. These delivery methods may use imaging
of the ventricular wall to guide the deposition of the treatment
agent to the site of the infarct zone such as deposition of the
gel-forming agents. In these or other embodiments the gel-forming
agent comprises aloe-derived pectin. The aloe-derived pectin can be
delivered directly to or near the infarct region. The delivery near
the infarct region may include delivery to a border region
surrounding the infarct region. In other embodiments, treatment
agents may induce angiogenesis.
[0019] In another embodiment, a method includes multi-component
treatments of the infarct zone. One multi-component method includes
the formation of a scaffold to facilitate the attachment of
fibroblasts and to deliver growth factors and other treatment
agents. In addition, the in-growth of new capillaries is encouraged
by the sustained release of angiogenic factors by the
microparticles that form the scaffold. The treatment agents may be
released for up to two months period. This technique would offer
maximum benefit for the regeneration of viable tissue.
[0020] In another embodiment, a different multi-component treatment
of the infarct zone introduces a scaffold system that provides a
matrix to facilitate cell growth and inhibit the remodeling event
post-MI. In addition the treatment includes a perfluorinated
compound that enhances the re-oxygenation of the tissue.
[0021] In another embodiment, a solution is delivered to a site in
a ventricle. The solution contains an agent(s) capable of
precipitating at a region for reinforcement of that region. Another
solution contains one or more agents that are delivered to a region
in a ventricle and remain in that region while the supporting
solution dissipates into surrounding tissue.
[0022] In one embodiment, the treatments proposed may occur at any
time after an infarction. In another embodiment, the treatments
proposed may occur within seven weeks of an MI event (or prior to
myocyte replacement). In another embodiment, the treatments
proposed may occur within two weeks of an MI event.
[0023] In any of these or other embodiments the gel-forming agent
comprises aloe-derived pectin.
[0024] In a further embodiment, a kit is disclosed. One example of
such a kit is a kit including an injectable composition having the
property of forming a gel once introduced to the treatment area.
The gel may be formed due to one or more environmental changes or
alternatively a response to one or more internal components. In
these or other embodiments the gel-forming agent comprises
aloe-derived pectin.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] The methods and compositions are illustrated by way of
example, and not limitation, in the figure of the accompanying
drawings in which:
[0026] FIG. 1A illustrates a longitudinally sectioned healthy
artery and blood flow therein.
[0027] FIG. 1B illustrates a longitudinally sectioned damaged
artery due to a tear or a spasm.
[0028] FIG. 1C illustrates a longitudinally sectioned occluded
artery due to fat and cholesterol build up.
[0029] FIG. 2A illustrates plaque build up in an artery that may
result restriction of blood and oxygen flow to the heart.
[0030] FIG. 2B illustrates the damage to the heart as a result of
the plague build-up in an artery that lead to an MI.
[0031] FIG. 3A illustrates a normal artery.
[0032] FIG. 3B illustrates an artery with arteriosclerosis (50
percent blockage) that may lead to an MI.
[0033] FIG. 3C illustrates normal myocardium.
[0034] FIG. 3D illustrates an example of myocardium of an early
acute myocardial infarction.
[0035] FIG. 3E illustrates an example of myocardium of an early
myocardial infarction whereby a myocardium demonstrates increasing
loss of cross striations.
[0036] FIG. 3F illustrates an example of myocardium of an acute
myocardial infarction and the loss of striations and the
nuclei.
[0037] FIG. 3G illustrates an example of myocardium of an acute
myocardial infarction resulting in neutrophilic infiltration and
necrosis.
[0038] FIG. 3H illustrates an example of the myocardium of an acute
myocardial infarction approximately one week after a myocardial
infarction occurred. The capillaries, fibroblasts and macrophages
fill with haemosiderin.
[0039] FIG. 3I illustrates an example of the myocardium a couple of
weeks after a myocardial infarction. A lot of collagen has been
deposited at the site of damage.
[0040] FIG. 3J illustrates myocardium several weeks after a
myocardial infarction. Many surviving myocytes appear hypertrophic
and their nuclei are dark in color. Interstitial fibrosis is also
observed.
[0041] FIG. 4 illustrates various ways to restructure remodeling of
the infarct region via retention and recruitment of fibroblasts and
delivering a swellable reinforcing material and/or introduce
additional tropoelastin to the infarct region.
[0042] FIGS. 5A-5E illustrate the introduction of a
pro-fibroblastic agent to an infarct zone and the formation of
structural scaffolding.
[0043] FIG. 6 illustrates a multi-component method for structural
reinforcing an infarct region.
[0044] FIG. 7 illustrates a multi-component method for structural
reinforcing an infarct region and/or facilitating oxygenation of an
infarct region.
[0045] FIG. 8 illustrates a general structure of the first and of
the second component of FIG. 7.
[0046] FIGS. 9A-9F illustrate introduction and action of the
multi-component method for structural reinforcement to an infarct
region, for example, FIG. 6 and/or FIG. 7.
[0047] FIG. 10 illustrates an ester bond formed by at least two of
the components of embodiments illustrated in FIG. 7 and FIG. 8.
[0048] FIGS. 11A-11F illustrate introduction of structural
reinforcement in the form of swellable microparticles to an infarct
zone.
[0049] FIG. 12 illustrates a flowchart of the several possible
structural reinforcing agents that may be introduced to an infarct
region.
[0050] FIG. 13 illustrates an expansion of FIG. 12 (1240)
disclosing possible dual component systems.
[0051] FIG. 14 illustrates introduction and action of the methods
illustrated in the flowchart of FIG. 13 in an infarct region.
[0052] FIG. 15 illustrates two possible methods to structurally
reinforce an infarct zone by bulking up a region.
[0053] FIG. 16 illustrates examples of bulking agents that may
structurally reinforce an infarct region.
[0054] FIG. 17 illustrates stabilizing the collagen in an infarct
zone by cross-linking.
[0055] FIG. 18 illustrates various agents that may cross-link the
collagen in an infarct region.
[0056] FIG. 19 illustrates various embodiments to clot the blood in
an infarct region post MI.
[0057] FIG. 20 illustrates various methods to reinforce an infarct
region using light sensitive components.
[0058] FIGS. 21A-21E illustrate a cross-sectional view of
introduction of an embodiment using a photo-polymerizable component
of FIG. 20 to an infarct region.
[0059] FIG. 22A illustrates a longitudinal view of a catheter
device that has a light source and at least one component
lumen.
[0060] FIG. 22B illustrates a cross-sectional view of a catheter
device that has a light source and at least one component
lumen.
[0061] FIG. 23 illustrates one example of a multi-component method
to reinforce the infarct region and/or re-oxygenate the infarct
region.
[0062] FIG. 24A illustrates a longitudinal view of a catheter
device that has two delivery ports and a control mechanism to
deliver one component prior the second component.
[0063] FIG. 24B illustrates a front view of the distal end of a
catheter device with two delivery ports.
[0064] FIG. 24C illustrates the distal end of a catheter device
where one delivery port may be extended while the second port may
be confined to the housing of the catheter.
[0065] FIGS. 25A-25D illustrate the introduction of two separate
components into an infarct region of the ventricle and formation of
a structural reinforcing composition at the infarct region using a
catheter with retractable dual delivery ports.
[0066] FIG. 26 illustrates the introduction of one component
through a vein and the second through an artery using the catheter
with retractable dual delivery ports.
DEFINITIONS
[0067] "a container"--a receptacle, such as a carton, can, vial,
tube, bottle, or jar, in which material is held or carried.
[0068] "cardiomyocyte-like"--a cell(s) capable of converting to a
cardiomyocyte(s) or a cell or components capable of functioning
like a cardiomyocyte.
[0069] "polymer-forming"--any agent or agents capable of forming a
gelatinous material either alone or in combination.
[0070] "delivery device"--an apparatus or system capable of
depositing a solution, powder, concentrate, a single reagent and/or
multiple reagents.
[0071] "pro-fibroblastic" agent--one or more compounds capable of
retaining, inducing proliferation of and/or recruiting fibroblasts
cells.
[0072] "compliance"--the ability of a blood vessel or a cardiac
chamber to change its volume in response to changes in pressure has
important physiological implications. In physical terms, the
relationship between a change in volume (.DELTA.V) and a change in
pressure (.DELTA.P) is termed compliance (C), where
C=.DELTA.V/.DELTA.P. Compliance, therefore, is related to the ease
by which a given change in pressure causes a change in volume. In
biological tissues, the relationship between .DELTA.V and .DELTA.P
is not linear. Compliance is the slope of the line relating volume
and pressure that decreases at higher volumes and pressures.
Another way to view this is that the "stiffness" of the chamber or
vessel wall increases at higher volumes and pressures. Changes in
compliance have important physiological effects in cardiac chambers
and blood vessels.
DETAILED DESCRIPTION
[0073] In the following section, several embodiments of, for
example, processes, compositions, devices and methods are described
in order to thoroughly detail various embodiments. It will be
obvious though, to one skilled in the art that practicing the
various embodiments does not require the employment of all or even
some of the specific details outlined herein. In some cases, well
known methods or components have not been included in the
description in order to prevent unnecessarily masking various
embodiments.
[0074] Methods and compositions to treat a ventricle after a
myocardial infarction (MI) are disclosed. In one embodiment, the
infarct region or the area of the ventricle containing the infarct
injury may be treated alone or in combination with other
treatments. One benefit to such treatment is that the region of
injury may be targeted with little or no affect on the outlying
healthy heart tissue. In addition, another benefit of such
treatment is that the treatment may prevent the loss of
functionality of a region of injury due to the normal remodeling
and scar forming procedure to mend an infarct region. Another
benefit may be that the treatment may increase the compliance of
the ventricle. Still another benefit is the reduction in thinning
of a ventricular wall of an infarct zone. In the following
description, structural reinforcement of the infarct region of the
ventricle is described. Since most myocardial infarctions occur in
the left ventricle most descriptions will be directed towards left
ventricle repair. But, it is appreciated that treatment of the
right ventricle may be achieved in a similar manner.
[0075] If the remodeling of the infarct region could be modified
prior to scar formation and ultimate thinning of the ventricular
wall, functional tissue may be rescued. The inhibition of scar
formation and guided regeneration of viable cells would lead to
increased wall strength and decreased collagen deposition, instead
of thinning and hypertrophied myocytes. Further, decreasing the
probability of wall thinning and fortifying the influx of
structural components such as fibroblasts might be beneficial and
preferred over the current treatment of an MI, namely continual
exposure to systemic drugs to treat the symptoms and not the
disease. Another benefit may be that any one of the treatments
herein may result in an increase in compliance of the ventricle.
Thus, any one or more combinations of these treatments may provide
a potential for healing the infarct region and prevention of
further complications.
[0076] In other embodiments, a kit (e.g., a pre-manufactured
package) is disclosed. A suitable kit includes at least one agent
and a lumen to house the agent. The agent has a property that may
increase the modulus (tensile strength, "stiffness") of elasticity
of the infarct region, increase compliance of the ventricle and/or
prevent or reduce thinning caused by remodeling. The kit may be
suitable, in one example, in the methods described.
Mapping of the Heart
[0077] In each of the methods described herein, it is appreciated
that specific areas of the heart may be targeted for application of
any of the incorporated methods, thus there are techniques
previously described that may be used for targeting the infarct
region. One example of targeting a specific region such as an
infarct zone uses a technique known as mapping the heart (U.S. Pat.
No. 6,447,504). The data are acquired by using one or more
catheters that are advanced into the heart. These catheters usually
have electrical and location sensors in their distal tips. Some of
the catheters have multiple electrodes on a three-dimensional
structure and others have multiple electrodes distributed over a
surface area. One example of the later catheter may be a sensor
electrode distributed on a series of circumferences of the distal
end portion, lying in planes spaced from each other. These
techniques provide methods to characterize the condition of the
heart in some situations using electrical potentials in the heart
tissue as well as using electromechanical mapping, ultrasonic
mapping to map the viable and the non-viable regions of the heart
for example the left ventricle and the infarct zone. In addition,
the ultrasound waves may be used to determine the thickness of the
heart tissue in the vicinity of the probe for example, sensing the
characteristic of the heart tissue by analyzing the ultrasound
signals to determine the depth of the channels. Another method
known as viability mapping (for example Spect, MRI, PET) may also
be used. Viability mapping may be used to identify areas of the
heart that are ischemic but still viable as well as area that have
lost their viability due to infarction. These maps are based on
electrophysiological data that indicate the flow of activation
signals through the heart tissue. In addition, the data may be
biomedical and/or mechanical data for example, variations in the
thickness of the heart wall between systolic and diastolic stages
of the heart cycle. The data that is used to analyze the heart by
mapping may also be a combination of electro-physiological and
biomedical data in order to more accurately locate and target the
infarct region. In absence of viability mapping devices, it is
appreciated that the location of the infarction may be also
assessed through LV angiography or echo, where location of the
akinetic or hypokinetic region may be identified.
Delivery Systems
[0078] Any one or more catheters may be used to deliver the any one
or multiple components of the embodiments to the infarct region
area. Several catheters have been designed in order to precisely
deliver agents to a damaged region within the heart for example an
infarct region. Several of these catheters have been described
(U.S. Pat. Nos. 6,102,926; 6,120,520; 6,251,104; 6,309,370;
6,432,119; 6,485,481). The delivery device may include an apparatus
for intracardiac drug administration, including a sensor for
positioning within the heart, a delivery device to administer the
desired agent and amount at the site of the position sensor. The
apparatus may include, for example, a catheter body capable of
traversing a blood vessel and a dilatable balloon assembly coupled
to the catheter body comprising a balloon having a proximal wall. A
needle may be disposed within the catheter body and includes a
lumen having dimensions suitable for a needle to be advanced
therethrough. The needle body includes an end coupled to the
proximal wall of the balloon. The apparatus also includes an
imaging body disposed within the catheter body and including a
lumen having a dimension suitable for a portion of an imaging
device to be advanced therethrough. The apparatus may further
include a portion of an imaging device disposed within the imaging
body adapted to generate imaging signal of the infarct region
within the ventricle. The apparatus may be suitable for accurately
introducing a treatment agent at a desired treatment site.
[0079] In another embodiment, a needle catheter used to deliver the
agent to the ventricle for example, the infarct region, may be
configured to include a feedback sensor for mapping the penetration
depth and location of the needle insertion. The use of a feedback
sensor provides the advantage of accurately targeting the injection
location. Depending on the type of agent administered, the target
location for delivering the agent may vary. For example, one agent
may require multiple small injections within an infarct region
where no two injections penetrate the same site.
[0080] In other embodiments, the catheter assembly may include a
maneuverable instrument. This catheter assembly includes a flexible
assembly. The catheter assembly may be deflectable and includes a
first catheter, a second catheter, and a third catheter. The second
catheter fits coaxially within the first catheter. At least one of
the first catheter and the second catheter include a deflectable
portion to allow deflection of that catheter from a first position
to a second position, and the other of the first catheter and
second catheter includes a portion which is pre-shaped (e.g., an
angled portion formed by two segments of the angled portion). The
third catheter has a sheath and a medical instrument positioned
within the sheath. The third catheter fits coaxially within the
second catheter. In another embodiment, a stabilizer, such as a
donut-shaped balloon, is coupled to a distal portion of the third
catheter. Each catheter is free to move longitudinally and radially
relative to the other catheters. The catheter assembly may be used
but not limited to the local delivery of bioagents, such as cells
used for cell therapy, one or more growth factors for fibroblast
retention, or vectors containing genes for gene therapy, to the
left ventricle. In one embodiment, the catheter assembly described
may be used in delivering cell therapy for heart failure or to
treat one or more portions of the heart that are ischemic. The
catheter assembly uses coaxially telescoping catheters at least one
or more being deflectable, to position a medical instrument at
different target locations within a body organ such as the left
ventricle. The catheter assembly may be flexible enough to bend
according to the contours of the body organ. The catheter assembly
may be flexible in that the catheter assembly may achieve a set
angle according to what the medical procedure requires. The
catheter assembly will not only allow some flexibility in angle
changes, the catheter assembly moves in a three coordinate system
allowing an operator greater control over the catheter assembly's
movement portion of the second catheter, allowing for the distal
tip of the third catheter to be selectively and controllably placed
at a multitude of positions. It will be appreciated that the
deflectable portion may alternatively be on the second catheter and
the preshaped portion may be on the first catheter.
