Note: Descriptions are shown in the official language in which they were submitted.
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~34Q996
Description
This application is a divisional application of
the Applicant's parent application Serial No. 609,264
filed 24 August, 1989.
Biodegradable Polymeric Endoluminal Sealing Process,
A~aratus and Polymeric Products For Use Therein
Background of the Invention
This invention relates to a novel method for the
in vivo paving and sealing of the interior of organs
or organ c;omponents and other tissue cavities, and to
apparatus and partially pre-formed polymeric products
for use in this method. The tissues involved may be
those organs or structures having hollow or tubular
geometry, for example blood vessels such as arteries
or veins, in which case the polymeric products are
deposited within the naturally occurring lumen.
Alternatively, the tissue may be a normally solid
organ in which a cavity has been created either as a
result of an intentional surgical procedure or an
accidental trauma. In this case, the polymeric
product is deposited in the .Lumen of the cavity.
Often times, the hollow or tubular geometry of
organs has functi.anal significance such as in the
facilitation of fluid or gas transport (blood, urine,
lymph, oxygen or respiratory gases) or cellular
containment (ova, sperm). Disease processes may
affect these organs or their components by encroaching
upon, obstructing or otherwise reducing the cross-
sectional area of the hollow or tubular elements.
Additionally, other disease processes may violate the
native boundaries of the hollow organ and thereby
affect its barrier function and/or containment
ability. The ability of the organ or structure to
properly function is then severely compromised. A
good example of this phenomena can be seen by
reference to the coronary arteries.
Coronary arteries, or arteries of the heart,
perfuse the actual cardiac muscle with arterial blood.
They also ;provide essential nutrients and allow for
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removal of metabolic wastes and for gas exchange.
These arteries are subject to relentless service
:errands for continuous blood flow throughout the life
of: the patient.
5 Despite their critical life supporting function,
coronary arteries. are often subject to attack through
several disease processes, the most notable being
atherosclerosis or hardening of the arteries.
Throughout the life of: thelpatient, multiple factors
10 contribute to the development: of microscopic and/or
macroscopic vascular Lesions known as plaques.
The development of a plaque lined vessel
typically leads to an irregular inner vascular surface
with a corresponding reduction of vessel cross-
15 sectional area. The progressive reduction in cross-
sectional ,area compromises flow through the vessel.
For example, the effect on the coronary arteries, is a
reduction in blood flow to the cardiac muscle. This
reduction in blood flow, with corresponding reduction
20 in nutriew:. and oxygen supply, often results in
clinical angina, unstable angina or myocardial infarc-
tion (heart attack) and death. The clinical
consequences of the above process and its overall
importance are seen in that atherosclerotic coronary
25 artery disease represents the leading cause of death
in the Unit:ed States today.
Historically, the treatment of advanced athero-
sclerotic coronary artery disease i.e. beyond that
amenable to thera;~y via medication alone, involved
30 cardio-thoracic surgery in the form of coronary artery
bypass graf-.'ting (CABG). The patient is placed on
cardio-pulmonary bypass and the heart muscle is
temporarily stopped. Repairs are then surgically
affected on the heart in the form of detour conduit
35 grafted vee;sels p,:oviding blood flow around obstruc-
tions. While CABC~ has been perfected to be quite
effective i.t carr:ies with it inherent surgical risk
and requires a several week, often painful
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recouperation period. In the United States alone
approximately 150-200 thousand people are subjected to
open heart surgery annually.
In 1977 a major advance in the treatment of
5 atherosclerotic coronary artery disease occurred with
the introduction of a technique known as Percutaneous
Transluminal Coronary Angioplasty (PTCA). PTCA
involves the retrograde introduction, from an artery
in the arm or leg, up to the area of vessel occlusion,
10 of a catheter with a small dilating balloon at its
tip. The catheter is snaked through the arteries via
direct fluoroscopic guidance and passed across the
luminal narrowing of the vessel. Once in place, the
catheter balloon is inflated to several atmospheres of
15 pressure. This results in "cracking", "plastic" or
otherwise rechanical deformation of the lesiow or
vessel with a subsequent increase in the cross-
sectional area. This in turn reduces obstruction, and
traps-lesional pressure gradients and increases blood
20 flow.
PTCA is an extremely effective treatment with a
relatively low morbidity and is rapidly becoming a
primary therapy in the treatment of atherosclerotic
coronary disease throughout t:he United States and the
25 world. By way of example, since its introduction in
1977, the number of PTCA cases now exceeds 150,000 per
annum in the United States and, for the first time in
1987, surpassed the number of bypass operations
performed. Moreover, as a result of PTCA, emergency
30 coronary artery bypass surgery is required in less
than four percent of patients. Typically,
atherosclerosis is a diffuse arterial disease process
exhibiting simultaneous patchy involvement in several
coronary arteries. Patients with this type of
35 widespread coronary involvement, while previously not
considered candidates for angioplasty, are now being
treated die to technical advances and increased
clinical experience.
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Desp9.te the major therapeutic advance in the
treatment of coronary artery disease which PTCA
represent~c, its success has been hampered by the
development of vessel renarrowing or reclosure post
5 dilation. During a period of hours or days post
procedure, signil:icant total vessel reclosure may
develop in up to 10~ of cases. This is referred to as
"abrupt re~closure~". However, the more common and
major limitation of PTCA, is the development of
10 progressive reversion of the vessel to its closed
condition, negating any gains achieved from the
procedure.
This more gradual renarrowing process is referred
to as "restenosi~,." Post-PTCA follow-up studies
15 report a 10-S0~ incidence (averaging approximately
30~) of restenosis in cases of initially successful
angioplasty. Studies of the time course of restenosis
have shown that it is typically an early phenomenon,
occurring slmost exclusively within the six months
20 following an angioplasty procedure. Beyond this siX-
month period, the incidence of restenosis is quite
rare. Despite recent pharmac;ologic and procedural
advances, little success has been achieved in
preventing either abrupt reclosure or restenosis
25 post-angioplasty.
