U.S. patent application number 13/245613 was filed with the patent office on 2012-01-19 for drug delivery catheters that attach to tissue and methods for their use.
This patent application is currently assigned to Biocardia, Inc.. Invention is credited to John D. Altman, Peter A. Altman, Simon Stertzer.
Application Number | 20120016311 13/245613 |
Document ID | / |
Family ID | 23657140 |
Filed Date | 2012-01-19 |
United States Patent
Application |
20120016311 |
Kind Code |
A1 |
Altman; Peter A. ; et
al. |
January 19, 2012 |
Drug Delivery Catheters That Attach to Tissue and Methods for Their
Use
Abstract
A drug delivery catheter suited for cardiac procedures. The
catheter an anchor associated with a needle, which can be used to
secure the catheter to tissue for delivery of therapeutic agents to
the tissue.
Inventors: |
Altman; Peter A.; (South San
Francisco, CA) ; Altman; John D.; (South San
Francisco, CA) ; Stertzer; Simon; (South San
Francisco, CA) |
Assignee: |
Biocardia, Inc.
|
Family ID: |
23657140 |
Appl. No.: |
13/245613 |
Filed: |
September 26, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
10190429 |
Jul 5, 2002 |
8027740 |
|
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13245613 |
|
|
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|
09418205 |
Oct 13, 1999 |
6416510 |
|
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10190429 |
|
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Current U.S.
Class: |
604/175 ;
604/272 |
Current CPC
Class: |
A61B 2018/00577
20130101; A61B 2017/00247 20130101; B82Y 5/00 20130101; A61B
2018/00392 20130101; A61B 2018/1435 20130101; A61B 18/1492
20130101; A61B 2018/1425 20130101; A61B 2218/002 20130101; A61K
9/1676 20130101; A61M 25/0084 20130101; A61B 2018/00011 20130101;
A61B 2018/00839 20130101; A61K 9/127 20130101; A61B 2018/00351
20130101; A61K 9/50 20130101; A61M 2025/0089 20130101; A61N 1/0575
20130101 |
Class at
Publication: |
604/175 ;
604/272 |
International
Class: |
A61M 5/00 20060101
A61M005/00 |
Claims
1. A catheter system comprising of: transendocardial catheter
having a distal end and a proximal end; a hollow penetrating
element comprising a curved needle disposed near the distal end of
the transendocardial catheter; at least one aperture in said needle
for the delivery of biologic or chemical or other therapeutic
agents; a reservoir of therapeutic agent comprising a
cytotherapeutic agent.
2. The catheter system of claim 1 wherein the cytotherapeutic agent
is chosen from the group consisting of cytotoxic agents,
chemotherapeutic agents, growth inhibitory agents, apoptotic
agents, and other agents to treat cancer, such as anti-HER-2, and
-anti CD20.
3. The catheter system of claim 1, wherein the at least one
aperture is disposed in a sidewall of the needle.
4. The catheter system of claim 1, wherein the curved needle is a
helical needle, and the at least one aperture is disposed in a
sidewall of the helical needle.
5. The catheter system of claim 1 wherein the reservoir is disposed
at the proximal end of the catheter, and the reservoir is in fluid
communication with the hollow penetrating element through a lumen
extending from the proximal end of the transendocardial catheter to
the hollow penetrating element.
6. A catheter system comprising of: a hollow penetrating element
that is a straight needle; at least one anchor associated with said
needle and catheter, operable at the catheter handle to secure the
transendocardial catheter to tissue for the stable delivery of
biologic or chemical or other therapeutic agents; at least one
aperture in said needle for the delivery of biologic or chemical or
other therapeutic agent; a reservoir of therapeutic agent chosen
from the group of metabolic agents, anti ischemic agents, growth
factors, antiarrhythmic agents, anti-inflammatory agents, and gene
therapy preparations, said reservoir in fluid communication with
the at least one aperture in the needle.
7. The catheter system of claim 6, wherein the at least one
aperture is disposed in a sidewall of the needle.
8. The catheter system of claim 6, further comprising a support
structure within the delivery sheath, the support structure
providing mechanical support for the hollow penetrating
element.
9. The catheter system of claim 6 wherein the reservoir is disposed
at the proximal end of the catheter, and the reservoir is in fluid
communication with the hollow penetrating element through a lumen
extending from the proximal end of the transendocardial catheter to
the hollow penetrating element.
Description
[0001] This application is a continuation of U.S. App. 10/190,429
filed Jul. 5, 2002, now U.S. Pat. No. 8,027,740, which is a
continuation of U.S. App. 09/418,205 filed Oct. 13, 1999, now U.S.