[0081] In a further embodiment, an apparatus is disclosed. In one
embodiment, the apparatus includes a first annular member having a
first lumen disposed about a length of the first annular member,
and a second annular member coupled to the first annular member
having a second lumen disposed about a length of the second annular
member, wherein collectively the first annular member and the
second annular member have a diameter suitable for placement at a
treatment site within a mammalian body. Representatively, distal
ends of the first annular member and the second annular member are
positioned with respect to one another to allow a combining of
treatment agents introduced through each of the first annular
member and the second annular member to allow a combining of
treatment agents at the treatment site. Such an apparatus is
particularly suitable for delivering a multi-component gel material
(e.g., individual components through respective annular members
that form a bioerodable gel within an infarct region of a
ventricle).
[0082] In the embodiments described herein, a substance delivery
device and a method for delivering a substance are disclosed. The
delivery device and method described are particularly suitable, but
not limited to, local drug delivery in which a treatment agent
composition (possibly including multiple treatment agents and/or a
sustained-release composition) is introduced via needle delivery to
a treatment site within a mammalian host. A kit of a treatment
agent composition is also described. One suitable application for a
delivery device is that of a catheter device, including a needle
delivery system. Suitable therapies include, but are not limited
to, delivery of drugs for the treatment of arterial restenosis,
therapeutic angiogenesis, or cancer treatment drugs/agents.
[0083] In other embodiments, larger doses of treatment agent may be
considered for example about 2 mL to about 250 mL that may require
any one or more of the delivery devices such as intra-venous retro
infusion, intra-arterial infusion and needle catheter systems
(INVIGOR available from Abbott Vascular, Santa Clara, U.S.A.) as
well as subxyphoid approaches.
[0084] Various apparatuses (devices) and methods described herein
can be used as a stand-alone injection needle/catheter during a
surgical procedure such as an open heart surgery (e.g., Coronary
Bypass Graft (CABG)) procedure in which areas of the heart may be
treated with, for example, growth factors, for affecting
therapeutic angiogenesis, or incorporated into a catheter-based
system to access locations that are commonly used in percutaneous
transluminal coronary artery (PTCA) procedures. The apparatuses and
methods may similarly be used in other surgical procedures such as
cancer-related procedures (e.g., brain, abdomen, or colon cancer
procedures or surgeries). Additionally, various apparatuses and
methods described herein can be used in conjunction with various
catheter-related or endoscopy procedures that generally require
minimal invasiveness to deliver a specific drug or growth factor
into tissue.
[0085] One concern of introducing any treatment agent composition,
whether adjacent a blood vessel to affect therapeutic angiogenesis,
adjacent to a tumor to inhibit tumor growth, or to induce or
stimulate collagen growth in endoscopic procedures, is that the
composition remains (at least partially) at the treatment site for
a desired treatment duration (or a portion of the treatment
duration). In this manner, an accurate amount may be placed at a
treatment site with reduced concern that the treatment agent will
disperse, perhaps with serious consequences. In one embodiment, a
composition and technique for retaining a treatment agent at a
treatment site (injection site) is described. In one embodiment, a
treatment agent and a bioerodable gel or non-bioerodable gel or
particle may be introduced at a treatment site (e.g., an injection
site). The gel or particle(s) may be introduced prior to, after, or
simultaneously with the treatment agent. In one embodiment, the gel
or particle(s) acts to retain the treatment agent at the treatment
site by, representatively, sealing the treatment site or sealing
the treatment agent at the treatment site. The use of a gel or
particle(s) with a treatment agent can reduce the amount of
treatment agent backflow from the injection site as well as reduce
the load requirement of the treatment agent at the treatment site.
For example, a bioerodable product such as a gel or particle may
decrease the local pressure thereby further resulting in backflow
reduction. A non-bioerodable product may also decrease the local
pressure to reduce the backflow in a more permanent fashion and at
the same time may also lead to an increase in compliance.
[0086] Using the above-mentioned techniques, an imaging modality
may be added such as a contrast-assisted fluorescent scope that
permits a cardiologist to observe the placement of the catheter tip
or other instrument within the heart chamber. The contrast-assisted
fluoroscopy utilizes a contrast agent that may be injected into
heart chamber and then the area viewed under examination by a
scope, thus the topography of the region is more easily observed
and may be more easily treated (U.S. Pat. Nos. 6,385,476 and
6,368,285). Suitable imaging techniques include, but are not
limited to, ultrasonic imaging, optical imaging, and magnetic
resonance imaging, for example, Echo, ECG, SPECT, MRI, Angiogram.
Therefore, mapping of the heart is one technique that may be used
in combination with the techniques proposed in the following
embodiments. In one embodiment, an echo angiograph may be performed
to confirm the occurrence and the location of the infarct region.
In another embodiment, a CAT scan may be performed to confirm an MI
has occurred and to confirm the location of the infarct region. In
another embodiment an EKG may be performed to identify the
occurrence and location of an infarct.
[0087] In another embodiment, a method may include introducing a
treatment agent in a sustained release composition. The preferred
period for sustained release of one or more agents is for a period
of one to twelve weeks, preferably two to eight weeks. Methods for
local delivery of sustained release agents include but are not
limited to percutaneous devices for example intra-ventricular
(coronary) or intravascular (coronary and peripheral) devices.
Fibroblast Retention and Recruiting Agents
Agents
[0088] FIG. 4 describes one embodiment of a method to treat an
infarct region of a left ventricle. This is an illustrative diagram
only and any of the treatments may be used in parallel (e.g., at
the same time) or sequentially or in any treatment combination.
According to the method illustrated in FIG. 4, a myocardial
infarction may be detected by an imaging process for example
magnetic resonance imaging, optical imaging or ultrasonic imaging
for example Echo ECG, spect, MRI, angiogram 410. Next, the area of
the left ventricle is reinforced 410 by retention or recruitment of
surrounding fibroblasts cells 420. In FIG. 4 one option to
encourage the fibroblast occupancy of the infarct zone includes the
use of swellable material 430 delivered to the infarct zone.
Another method, summarized in FIG. 4 (440) to encourage the
occupancy of fibroblasts to the infarct zone includes the delivery
of tropo-elastin to the site. It has been demonstrated that
injections of fibroblasts into a scar region may improve the
structural integrity of a terminally injured heart in a rabbit
model. See Hutcheson, K. A., et al., Comparison of Benefits on
Myocardial Performance of Cellular Cardiomyoplasty with Skeletal
Myoblasts and Fibroblasts, Cell Transplant, May-June 2000, pp.
359-368, 9(3). Since the fibroblasts naturally infiltrate the scar
during the healing process, it would be beneficial to attract these
cells in larger numbers, or to induce their proliferation in the
infarct region such that fibroblasts are encouraged to remain in
the region for a prolonged period or permanently remain in the
region. In addition, a further benefit of retaining fibroblasts in
an infarct region may be to convert the fibroblast phenotype such
as influencing the conversion from non-contractile cell to a
muscular cell. The conversion is promoted in the presence of growth
factors for example TGF-.beta.1 (transforming growth factor beta
1). Therefore, the infarct region may be treated with agents that
encourage fibroblast retention and recruitment. Suitable treatment
agents that may modify or recruit fibroblasts include but are not
limited to, Angiotensin II, fibroblast growth factor (FGF basic and
acidic), insulin growth factor (IGF), TGF-.beta. in any of its
isoforms, vascular endothelial growth factor (VEGF) in any of its
isoforms, tumor necrosis factor-alpha (TGF-.alpha.),
platelet-derived growth factor-BB (PDGF-BB), angiogenin,
angiopoietin-1, Del-1, follistatin, granulocyte colony-stimulating
factor (G-CSF), pleiotrophin (PTN), proliferin, transforming growth
factor-alpha (TGF-(.alpha.), vascular permeability factor (VPF),
and LIH (leukemia inhibitory factor) genes that encode these
proteins, transfected cells carrying the genes of these proteins,
small molecules and pro-proteins that also contain these recruiting
properties.
[0089] In one embodiment, basic fibroblast growth factor may be
introduced to the infarct region by at least one of the methods
described. In one embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 1
ml. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 300
.mu.l. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 100
.mu.l. In a preferred embodiment, the any of the described agents
may be introduced in one or more doses in a volume of about 1 .mu.l
to 50 .mu.l.
[0090] In alternate embodiments, the treatment volume may be larger
(e.g., intravenous pressure perfusion (IV) route). These volumes
may range from about 2 ml to about 250 ml. Alternatively, these
volumes may range from about 2 ml to about 100 ml. In other
embodiments, these volumes may range from about 2 ml to about 30
ml.
Sequence of Treatment
[0091] FIG. 4 illustrates a flow chart of a process for treating MI
by retaining and recruiting fibroblasts. FIGS. 5A-5E illustrate the
introduction and action of fibroblast retention and recruitment.
Detection of acute myocardial necrosis may be performed using an
ECG (electrocardio-cardiogram) or by a more modern technology. For
example, one technology such as .sup.99mTechnetium-pyrophosphate or
.sup.111In-antimyosin antibody imaging has recently been approved
by the Food and Drug Administration. With both these two tracers,
results are obtained only 24-48 hours after acute infarction and
therefore, the clinical utility of these techniques have been
limited. There is another new agent called .sup.99mTc-glucurate
that produces results within an hour after acute myocardial
infarction. See Iskandrian, A. S., et al., Nuclear Cardiac Imaging:
Principles and Applications, 1996, 2.sup.nd Ed. Once the MI is
detected the exact location of the infarct may be identified using
a magnetic resonance imaging then the ventricle infarct region may
be treated by reinforcement 501. An agent 520 (for example,
tropoelastin) is introduced to the infarct region 510. One way the
agent may be introduced to the area is percutaneously, with the use
of a catheter. A distal end of the catheter is advanced to the
infarct zone 530, 540, or 550 and the agent 520 is released. Then
the fibroblasts 560 are recruited to the site or retained 570. FIG.
5E illustrates the fibroblast reinforcement of the infarct
area.
Description of Several Possible Treatment Agent(s) and
Deliveries
[0092] Tropoelastin
[0093] FIGS. 5A-5E describe the combination of promoting fibroblast
retention and migration into the infarct region with the addition
of, for example, tropoelastin 520. Elastin is a highly pliable
extracellular protein. In vivo, it is usually in a cross-linked
insoluble state. A linear uncross-linked soluble precursor is
available that is referred to as tropoelastin. Tropoelastin 520 can
be made by recombinant methods and is commercially available.
Tropoelastin is an approximately 70-kDa protein consisting of
alternating hydrophobic regions, responsible for elasticity, and
cross-linking domains. Additionally, it ends with a hydrophilic
carboxy-terminal sequence containing its only two
cysteine-residues. Tropoelastin is a protein that is prominent in
the skin of an infant and as one matures less and less of this
protein is made. Tropoelastin is sometimes used as an important
marker of some heart conditions such as MI since it is released
into the bloodstream following heart injury. The production of
recombinant tropoelastin in bacterial systems has greatly
simplified the availability of tropoelastin. In addition, it
provides a valuable means for obtaining human tropoelastin.
Purification from human aortas was greatly simplified compared with
tissue extraction methods but relatively low yields were obtained.
The purification from the aortas posed the potential for
degradation of the polypeptide. Recently, human tropoelastin cDNA
has also been expressed in bacteria as a fusion with influenza NS1
protein. See Indik, Z., et al., Production of Recombinant Human
Tropoelastin: Characterization and Demonstration of Immunologic and
Chemotactic Activity, Arch. Biochem. Biophys., July 1990, pp.
80-86, 280(1). This isoform of tropoelastin, containing exon 26A
and the signal peptide, was the first form of human tropoelastin to
be obtained for study. In view of tropoelastin's extreme amino acid
usage, a synthetic human tropoelastin gene has been constructed
containing codons designed to optimize expression in E. coli. See
Martin, S. L., et al., Total Synthesis and Expression in
Escherichia coli of a Gene Encoding Human Tropoelastin, Gene, Mar.
10, 1995, pp. 154-166, 154(2). This synthetic gene is expressed at
high levels in soluble form both as a fusion with glutathione
S-transferase and directly, as the mature polypeptide.
Alternatively, a simplified purification scheme using alcohol
dissolution and eliminating the need for cyanogen bromide (CNBr)
treatment resulted in significantly higher yields. Therefore,
purified or genetically engineered tropoelastin is available.
Recombinant forms of tropoelastin have proved to be viable
alternatives to tissue-derived tropoelastin. Recombinant
tropoelastin reacts with elastin antibodies, is a chemotactic
agent, demonstrates coacervation ability and has the some similar
characteristics to naturally occurring tropoelastin (i.e., circular
dichroism).
[0094] In one embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 1
ml. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 300
.mu.l. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 100
.mu.l. In a preferred embodiment, any of the described agents may
be introduced in one or more doses in a volume of about 1 .mu.l to
about 50 .mu.l.
Microparticles and Growth Factors Delivery
[0095] One embodiment of a composition suitable for the described
method includes the use of a bioerodable microparticle harboring
one or more of the aforementioned growth factors. The bioerodable
microparticle may consist of a bioerodable polymer such as poly
(lactide-co-glycolide). The composition of the bioerodable polymer
is controlled to release the growth factor over a period of 1-2
weeks. It was previously demonstrated that biodegradable
microparticles for example, poly (lactide-co-glycolide) were
capable of controlled release of an oligonucleotide. These
microparticles were prepared by the multiple emulsion-solvent
evaporation technique. In order to increase the uptake of the
oligonucleotide into the microparticles it was accompanied by
polyethylenimine (PEI). The PEI also tended to make the
microparticles more porous thus facilitating the delivery of the
oligonucleotide out of the particles. See De Rosa, et al.,
Biodegradable Microparticles for the Controlled Delivery of
Oligonucleotides, Int J. Pharm., Aug. 21, 2002, pp. 225-228,
242(1-2). In one preferred embodiment of a composition, the
bioerodable microparticle may be a PLGA polymer 50:50 with
carboxylic acid end groups. PLGA is a base polymer often used for
controlled release of drugs and medical implant materials (i.e.,
anti-cancer drugs such as anti-prostate cancer agents). Two common
delivery forms for controlled release include a microcapsule and a
microparticle (e.g., a microsphere). The polymer and the agent are
combined and usually heated to form the microparticle prior to
delivery to the site of interest (Mitsui Chemicals, Inc). As the
microparticles erode 560, a porous network of the microparticle
composition is formed 570 in the infarct region resulting in a
matrix with a controlled pore size 580. As the porous network is
formed at least one angiogenic and/or pro-fibroblastic factor may
be released encouraging the in-growth of new capillaries. One
embodiment, the bioerodable polymer harbors the growth factor
TGF-.beta.1. In one embodiment, the PLGA polymer 50:50 with
carboxylic acid end groups harbors TGF-.beta.1 for slow release. It
is preferred that each microparticle may release at least 20
percent of its contents and more preferably around 90 percent of
its contents. In one embodiment, the microparticle harboring at
least one angiogenic and/or pro-fibroblastic agent will degrade
slowly over time releasing the factor or release the factor
immediately upon contact with the infarct area in order to rapidly
recruit fibroblasts to the site. In another embodiment, the
microparticles may be a combination of controlled-release
microparticles and immediate release microparticles. A preferred
rate of deposition of the delivered factor will vary depending on
the condition of the subject undergoing treatment.