Restenosis has become even more significant with
the increasing use of multi-vessel PTCA to treat
complex coronary artery disease. Studies of
restenosis in cases of multi-vessel PTCA reveal that
30 after mult.i-lesion dilatation, the risk of developing
at least one recurrent coronary lesion range from 26%
to 54~ and appears to be greater than that reported
Eor single vessel PTCA. Moreover, the incidence of
restenosis increases in parallel with the severity of
35 the pre-anc3ioplasty vessel narrowing. This is
significant: in li~3ht of the growing use of PTCA to
treat increasingly complex multi-vessel coronary
artery disease.
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The 30% overall average restenosis rate has
significant costs including patient morbidity and
risks as well as medical economic costs in terms of
follow-up medical care, repeat hospitalization and
recurrent: catherization and angioplasty procedures.
Most significant=ly, prior to recent developments,
recurrent: restenosis following multiple repeat
angiopla~;ty atts~mpts could only be rectified through
cardiac :surgery with the inherent risks noted above.
In 7.987 a,rnechanical approach to human coronary
artery restenos:Ls was introduced by Swiss
investigators referred to as, "Intracoronary
Stenting". An untracoronary stem is a tubular device
made of fine wire mesh, typically stainless steel.
The Swiss invest=igators utilized a stent of the
Wallsten design as disclosed and claimed in U.S.
Patent No. 4,655,771. The device can be configured in
such a manner as to be of low cross-sectional area.
In this "low profile" condition the mesh is placed in
or on a catheter similar to those used for PTCA. The
stent is then positioned at the site of the vascular
region to be trE~ated. Once in position, the wire mesh
stent is releasEad and allowed to expand to its desired
cross-sectional area generally corresponding to the
internal diameter of the vessel. Similar solid stents
are also disclo:;ed in U.S. Patent No. 3,868,956 to
Alfidi et al.
The metal ;tent functions as a permanent intra-
vascular scaffold. By virtue of its material
properties, the metal stent provides structural
stability and direct mechanical support to the
vascular wall. Stents of the Wallsten design are
self-expanding clue to their helical "spring" geometry.
Recently, U.S. investigators introduced slotted steel
tubes and extended spring designs. These are deployed
through application of direct radial mechanical
pressure conveyed by a balloon at the catheter tip.
Such a device an,d procedure are claimed -in U.S. Patent
1 340 99 6
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No. 4,733,665 to Palmaz. Despite the significant
limitations and potentially serious complications
discussed below, this type of stenting has been
successful with an almost 100 acute patency rate and
5 a marked reduction in the restenosis rate.
The complications associated with permanent
implants such as the Palmaz device result from both
the choice of material, i.e., metal or stainless
steel, as well as the inherent design deficiencies in
10 the stenting devices. The major limitation lies in
the permanent placement of a non-retrivable, non-
degradable, foreign body in a vessel to combat
restenosis which is predominately limited to the six-
month time period post-angiaplasty. There are
15 inherent, significant risks common to all permanent
implant devices. Moreover, recent studies have
revealed that atrophy of the media, the middle
arterial Layer of a vessel, may occur as a specific
complication associated with metal stenting due to the
20 continuou:~ lateral expansile forces exerted after
implantation.
These problems are even more acute in the
placement of a permanent metallic foreign body in the
vascular tree associated with the cardiac muscle.
25 Coronary arteries are subjected to the most extreme
service dE~mands requiring continuous unobstructed
patency w:lth unimpeded flow throughout the life of the
patient. Failure in this system will lead to
myocardial. infar~~tion (heart attack) and death. In
30 addition, the torsional and other multi-directional
stresses eancountered in the heart due to its
continuous oscil:Latory/cyclic motion Further amplifies
the risks associated with a permanent, stiff metallic
intra-arterial irnplant in the coronary bed.
35 It has been observed that, on occasion, recurrent
intravascular narrowing has occurred post-stmt
placement in vessels during a period of several weeks
to months. Typi<:ally, this occurs "peri-stent", i.e.,
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immediately up or down stream from the stmt. It has
been suggested that this may relate to the
significar;tly dil:ferent compliances of the vessel and
the stent, somet:~mes referred to as "compliance
mismatch". Aside from changes in compliance another
important mechan:.sm leading to luminal narrowing above
and below the stE~nt may be the changes in shear forces
and fluid flows encountered across the sharp
transitions of the stent-vessel interface. Further
supportinc evidence has resulted from studies of
vascular drafts which reveal a higher incidence of
thrombosis and eventual luminal closure also associ-
ated with significant compliance mismatch.
To date known stent designs, i.e. tubular, wire
helical or spring, scaffold design have largely been
designed empirically without consideration or'
measurement of their radial stiffness. Recent studies
measuring the re7.ative radial compressive stiffness of
known wire stent:~, as compared to physiologically
pressurized arteries, have found them to be much
stiffer than the actual biologic tissue. These
studies lend support to the concept of poor mechanical
biocompatibility of currently available stents.
Conventional. metal stenting is severely limited
since it is device dependent and necessitates a myriad
of individual stents as well as multiple deployment
catheters of varying lengths and sizes to accommodate
individual applications. Additionally, metal stents
provide a relatively rigid nonflexible structural
support which is not amenable to a wide variety of
endoluminal geome~tries, complex surfaces, luminal
bends, curves or bifurcations.
These identified risks and limitations of metal
stents have severely limited their utility in coronary
artery applications. As of 1988, a partial self-
imposed moratorium exists in the use of helical metal
ste ms to treat Human coronary artery diseases.
Presently in the United States, a spring-like wire
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coil stent has been approved only for short term use
as an emergency device for patients with irreparably
closed coronary arteries following failed PTCA while
in transit to emergency bypass surgery. An
alternative to the use of stents has now been found
which has broad applications beyond use in coronary
artery applications for keeping hollow organs open and
in good health.
Summary of the Invention
The ~aresent invention provides a solution to the
problem of restenosis following angioplasty, without
introducing the problems associated with metal stents.