Pat. No. 6,416,510.
FIELD OF THE INVENTIONS
[0002] The inventions described below relate to site specific
delivery of therapeutic agents, structures and catheter systems to
achieve site specific delivery of therapeutic agents, and means for
implanting and using these systems to enable delivery of
therapeutic agents to the body.
[0003] These systems also have importance for new procedures that
have been called percutaneous transmyocardial revascularization or
PTMR.
BACKGROUND OF THE INVENTIONS
[0004] It is possible to identify particular sites within the
myocardium which may benefit from local drug release therapy.
Examples of problematic tissue which may benefit from local drug
release therapy are ischemic sites and arrhythmogenic sites.
Different means and methods for delivering agents to these sites
will be disclosed in detail. These specific discussions should in
no way limit the scope of the devices disclosed for treating other
tissues with other agents.
Ischemic Sites
[0005] Ischemic tissue is characterized by limited metabolic
processes which causes poor functionality. The metabolism is
limited because the tissue lacks oxygen, nutrients, and means for
disposing of wastes. In turn this hinders the normal functioning of
the heart cells or myocytes in an ischemic region. If an ischemic,
or damaged, region of the heart does not receive enough nutrients
to sustain the myocytes they are said to die, and the tissue is
said to become infarcted. Ischemia is reversible, such that cells
may return to normal function once they receive the proper
nutrients. Infarction is irreversible.
[0006] A number of methods have been developed to treat ischemic
regions in the heart. Noninvasive systemic delivery of
anti-ischemic agents such as nitrates or vasodilators allows the
heart to work less by reducing vascular resistance. Some vascular
obstructions are treated by the systemic delivery of
pharmacological agents such as TPA, urokinase, or antithrombolytics
which can break up the obstruction. Catheter based techniques to
remove the vascular obstructions such as percutaneous transluminal
coronary angioplasty (PTCA), atherectomy devices, and stents can
increase myocardial perfusion. More drastic, but very reliable
procedures such as coronary artery bypass surgery can also be
performed. All of these techniques treat the root cause of poor
perfusion.
[0007] It should be noted that these therapies are primarily for
the treatment of large vessel disease, and that many patients
suffer from poor perfusion within many of the smaller vessels.
These smaller vessels cannot be treated with conventional
therapies.
[0008] The delivery of angiogenic growth factors to the heart via
the coronary arteries by catheter techniques, or by implantable
controlled release matrices, can create new capillary vascular
growth within the myocardium. Recent work has shown substantial
increases in muscular flow in a variety of in vivo experimental
models with growth factors such as basic fibroblast growth factor
(bFGF), vascular endothelial growth factor (VEGF), and acidic
fibroblast growth factor (aFGF). The methods of delivering these
agents to the heart have included implantable controlled release
matrices such as ethylene vinyl acetate copolymer (EVAC), and
sequential bolus delivery into the coronary arteries. Recently
similar techniques have been attempted in peripheral vessels in
human patients with the primary difficulty being systemic effects
of the agents delivered. "Angiogenic agents" and "endothelial
agents" are active agents that promote angiogenesis and/or
endothelial cell growth, or if applicable, vasculogenesis. This
would include factors such as those discussed that accelerate wound
healing such as growth hormone, insulin like growth factor-I
(IGF-I), VEGF, VIGF, PDGF, epidermal growth factor (EGF), CTGF and
members of its family, FGF, TGF-a and TGF B. The most widely
recognized angiogenic agents include the following: VEGF-165,
VEGF-121, VEGF-145, FGF-2, FGF-I, Transforming Growth Factor
(TGF-B), Tumor Necrosis Factor a (TMF a), Tumor Necrosis Factor B
(TMF B), Angiogenin, Interleukin-8, Proliferin, Prostaglandins
(PGE), Placental Growth factor, Granulocyte Growth Factor, Platelet
Derived Endothilail Cell Growth Factor, Hepatocyte Growth Factor,
DEL-1, Angiostatin-1 and Pleiotrophin.
[0009] "Angiostatic agents" are active agents that inhibit
angiogenesis or vasculogenesis or otherwise inhibit or prevent
growth of cancer cells. Examples include antibodies or other
antagonists to angiogenic agents as defined above, such as
antibodies to VEGF or Angiotensin 2. They additionally include
cytotherapeutic agents such as cytotoxic agents, chemotherapeutic
agents, growth inhibitory agents, apoptotic agents, and other
agents to treat cancer, such as anti-HER-2, anti CD20, and other
bioactive and organic chemical agents.