[0096] Another embodiment of a composition suitable for the
described method includes the use of non-bioerodable microparticles
that may harbor one or more of the aforementioned growth factors.
The growth factors may be released from the microparticle by
controlled-release or rapid release. The microparticles may be
placed directly in the infarct region. By directly placing the
particles in the infarct region, they may also provide bulk for the
region for reinforcement. The non-bioerodable microparticle may
consist of a non-bioerodable polymer such as an acrylic based
microsphere, for example, a tris acryl microsphere (provided by
Biosphere Medical). In one embodiment, non-bioerodable
microparticles may be used alone or in combination with an agent to
increase compliance of a ventricle. In another embodiment,
non-bioerodable microparticles may be used alone or in combination
with an agent to recruit fibroblasts and/or stimulate fibroblast
proliferation. In addition, non-bioerodable microparticles may be
used to increase compliance and recruit fibroblasts to an infarct
region of a ventricle.
[0097] In one embodiment, the treatment agent compositions suitable
for reinforcement of the infarct zone are rendered resistant to
phagocytosis by inhibiting opsonin protein absorption to the
composition of the particles. In this regard, treatment agent
compositions including sustained release carriers include particles
having an average diameter up to about 10 microns. In other
situations, the particle size may range from about 1 mm to about
200 mm. The larger size particles may be considered in certain
cases to avoid macrophage frustration and to avoid chronic
inflammation in the treatment site. When needed, the particle size
of up to 200 mm may be considered and may be introduced via an
intraventricular catheter or retrograde venous catheter for any of
the embodiments herein to avoid chronic inflammation due to
macrophage influx into the treatment site.
[0098] One method of inhibiting opsonization and subsequent rapid
phagocytosis of treatment agents is to form a composition
comprising a treatment agent disposed with a carrier for example a
sustained release carrier and to coat the carrier with an opsonin
inhibitor. One suitable opsonin-inhibitor includes polyethylene
glycol (PEG) that creates a brush-like steric barrier to
opsonization. PEG may alternatively be blended into the polymer
constituting the carrier, or incorporated into the molecular
architecture of the polymer constituting the carrier, as a
copolymer, to render the carrier resistant to phagocytosis.
Examples of preparing the opsonin-inhibited microparticles include
the following.
[0099] For the encapsulation polymers, a blend of a polyalkylene
glycol such as polyethylene glycol (PEG), polypropylene 1,2-glycol
or polypropylene 1,3-glycol is co-dissolved with an encapsulating
polymer in a common organic solvent during the carrier forming
process. The percentage of PEG in the PEG/encapsulating polymer
blend is between five percent and 60 percent by weight. Other
hydrophilic polymers such as polyvinyl pyrolidone, polyvinyl
alcohol, or polyoxyethylene-polyoxypropylene copolymers can be used
in place of polyalkylene glycols, although polyalkylene glycols and
more specifically, polyethylene glycol is generally preferred.
[0100] Alternatively, a diblock or triblock copolymer of an
encapsulating polymer such as poly (L-lactide), poly (D,L-lactide),
or poly (lactide-co-glycolide) with a polyalkylene glycol may be
prepared. Diblocks can be prepared by: (i) reacting the
encapsulating polymer with a monomethoxy polyakylene glycol such as
PEG with one protected hydroxyl group and one group capable of
reacting with the encapsulating polymer, (ii) by polymerizing the
encapsulating polymer onto the monomethoxy polyalkylene glycol,
such as PEG, with one protected group and one group capable of
reacting with the encapsulating polymer; or (iii) by reacting the
encapsulating polymer with a polyalkylene glycol such as PEG with
amino functional termination. Triblocks can be prepared as
described above using branched polyalkylene glycols with protection
of groups that are not to react. Opsonization resistant carriers
(microparticles/nanoparticles) can also be prepared using the
techniques described above to form sustained-release carriers
(microparticles/nanoparticles) with these copolymers.
[0101] A second way to inhibit opsonization is the biomimetic
approach. For example, the external region of cell membrane, known
as the "glycocalyx," is dominated by glycoslylated molecules that
prevent non-specific adhesion of other molecules and cells.
Surfactant polymers consisting of a flexible poly (vinyl amine)
backbone randomly-dextran and alkanoyl (hexanoyl or lauroyl) side
chains which constrain the polymer backbone to lie parallel to the
substrate. Hydrated dextran side chains protrude into the aqueous
phase, creating a glycocalyx-like monolayer coating that suppresses
plasma protein deposition on the foreign body surface. To mimic
glycocalyx, glycocalyx-like molecules can be coated on the carriers
(e.g., nanoparticles or microparticles) or blended into a polymer
constituting the carrier to render the treatment agent resistant to
phagocytosis. An alternate biomimetic approach is to coat the
carrier with, or blend in, phosphorylcholine or a synthetic mimetic
of phosphatidylcholine, into the polymer constituting the
carrier.
[0102] For catheter delivery, a carrier comprising a treatment
agent (e.g., the composition in the form of a nanoparticle or
microparticle) may be suspended in a fluid for delivery through the
needle, at a concentration of about one percent to about 20 percent
weight by volume. In one embodiment, the loading of the treatment
agent in a carrier is about 0.5 percent to about 30 percent by
weight of the composition. Co-encapsulated with protein or small
molecule treatment agents could be stabilizers that prolong the
biological half-life of the treatment agent in the carrier upon
injection into tissue. Stabilizers may also be added to impart
stability to the treatment agent during encapsulation. Hydrophilic
polymers such as PEG or biomimetic brush-like dextran structures or
phosphorylcholine are either coated on the surface or the carrier,
grafted on the surface of the carrier, blended into the polymer
constituting the carrier, or incorporated into the molecular
architecture of the polymer constituting the carrier, so the
carrier is resistant to phagocytosis upon injection into the target
tissue location.
[0103] Any one or more catheters may be used to deliver the any one
or multiple components of the embodiments to the infarct region
area. Several catheters have been designed in order to precisely
deliver agents to a damaged region within the heart, for example,
an infarct region. Several of these catheters have been described
(U.S. Pat. Nos. 6,309,370; 6,432,119; 6,485,481). The delivery
device may include an apparatus for intracardiac drug
administration, including a sensor for positioning within the
heart, a delivery device to administer the desired agent and amount
at the site of the position sensor.
Angiogenesis
[0104] After an MI, the infarct tissue as well as the border zone
and the remote zone begin to remodel. The scar tissue forms in the
infarct region as the granulation is replaced with collagen,
causing the scar to thin out and stretch. The perfusion in this
region is typically 10% of the healthy zone, decreasing the number
of active capillaries. Increasing the number of capillaries may
lead to an increase in compliance of the ventricle due to filling
up with blood. Other benefits of increasing blood flow to the
infarcted region include providing a route for circulating stem
cells to seed and proliferate in the infarct region. Angiogenesis
may also lead to increased oxygenation for the surviving cellular
islets within the infarct region, or to prime the infarct region
for subsequent cell transplantation for myocardial regeneration. In
the border zone, surviving cells would also benefit from an
increase in blood supply through an angiogenesis process. In the
remote zone, where cardiac cells tend to hypertrophy and become
surrounded wit some interstitial fibrosis, the ability of cells to
receive oxygen and therefore function to full capacity are also
compromised; thus, angiogenesis would be beneficial in these
regions as well. In one embodiment, angiogenesis will be stimulated
in ay region of the heart--infarct, border or remote--through
delivery of agiogenesis-stimulating factors. Examples of these
factors include but are not limited to isoforms of VEGF (e.g.,
VEGF121), FGF (e.g., b-FGF), Del 1, HIF 1-alpha (hypoxia inducing
factor), PR39, MCP-1 (monocyte chemotractant protein), Nicotine,
PDGF (platelet derived growth factor), IGF (Insulin Growth Factor),
TGF alpha (Transforming Growth Factor), HGF (Hepatocyte growth
factor), estrogens, Follistatin, Proliferin, Prostaglandin E1, E2,
TNF-alpha (tumor necrosis factor), Il-8 (Interleukin 8),
Hemotopoietic growth factors, erythropoietin, G-CSF (granulocyte
colony-stimulating factors), PD-ECGF (platelet-derived endothelial
growth factor), Angiogenin. In other embodiments, these factors may
be provided in a sustained release formulation as an independent
factor or in combination with other factors or appropriate gene
vectors with any of the gel or microparticle components described
in this application.
Microparticles and Angiogenic and Pro-Fibroblastic Agents
[0105] The microparticles may be prepared as microparticles
harboring anangiogenic and/or pro-fibroblastic agent. On the other
hand, the microparicles may be prepared and then the angiogenic
and/or pro-fibroblastic agent introduced into the microparticle,
for example, by diffusion prior to introduction to the infarct
region. In the later example. the microparicles might also be
coated with the factor and upon introduction to the infarct region
the factor immediately recruits fibroblasts to the area.
Additionally, the microparticle-factor composition might consist of
any combination of the above-mentioned treatments. In other
embodiments, it may be necessary to add at least one
pharmaceutically acceptable inhibitor to the microparticles that
prevents decomposition of the angiogenic or pro-fibroblastic
agent.
Microparticle Components
[0106] FIG. 4 describes a method to structurally reinforce the
infarct region. This method may be combined with any of the methods
describing introducing angiogenic and/or fibroblast-recruiting
agents, for example growth factors, to the infarct region to retain
and/or promote fibroblast migration to this zone. Microparticles
capable of taking up fluid will be introduced to the infarct
region. Examples of these microparticles include swellable
non-biological or synthetic biological particles. The
microparticles are introduced to the infarct zone and become
trapped in the tissue. The microparticles tend to immediately start
to swell. The swollen microparticles remain lodged in the tissue
and provide reinforcement to the ventricular wall and add thickness
to the thinning infarct region.
[0107] The dimensions of the infarct zone may determine the size
range of the microparticles and the number of microparticles
introduced to the infarct region. This will insure that the optimum
post-hydrated microparticle mass is achieved. An embodiment relates
to microparticles that are about 200 microns or less in diameter.
In another embodiment the microparticles may be about 20 microns or
less in diameter. In a preferred embodiment, the particle size may
be about 5-10 microns in diameter. Particles of about 20 microns or
less may also include an opsonization inhibitor (previously
discussed). The swellable microparticles may be a range of sizes
introduced to the infarct region. In one embodiment, the swellable
non-biological material may be a hydrogel microsphere material.
These microparticles are available commercially (A.P. Pharma or
BioSphere Medical). These microparticles are resistant to
non-specific absorption and are bio-stable.
[0108] In other embodiments, hydrogels may be used as a treatment
for a myocardial infarction. Examples of hydrogel materials are
high molecular weight polyacrylamide or high molecular weight
polyvinylpyrrolidone (PVP). Typically, the monomer supplied in
these products contains di-functional monomers such as di-vinyl
benzene, ethylene glycol dimethylacrylate or bis-acrylamide acetate
resulting in the formation of a cross-linked network resistant to
dissolution in an aqueous environment or to stimulate controlled
magnitude angiogenic response. These components may be used to
generate microspheres. Alternatively the di-functional polymers may
be used to synthesize a hydrogel microsphere.
[0109] In one embodiment of the invention the first component of a
biosynthetic polymeric gel may be (acrylamidomethyl) cellulose
acetate propionate and the second component may be a dithiol
functional polyethylene glycol polymer (such as sold by Shearwater
Polymers). In another embodiment, the first component of a
biosynthetic polymeric gel may be (acrylamidomethyl) cellulose
acetate propionate and the second component may be a reduced
peptide sequence. In a further embodiment, the reduced peptide
sequence could be biologically derived such as the amino acid
sequence,
glycine-cysteine-tyrosine-lysine-asparagine-ginine-aspartic
acid-cysteine-glycine. A dual bore needle system may deliver both
components separately one at a time or simultaneously to an infarct
zone. The thiol-group(s) of the thiol-containing component may
undergo nucleophilic addition to the acrylamide functional group of
the first component. This forms the elastomeric structural
reinforcing gel.
[0110] In other embodiments, the delivery of a nonbiologic or
synthetic gel may be combined with angiogenic and/or fibroblast
recruiting agents utilizing microparticles capable of releasing the
agents at a rate optimal for fibroblast retention and migration in
the infarct region.
[0111] In one embodiment, tropoelastin suspended in a solution,
such as saline, is introduced to the infarct region for structural
reinforcement of the ventricular wall. Another embodiment includes
the introduction of tropoelastin suspended in saline in the
presence of copper ions. Another embodiment includes the
introduction of tropoelastin in the presence of a converting
enzyme. Another embodiment includes the introduction of
tropoelastin in the presence of lysyl oxidase. Once introduced to
the infarct zone, the solution forms elastin by cross-linking via a
lysine residue oxidation. The cross-linked elastin remains in the
infarct region to fortify the tissue and enhance the modulus (wall
strength/elongation=modulus) of elasticity.
Methods for Introduction and Action
[0112] FIGS. 5A-5E illustrate the introduction and action of
pro-fibroblastic agents to the infarct region to recruit fibroblast
cell growth. The pro-fibroblastic agent may be introduced to the
site 500 by a minimally invasive procedure 510. The solution may be
injected in the infarct zone during an open chest procedure 520.
The introduction of the pro-fibroblastic agent(s) includes one of
the following procedures: sub-xiphoid and percutaneously 530. The
mode of introduction of the pro-fibroblastic agent(s) by a
percutaneous injection includes one of the following consisting of
an intraventricular (coronary) catheter, a transvascular needle
catheter, IC infusion and retrograde venous perfusion. One
percutaneous route for a catheter is via a femoral artery
traversing through and then across the aortic arch into the left
ventricle. Imaging techniques can guide the catheter to the infarct
region. The infarct region for example may be distinguished from
healthy tissue using MRI techniques. A catheter having imported the
MRI data may then be guided directly to the infarct region. Once
the agent 540 is distributed through out the infarct region 510,
the fibroblasts 560 may be attracted to the area by chemotactic
responses. The fibroblast cells that infiltrate the area may
proliferate in the area. Once the fibroblasts proliferate they form
a reinforcing mass to the region and strengthen the damaged site
510. The fibroblast in this aspect of the present invention may act
as a structural reinforcing agent in the infarct zone 570. These
cells add bulk to the area and replace the degraded myocytes that
normally lead to a thinning of the infarct regional wall. In turn,
the viable fibroblast cells release factors that may recruit other
cells into the area for further reinforcement of the infarct
zone.
[0113] In one embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 1
ml. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 300
.mu.l. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to
about 100 .mu.l. In a preferred embodiment, the any of the
described agents may be introduced in one or more doses in a volume
of about 1 .mu.l to about 50 .mu.l. If an agent is introduced via
an IV or an IC route the volumes may range from about 1 ml to about
500 ml.