Specifically, the invention provides a novel method
for endoluminal paving and sealing (PEPS) which
involves ,application of a polymeric material to the
interior aurface of the involved blood vessel. In
accordance with this method, a polymeric material,
either in the form of a monomer or prepolymer solution
or as an at least partially pre-formed polymeric
product, is introduced into the lumen of the blood
vessel and positioned at the point of the original
stenosis. The polymeric product is then reconfigured
to conform to and maintain intimate contact with the
interior ;surface of the blocd vessel such that a
paving and sealing coating is achieved.
The 1?EPS approach is not limited to use in
connection with restenosis, however, and can also be
effectively employed in any hollow organ to provide
local structural support, a smooth surface, improved
flow and sealing of lesions. In addition, the
polymeric paving and sealing material may incorporate
therapeutic agents such as drugs, drug producing
cells, c ell rege:;eration factors or even progenitor
cells of t_he sa-;,e type as the involved organ or
histologi~~ally different to accelerate healing
processes. Such materials with incorporated
therapeutic agents may be effectively used to coat or
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plug surgically or traumatically Formed lumens in
normally solid organs as well as the native or disease
generated lumens of hollow or tubular organs.
For use in these applications, the present
5 invention provides at least partially preformed
polymeric products. These products may have any of a
variety of physical shapes and sizes in accordance
with the particular application. The invention also
provides apparatus specially adapted for the
10 positioning of the polymeric material, these including
partially pre-formed polymer.i.c products, at the
interior surface of an organ and for the subsequent
chemical or physical reconfiguration of she polymeric
material such that it assumes a desired molded or
15 customized final configuration.
Brief Description of the Drawing
Fig. 1 shows an amorphous geometry of the PEPS
polymer coating before and after deployment;
Fig. 2 shows a stellate geometry of the PEPS
20 polymer coating before and after deployment;
Fig. 3 shows a linear feathered polymer strip
applied to "one" wall before and after deployment;
Fig. 4 shows a large patch of sprayed on polymer
material before and after deployment;
25 Fig. 5 shows a porous tubular form geometry
before and after deployment;
Fig. 6 shows a spot geometry of the PEPS process
before and after deployment;
Fig. 7 shows a spiral form application of the
30 PEPS process before and after deployment;
Fig. B shows an arcuate (radial, arc) patch
gec retry of the PEPS polymer before and after
deployment;
Fig. 9 shows a process for using PEPS to treat an
35 artificially created tissue lumen;
Fig. 10 shows two lumen catheters according to
the invention;
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Fig. 11 shows surface contours of expansile
members useful ir, catheters according to the
invention;
Fig. 12 shows three catheters according to
the
S invention;
Fig. 13 shows four lumen catheters according
to
the invention;
Fig. 14 shows five lumen catheters according
to
the invention;
Fig. 15 shows six lumen catheters according
to
the invention;
Fig. 16 shows seven lumen catheters according
to
the invention;
Fig. 17 shows a distal occlusion catheter
and a
polymer delivery atheter in a vessel;
c
Fig. 18 shows in cross-section a polymeric
sleeve
before insertion n a blood vessel; the sleeve
i after
insertion in the essel and after expansion;
v
Fig. 19 is a cross-sectional comparison
of an
initial polymericsleeve and an expanded polymeric
sleeve.
Fig. 20 shows enmeshed discontinuous polymeric
material arrayed n a catheter with a retractable
o
sheath; and
Fig. 21 shows variations in apertures for
polymer
delivery t~o a
tissue lumen.
Detailed D~escrigtion of the Invention
In ge:zeral, PEPS involves the introduction of a
polymeric material into a selected location within a
lumen in tissue, i.e. an organ, an organ component or
cavernous ~~omponent of an organism, and the subsequent
reconfigur;ition of the polymeric material to form a
sealing in intimate and conforming contact with or
paving the interior surface. As used herein, the term
"sealing" or "seal" means a coating of sufficiently
low porosi~~y that the coating serves a barrier
function. The term "paving" refers to coatings which
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are porous or perforated. Sy appropriate selection of
the polymeric material employed and of the
configuration of the coating or paving, PEPS provides
a unique customizable process, which can be utilized
as a given biological or clinical situation dictates.
The b;3sic requirements for the polymeric material
to be used in the PEPS process are biocompatibility
and the capacity to be chemically or physically
reconfigured under conditions which can be achieved in
vivo. Suc'~ reconfiguration conditions may involve
heating, c~~oling, mechanical deformation, e.g.,
stretching, or chemical reactions such as
polymerization or crosslinking.
Suita'~le polymeric materials for use in the
invention include polymers and copolymers of
carboxylic acids such as glycolic acid and lactic
acid, polyurethanes, polyesters such as polyethylene
terephthal~ate), polyamides such as nylon,
polyacrylonitriles, polyphosphazines, polylactones
such as polycaprolactone, and polyanhydrides such as
poly(bis(p-carboxyphenoxy)propane anhydride) and other
polymers or copolymers such as polyethylene, polyvinyl
chloride and ethylene vinyl acetate.
Other bioabsorbable polymers could also be used
either sin3ly or in combination, or such as
homopolymers and copolymers of delta-valerolactone,
and p-dioxanone as well as their copolymers with
caprolactone. Further, such polymers can be cross-
linked with bis-caprolactone.
Preferably PEPS utilizes biodegradable polymers,
with specific degradation characteristics to provide
sufficient lifespan for the particular application.
As noted above, a six month lifespan is probably
sufficient for use in preventing restenosis; shorter
or longer periods may be appropriate for other
therapeutic applications.
Polycaprolactone as disclosed and claimed in U.S.
Patent No. 4,702,917 to Schindler
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is a highly suitable bioabsorbable
polymer for use in the PEPS process, particularly for
prevention of restenosis. Polycaprolactone possesses
adequate mechanical strength being mostly crystalline
even under quenching conditians. Despite its
structural stability, polycaprolactone is much less
rigid than the metals used in traditional stenting.
This minimizes the risk of acute vessel wall damage
from sharp or rough edges., Furthermore, once poly-
caprolactone has been deployed its crystalline
structure will maintain a constant outside diameter.
This eliminates the risks often associated with known
helical or spring metal stents which after being
expanded in vivo have a tendency to further expand
exerting increasing pressure on the vessel wall.
The rate of bioabsorption of polycaprolactone is
ideal for this application. The degradation process
of this polymer has been well characterized with the
primary de~3radation product being nonparticulate,
nontoxic, S-hydroxy hexanoic acid of low acidity. The
time of biodegradation of polycaprolactone can be
adjusted through the addition of various copolymers.
Polyc,iprolactone is a preferred polymer for use
in the PEPS process because it has attained favorable
clinical ar_ceptability and is in the advanced stages
of FDA approval. Polycaprolactone has a crystalline
melting point of 60°C and can be deployed in vivo via
a myriad o:E techniques which facilitate transient
heating anti varying degrees of mechanical deformation
or applicai~ion as dictated by individual situations.
This differs markedly from other bioabsorbable
polymers such as polyglycolide and polylactide which
melt at much higher temperatures of 180°C and pose
increased i_echnical constraints as far as the delivery
system affording polymer sculpting without deleterious
tissue exposure to excessive temperatures or
mechanica= forces.
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Polyanhydrides have been described for use as
drug carrier matrices by Leong et al., J. Biomed. Mat.
Res. 19, 541-955 (1985). These materials Frequently
have fairly low cllass transition temperatures, in some
5 cases near norma:L body temperature, which makes them
mechanically deformable with only a minimum of
localized heatin<1. Furthermore, they offer erosion
times varying from several months to several years
depending on pari:icular polymer selected.
10 The polymer:~c materials may be applied in custom
designs, u~ith varying thicknesses, lengths, and
three-dime~nsiona7_ geometries (e. g. spot, stellate,
linear, cylindrical, arcuate, spiral) to achieve
varying finished geometries as depicted in Figs. 1-8.
15 Further, F~EPS may be used to apply polymer to the
inner surfaces of: hollow, cavernous, or tubular
biological structures (whether natural or artificially
formed) in either single or multiple polymer layer
configurations. PEPS may also be used, where
20 appropriate, to occlude a tissue lumen completely.
The F~olymeric material used in PEPS can be
combined with a variety of therapeutic agents for on-
site delivery. Examples for use in coronary artery
applications are anti-thrombotic agents, e.g.,
25 prostacyclin and salicylates, thrombolytic agents e.g.
streptokinase, urokinase, tissue plasminogen activator
(TPA) and anisoyl.ated plasminogen-streptokinase
activator compler: (APSAC), vasodilating agents i.e.
nitrates, calcium channel blocking drugs, anti-
30 proliferative agents i.e. colchicine and alkylating
agents, intercalating agents, growth modulating
factors such as interleukins, transformation growth
factor S and congeners of platelet derived growth
factor, monoclonal antibodies directed against growth
35 Factors, anti-inflammatory agents, both steriodal and
non-steroidal, ar.d other agents which may modulate
vessel tone, function, arteriosclerosis, and the
healing response to vessel or organ injury post
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intervention. In applications where multiple polymer
layers are used different pharmacological agents could
be used in different polymer layers. Moreover, PEPS
may be used to effect pharmaceutical delivery focally
within the vessel wall, i.e. media.
The polymeri~~ material in accordance with the
invention may also have incorporated in it living
cells to serve any of several purposes. For examples,
the cells may be ;elected, or indeed designed using
principles of rec~~mbinant DNA technology, to produce
specific a<ients such as growth factors. In such a
way, a conl:inuously regenerating supply of a
therapeutic: agent may be provided without concerns for
stability, initial overdosing and the like.
Cells incorporated in the polymeric material may
also be progenitor cells corresponding to the t'.ype of
tissue in t:he lumen treated or other cells providing
therapeutic: advantage. For example, liver cells might
be implanted in tile polymeric material within a lumen
created in the liver of a patient to facilitate
regeneration and ~~losure of that lumen. This might be
an appropriate therapy in the case where scar tissue
or other diseased, e.g. cirrhosis, fibrosis, cystic
disease or malign;3ncy, or non-functional tissue
segment has forme~j in the liver or other organ and
must be removed. The process of carrying out such
treatment, shown schematically in Fig. 9, involves
first inserting a catheter 91 into a lumen 92 within a
diseased organ se~3ment 93. The lumen 92 can be a
native vessel, or it can be a man-made lumen, for
example a cavity produced by a laser. The catheter 91
is used to introd,sce a polymeric plug 94 into the
lumen 92. The catheter is then removed, leaving the
plug 94 in place to act as a focus for new growth
stemming from cells implanted along with the polymeric
plug 94. 7:f the desire is for a more tubular
structure, the plug 94 can be appropriately
reconf igure~d.
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Optional additions to the polymeric material such
as barium, iodine or tantalum salts for X-ray radio-
opacity allow visualization and monitoring of the
coating.
The technique of PEPS preferably involves the
percutaneous application of a polymeric material,
preferably a biodegradable polymer such as
polycaprolactone, either alone or mixed with other
biodegradable polymeric materials, which may
optionally contain various pharmaceutical agents for
controlled sustained release of the pharmaceutical or
for selective soluble factor adsorption and trapping.
The polymeric material is typically applied to the
inside of an organ surface employing combined thermal
and mechanical means to manipulate the polymeric
material. Although capable of being used durihg
surgery, PEPS will generally be applied without the
need for a surgical procedure using some type of
catheter, for example novel modifications of the known
catheter technology described above for (PTCA). PEPS
is preferably apF~lied using a single catheter with
multiple balloons and lumens. The catheter should be
of relatively low cross-sectional area. Typically a
long thin tubular catheter manipulated using
fluoroscopic guidance can access deep into the
interior of organ or vascular' areas.
The polymer may be deplayed in the interior of
the vessel or organ from the surface or tip of the
catheter. Alternatively, the polymer could be
positioned on a balloon such as that of a standard
angioplasty balloon catheter. Additionally, the
polymer could be applied by spraying, extruding or
otherwise internally delivering the polymer via a long
flexible tubular device consisting of as many lumens
as a parti~~ular application may dictate.