[0114] Any one or more catheters may be used to deliver the any one
or multiple components of the embodiments to the infarct region
area. Several catheters have been designed in order to precisely
deliver agents to a damaged region within the heart for example an
infarct region. Several of these catheters have been described
(U.S. Pat. Nos. 6,309,370; 6,432,119; 6,485,481). The delivery
device may include an apparatus for intracardial drug
administration, including a sensor for positioning within the
heart, a delivery device to administer the desired agent and amount
at the site of the position sensor.
Multiple Component Systems for Infarct Reconstruction
Component One
[0115] To prevent heart failure, it has been proposed that
cardiomyocytes can be directly introduced into the infarct region
to restore cardiac function cells of various origins, including
embryonic and adult stem cells. The viability of tissue engineering
for a myocardial infarct zone requires that oxygen and nutrient
supplies are readily available, as well as a mode for removal of
waste products from cell metabolism. The cells in these areas also
need a supporting structure for adherence. The bioerodable gel with
angiogenic and/or fibroblast recruiting agents previously discussed
provides this later supporting structure. In the literature, it is
known that the introduction of scaffolding with a bore size of less
than 10 microns leads to a tightly fibrotic encapsulated scaffold
with poor capillary in-growth. On the other hand, as demonstrated
in FIG. 6 and 9, if the scaffolding pore diameter is around 20
microns, cellular encapsulation of the scaffold system is well
perfused with capillary in-growth leading to fibrotic poor cellular
rich region. One embodiment includes scaffolding that is introduced
to the infarct zone 610, 910 and acts as a mechanical
reinforcement. The force is distributed more evenly 990 at the
infarct region and ventricular remodeling is prevented.
[0116] In one embodiment, separate components are included to
provide a network such as described above. One example is described
in FIG. 6. A multi-component composition includes the first
component including the previously illustrated bioerodable matrix
or scaffolding 630, 990. In this particular composition, the matrix
(first component) provides a porous scaffolding to enhance
capillary in-growth. The microparticles of the first component may
be approximately 20 microns. In another embodiment, the first
component of the composition may be introduced by a minimally
invasive procedure 960; for example, the first component of the
composition may be introduced percutaneously. A distal end of the
catheter is advanced to the infarct zone 910 and the bioerodable
microparticles 920 are released. In a further embodiment, the first
component of the composition may be introduced via an
intra-ventricular needle device 930 to the infarct region. In a
further embodiment, an intra-ventricular needle device including
introducing multiple injections to the infarct region may introduce
the first component of the composition. The first component may
serve in one aspect as a domain to promote cell growth. In
addition, porosity may be controlled that leads to capillary
in-growth. The first component 920 may be a bioerodable
microparticle with growth factor and angiogenic potential. The
factor or other agent may release over a 1-2 week period. One
embodiment may be that the first component includes PLGA 50:50
(previously described) with carboxylic acid end groups. An example
of capillary in-growth to the domain provided by the first
component may be facilitated by the release of angiogenic factors
980. One embodiment includes microparticles containing angiogenic
factors 980 that release rapidly after introduction to the infarct
region. This tends to result in a rapid angiogenic response.
[0117] Biomaterials have been employed to conduct and accelerate
otherwise naturally occurring phenomena, such as tissue
regeneration in wound healing in an otherwise healthy subject; to
induce cellular responses that might not normally be present, such
as healing in a diseased subject or the generation of a new
vascular bed to receive a subsequent cell transplant; and to block
natural phenomena, such as the immune rejection of cell transplants
from other species or the transmission of growth factor signals
that stimulate scar formation in certain situations.
Component Two
[0118] A second component 640 of the multi component composition
according to the method may be an acrylate agent that is
biocompatible. A second component serves in one aspect to disperse
the first component in order to form a more uniform scaffold over
the entire infarct zone and may include border zone as well. It may
be an oligomeric, di- (or multi-) functional acrylate agent 930
based on a component that is biocompatible. An embodiment of the
two-component composition may include a second component 930
comprising the following group di-acryloyl polyethylene glycol,
tetra-acryloyl polyethylene glycol (PEG) or (acrylamidomethyl)
cellulose acetate propionate. In order to dissolve the acrylamide
functional cellulose component ethanol or a biocompatible is
required. The second component 930 disperses the microparticles
970/990 acting as a suspending media. It is known that PEG-coated
microparticles 990 are less inflammatory and are seen not to elicit
a fibrotic response. Thus, it in one aspect may serve as an
anti-opsonization agent. Thus, they serve as a camouflage from the
immune system for introduction of the microparticles to the infarct
region. One embodiment includes the injection of both the growth
factor containing microparticles and the scaffold-forming matrix
(acryloyl functional macromer) using a dual bore needle. FIG. 9D
illustrates the final formation of the scaffold gel 915. The
introduction of the two solutions simultaneously creates the near
instantaneous (around 10 seconds) formation of the gel with a
microparticle network embedded within the scaffold gel 915. As the
microparticles 925 decompose, growth factors are released promoting
the capillary formation within the matrix. In addition, cells begin
to grow in the infarct area 935. These cells release proteases that
may result in the decomposition of the scaffolding ultimately
creating additional area for cellular in-growth. In addition, the
cells secrete their own extracellular matrix, the polymer degrades
and the resulting tissue may eventually become a completely natural
environment. The decomposition products may be cleared from the
area by the renal system since capillary re-growth may occur.
Component Three
[0119] Another component of a multi component composition and
method is illustrated in 650 and 905. A third component includes
one of the following: thiol-containing peptide or a di- or
multi-functional biocompatible such as dithio-PEG. An example of a
thiol-containing peptide 905 may be polycysteine oligomers. An
example of this is a protected form of a polycysteine oligomer,
Poly-S-CBZ-L-cysteine or Poly-S-benzyl-L-cysteine (Sigma Chemical
P0263 and P7639 respectively). These agents can be de-protected
using standard organic chemistry protocols. See Berger, et al.,
Poly-L-cysteine, J. Am. Chem. Soc., Sep. 5, 1956, pp. 4483-4488,
78. The preparation of these thiol-containing agents is well known.
See Zervas, L., et al., On Cysteine and Cystine Peptides. II.
S-Acylcysteines in Peptide Synthesis, J. Am. Chem. Soc., May 5,
1963, pp. 1337-1341, 85(9). Additional agents that may function as
the third component of a multi-component composition may be
naturally occurring peptides. In one embodiment, the third
component of the multi-component scaffolding may be one of the
following consisting of Poly-S-CBZ-L-cysteine and
Poly-S-benzyl-L-cysteine. In another embodiment of a
multi-component composition, the third component of the
multi-component scaffolding may be a naturally occurring peptide.
In a further embodiment of a multi-component composition the third
component of a multi-component scaffolding may be the naturally
occurring peptide
glycine-cysteine-tyrosine-lysine-asparagine-arginine-aspartic
acid-cysteine-glycine peptide sequence. The third component
preferably contains at least two thiol groups. FIGS. 9A-9F
illustrate the introduction of the three components to the infarct
region to treat an MI. One embodiment may be the introduction of
the first component and the second component 920/930 through a dual
bore needle and then the introduction of a thiol-containing third
component 905 through a second needle. FIG. 9D illustrates a
schematic of the final structure 915 that subsequently recruits
fibroblast growth 935 and capillary 945 in-growth into the infarct
region. The thiol-containing component 905 may be used to decrease
the rate of decomposition of the scaffold and control release of
the fibroblast recruiting components of the microparticles.
[0120] Any one or more catheters may be used to deliver the any one
or multiple components of the embodiments to the infarct region
area. Several catheters have been designed in order to precisely
deliver agents to a damaged region within the heart for example an
infarct region. Several of these catheters have been described
(U.S. Pat. Nos. 6,309,370; 6,432,119; 6,485,481). The delivery
device may include an apparatus for intracardiac drug
administration, including a sensor for positioning within the
heart, a delivery device to administer the desired agent and amount
at the site of the position sensor.
Multi Component System for Infarct Reconstruction and Infarct
Reoxygenation
[0121] The progression of heart failure after an MI is a result of
the remodeling of the heart after infarct. In the remodeling
processes the heart becomes thinner and the diameter increases in
response to a decrease in heart output, in an effort to maintain a
continual cardiac output. This process of thinning results in an
increase in the radius of the heart and the stresses on the heart
increase.
[0122] It has been shown that perfluorocarbon compounds have a high
affinity for gases, for example carbon dioxide and oxygen. The
ability of perfluorocarbons to transport oxygen is approximately
eighteen times greater than blood plasma in a comparable volume of
each component. In addition, it was shown that the half-life for
oxygenation/deoxygenation is approximately three and one half times
faster for many perfluorinated compounds as compared to hemoglobin.
Thus, perfluoro compounds may be used in tissues to aid in the
reoxygenation of an affected region such as an infarct region. A
few examples that demonstrate biocompatibility in a subject are
identified in Table 1.
[0123] FIG. 7 illustrates the multi-component system in a
flowchart. The myocardial infarction is located 720. Then, the
components are delivered to the region via a minimally invasive
procedure by methods previously described and/or by catheter
delivery. It was previously disclosed that the addition of a thiol
functionality (FIG. 6, component 3) in the presence of an electron
deficient double bond, such as an acyloyl functionality (FIG. 6,
component 2), can undergo a Michael addition reaction. Under basic
conditions, the thiol functionality becomes hypernucleophilic and
rapidly (<10 seconds) forms a bond with the acryloyl
functionality (see FIG. 10). As illustrated in FIG. 6, a gel may be
formed to prevent infarct expansion and/or bulking, thus preventing
a remodeling of the heart that may lead to heart failure. FIG. 7
(730) illustrates the first component that includes a bioerodable
gel and 740 illustrates the gel accompanied by a perfluorinated
compound as the second component to enhance oxygenation of the
tissue. The gel is formed by a three-component system. The first
component includes a biocompatible polymer as previously described
with a multifunctional spacer group 730. The second component 840
includes a difunctional or multifunctional perfluorinated molecule
810. The third component 750 includes a hetero-functional molecule
with a reactive functionality on one side of the spacer group, and
a cell binding peptide sequence, such as the peptide sequences
previously described, on the terminal end. One example of a peptide
sequence includes the RGD sequence. FIG. 8 illustrates in schematic
form the reaction of the thiol component 800 and the acyloyl
functional group 820 to form one compound 830 of the
three-component system of FIG. 7. This three-component system may
be introduced to the infarct region by similar minimally invasive
methods as described for the methods of FIG. 6 that may be guided
by mapping the heart prior to administration of an agent. Examples
of this three-component system are discussed in the example
section.
[0124] In one embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 1
ml. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 300
.mu.l. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 100
.mu.l. In a preferred embodiment, the any of the described agents
may be introduced in one or more doses in a volume of about 1 .mu.l
to 50 .mu.l. IV and IC routes may be required which would involve
larger treatment volumes (for example about 2 ml to about 250
ml).
[0125] FIG. 10 illustrates the ester bond formed between the second
component (1000) and the third component (1010) of a
multi-component composition of FIG. 6. This bond (1020) is
necessary for delaying the degradation of the scaffolding and
release of the active agents within the microparticles. This bond
tends to resist degradation for approximately 2 months.
Swellable Agent Systems for Reinforcement
[0126] FIGS. 11A-11F illustrate the introduction of a swellable
non-biologic material to structurally reinforce and/or bulk the
infarct region. FIG. 11A illustrates the introduction of
microparticles 1130 to an infarct region 1110. Microparticles 1130
are shown accumulated in a mass at the site of the left ventricle
1100 within the infarct zone. One method for introduction of the
microparticles 1120 is percutaneously with the use of a catheter
1130. A distal end of the catheter is advanced to the infarct
region 1110 and the microparticles 1130 are released. The
microparticles become lodged in the infarct tissue 1140. FIG. 11B
illustrates microparticles 1130 acquiring the necessary surrounding
fluid 1150 to swell 1160/1170. One embodiment includes the use of
microparticle beads capable of fluid uptake in the infarct region
to structurally reinforce the region. The particles will range in
size from approximately 5 to approximately 10 microns. The
microparticles will be less than 10 microns so that the completely
swollen particle becomes lodged in the site (1180) but is not too
large to become an obstruction in the area. In addition, the
swollen microparticles provide mechanical strength and thickness to
the damaged area by replacing the dead and degraded myocardial
cells.
Agents
Hydrogels Spheres
[0127] Examples include hydrogel spheres composed of cross-linked
polyacrylamide or cross-linked PVP. The monomeric form of these
products will contain di-functional monomers such as di-vinyl
benzene, ethylene glycol dimethylacrylate or bis acrylamido acetic
acid. These agents form a cross-linked network that is resistant to
dissolution in aqueous systems.
Commercial Products
[0128] Several commercial products are available that may be used
such as microparticles obtained from A. P. Pharma or Biosphere
Medical. These microparticles resist non-specific protein
absorption and have bio-stable backbone linkages. These
microparticles are not bioerodable or bioabsorbable. FIG. 11E
illustrates the microparticles dispersed in the infarct region
taking up the surrounding fluid and swelling until they become
lodged in the region (FIG. 11F).
Structural Reinforcement Compositions and Materials
[0129] FIG. 12 illustrates several possible methods to reinforce
the ventricular wall of the infarct region of an MI subject.
Restraining the infarct zone by suturing an epicardial polymer mesh
was previously demonstrated. See Kelley, S. T., et al., Restraining
Infarct Expansion Preserves Left Ventricular Geometry and Function
After Acute Anteroapical Infarction, Circ., 1999, pp. 135-142, 99.
Due to the nature of this technique suturing the mesh directly into
the tissue was necessary. This may cause further damage. This
procedure requires invasive surgery. In addition, the polymer mesh
does not degrade over time and this may also be a problem. By
injecting a reinforcing agent directly into the affected area by
minimally invasive procedures, this avoids the intrusive suturing
protocol. The solution may be injected in the infarct zone during
an open chest procedure. In one embodiment, the introduction of the
reinforcing solution comprises the following procedures consisting
of sub-xiphoid and percutaneously. In another embodiment, the mode
of introduction of the reinforcing solution by a percutaneous
injection comprises one of the following consisting of an
intraventricular catheter, a transvascular needle catheter and
retrograde venous perfusion.
Single Component Systems
[0130] FIG. 12 (1210/1220/1230) illustrates the identification and
reinforcement of the MI region prior to intervention by a
reinforcing agent. FIG. 12 (1210) describes the use of a single
component injected into the infarct region. This example
constitutes a single pseudoplastic or thixotropic material capable
of forming a gel-like reinforcement to the infarct region wall.
Several examples of these materials exist. In one embodiment, the
structural reinforcing agent includes one of the following
consisting of hyaluronic acid, bovine collagen, high-molecular
weight ultra-pure polyacrylamide and polyvinyl pyrrolidone.
[0131] In one specific embodiment of the present invention, the
single component for structural reinforcement comprises bovine
collagen dispersed with PMMA (polymethyl methylacrylate) beads.
These beads may be manufactured under the trade name of ARTECOLL
(Rofil Medical International, Breda, The Netherlands). PMMA is one
of several cross-linked or highly insoluble microparticles. PMMA
was discovered in the early 1900's and was used initially in dental
prosthesis. Recently, it has been used in bone replacement of the
jaw and hip. In addition, it has been used for artificial eye
lenses, pacemakers and dentures. ARTECOLL.TM. has principally been
used in filling folds and wrinkles of the face, augmenting lips,
adjusting an irregular nose.