The simplest PEPS coating is a continuous coating
over a designated portion of a tissue lumen. Such a
coating ca n be applied with a simple two lumen
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catheter such as those shown in Fig. 10. Looking
first to Fig. 10a, a suitable catheter is formed from
a tubular body 100 having a proximal end 101 and a
distal end 102. The interior' of the tubular body 100
is divided into two conduits 103 and 104 which extend
from the proximal end 101 to apertures 105 and 106 in
the tubular body. (Figs. lOb and lOc) Conduits 103
and 104 thus connect apertures 105 and 106 with the
proximal end 101 of the tubular body 100 to allow
fluid flow therebetween. The proximal ends of
conduits 103 and 104 are preferably equipped with
connectors 108 which allow connection with fluid
supplies. Pressure connectors such as Luer~ locks are
suitable.
The catheter may also include markers 109 in one
or more locations to aid in :Locating the catheter.
These markers can. be, for example, fluoroscopic
radio-opaque bands affixed to the tubular body 100 by
heat sealing.
The catheter shown in Figs. lOb and lOc has an
expansile member in the form of an inflatable balloon
107 disposed over the distal aperture 105. In use, an
at least a partially preformed polymeric layer or
partial layer is positioned over the balloon 107 and
the catheter is inserted into an appropriate position
in the tissue lumen. Fluid flow through conduit 103
will cause the balloon 107 to inflate, stretch and
deform the polymer layer until it comes into contact
with the walls of: the tissue lumen. The other
aperture 105 and conduit 103 are used to control the
reconfiguration of the polymeric sleeve, for example
by supplying a flow of heated liquid to soften the
sleeve and render it more readily stretchable or to
stimulate polymerization of a partially polymerized
sleeve.
Variations on this basic two lumen catheter can
be made, examples of which are shown in Figs. lOd and
10e. For examplE~ Fig. lOd has a shapable wire affixed
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to the tip of thc~ catheter to aid in insertion and a
traumatic and directed passage through the organism,
i.e. to act as a guide wire. In Fig. 10e, the
expansile member is incorporated as part of the
tubular be>dy as a continuous element, preferably a
unitary element. In this case, the distal tip 107a of
the catheter exps~nds in response to fluid flow in
conduit 103. Conduit 104 can be formed by bonding in
or on the extruded catheter body a piece of the same
or different matE~rial in a tubular form. This type of
design can also be used in more complicated multi-
lumen catheters discussed below.
The polymer:.c material may take the form of a
sleeve designed ':o be readily insertable along with
the catheter into the tissue lumen, and then to be
deployed c>nto the' wall of the lumen to form the
coating. This deployment can be accomplished by
inflating a balloon, such as balloon 107 using fluid
flow through conduit 103. Inflation of balloon 107
stretches the po:'.ymeric sleeve causing it to press
against the walls of the tissue lumen and acquire a
shape corresponding to the lumen wall. This shape is
then fixed, and t:he catheter removed leaving behind a
polymeric paving or seal on the lumen wall.
The process of fixing the shape of the polymeric
material can be accomplished in several ways,
depending on the character of the original polymeric
material. For e~;ample, a partially polymerized
material can be expanded using the balloon after which
the conditions are adjusted such that polymerization
can be completed,. e.g., by increasing the local
temperature or providing W radiation through an
optical fiber. f, temperature increase might also be
used to soften a fully polymerized sleeve to allow
expansion and facile reconfiguration and local
molding, after which it would "freeze" in the expanded
position when the' heat source is removed. Of course,
if the polymeric sleeve is a plastic material which
.. ___ _.._. _.. ..____u..~.____ _ __..m .w.~.-...._.._-
~,....~.~..,_,_.~......~.~._ ... _.___...-..-_._...__...~ _... _..._..
1 340 gg 6
-ls-
will permanently deform upon stretching (e. g.,
polyethylene, polyethylene terephthalate, nylon or
polyvinyl chloride), no special fixation procedure is
required.
S As depicted in Fig. lOb, local heating can be
provided by a flow of heated liquid directly into the
tissue lumen. Thermal control can also be provided,
however, using a fluid flow through or into the
expansile member or using a "leaky" partially
perforated balloon such that temperature control fluid
passes through the expansile member, or using
electrical resistive heating using a wire running
along the length of the catheter body in contact with
resistive heating elements. This type of heating
element can make use of DC or radiofrequency (RF)
current or external RF or microwave radiation.. Other
methods of achieving temperature control can also be
used, including laser heating using an internal
optical fiber (naked or lensed) or thermonuclear
elements.
In addition to the smooth shape shown in Fig. 10,
the balloon used to configure the polymer can have
other surface shapes for formation of the coatings to
provide specific polymeric deployment patterns. For
example, the balloon may be a globular shape intended
for deployment from the tip of a catheter device.
(Fig. lla) Such an arrangement would be preferred
when the paving operation is being carried out in a
cavity as opposed to a tubular organ. The balloon
might also be thickened at the ends (Fig. llc) or
substantially helical (Fig. lld) providing a variation
in coating thickness along the length of the paved or
sealed area. Such a configuration might prove
advantageous in the case where additional structural
support is desired and to provide a tapered edge to
minimize flow disruption. Variations in coating
thickness which provide ribs running the length of the
tissue lumen might be achieved using a stellate
134099fi
-19-
balloon (Fig. lle). This type of polymer coating
would be useful in the case where additional
structural support is desirous combined with more
continuous flow properties. In addition balloon shape
may Facilitate insertion in some cases.
Variations in the ultimate configuration of the
PEPS coating can also be achieved by using more
complex deployments of the,polymer on the expansile
number. for example, the polymer can be in the form
of a perforated tubular sleeve, a helical sleeve or in
the form of discontinuous members of various shapes.
These may be affixed to the expansile member directly,
for example with an adhesive or by suction through
perforations and the like, or to an overcoating such
as dissolvable gauze-like or paper sheath (i.e. spun
saccharide) or held in place by or a retractable
porous sheath which will be removed with the catheter
after application.