[0132] Possibly one of the most important features of the insoluble
microparticles is the surface of the microparticles must be smooth
to induce collagen deposition. A rough surface promotes macrophage
activity while discouraging collagen deposition. The methods
incorporate the use of smooth surface particles. The components may
act as a substrate for endogenous collagen deposition. As the
reinforcing gel degrades, the highly stable and smooth
microparticles may be exposed to the fibroblast cell population
occupying the site. This triggers the production of collagen to
replace the decomposing gel. Therefore, the infarct zone may be
reinforced by the collagen replacement of the temporary gel. In one
embodiment, the dispersing material includes one of the following
group of microparticle materials consisting of PMMA (polymethyl
methylacrylate), P(MMA-co BMA) (polymethyl methylacrylate-co butyl
methylacrylate), carbon microparticles (Durasphere), polystyrene,
cross-linked acrylic hydrogels and PLGA. In another embodiment, the
cross-linked acrylic hydrogel may include the following HEMA
(2-hydroxyethyl methacrylate), AA (acrylic acid), AMPS
(acrylamido-methyl-propane sulfonate), acrylamide, N,N,di-methyl
acrylamide, diacetone acrylamide, styrene sulfonate, and di- or
tri-functional monomers. The di or tri-functional monomers may be
EGDMA (ethylene glycol di-methacrylate) and DVB (di-vinyl benzene).
In addition, the use of highly crystalline (and hydrolysis
resistant) PLGA microparticles may outlast the carrier gel and also
provide a useful substrate for collagen deposition.
[0133] Another single solution introduced to the infarct zone may
be hyaluronic acid dissolved in sodium salt in water. This is a
manufactured gel sold as a dermal augmentation gel (RESTYLANE.TM.).
Hyaluronic acid hydrogel has also been used in the past for control
of delivery of therapeutic agents in wound sites (Luo, Y. et al.
Cross-linked hyaluronic acid hydrogel films: new biomaterials for
drug delivery" Journal of Controlled Release (2000) 69:169-184).
Other possible single introduced components include bovine collagen
(ZYDERM.TM. or ZYPLAST.TM.), another dermal augmentation gel
developed by Collagen Corp. The high molecular weight, ultrapure
polyacrylamide in water may be FORMACRYL.TM. or BIOFORM.TM. other
dermal augmentation gels. The bovine collagen may be dispersed by
the PMMA product ARTECOLL.TM.. ARTECOLL.TM. is best known for its
success as a biocompatible dermal augmentation gel for
reconstruction. RESOPLAST.TM. (Rofil Medical International, Breda,
The Netherlands) may also be used as a single component gel.
[0134] FIG. 12 (1220) illustrates another method to reinforce the
infarct zone of the ventricle using a single component system. This
example utilizes the introduction of a single component that forms
a gel after reacting with an endogenous component. One such
component may be tropoelastin (detailed previously). Elastin is the
insoluble, elastic protein of high tensile strength found in
connective tissue of the large arteries, trachea, bronchi and
ligaments. Rarely seen endogenously as tropoelastin (the
uncross-linked form), it rapidly cross-links to lysine residues in
a process of oxidative deamination by the enzyme lysyl oxidase when
introduced in vivo. As stated previously, tropoelastin is available
commercially as a recombinant bacterial product. When heated in
water tropoelastin forms a coacervate and this may be injected into
the infarct region where lysyl oxidase induces lysine cross-linking
by the oxidative deamination process. In one embodiment,
tropoelastin may be introduced to the infarct region. In another
embodiment, tropoelastin may be introduced to the infarct region
after the introduction of the highly insoluble microparticles
described above. Another reactive single-component may be
cyanoacrylate adhesive. This is a widely used plastics binding
agent. In one embodiment the cyanoacrylate may be octyl
cyanoacrylate. The octyl cyanoacrylate may be the manufactured
product called Dermabond.TM. (Johnson and Johnson). This product
was recently approved for use as a tissue adhesive for wound
closure. Octyl cyanoacrylate may be introduced to the infarct
region as a liquid. Once it contacts the infarct region, it
solidifies due to its exposure to moisture. In another embodiment,
the octyl cyanoacrylate may be introduced to the infarct region
after the introduction of the highly insoluble, stable
microparticles described above.
[0135] In another embodiment, a reactive single component includes
a component that is temperature sensitive. This is illustrated in
FIG. 12 (1230). One example of this type of component is a
component that may be a liquid at room temperature, and, once
exposed to a temperature approximately equal to body temperature,
the component gels. A more specific component includes introducing
block co-polymers of silk protein-like sub units and elastin-like
sub units. An example of the block co-polymer synthetic protein may
be ProLastin (PPTI, Protein Polymer Technologies). These components
gel due to non-covalent interactions (hydrogen bonding and
crystallization of silk-like subunits) at elevated temperatures for
example approximately equal to body temperature. With these
components, no lysine residues are present, so cross-linking due to
endogenous lysyl oxidase does not occur. The formation of the gel
via a change in temperature may be adjusted using additives. These
additives include but are not limited to sodium chloride, Diglyme
(Diethylene Glycol Dimethyl Ether; 2-Methoxyethyl Ether;
Bis(2-Methoxy Ethyl Ether), and ethanol.
[0136] Many thermal reversible materials may be used for
reinforcement of the myocardial tissue. Generally, thermal
reversible components at temperatures of approximately 37 degrees
Celsius ad below are liquid or soft gel. When the temperature
shifts to 37 degrees Celsius or above, the thermal reversible
components tend to harden. In one embodiment, the temperature
sensitive structural reinforcing component may be Triblock
poly(lactide-co-glycolide)-polyethylene glycol copolymer. This is
commercially available (REGEL.TM. Macromed, Utah). In another
embodiment, the temperature sensitive structural reinforcing
component may include the following consisting of
poly(N-isopropylacrylamide) and copolymers of polyacrylic acid and
poly(N-isopropylacrylamide). Another temperature sensitive
structural reinforcing component commercially available is
PLURONICS.TM. (aqueous solutions of PEO-PPO-PEO (poly(ethylene
oxide)-poly(propylene oxide)-poly(ethylene oxide) tri-block
copolymers BASF, N. J.) (Huang, K. et al. "Synthesis and
Characterization of Self-Assembling Block copolymers Containing
Bioadhesive End Groups" Biomacromolecules 2002, 3, 397-406).
Another embodiment includes combining two or more of the single
components in order to structurally reinforce the infarct region.
For example, silk-elastin, collagen and Laminin may be used as a
one-part system. The silk-elastin would likely form in situ
cross-links due to the silk blocks.
[0137] In another embodiment, a reactive single component includes
a component that is pH sensitive. The component remains in a liquid
state if it is sufficiently protonated preventing gelation. In
another embodiment, the component is initially maintained at a low
pH for example pH 3.0 and later introduced to the treatment area
which results in gelation of the component due to the physiological
pH of the environment. One example of this is discussed in Example
3. Several possible cationic agents may be, but are not limited to,
one of the following cationic agents that remain protonated at low
pH, poly(allyl amine), DEAE-Dextran, ethoxylated
Poly(ethylenimine), and Poly(lysine). Other examples may one of,
but are not limited to, the following anionic agents: dextran
sulfate, carboxymethyl dextran, carboxymethylcellulose, polystyrene
sulfanate and chrondroitin sulfate.
[0138] Additionally, any of these microparticle components may be
accompanied by one or more contrast agent and/or suitable agent(s)
for treatment of the region. The contrast agent or treatment agent
may be conjugated to or dissolved into the structural component
prior to introduction to the infarct area. The agents that may
accompany the reinforcing component(s) may include, but are not
limited to, angiogenic agents, ACE inhibitors, angiotensin receptor
blockers, SRCA (sercoplasmic reticulum calcium pump) pump
increasing agents, phospholamban inhibitors and anti-apoptotic
drugs. These agents may be in the form of small molecules,
peptides, proteins or gene products. The small molecules may be
optionally conjugated to a component of the solution, dispersed in
solution, or dissolved in solution to improve the adhesion of the
reinforcing components to the tissue. One embodiment is to
conjugate a peptide with a conserved region that mediates adhesion
processes. A conserved region of a peptide may be a sequence of
amino acids having a special function of identification that has
been conserved in a protein family over time. Another embodiment
includes the use of a specific peptide conjugate with a conserved
RGD (arginine(R)-glycine(G)-asparagine(D)) motif in the presence of
the reinforcing component. In further embodiments, the RGD motif
peptide may include the following: von Willebrand factor,
osteopontin, fibronectin, fibrinogen, vitronectin, laminin and
collagen. One embodiment seeks to minimize thinning during
remodeling of the infarct region. Thus, bulking and reinforcing the
infarct region post-MI may preserve the geometry of the
ventricle.
[0139] Any one or more catheters may be used to deliver the any one
or multiple components of the embodiments to the infarct region
area. Several catheters have been designed in order to precisely
deliver agents to a damaged region within the heart for example an
infarct region. Several of these catheters have been described
(U.S. Pat. Nos. 6,309,370; 6,432,119; 6,485,481). The delivery
device may include an apparatus for intracardiac drug
administration, including a sensor for positioning within the
heart, a delivery device to administer the desired agent and amount
at the site of the position sensor.
Dual Component Systems
[0140] FIG. 12 (1240) illustrates the use of dual component systems
for the formation of structural reinforcing gels for application to
the infarct region. Initially, the infarct region is identified
(1300) by imaging methods previously discussed. FIG. 13
(1330/1340/1350/1360/1370/1380/1390) illustrates a flowchart
further describing dual component systems to form a structural
reinforcing gel in the infarct region 1320. In one example 1330,
two components are combined at the infarct zone at around
physiological pH. Component one is a principally anionic solution
and the second component is principally a cationic solution at
approximately physiological pH. When the two components are mixed
together at the infarct zone, a gel forms rapidly and irreversibly.
In one embodiment, a dual component system may comprise poly
(acrylic acid) as a first component and poly (allyl amine) as a
second component as illustrated in FIG. 13 (1330). In another
embodiment, a dual component system may comprise poly (acrylic
acid) as a first component and poly (allyl amine) as a second
component that may be delivered by a catheter with dual injection
lumens. Other dual component systems to form a structural
reinforcing gel in the infarct region may include elastin as a
first component and lysyl oxidase as a second component 1340;
sodium alginate as a first component and an aqueous solution of
calcium chloride as a second component 1350, and tropoelastin and
collagen as a first component and cross-linker lysyl dehydrogenase
as a second component and laminin 1395 may be added to this
combination later. The composition of each component will depend on
the mechanical property of the final cross-linked system. Other
substances that can replace the lysyl dehydrogenase or complement
its cross-linking ability might be used such as glutaraldehyde,
and/or photoactivatable crosslinkers, for example, blue dye used to
cross-link. Additionally, these dual component systems may be
combined with other individual system utilizing commercial products
such as AVITENE.TM. (Microfibrillar Collagen Hemostat),
SUGICEL.TM., (absorbable haemostat, Johnson & Johnson),
GELFOAM.TM., FLOSEAL.TM. (Baxter, matrix hemostatic sealant with a
granular physical structure and thrombin), FOCAL SEAL.TM. (Focal,
Inc.) or FIBRIN SEAL.TM. (FS). FLOSEAL.TM. is a gel constituting
collagen derived particles and topical thrombin capable of being
injected. It has been approved for uses including vascular sealing.
Several other possible cationic agents may be, but are not limited
to, one of the following cationic agents that remain protonated at
low pH: poly(allyl amine), DEAE-Dextran, ethoxylated
Poly(ethylenimine), and Poly(lysine). Other examples may be one of,
but are not limited to, the following anionic agents: dextran
sulfate, carboxymethyl dextran, carboxymethylcellulose, polystyrene
sulfanate and chrondroitin sulfate. In a preferred embodiment, the
first material may be DEAE Dextran and the second material may be
polystyrenesulfonate.
[0141] FIG. 13 (1370) illustrates the use of another dual component
system, DOPA (3,4-dihydroxyphenyl-L-alanine), a principle component
responsible for muscle adhesive proteins, capable of forming a
hydrogel in conducive conditions. Specifically, a component known
as star block DOPA-block-PEG undergoes cross-linking in situ
forming the hydrogel after an oxidation process converts the DOPA
to O-quinone. This process forms a stable in situ hydrogel. Other
examples are represented as dual components in FIG. 13 (1370/1380).
FIG. 13 (1380) includes the use of an acrylate macromer solution
and a dithiol solution injected into the infarct region for
structural reinforcement. These components when mixed at the
infarct site undergo a cross-linking reaction leading to the
formation of a hydrogel. A specific embodiment may comprise the use
of PEG triacrylate as the first component and PEG thiol as the
second component introduced to the infarct zone via a dual lumen
needle system discussed previously. In FIG. 13 (1390), a glue-like
component system may be employed. One embodiment may include the
use of GRF glue that is made up of gelatin, resorcinol and
formaldehyde (GRF) as a structural reinforcing agent introduced to
the infarct zone. To accomplish this, a two-part system may be used
to induce cross-linking upon admixture of the components at the
infarct zone. In other embodiments, the following structural
reinforcing components may be added along with GRF: cross-linking
agents such as polyglutamic acid, polylysine and WSC (water-soluble
carbodimides).
[0142] FIG. 14 illustrates the introduction and action of a single
component or dual components to the infarct region for structural
reinforcement. FIG. 14 illustrates the identification of the
infarct region 1410 of the ventricle 1400 by methods previously
described and subsequent multi-injection of the separate components
to the site of damage 1420. In a dual component system, the two
components 1430/1440 contact each other at the site and form
reinforcing structural scaffold 1430/1440. In FIG. 15B, a single
pseudoplastic or thixotropic agent is introduced to the area in
multiple injections 1450 and structurally reinforces the wall 1460.
These agents are introduced in final form and require no additional
agents. FIG. 14 illustrates the addition of at least one agent
1430/1440/1450/1480 by multiple injections each at a different site
1405/1415 that requires an endogenous component or a temperature
change 1460/1490 to convert to a structural reinforcing form
1450/1470/1495. The structural reinforcing agent(s) is localized to
the infarct region via minimally invasive procedures discussed
previously.
[0143] In addition, biocompatible viscosifiers, for example, type 1
gels may be added in combination with any of the single or multiple
component systems illustrated. For example, hyaluronic acid or PVP
may be used to increase the resistance of the active formula from
natural degradation once introduced to the infarct zone. In one
embodiment the viscosity of the treatment agent may be about 0-100
centipoise. In other embodiments, the viscosity of the treatment
agent may be about 0-50 centipoise. In a preferred embodiment, the
viscosity of the treatment agent may be about 25-40 centipoise. In
a preferred embodiment, the viscosity of the treatment agent may be
about 35 centipoise.
[0144] In one embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 1
ml. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 300
.mu.l. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 100
.mu.l. In a preferred embodiment, the any of the described agents
may be introduced in one or more doses in a volume of about 1 .mu.l
to 50 .mu.l. IV and IC routes may be required which would involve
larger treatment volumes (for example about 2 ml to about 250
ml).
[0145] Biocompatible dyes may be added to any single or combination
components of any of the described embodiments to trace the
components in the infarct region in any procedure. Other dyes may
be added for experimental purposes to trace the deposition of any
agent for example in a rat heart. Some examples of these dyes
include but are not limited to Sudan Red B, Fat Brown RR, Eosin Y
and Toluidine blue.
[0146] On the other hand, tissue adhesive components may also be
added in combination with any of the single or dual component
systems illustrated in FIGS. 12, 13 and 14. For example, Laminin-5,
polyacrylic acid, Chitosan and water-soluble chitosan may be used
to increase the tissue retention of the active formulation.