For example, Fig. 20(a) shows an array of polymer
dots. These dot:r are enmeshed in a dissolvable mesh
substrate Fig. 2(1(b) which in turn is wrapped around
the expans,ile member 107 of a catheter according to
the invention (Fi.g. 20c). An exemplary two lumen
catheter is shown in Fig. 20d (numbered as in Fig.
lOb) where a retractable sheath 205 surrounds the
polymer do>ts 206 for insertion. When the catheter
reaches the application site, the sheath 205 is
retracted (Fig. 20e) and the balloon 107 expanded.
It will be recognized, that the catheter depicted
in Fig. 10 represents a minimalist approach to PEPS
catheter design, and that additional lumens may be
included within t:he catheter body to provide conduits
for inflation of positioning balloons, optical fibers,
additional. polymf~r molding balloons, temperature
control means, and passage of steering or guide wires
or other diagnosi:ic devices, e.g. ultrasound catheter,
or therapeutic devices such ,~s atherectomy catheter or
other lesion modifying device. For example, three
. .._.W._._~ . ._._._ ,. _~_. _oa_.._._...._.._..._..~~..._.._,~.....w ~ .,
_.....-....~,_._._._._w~ .
.rr
1340996
-20-
lumen catheters (Fig. 12), four lumen catheters (Fig.
13), five lumen catheters (Fi.g. 14), six lumen
catheters (Fig. 15) and seven lumen catheters (Fig.
16) might be employed. A retractable sheath may also
be provided which extends over the polymer during
insertion to prevent premature separation of the
polymer from the catheter. In addition, catheters may
have telescoping sections such that the distance
between the occluding balloons can be varied.
Looking for example at t:he six lumen catheters in
Fig. 15b, two positioning balloons 150 and 151, both
connected to conduit 152. Positioning balloons 150
and 151 serve to fix the position of the tubular body
100 within a tissue lumen and isolate the portion of
the tissue lumen between them where the PEPS coating
will be applied. Expansile member 153 is provided
with circulating flow via conduits 154 and 155. This
can be used to provide temperature control to the
isolated portion of the tissue lumen, as well as
acting to configure the polymeric coating formed by
expanding a polymeric sleeve and other deployed form
fitted over expansile member 153. In the catheter
shown in Fig. 15b, a temperature control solution or a
therapeutic solution is advantageous provided through
conduit 156, with conduit 157 acting as a drain line
(or vice versa) to allow flow of fluid through the
isolated portion of the tissue lumen ("superfusion").
Such a drain line is not required, however, and a
simple infusion Gather could omit one of the conduits
156 or 157 as in the five lumen designs of Fig. 14.
The sixth conduit 158 is also optional, but can be
advantageously used for guide wires, diagnostic or
therapeutic device passage, or distal fluid perfusion.
If conduit 158 has an aperture proximal to balloon
151, it can be used as a by-pass conduit for passive
perfusion during occlusion.
The incorporation in the catheter of positioning
balloons which occlude a section of the tissue lumen
1340996'
-21-
makes it possible to utilize solutions of monomers or
prepolymers and Eorm the coating in situ. Looking for
example at four lumen catheters shown in Fig. 13b, an
isolation zone is created by inflating balloons 131
and 132 so that they press against the tissue lumen.
While expansile member 133 could be used to deform a
polymeric sleeve or other deployment form, it can also
be used to define the size and environmental
conditions (e. g. temperature) of the lumen region.
Application of the polymeric material may be
accomplished by extruding a solution of monomers or
prepolymers through the aperture 134 to coat or Fill ,
the tissue lumen. The formation of a polymer coating
can be controlled by introducing crosslinking agents
or polymerization catalysts together with the monomer
or prepolymer solution and then altering the '
conditions such that polymerization occurs. Thus, a
flow of heated fluid into expansile member 133 can
increase the local temperature to a level sufficient ,
to induce or accelerate polymerization.
Alternatively, tree monomer/prepolymer solution might
be introduced cold, with metabolic temperature being
sufficient to induce polymerization. The other lumen
135 acts as a drain line in :auperfusion applications.
The polymeric material c:an be introduced to the
tissue lumen through a simple aperture in the side of
the tube as shown in Fig. 2lsr, or through a raised
aperture (Fig. 27.b). A shaped nozzle which is
extendable away from the surl:ace of the tubular body
(Fig. 21e) can a7.so be used. The material can be
extruded through, or it can be subjected to flow
restriction to yield a spray application. This flow
restriction can tie adjustable to control the spray.
In addition, localized acceleration at the tip of the
nozzle can be usE:d, for example, via a piezoelectric
element to provi~te sprayed application.
The catheter's bodies for. use in this invention
can be made of any known material, including metals,
1 3 40 9g s ,.
-22-
e.g. steel, and thermoplastic polymers. Occluding
balloons m.ay be made from compliant materials such as
latex or silicone, or non-compliant materials such as
polyethyleneterephthalate (PET). The expansile member
S is preferably made from non-compliant materials such
as PET, PVC, polyethylene or nylon. The expansile
number may optionally be coated with materials such as
silicones, polyte~tra-fluoroet:hylene (PTFE),
hydrophilic materials like hydrated hydrogels and
10 other lubricious materials to aid in separation of the
polymer coating.
In addition to arteriesr i.e. coronary, femero-
iliac, carotid and vertebro-basilar, the PEPS process
may be utilized for other applications such as paving
15 the interior of veins, ureters, urethrae, bronchi,
biliary and pancreatic duct systems, the gut, pye and
spermatic and fallopian tubes. The sealing and paving
of the PEPS process can also be used in other direct
clinical applications even at: the coronary level.
20 These include but. are not limited to the treatment of
abrupt vessel reclosure post PCTA, the "patching" oP
significant vessel dissection, the sealing of vessel
wall "flaps". i.e~. secondary to catheter injury or
spontaneously occurring, the sealing of aneurysmal
25 coronary dilations associated with various
arteritidies. Further, PEPS provides intro-operative
uses such as sealing of vessel anostomoses during
coronary artery bypass grafting and the provision of a
bandaged smooth polymer surface post endarterectomy.