Laminin-5 is a basement membrane extracellular matrix macromolecule
that provides an attachment substrate for both adhesion and
migration in a wide variety of cell types, including epithelial
cells, fibroblasts, neurons and leukocytes. Chitosan is the only
natural positive ion polysaccharide obtained from deacetylated
chitin. It possesses decomposability, good membrane forming state,
biocompatibility, anti-fungal and anti-tumor function. Chitosan has
excellent viscosity, compressibility and fluidity.
[0147] Another two component system is based on a pectin material
and could be referred to as a pseudo-one-component system because
it gels on exposure to bodily fluids (such as intercellular fluid).
This system uses pectin as the gelling material or component. In
some embodiments this system uses aloe-derived-pectin as the first
component for the gelling material or component. Alternatively, if
an aloe-derived pectin embodiment using bodily fluids for gelation
was not uniform or consistent, gelation could arise from
separately, but simultaneously, providing an additional ion
solution. This solution could be delivered through the catheter
sheath or a second needle.
[0148] Many naturally derived polysaccharides provoke
pro-inflammatory responses of various degrees, e.g. alginate,
especially in easily sensitized animals such as pigs. Aloe-derived
pectin of appropriate purity will show a more benign response and
could in some cases demonstrate a pro-healing effect. Pectin has
long been used in the food industry and the FDA classifies it as
generally regarded as safe. A specific example of such aloe-derived
pectin is known by the trade name GelSite (manufactured by
GelSite). This aloe-derived pectin is biodegradable and animal
studies have shown it to be well tolerated. Aloe-derived-pectin,
in-situ-gelling, drug delivery systems are based on
high-molecular-weight pectins extracted and purified from aloe
plants. Chemically, the aloe-derived pectin polymer is an
alpha-1-4-linked polygalacturonic acid with a molecular weight of
380.+-.40 kDa. This water soluble polymer has in situ gelling
properties. The aloe-derived-pectin drug delivery system (polymer
concentration .gtoreq.0.25%, w/v) transforms from a liquid into a
gel upon contact with body fluid and provide one or more days to
one-week of delivery period. Unlike other in situ gelling systems,
the gelation of aloe-derived-pectin system is not pH or temperature
dependent. The aloe-derived-pectin polymer is sensitive to calcium
and can form a calcium gel. The aloe-derived-pectin polymer can
bind and stabilize heparin-binding growth factors. This polymer gel
may provide myocardial reinforcement or regeneration, and can aid
cell retention in cardiomyoplasty. Since it binds growth factors or
other cytokines, it could be useful as a controlled release medium
for delivering such factors or cytokines directly to tissue such as
cardiac or vascular tissue. It can be used as a single-component
gel by dissolving it in water. The solution would gel upon contact
with the myocardium: intercellular fluid would provide enough ions
for gelation. This material would have a low osmolarity, low enough
to cause distress in the delivered cells if used for cell therapy
applications (such as delivering cells to tissue). But using
2-component delivery through a dual needle, one component
containing cells in phosphate-buffered saline, and the other
containing aloe-derived-pectin in sterile water, would allow the
system to function in cell therapy applications. If an embodiment
using aloe-derived pectin with gelation from intercellular fluid
was not uniform or consistent, ions of low concentration could be
added to the cell solution (at low concentration to prevent cell
death) or in a separate third component, which could be delivered
through the catheter sheath or a second inner needle. For cell
therapy, an alternate approach would be to dissolve an
aloe-derived-pectin polymer into an ammonium chloride or sucrose
solution of physiological osmolarity and disperse the cells into
it. Sucrose and ammonium chloride are cytocompatible and neither
will cause gelation of the pectin. The advantage of this approach
is that delivery could be accomplished using a single lumen or
single needle device.
[0149] Aloe-derived pectin molecular weight and polymer
concentration can be modified for the appropriate gel modulus and
degradation rate appropriate for the therapy. Aloe-derived pectin
can also be blended with other biomaterial gels such as those based
on natural materials like fibrinogen, alginate, chitosan, collagen,
gelatin, and hyaluronan or synthetics such as those based on
poly(ethylene glycol) or poly(vinyl alcohol) in order to produce
gels of desired mechanical, biological and degradative properties.
For example blending with another ionotropic gel such as sodium
alginate may serve to reduce the inflammatory response seen with
implantation of alginate alone. As a by-product and additional
benefit of this therapy, any aloe inadvertently dispersed into the
circulation could act as a drag reducer and improve perfusion.
Pectins derived from aloe species other than the
aloe-derived-pectin system may also be utilized in any of the above
embodiments as desired by one of ordinary skill in the art.
Single Components Suspended in a Delivery Medium
[0150] FIG. 15 illustrates flowcharts describing other methods to
prevent the remodeling and ultimate thinning of the infarct region.
As with several of the previously discussed methods, these methods
provide a bulking or structural reinforcing agent to the infarct
region. In FIG. 15 (1510), an agent comprising microparticles in
solution (a dispersion) is introduced to the infarct region after
identification of the infarct region as described previously. The
microparticles may be a predetermined range of about 1 to about 200
microns. In one embodiment, the microparticles may be 20 microns or
less. In a preferred embodiment, the microparticles may be 10
microns or less. The microparticle size delivered to an infarct
region may be determined by the delivery method used. For example,
an intraventricular catheter may be used to deliver particles up to
200 microns that may avoid the risk of an embolism. One suspending
solution for the microparticles may be water. On the other hand,
the suspending solution may also be a solvent, for example,
dimethylsulfoxide (DMSO) or ethanol adjuvants. In one embodiment, a
suspending solution along with the microparticles may be introduced
as a dispersion to an infarct region and the microparticles remain
in the region as the solution dissipates into the surrounding
tissue. Thus, the microparticles provide a structural reinforcing
bulk to the region. This may result in reduction of stress to the
post infarct myocardium. It may also serve as a substrate for
additional site for collagen deposition. In one embodiment, the
dispersion (detailed above) may be injected into the infarct zone
during an open chest procedure via a minimally invasive procedure.
In another embodiment, the minimally invasive procedure includes at
least one of subxiphoid and percutaneously. In another embodiment,
the percutaneous introduction into the infarct zone may include one
of intra-ventricular needle, transvascular catheter and retrograde
venous perfusion.
[0151] FIG. 15 (1520) illustrates a flow chart of an additional
method similar to FIG. 15 (1510) except that the microparticles
precipitate out of the solution (the dispersion). In FIG. 15
(1520), an agent including microparticles in solution (a
dispersion) is introduced to the infarct region. The microparticles
may be a predetermined size of 0 to 200 microns. In a preferred
embodiment, the microparticles are 10 microns or less. In one
embodiment, the suspending solution along with the microparticles
may be introduced to the infarct region and the microparticles
precipitate out of the dispersion in the region. Thus, the
microparticles provide a structural reinforcing bulk to the region.
This may result in reduction of stress to the post infarct
myocardium. It may also serve as a substrate for additional site
for collagen deposition. In one embodiment, the dispersion
(detailed above) may be injected in to the infarct zone during an
open chest procedure via a minimally invasive procedure. In another
embodiment, a minimally invasive procedure including sub-xiphoid
and percutaneously methods may be employed. In another embodiment,
a percutaneous introduction into the infarct zone may include one
of an intra-ventricular needle, transvascular needle catheter and
retrograde venous perfusion.
[0152] Several examples of the microparticles of FIG. 15 (1510) and
(1520) are illustrated in FIG. 16. FIG. 16 (1610) illustrates the
viscous liquid sucrose acetate isobutyrate (SAIB). SAIB is
water-insoluble. SAIB may be dissolved in a solvent or a
combination of solvents for example, ethanol, dimethylsulfoxide,
ethyl lactate, ethyl acetate, benzyl alcohol, triacetin,
2-pyrrolidone, N-methyl pyrrolidone, propylene carbonate or
glycofurol. These solvents decrease the viscosity of SAIB in order
to facilitate the introduction of this agent through a needle or
lumen. In one embodiment, SAIB may be introduced accompanied by a
solvent to the infarct region and the solvent dissipates at the
site leaving behind the viscous SAIB in the region.
[0153] Other biocompatible polymer systems may be introduced to an
infarct zone (FIG. 16, 1620). Some of these agents are not only
biocompatible but also substantially water-insoluble similar to
SAIB. Solvents or mixtures of solvents may be used to dissolve the
polymer in order to facilitate introduction to the infarct zone. In
one embodiment, a biocompatible water-insoluble polymer may include
the following consisting of polylactides, polyglycolides,
polycaprolactones, polyanhydrides, polyalkylene oxates, polyamides,
polyurethanes, polyesteramides, polydioxanones,
polyhydroxyvalerates, polyacetals, polyketals, polycarbonates,
polyorthoesters, polyphosphazenes, polyhydroxybutyrates,
polyalkylene succinates, and poly(amino acids). Any one of these
insoluble polymers may be dissolved in solvents, for example,
Diglyme, dimethyl isosorbide, N-methyl-2-pyrrolidone,
2-pyrrolidone, glycerol, propylene glycol, ethanol, tetraglycol,
diethyl succinate, solketal, ethyl acetate, ethyl lactate, ethyl
butyrate, dibutyl malonate, tributyl citrate, tri-n-hexyl
acetylcitrate, dietyl glutarate, diethyl malonate, triethyl
citrate, triacetin, tributyrin, diethyl carbonate, propylene
carbonate acetone, methyl ethyl ketone, dimethyl sulfoxide dimethyl
sulfone, tetrahydrofuran, capralactum, N,N-diethyl-m-toluamide,
1-dodecylazacycloheptan-2-one,
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and glycerol
formal to form an injectible polymer solution. The dispersion may
be introduced into the infarct region of the heart wherein the
solvent may dissipate and the polymer may precipitate out of the
dispersion to structurally reinforce the infarct regional wall. In
one embodiment, the disclosed polymers may be used in any
combination as co-polymers of two or more polymers introduced to
the infarct region.
[0154] FIG. 16 (1630) illustrates a flowchart describing the use of
a vinyl polymer and acrylate biocompatible polymer system. Once
injected into an infarct zone, the vinyl polymer/acrylate agent
contacts water and the polymer precipitates thus reinforcing the
surrounding tissue of the infarct region. In one embodiment, the
vinyl polymer/acrylate agent includes the following such as
polyvinyl butyral, PBMA-HEMA, PEMA-HEMA, PMMA-HEMA and other
acrylate copolymers that dissolve in ethanol, acetone and I-PA. In
another embodiment, the vinyl polymerlacrylate agent introduced to
the infarct region may be EVAL.TM. that has a solid phase or melt
phase forming process. EVAL.TM. Resins have a high crystalline
structure. Thermoforming grades of EVAL.TM. resins have monoclinic
crystalline structure while most polyolefins have either a
hexagonal or orthorhombic type structure. This characteristic
provides flexibility within its thermoforming capabilities. In
another embodiment, the vinyl polymer/acrylate agent introduced to
the infarct region may be BUTVAR.TM. (polyvinyl butyral). In one
embodiment, the agent may be P(BMA co-MMA) (Aldrich Chem.) in
Diglyme. In another embodiment, the agent may be EVAL.TM., a
co-polymer of ethylene and vinyl alcohol (EVAL Co. of America,
Houston, Tex.) in dimethyl acetamide. In another embodiment, the
polymer may be PLGA poly(lactide co-glycolide) (Birmingham
Polymers, Birmingham, Ala.) in Diglyme.
[0155] Other components may act as a substrate for endogenous
collagen deposition and protect the precipitated or remaining
microparticles described in FIG. 16 from erosion. As the
reinforcing gel degrades, the highly stable and smooth
microparticles may be exposed to the fibroblast cell population
occupying the site. This triggers the production of collagen to
replace the decomposing gel. Therefore, the infarct zone may be
reinforced by the collagen replacement of the temporary gel. The
dispersed material includes the following group of microparticle
materials: PMMA, P(MMA-co BMA), carbon microparticles (Durasphere),
polystyrene, cross-linked acrylic hydrogels and PLGA. In another
embodiment, the cross-linked acrylic hydrogel may include the
following: HEMA, AA, AMPS, acrylamide, N,N,di-methyl acrylamide,
diacetone acrylamide, styrene sulfonate, and di or tri functional
monomers. The di or tri-functional monomers may be EGDMA and DVB.
Another example of durable microparticles includes pyrolytic
carbon-coated microparticles. One example of pyrolytic
carbon-coated microparticles was originally produced for urinary
incontinence (Carbon Medical Technologies) and trisacryl gelatin
microparticles for use as embolization particles (Biosphere). In
addition, the use of highly crystalline (and hydrolysis resistant)
PLGA microparticles may outlast the carrier gel and also provide a
useful substrate for collagen deposition.
[0156] One or more contrast agents 1540 and/or suitable treatment
agent(s) 1550 may accompany the previously detailed components as a
treatment of the infarct region. The contrast agent or treatment
agent may be conjugated to or dissolved into the structural
component prior to introduction to the infarct area. The contrast
agents may be used for detection in X-ray or MR analysis. The
agents that may accompany the reinforcing component(s) may include,
but are not limited, to angiogenic agents, ACE inhibitors,
angiotensin receptor blockers, SRCA pump (sarcoplasmic reticulum
calcium pump) increasing agents, phospholamban inhibitors and
antiapoptotic drugs. These agents may be in the form of small
molecules, peptides, proteins or gene products. The small molecules
may be optionally conjugated to a component of the solution,
dispersed in solution, or dissolved in solution to improve the
adhesion of the reinforcing components to the tissue. One
embodiment is to conjugate a peptide with a conserved region that
mediates adhesion processes. Another embodiment includes the use of
a specific peptide conjugate with a RGD
(arginine-glycine-asparagine) motif in the presence of the
reinforcing component. In further embodiments, the RGD motif
peptide may include von Willebrand factor, osteopontin,
fibronectin, fibrinogen, vitronectin, laminin and collagen.
[0157] In one embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 1
ml. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 300
.mu.l. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 100
.mu.l. In a preferred embodiment, the any of the described agents
may be introduced in one or more doses in a volume of about 1 .mu.l
to 50 .mu.l.
Collagen Cross-Linking Agents for Structural Reinforcement
[0158] FIG. 17 illustrates a flowchart describing a method to
structurally reinforce the infarct region of the ventricle 1710. As
previously mentioned, thinning is a key factor in the cascade of
events following remodeling of the infarct region. One factor
contributing to the thinning is collagen degradation by MMPs
(matrixmetalloproteinases) and collagen helix slippage due to
hemodynamic stress. The collagen slippage generates infarct scar
expansion that leads to additional remodeling and remote zone
hypertrophy. Previous inventions to prevent collagen slippage
include a suturing procedure. See Kelley, S. T., et al.,
Restraining Infarct Expansion Preserves Left Ventricular Geometry
and Function After Acute Anteroapical Infarction, Circ., 1999, pp.
135-142, 99. This involves directly suturing a epicardial polymer
mesh to the region. According to one embodiment, agents will be
introduced to the region by a minimally invasive procedure to
prevent collagen slippage. An agent or dispersion will be
introduced in one embodiment by multiple injections to the infarct
zone then the agent will react with the collagen scar directly to
cross-link it. This results in prevention of slippage and strength
to the regional wall. In one embodiment, the agent (detailed above)
may be injected into the infarct zone during an open chest
procedure via a minimally invasive procedure. In another
embodiment, the minimally invasive procedure may include
sub-xiphoid and percutaneously methods. In another embodiment, the
percutaneous introduction into the infarct zone may comprise one of
intra-ventricular needle, transvascular needle catheter and
retrograde venous perfusion.