30 The unique pharmaceutical delivery function of
the PEPS process may be readily combined with
"customizable" deployment geometry capabilities to
accommodate the interior of a myriad of complex organ
or vessel surface~~. Most importantly, this customized
35 geometry can be ;,jade from structurally stable yet
biodegradable polymers. The ability to tailor the
external shape of the deployed polymer through melted
polymer flow into uneven surface interstices, while
X340996
_23_
maintaining a smooth interior surface with good flow
characteristics, will facilitate better structural
support for a variety of applications including
eccentric coronary lesions which by virtue of their
geometry are not well bridged with conventional metal
stents.
As noted above, the polymer substrate used in
PEPS may b~e fashioned, for example, out of extruded
tubes of p~~lycaprolactone and/or copolymers. The
initial pr~edeployment design and size of the polymer
sleeve will be dictated by the specific application
based upon the final deployed physical, physiological
and pharma~~ological properties desired.
For coronary artery application, predeployment
tubes of a bout 10 to 20 mm in length and about 1 to 2
mm in diameter would be useful. The initial wall
thickness of the resulting in vivo polymer layer may
be varied dependi,~g upon the nature of the particular
application. In ~3eneral coating procedures require
polymer la~,rers of about 0.005mm to 0.50mm while layers
which are designed to give structural support can vary
from 0.05mm to 5.Omm.
The polymer tube walls may be processed prior to
insertion cvith either laser or chemical etching,
pitting, s:Litting or perforation depending upon the
application. In ,addition, the shape of any micro
(lOnm to 1 um) or macro (>1 um up to about 15 um)
perforation may be further geometrically modified to
provide various surface areas on the inner versus
outer seal surfacE~. The surfaces of the predeployed
polymer may be further modified with bound, coated, or
otherwise applied agents, i.e., cyanoacrylates or
biological adhesives such as those derived from fungal
spores, the' sea m.issel or autologous fibrinogen
adhesive derived l:rom blood.
For PEPS app~:ications involving the coronary
arteries, t:he polymer tubes (if in an initial tubular
configuration), should preferably have perforations or
1340996
_2q~
pores, of a size dictated by the particular
application. This will ensure a symmetric expansion
of the encasing polymeric sealant. By using a
fragmented tubular polymer surface with corresponding
expansions along predicted perforations (i.e., the
slots) a significant mechanical stabililty is
provided. In addition, this minimizes the amount of
foreign material placed within the vessel.
Depending upon the polymer and pharmaceutical
combination and the configuration, PEPS may be used to
coat or bandage the organ inner surface with a thin
adhesive partitioning polymer film or layer of about
O.OOSmm tc O.SOmrri. Biodegradable polymers thus
applied tc an internal organ or vessel surface will
act as an adherent film "bandage." This improved
surface, with desirable rheologic and adherence
properties, facilitates improved fluid or gas
transport in and through the body or lumen of the
vessel or hollow organ structure and acts to reinstate
violated native surfaces and boundaries.
The ultimate in vivo deployed geometry of the
polymer dictates the final function of the polymer
coating. The thinner applications allow the polymer
film to function as a coating, sealant and/or
partitioning barrier, bandage, and drug depot.
Complex internal applications of thicker layers of
polymer, such as intro-vessel or intro-luminal
applications, may actually provide increased
structural support and depending on the amount of
polymer used in the layer may actually serve in a
mechanical role t.o maintain vessel or organ potency.
For example, lesions which are comprised mostly
of fibromuscular components have a high degree of
visco-elastic recoil. These lesions would require
using the PEP process to apply an intraluminal coating
of greater thickness and extent so as to impart more
structural. stabi7.ity thereby resisting vessel radial
compressive forces. The PEPS process in this way
X340996
-25-
provides structural stability and is generally
applicable for the maintenance of the intraluminary
geometry cf all tubular biological organs or
substructure. It may be used in this way following
the theraFeutic return of normal architecture
associated with either balloon dilation (PTCA),
atherectomy, lesion spark, thermal or other mechanical
erosion, "G-lazing", welding or laser recanalization.
An important. feature of the PEPS technique is the
ability tc customize the application of the polymer to
the internal surface of a vessel or organ as dictated
by the particular application. This results in a
variety of possible geometries of polymer as well as a
variety of forms. These mult:i-geometry, multi-form
polymer structures may be adjusted to correspond to
particular functions. (Figs. 1-8)
With particular reference to Figs. 1-8 the PEPS
process may be affectuated so that the focal
application of polymer to the vessel or organ results
in either an amorphous geometry, Fig. 1, stellate
geometry, Fig. 2, or spot geometry, Fig. 6.
Additional geometries could include a linear feathered
polymer strip apF~lied to a particular area of the
vessel wall as shown in Fig. 3. Fig. 4 shows a large
patch of polymer which can be sprayed on using a
variety of known techniques. Another form of the PEPS
application to be utilized in instances, e.g., where
structural stability need be imparted to the vessel
would be the porous tubular form shown in Fig. S.
Other types of PEPS applications which would impart
structural stability to the vessel would be the spiral
form application shown in Fig. 7, or the arcuate
(radial, arc) patch as shown in Fig. 8.
Conversely, in cases where the severely denuded
lesions have irregular surfaces with less
fibromuscular components, the PEPS process can be used
to provide only a thin polymer film to act as a
bandage.
X340996
-26-
The F~EPS' process is significantly different and
is conceptually yin advance beyond stents and stenting
in achieving ves=gel patency. Stents have been
designed with thc~ underlying primary Function of
5 providing a relai_ively stiff structural support to
resist post PTCA,, vessel reclosure caused by the
vessel's ~;pring-:Like characteristics. It has been
increasingly demonstrated that cellular and
biochemical mechanisms as opposed to physical
10 "spring-like" co:Lls, are of a much greater
significance in preventing vessel reclosure and PEPS
addresses these mechanisms.
The specifics object and features of the PEPS
process are best understood by way of illustration
15 with reference to the following examples and figures.
Example 1 '
The invention may be readily understood through a
description of an experiment performed in vitro using
a mock blood ves:~el made from transparent plastic
20 tubing us:.ng a heat-balloon type deployment catheter
reference to Fig. 17.