[0159] A contrast agent or treatment agent may be conjugated to or
dissolved into the structural component prior to introduction to
the infarct area, such as those described previously.
[0160] Several possible cross-linking agents are illustrated in
FIG. 18 to illustrate the possible agents of 1720 to prevent
collagen slippage 1730. The agent injected into the infarct region
may be polyfunctional (either hetero or homopolymer). Another
important feature of the cross-linking agent is the ability of the
agent to cross-link to the side groups of the amino acids of the
collagen (type I and III). In one embodiment, the agent is soluble
in a biocompatible water miscible solvent that is capable of being
drawn out of the dispersion by aqueous fluid present in the
myocardium. This enables the cross-linking agent the ability to
precipitate out into the infarct region minimizing migration of the
cross-linking agent out of the area. In another embodiment, the
biocompatible solvent used in the presence of the cross-linking
agent may be the following: Diglyme and dimethyl isosorbide.
Collagen is made up of a large number of lysine and hydroxyproline
residues that carry reactive side groups of primary amines and
hydroxyl groups respectively. In the following examples, the
cross-linking agents react with at least one of these side groups.
FIG. 18 (1810) illustrates a flowchart describing a method using
polyepoxy functional resins for cross-linking the collagen. In one
embodiment a polyepoxyl functional resin may be introduced to the
infarct region. In another embodiment, the polyepoxy functional
resin may comprise the following: Bisphenol A epoxies (Shell 828),
Epoxy-Novolak resins (Ciba 1138 and 1139, Dow 431), homopolymers of
glycidyl methacrylate (GMA) or copolymers of GMA with other
acrylates. In another embodiment, the polyepoxy functional resins
may include a multifunctional epoxide. In another embodiment, the
polyepoxy functional resins may include an acrylate. The later
resins, multifunctional epoxides and acrylate, are based on a cubic
silicone with eight epoxide or acrylate functionalities
(silsesquioxanes). In another embodiment, the polyepoxy functional
resins may include a tetra-functional epoxide silicone. In another
embodiment, the polyepoxy functional resins may include
di-functional epoxide silicone.
[0161] FIG. 18 (1820) illustrates a flowchart describing the use of
polyisocyanates as the cross-lining agent. In one embodiment, the
cross-linking agent used to link the collagen may comprise a
polyisocyanate. In another, the polyisocyanate may include the
following: the biuret of hexamethylene di-isocyanate and
isocyanurate of hexamethylene di-isocyanate. Both of these products
are manufactured commercially under the name DESMODUR N 100 and
DESMODUR 3300 respectively (commercially available from Bayer).
FIG. 18 (1830) illustrates a flowchart describing the use of
aromatic halogenated compounds as a possible collagen cross-linking
agent. In one embodiment, the agent used to cross-link the collagen
to prevent slippage and structurally reinforce the infarct region
may include a halogenated compound. In another embodiment, the
halogen compound used to cross-link the collagen may include
1,5-difluoro-2,4-dinitrobenzene (DFNB).
[0162] Polyhydroxyl aromatics (resorcinol groups) such as vegetable
tannins have been used to cross-link collagen for processing animal
hides into leather. FIG. 18 illustrates a flowchart describing the
use of these resorcinol groups for collagen cross-linking. Solvent
soluble resorcinol-formaldehyde resins contain numerous resorcinol
groups. A methylene bridge and/or an ether bridge connect the
resorcinol groups. RESORCINOL.TM. is capable of cross-linking
collagen but one problem is that it is corrosive and water miscible
in its monomeric form. In one embodiment, the cross-linking agent
to secure the collagen and structurally reinforce the infarct
region may be a resorcinol-formaldehyde resin.
[0163] FIG. 18 (1850) illustrates a flowchart describing the use of
agents that terminate in an acrylate group as a potential
cross-linking agent to prevent collagen slippage in the infarct
region and structurally reinforce the ventricular wall. These
acrylate-terminating agents react with the primary amine groups of
the collagen and form a stabilizing cross-link. In one embodiment,
the cross-linking agent may be an acrylate-terminating agent. In
another embodiment, the acrylate-terminating agent used to
cross-link the collagen may include one of the following
water-insoluble agents urethane-acrylates and epoxy-acrylates.
These compounds are commercially available (Cognis Corp, Ohio,
U.S.A.). Another example of a cross-linking agent is illustrated in
the flowchart of FIG. 18 (1860). Lysyl oxidase discussed earlier
may be use alone or in combination with other agents to cross-link
the collagen for prevention of slippage and as a structural
reinforcing agent in the infarct region. Lysyl oxidase is an enzyme
that oxidatively deaminates lysine side groups and forms reactive
aldehyde groups capable of forming strong cross-linking bonds with
the collagen. In one embodiment, lysyl oxidase may be introduced to
the infarct region to cross-link the existing collagen for
prevention of slippage.
[0164] In the final flowchart example of FIG. 18 (1870) illustrates
a flowchart describing the use of microparticles to cross-link and
stabilize the collagen in the infarct region. One example includes
the use of surfactant free styrene latex particles in narrow size
distributions that also contain the following functional surface
groups comprising chloromethyl, epoxy and aldehyde. The aldehyde
surface groups may be tightly packed therefore borohydride
reduction would not be necessary for a stable linkage. Chloromethyl
groups react with primary and secondary amines thus forming a
stable cross-link. Other possible functional reacting groups may
include succinimidyl ester, benzotriazole carbonate and
p-nitrophenyl carbonate. Other possible functional groups may be
used. In one embodiment, the size limitation of the microparticles
may include submicron to single digit micron size. This size range
prevents the microparticles that may back-wash out of the site from
causing an embolic hazard. In other embodiments, the cross-linking
agent may be a functionalized surfactant free styrene latex
microparticle. Several examples exist of these styrene
microparticles. Examples of commercially available functional
stryrene microparticles are manufactured by Interfacial Dynamics
Corporation and Magsphere.
[0165] Additionally, any one of these agents illustrated in FIGS.
17 and 18 may be accompanied by one or more contrast agent 1740
and/or suitable agent(s) 1750 for treatment of the region. The
contrast agent or treatment agent may be conjugated to or dissolved
into the structural component prior to introduction to the infarct
area. The agents that may accompany the reinforcing component(s)
may include, but are not limited, to angiogenic agents, ACE
inhibitors, angiotensin receptor blockers, SRCA pump increasing
agents, phospholamban inhibitors and anti-apoptotic drugs. These
agents may be in the form of small molecules, peptides, proteins or
gene products. The small molecules may be optionally conjugated to
a component of the solution, dispersed in solution, or dissolved in
solution to improve the adhesion of the reinforcing components to
the tissue. One embodiment is to conjugate a peptide with a
conserved region that mediates adhesion processes. Another
embodiment includes the use of a specific peptide conjugate with a
RGD (arginine-glycine-asparagine) motif in the presence of the
reinforcing component. In further embodiments, the RGD motif
peptide comprises the following: von Willebrand factor,
osteopontin, fibronectin, fibrinogen, vitronectin, laminin and
collagen.
Prevention of Myocardial Edema and "Cementing" of the Infarct
Region
[0166] FIG. 19 illustrates flowcharts describing the introduction
of clotting factors immediately after an MI 1900. One of the
initial responses of the process post-MI is myocardial edema. The
edema is composed of extravasated blood evident within a few hours
after infarction. This is followed by its dissolution within the
next few hours. The process that occurs immediately post-MI is that
the infarct regional wall thickens and then it thins. The present
invention illustrated in FIG. 19 introduces one or more clotting
factors to the region thereby "cementing" the now clotted blood to
reinforce the wall and thicken the wall 1910. FIG. 19 (1920/1930)
illustrates one method to clot the blood using a dual solution
technique. In one embodiment, the first solution includes calcium
chloride and thrombin 1920 and the second solution 1930 includes
fibrinogen and transexamic acid. Transexamic acid is an
anti-fibrinolytic agent. The introduction of these two solutions to
the infarct region sequentially result in localized clotting of the
blood that forms a structural reinforcing mass 1940 within the
region preventing thinning of the infarct site. In another
embodiment, intra-venous pressure perfusion may be used to deliver
the clot inducing solutions to the infarct zone. This prevents the
possibility of the clot releasing into the arterial circulation.
FIG. 19 (1950) illustrates a flowchart describing the use of
shear-activated platelet fraction to induce localized clotting.
This platelet fraction may be isolated from the MI subject's own
blood or another source. FIG. 19 (1960) illustrates a flowchart of
other initiators of the clotting cascade. These factors encompass
factors that are termed intrinsic and extrinsic factors. Intrinsic
factors initiate clotting in the absence of injury. Extrinsic
factors initiate clotting that is caused by injury. In one
embodiment, the clotting factor used to cease myocardial edema and
reinforce the ventricular wall at the infarct zone may comprise the
following: von Willebrand Factor (vWF), High Molecular Weight
Kininogen (HMWK), Fibrinogen, Prothrombin, and Tissue Factors
III-X. In another embodiment of the present invention, any
combination of the clotting factors mentioned previously may be
used that may provide increased tensile strength the infarct
regional wall.
Matrix Metalloproteinase Inhibitors Use in the Infarct Region
[0167] After an MI injury occurs macrophages tend to infiltrate the
infarct region. The macrophages release matrix metalloproteinases
(MMPs). As members of a zinc-containing endoproteinase family, the
MMPs have structural similarities but each enzyme has a different
substrate specificity, produced by different cells and additionally
have different inducibilities. These enzymes cause destruction in
the infarct zone. One important structural component destroyed by
MMPs is the extracellular matrix (ECM). The ECM is a complex
structural entity surrounding and supporting cells that are found
within mammalian tissues. The ECM is often referred to as the
connective tissue. The ECM is composed of 3 major classes of
biomolecules: structural proteins, for example, collagen and
elastin; specialized proteins, for example, fibrillin, fibronectin,
and laminin; and proteoglycans. These are composed of a protein
core to which is attached long chains of repeating disaccharide
units termed of glycosaminoglycans (GAGs) forming extremely complex
high molecular weight components of the ECM. Collagen is the
principal component of the ECM and MMP induce ECM degradation and
affect collagen deposition. Inhibitors of MMP(s) exist 1970 and
some of these inhibitors are tissue specific. It was previously
demonstrated that acute pharmacological inhibition of MMPs or, in
some cases, a deficiency in MMP-9, that the left ventricle
dilatation is attenuated in the infarct heart of a mouse. See
Creemers, E., et al., Matrix Metalloproteinase Inhibition After MI:
A New Approach to Prevent Hear Failure? Circ., 2001, pp. 201-210,
89. The inhibitors of MMPs are referred to as tissue inhibitors of
metalloproteinases (TIMPPs). Synthetic forms of MMPIs also exist,
for example, BB-94, AG3340, Ro32-355b and GM 6001. It was
previously shown that MMPIs reduce the remodeling in the left
ventricle by reducing wall thinning. These experiments were
performed on rabbits. In addition, this study also demonstrated
that MMPI increases rather than decreases neovascularization in the
subendocardium. See Lindsey, M. L., et al., Selective Matrix
Metalloproteinase Inhibitors Reduces Left Ventricular Remodeling
but Does Not Inhibit Angiogenesis After Myocardial Infarction,
Circ., Feb. 12, 2002, pp. 753-758, 105(6). In one embodiment, MMPIs
may be introduced to the infarct region to delay the remodeling
process by reducing the migration of fibroblasts and deposition of
collagen and prevent ECM degradation, reduce leukocyte influx and
also reduce wall stress. In one embodiment, the MMPIs may include
the following: o TIMP-1, TIMP-2, TIMP-3 and TIMP-4, which can be
introduced to the infarct region in combination with the
introduction of any of the described structural reinforcing agents.
In another embodiment, naturally occurring inhibitors of MMPs may
be increased by exogenous administration of recombinant TIMPs. In
another embodiment, the MMPI comprises a synthetically derived MMPI
introduced to the infarct region in combination with the
introduction of any of the described structural reinforcing agents.
The introduction of MMPIs to the infarct zone may be accomplished
by several different methods. It is critical that the introduction
of these MMPI agents be accomplished by a minimally invasive
technique. In one embodiment, MMPI agents will be introduced to the
region by a minimally invasive procedure to prevent ECM
degradation. An agent or dispersion will be introduced, in one
embodiment, by multiple injections to the infarct region. This
results in prevention of ECM degradation and increased strength to
the regional wall. In one embodiment, the MMPI agent may be
injected into the infarct zone during an open chest procedure via a
minimally invasive procedure. In another, the minimally invasive
procedure may include one of sub-xiphoid and percutaneous methods.
In another embodiment, the percutaneous introduction into the
infarct zone may include one of intra-ventricular needle,
transvascular needle catheter and retrograde venous perfusion. In
addition, the MMPI agents may be introduced via suspension or
sustained release formula, for example, introduced in
microparticles detailed in the three-component system of FIG. 6. In
one embodiment, the introduction of MMPIs may follow any of the
cross-linking events that prevent collagen slippage. In another
embodiment, the cross-linking agent may be cleared from the
targeted infarct area prior to introducing the MMPI(s).
[0168] After an MI, the myocardium may be significantly affected
resulting in a percentage of the tissue being akinetic or
dyskinetic. This often occurs when the MI is caused by an occluded
left anterior descending artery. Moderate infarct where 20 to 40
percent of the tissue is affected decreased cardiac output occurs
resulting in the activation of the neurohormonal system (via a RAAS
(renin-angiotensin-aldosterone) system). Thus, the neurohormonal
activation causes an increase in blood pressure resulting in
further stress to the myocardium. The induced necrosis results in
an inflammatory response that clears the site of the necrotic
tissue and ultimately leads to thinning of the myocardium. The
cycle continues with an increase in stress on the myocardium and
may result ultimately in heart failure.
Structural Reinforcement of the Infarct Zone by Inducible Gel
Systems
[0169] FIG. 20 illustrates a flowchart describing the introduction
of photo-polymerizable hydrogels to the infarct region 2000 for
structural reinforcement of the infarct zone. Hydrogels have been
used before in tissue engineering applications. These gels are
biocompatible and do not cause thrombosis or tissue damage. These
hydrogels may be photo-polymerized in vivo and in vitro in the
presence of ultraviolet (UV) or visible light depending on the
photo initiation system. Photo-polymerizing materials may be
spatially and temporally controlled by the polymerization rate.
These hydrogels have very fast curing rates. A monomer or macromer
form of the hydrogel may be introduced to the infarct zone for
augmentation with a photoinitiator. Examples of these hydrogel
materials include PEG acrylate derivatives, PEG methacrylate
derivatives or modified polysaccharides.
[0170] Visible light 2030/2160 may be used to initiate interfacial
photopolymerization of a polyoxyethylene glycol
(PEG)-co-poly(alpha-hydroxy acid) copolymer 2100 based on PEG 8000
macromonomer in the presence of an initiator, for example,
Quanticare QTX. Initiator
2-hydroxy-3-[3,4,dimethyl-9-oxo-9H-thioxanthen-2-yloxy]N,N,N-trimethyl-1--
propanium chloride photo-initiator may be obtained as Quantacure
QTX. This is a specific water-soluble photoinitiator that absorbs
ultraviolet and/or visible radiation and forms an excited state
that may subsequently react with electron-donating sites and may
produce free radicals. This technology has been used to demonstrate
adherence to porcine aortic tissue, resulting in a hydrogel barrier
that conformed to the region of introduction. The resulting matrix
was optimized in vitro and resulted in the formation of a 5-100
microns thick barrier. See Lyman, M. D., et al., Characterization
of the Formation of Interfacially Photopolymerized Thin Hydrogels
in Contact with Arterial Tissue, Biomaterials, February 1996, pp.
359-364, 17(3). Scaffolding 2040/2130 may be directed to only the
desired area of the ventricle using minimally invasive procedures
discussed previously. The structural reinforcement could remain in
place until it is cleared or degraded 2050/2170.
[0171] One embodiment includes introduction to the infarct zone of
benzoin derivatives, hydroxalkylphenones, benziketals and
acetophenone derivatives or similar compounds. These
photoinitiators form radicals upon exposure to UV light by either
photocleavage or by hydrogen abstraction to initiate the reaction
see FIGS. 21A-21E. The source of the UV or visible light may be
supplied by means of a catheter 2160, for example, a fiber optic
tip catheter or lead on a catheter illustrated in FIG. 21C, or,
transdermally. FIGS. 22A-22B illustrate a catheter assembly that
may be used to deliver a light-sensitive material. The catheter
2210 is designed to provide a delivery device with at least one
lumen for one or more agent(s) 2230 and a light source 2220 for
modification of the delivered agent. The catheter controller 2240
may house a switch 2250 for the light source 2220 and a controller
for agent delivery 2260. In another embodiment, the photoinitiator
Camphorquinone may be used. Camphorquinone has been used
extensively in dental applications and has a .lamda..sub.max of 467
nanometers. For example, this agent can be activated by a GaN blue
LED on the tip of a catheter. One embodiment includes the use of
visible light at the end of the delivery catheter to induce the
polymerization event in the presence of a light sensitive
initiator. Another embodiment includes the use of the
photoinitiator, Camphorquinone, that may facilitate the
cross-linking of the hydrogel by a light on the tip of a catheter
within the infarct region. Another embodiment includes the use of
the photoinitiator, Quanticare QTX, that may facilitate the
cross-linking of the hydrogel by a light on the tip of a catheter
within the infarct region. Another embodiment includes the use of a
catheter with a UVA light source to induce the polymerization event
in the presence of a light sensitive initiator. Other initiators of
polymerization in the visible group include water-soluble free
radical initiator
2-hydroxy-3-[3,4,dimethyl-9-oxo-9H-thioxanthen-2-yloxy]N,N,N-tr-
imethyl-1-propanium chloride. This cascade of events provides the
necessary environment for initiation of polymerization of suitable
vinyl monomers or pre-polymers in aqueous form within the infarct
region. See Kinart, et al., Electrochemical Studies of
2-hydroxy-3-(3,4-dimetlyl-9-oxo-9H-thioxanthen-2-yloxy)N,N,N-trimethyl-1--
propanium chloride, J. Electroanal. Chem., 1990, pp. 293-297,
294.
[0172] One possible method of introducing a photo-polymerizable
agent to the infarct region is illustrated in FIGS. 21A-21E. In one
embodiment, the photo-polymerizable material is introduced to the
infarct region during an open chest procedure or via a minimally
invasive procedure 2130. In another embodiment, the minimally
invasive procedure includes sub-xiphoid and percutaneous methods.
In another embodiment, the percutaneous introduction into the
infarct zone may comprise one of the following: intra-ventricular
needle, transvascular needle catheter and retrograde venous
perfusion. A single bore needle catheter 2120 may be used to
introduce the photo-polymerizable material into the infarct zone
2140. Once the agent is introduced to the region, several
heartbeats clear the excess agent into the ventricle 2150, and this
excess agent is cleared from the cardiac region. Once the excess
material is cleared, the light source 2160 may be introduced to
induce polymerization 2170. Thus, the structural reinforcement is
confined to the local area of damage where tissue augmentation is
required. As illustrated in FIG. 20, the scaffolding may be made up
of a resistant material or a biodegradable material 2050. Some
examples of biodegradable materials include PEG-co-poly
(.alpha.-hydroxy acid) diacrylate macromers, derivatives of this
material that vary the length and composition of the
.alpha.-hydroxy acid segment in the co-polymer, poly(propylene
fumarate-co-ethylene)glycol and hyaluronic acid derivatives. The
degradation rates of the polymers may be varied according to the
optimum length of time the material is required to remain in the
infarct region. It has been shown that the degradation rates of
theses gels can be modified by the appropriate choice of the
oligo(.alpha.-hydroxy acid) from less than one day to as long as 4
months. See Sawhney, A. S., et al., Bioerodable Hydrogels Based on
Photopolymerized Poly(ethylene glycol)-co-poly(a-hydroxy acid)
Diacrylare Macromers, Macromolecules, 1993, pp. 581-587, 26. Any of
these polymer chains may be formed in the presence of a
photoinitiator, such as Quanticare QTX, and a light source.
[0173] FIGS. 21A-21E illustrate the process of introduction of a
potential photopolymerizable material to the infarct zone. FIG. 21A
and FIG. 21B illustrate the introduction of the material to the
site 2100 and 2110. FIG. 21C illustrates the clearing of the excess
material into the ventricle 2150. Then, in FIG. 21C the light
source may be introduced via a catheter to polymerize the material
2160. The material remains in the site 2170 as structural
reinforcement until at which time it degrades or not depending on
the material used.
[0174] In one embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 1
ml. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 300
.mu.l. In another embodiment, any of the described agents may be
introduced in one or more doses in a volume of about 1 .mu.l to 100
.mu.l. In a preferred embodiment, the any of the described agents
may be introduced in one or more doses in a volume of about 1 .mu.l
to 50 .mu.l.
[0175] FIG. 24A and FIG. 24B illustrate a catheter assembly that
may be used to deliver a dual component composition. In FIG. 24A,
component 1 (2410) and component 2 (2420) are housed 2430 in
separate lumens of a delivery device. Delivery of the components is
controlled by a handle 2470 at the base of the device. The handle
2470 is rotated to allow one needle to extend and then the other.
Only one needle is engaged at a time. A cross-sectional view
illustrated in FIG. 24B illustrates the first needle port 2450 and
the second needle port 2460 and the central tendon 2480 that
controls the needle extension. At the distal end 2490 of the
device, FIG. 24C, the handle is turned and the needle extends while
retracting the other needle. In one embodiment, this catheter
device may be used to deliver components to the infarct region of a
left ventricle intramyocardium. In another embodiment, this
catheter device may be used to deliver a first component to the
area and a second component after the excess first component is
allowed some time to wash away.
[0176] FIGS. 25A-25D illustrate the introduction of dual components
using the catheter device of FIG. 24 to an infarct region while
avoiding the possibility of injecting the agents into the exact
same site. The delivery device of FIG. 24 is used to deliver the
components to the infarct region. The infarction is illustrated as
a region between the endocardium and the epicardium. The device
2540 is advanced to this site and the first component is delivered
by extending needle 2550 and the component 2560 is dispersed in the
infarct area. Then this needle 2550 is retracted while the second
needle 2570 is extended. The second component 2580 is dispersed.
The delivery of the two components to the area is capable of
forming a gel 2590.
[0177] FIG. 26 illustrates the delivery of the catheter device
illustrated in FIGS. 24 and 25. Both of the components are
delivered through a lumen of a catheter (for example a balloon
catheter) 2630/2640 at the same time. For example, the first
component 2650 may be delivered through a venous route 2610 and the
second component 2660 may be delivered through an arterial route
2620. This procedure ensures the appropriate pressure balance to
contain the components in the microcirculation. This avoids leakage
to either the venous or arterial side. The driving pressure for the
venous side is greater than 100 mm Hg (.DELTA.P) 2670 is calculated
to ensure the confinement of the component in capillary level) and
the arterial side does not require an external pressure gradient.
The arterial side may be accomplished by infusion. In one
embodiment, the catheter may be used to deliver the first component
through the venous tree followed by the second component through
the arterial tree. This device may be used to deliver any of the
component combination methods described in the embodiments detailed
previously.
Ventricular Plugs
[0178] Another method for reinforcing the damaged wall of a
ventricle may include introduction of a solid material to the
damaged area. The solid material may be used to fill or bulk the
region by introducing plugs of the solid material to the site and
may increase the compliance of the ventricle. These materials may
be made of organic or silicon-based polymers, biodegradable
polymers, non-biodegradable polymers, engineered biomaterials
and/or metals. In one embodiment. the plug may have barbs or
pointed ends in order to lodge the material into the area and
ensure it remains there. In other embodiments, the sealant or plug
may add bulk to the thinning wall of an infarct post myocardial
infarction. This may result in an increase in the modulus of
elasticity of the damaged area. In other embodiments, the sealant
or plug may invoke an inflammatory response to the infarct region.
The inflammatory response will result in the increase in angiogenic
response capable of causing recruitment and activation of
fibroblasts that deposit additional collagen to bulk the thinning
infarct region and increase the modulus of elasticity of this
region. Still, other embodiments include the addition of a plug to
the damaged region of a ventricle that may add strength to the wall
and also cause an inflammatory response to the region.
[0179] In one embodiment, the plug supplied to the damaged region
of the ventricle may include biocompatible organic components. In
other embodiments, the plug supplied to the damaged region of the
ventricle may include a biocompatible silicone-based polymer. In
other embodiments, the plug supplied to the damaged region of the
ventricle may include biocompatible biodegradable polymers for
example PLGA, Poly(hydroxyvalerate) and poly ortho esters. In other
embodiments, the plug supplied to the damaged region of the
ventricle may include biocompatible non-biodegradable material, for
example, polypropylene and PMMA. In still further embodiments, the
plug supplied to the damaged region of the ventricle may include
biocompatible metal compounds, for example, 316L, Co--Cr alloy,
tantalum and titanium. Another advantage to using a plug directly
implanted in the region of interest may be to add additional
surface components to the plug such as side groups. These side
groups may contain reactive side groups that react with exogenously
supplied or endogenous collagen, for example, type I and type III
collagen. Since collagen contains a significant number of lysine
and hydroxyproline residues, these residues harbor primary amine
and hydroxyl groups capable of reacting with other moieties. In one
embodiment, the plug supplied to the damaged region of the
ventricle may include surface aldehyde groups capable of reacting
with the primary amines of lysine in collagen.
[0180] The size and the shape of the plugs may vary depending on
the situation. For example, polymeric plugs mentioned previously
may be machined, injection molded, extruded or solution cast. In
one embodiment, the shape of the plug may be elongated and thin in
order to facilitate delivery by a catheter device. These plugs may
also possess a barb or side protrusion to prevent the plug from
slipping out of the site once it is introduced to the damaged
region of the ventricle. In other embodiments, the plug may be
created in the shape similar to a screw or a helix. In one
embodiment, the plug may be a polymeric material. In other
embodiments, the plug may be a polymeric material with SS anchors
for example, a plug with a stainless steel band with anchors for
embedding the plug into the site of interest. The size of the plug
may also vary. In one embodiment, the radial diameter of the plug
may be from about 0.1 mm to about 5 mm. In other embodiments, the
radial diameter of the plug may be about 0.2 mm to about 3 mm. In
other embodiments, the length of the plug may be from about 1 mm to
about 20 mm. In other embodiments, the length of the plug may be
about 2 mm to about 12 mm. In addition to the size and shape of the
plug, the number of plugs supplied to a region in the ventricle may
also vary depending on the extent of damage and the condition of
the subject. In one embodiment, the number of plugs supplied to the
region may about 1 to about 200. In other embodiments, the number
of plugs supplied to the region may be about 5 to about 50. In
still further embodiments, the number of plugs supplied to the
region may be about 2 to about 20.
[0181] In a preferred embodiment, the plug may be a processed
biocompatible biomaterial. This biomaterial may be advantageous for
recruiting cells to the damaged region for additional strength to
the site. One example of a biomaterial includes porcine derived
Small Intestine Submucosa, termed SIS. This engineered biomaterial
may be supplied from DePuy Inc and the Cook Group. It is available
in sterile sheets. SIS includes the complete small intestinal
submucosa, including de-cellularized extracellular matrix (ECM) in
a native configuration. It also includes important endogenous
growth factors adhered to the matrix. SIS has previously been shown
to recruit pluripotent bone marrow-derived stem cells that adhere
to the SIS and induce healing. SIS has previously been used to
repair rotator cuff injuries, diabetic foot ulcers and hip joints.
SIS has been shown to re-absorb after a period of approximately 3
to 4 months. After re-absorption, the healed live tissue has
replaced the matrix. In one embodiment, small disks of SIS may be
supplied to a region in the ventricle for example an infarct
region. The SIS disks may provide similar recruitment of cells into
the damaged myocardium. These cells may then transform into viable
muscle tissue and may form contractile myocytes.
[0182] There are several methods that may be used to introduce any
of the plugs described. An optimum approach for introduction of the
plugs may include, but is not limited to. introduction to the
infarct region and/or the border zone of an infarct region during
an open-heart procedure; or through a minimally invasive procedure
for example sub-xiphoid or percutaneously for example with an
intra-ventricular catheter or transvascular catheter (venous or
arterial). One embodiment for introducing the plugs to the infarct
region may include directly introducing the plugs to the site
during an open-heart surgical procedure.
[0183] One or more contrast agents and/or suitable treatment
agent(s) may accompany the previously detailed components. The
contrast agent or treatment agent may be dispersed into, conjugated
to, or dissolved into the plug component prior to introduction to
the infarct area. The contrast agents may be used for detection in
X-ray or MR analysis. The agents that may accompany the reinforcing
component(s) may include, but are not limited, to angiogenic
agents, ACE inhibitors, angiotensin receptor blockers, SRCA pump
(sarcoplasmic reticulum calcium pump) increasing agents,
phospholamban inhibitors and anti-apoptotic drugs. These agents may
be in the form of small molecules, peptides, proteins or gene
products. The agents may be optionally conjugated to a component of
the resin mix that makes the plug, dispersed in the plug solution
prior to forming the plug, or dissolved in the plug solution prior
to forming the plug, or packed into machined pockets or reservoirs
in the plug to elicit a biological effect (e.g., improve implant
adhesion, recruit cells, promote healing). One embodiment is to
conjugate a peptide with a conserved region that mediates adhesion
processes. Another embodiment includes the use of a specific
peptide conjugate with a RGD (arginine-glycine-asparagine) motif or
the peptide receptor to RGD, such as DDM
(aspartate-aspartate-methionine) in the presence of the reinforcing
component. In further embodiments, the RGD motif peptide may
include von Willebrand factor, osteopontin, fibronectin,
fibrinogen, vitronectin, laminin and collagen.
[0184] In the foregoing specification, the embodiments have been
described with reference to specific exemplary embodiments. It
will, however, be evident that various modifications and changes
may be made without departing from the broader spirit and scope of
the invention as detailed in the appended claims. The specification
and drawings are, accordingly, to be regarded in an illustrative
rather than a restrictive sense.
EXAMPLES
Prophetic Example 1
[0185] As a treatment for severe MI or heart failure, a 0.1%
solution of GelSite aloe pectin is dissolved in 300 mOs/kg Ammonium
Chloride. To this solution, one adds human mesenchymal stem cells
(5M to 20M cells per ml) and disperses the cells gently using a
pipettor or alternate method. This cell suspension is delivered to
the border and infarct zones of the patient myocardium using an
intramyocardial catheter such as the Maserati. Endogenous Calcium
ions are present at a sufficient concentration within the tissue to
gel the pectin and cause an enhancement of cells retained within
the myocardium.
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