The galloon delivery catheter 170 is first
positioned in the vessel 171 at the area of the
occlusion. Before insertion, a polycaprolactone
25 polymer s:Leeve 1'72 containing additives, e.g. to aid
X-ray radio-opacity, for drug delivery or to promote
surface adhesion, is placed in a low profile condition
surrounding a balloon at the distal end of the
deli~~ery catheter 170. The delivery catheter with the
30 polycapro:lactone tube is then inserted balloon end
first into the vessel 171 and manipulated into
position, i.e., the area of the vessel to be treated.
A separate occlusion catheter 173 is employed to
restrict 'blood" Elow through the vessel. The distal
35 end of the occlusion catheter 173 is inflated to
create a atagnant column of "blood" in the vessel
around the balloon delivery catheter and
polycaproLactone tube. Saline solution at about 60-
X340996
-27-
80°C is iizjected through a lumen in the occlusion
catheter 173 or the delivery catheter 170 in the case
of using .3 catheter according to the invention into
the area surrounding the delivery catheter, balloon
and polyc~~prolactone tube. Once the polycaprolactone
tube becomes pliable, the delivery catheter balloon is
inflated to push the polycaprolactone sleeve out
against the interior wall thereby locally sealing
and/or paving the vessel.
The polycaprolactone expands and/or flows,
conforming to the inner surface of the vessel, Flowing
into and Filling i~ surFace irregularities thereby
creating a "tailored" Fit. Further, the deployed
interior surface of the PEPS polymer is smooth
providing an increased vessel (lumen) cross-section
diameter and a rheologically advantageous surface with
improved blood flow. Upon removal of heated saline
solution the polymer recryst:allizes to provide a paved
surface of the vessel wall interior.
The deployment catheter balloon is then deflated
leaving the polycaprolactone layer in place. The
balloon section of the occlusion catheter is deflated
and, blood flow was allowed to return to normal and
the deployment catheter was removed leaving the
recrystallized polycaprolactone layer in place within
the vessel.
Over the course of time the polycaprolactone seal
will become covered with a proteinaceous biologic thin
film coat. Depending upon r_he exact seal chemical
composition, the polymer will then biodegrade, at a
predetermined rate and "dissolve" into the bloodstream
or be absorbed into the vessel wall. While in
intimate contact: with the vessel wall, pharmacological
agents .if embedde~3 or absorbed in the polycaprolactone
will have a "downstream" effect if released slowly
into the bloodstream or may have a local effect on the
blood vessel wall, thereby facilitating healing of the
angioplasty site', controlling or reducing exuberant
1340996
-28-
medial smooth muscle cell proliferation, promoting
effective lesion endothelialyation and reducing lesion
thrombogen.icity.
Example 2
Polycaprolac:tone in an initial macroporous
tubular configuration was placed in a low profile form
in bovine coronary arteries and canine carotid
arteries. In the' process of deployment the vessels
were purposely overextended and sealed through thermal
and mechanical deformation of the polymer. Fig. 18
shows a cross-section of the polymer tube 180 before
insertion in the bovine artery. after insertion in the
artery 181, and after expansion 182. The initial
polymer tube 180,. is smaller in diameter than the
artery 181. After deployment, the thin film of
polymer 182 can be seen coating the inner surface of
the sealed vessel. with the vessel remaining erect.
The vessel remained dilated to about 1.5 times the
original diameter because of the ability of the
polymer to keep i.t fixed. Fig. 19 shows a cross-
section of the polymer before insertion 190 and
removed after in;~ertion and reconfiguration 191 in a
canine artery. This figure clearly shows the
stretching and thinning of the polymer wall.
All F~olymer sealed vessels remained dilated with
a thin layer of macroporous polymer providing a new
barrier surface between the vessel lumen and the
vessel wall constituents. The unsealed portion of the
vessels did not remain dilated.
These examples demonstrate that the PEPS process
may if desired provide polymer application with a
relatively large degree of surface area coverage and
an effective polymer barrier shield. As such, the
polymer barrier-~;~ield may, if desired, impart
sufficient struc!:ural stability to maintain a selected
vessel diameter. The selected final vessel diameter
at which a vessel. is sealed is dictated by the
~3~o99s'
-29-
particular physiological variables and therapeutic
goals which confront the PEPS user.
The geometry of the pre and post PEPS application
sites may be readily varied. PEPS may be used to
5 merely coat an e~:isting vessel or organ geometry.
Alternatively, the PEPS process may be used to impart
structural stability to a vessel or organ the geometry
of which was altered prior to the PEPS application.
In addition, the PEPS process may itself alter the
10 geometry of the vessel or organ by shaping the
geometry. With reference to Fig. 18 this latter
process was used to expand th a vessel 181.
A specific a.nd important. attribute of the PEPS
technique and they polymers which are employed is the
15 significantly lower degree of compliance mismatch or
similarities of stiffness (inverse of compliance)
between the vessel and the polymer seal as compared to
metal stents. The vessel damage from compliance
mismatch discussed above may be eliminated by the PEPS
20 process utilizing a variety of available polymers.
Additionally, compliance mismatch greatly modifies the
characteristics of fluid wave transmission along the
vessel with resultant change in local flow properties,
development of regional change in shear forces and a
25 subsequent vessel wall hypertrophy which acts to
reduce vessel cross-sectional area and reduces blood
flow. Further, the substruct:ural elimination of
compliance mismatch of the PEPS technique at first
minimizes and then, upon dissolution eliminates local
30 flow abnormalities and up and downstream transition
zone hypertrophy associated with metal sterling.
PEPS has the flexibility of being safely and
effectively used prophylactically at the time of
initial PTCA in selected patients or being
35 incorporated as ~~art of the original dilation
procedure as a second stage prophylactic vessel
surface "finishin.g" process. For example, the
invasive cardiologist may apply the PEPS technique on
X340996
-31)-
a wide clinical basis after the first episodes of
restenosis. In addition, because the PEPS technique
significantly aids in the vascular healing process
post intervention, it may be readily used prophyl-
5 actically after initial angioplasty prior to any
incidence of restenosis. This would free the patient
from the risks of repeat intracoronary procedure as
well as those a~~sociated wii:h metal stenting.