[0010] Polypeptide agents may be introduced by expression in vivo,
which is often referred to as gene therapy. There are two major
approaches for getting the nucleic acid (optionally containing a
vector) into the patients cells: in vivo and ex vivo. For in vivo
delivery, the nucleic acid is injected directly into the patient,
usually at the site where desired. For ex-vivo delivery, the
patients cells are removed, the nucleic acid is introduced into
these isolated cells, and the modified cells are administered to
the patient either directly or via encapsulation within porous
membranes that are implanted into the patient (see U.S. Pat. Nos.
4,892,538 and 5,283,187).
[0011] The preferred embodiment of this invention is the delivery
of therapeutic molecules from micro drug delivery systems such as
liposomes, nanoparticles, biodegradable controlled release polymer
matrices, and biodegradable microspheres which are well known in
the literature. These have been described briefly in U.S.
application Ser. No. 08/816,850.
[0012] The agents to be delivered may include one or more small
molecules, macromolecules, liposomal encapsulations of molecules,
microdrug delivery system encapsulation of therapeutic molecules,
covalent linking of carbohydrates and other molecules to a
therapeutic molecules, and gene therapy preparations. These will be
briefly defined.
[0013] "Small molecules" may be any smaller therapeutic molecule,
known or unknown. Examples of known small molecules relative to
cardiac delivery include the antiarrhythmic agents that affect
cardiac excitation. Drugs that predominantly affect slow pathway
conduction include digitalis, calcium channel blockers, and beta
blockers. Drugs that predominantly prolong refractoriness, or time
before a heart cell can be activated, produce conduction block in
either the fast pathway or in accessory AV connections including
the class IA antiarrhythmic agents (quinidine, procainimide, and
disopyrimide) or class IC drugs (flecainide and propefenone). The
class III antiarrhythmic agents (sotolol or amiodorone) prolong
refractoriness and delay or block conduction over fast or slow
pathways as well as in accessory AV connections. Temporary blockade
of slow pathway conduction usually can be achieved by intravenous
administration of adenosine or verapamil. [Scheinman, Melvin:
Supraventricular Tachycardia: Drug Therapy Versus Catheter
Ablation, Clinical Cardiology Vol 17, Suppl. II-11-II-15 (1994)].
Many other small molecule agents are possible, such as poisonous or
toxic agents designed to damage tissue that have substantial
benefits when used locally such as on a tumor. One example of such
a small molecule to treat tumors is doxarubicin.
[0014] A "macromolecule" is any large molecule and includes
proteins, nucleic acids, and carbohydrates. Examples of such
macromolecules include the growth factors, Vascular Endothelial
Growth Factor, basic Fibroblastic Growth Factor, and acidic
Fibroblastic Growth Factor, although others are possible. Examples
of macromolecular agents of interest for local delivery to tumors
include angiostatin, endostatin, and other anti-angiogenic
agents.
[0015] A "Liposome" refers to an approximately spherically shaped
bilayer structure comprised of a natural or synthetic phospholipid
membrane or membranes, and sometimes other membrane components such
as cholesterol and protein, which can act as a physical reservoir
for drugs. These drugs may be sequestered in the liposome membrane
or may be encapsulated in the aqueous interior of the vesicle.
Liposomes are characterized according to size and number of
membrane bilayers.
[0016] A "gene therapy preparation" is broadly defined as including
genetic materials, endogenous cells previously modified to express
certain proteins, exogenous cells capable of expressing certain
proteins, or exogenous cells encapsulated in a semi-permeable micro
device. This terminology is stretched beyond its traditional usage
to include encapsulated cellular materials as many of the same
issues of interstitial delivery of macrostructures apply.
[0017] The term "genetic material" generally refers to DNA which
codes for a protein, but also encompasses RNA when used with an RNA
virus or other vector based upon RNA. Transformation is the process
by which cells have incorporated an exogenous gene by direct
infection, transfection, or other means of uptake. The term
"vector" is well understood and is synonymous with "cloning
vehicle". A vector is nonchromosomal double stranded DNA comprising
an intact replicon such that the vector is replicated when placed
within a unicellular organism, for example by a process of
transformation. Viral vectors include retroviruses, adenoviruses,
herpesvirus, papovirus, or otherwise modified naturally occurring
viruses. Vector also means a formulation of DNA with a chemical or
substance which allows uptake by cells. In addition, materials
could be delivered to inhibit the expression of a gene. Approaches
include: antisense agents such as synthetic oligonucleotides which
are complimentary to RNA or the use of plasmids expressing the
reverse compliment of a gene, catalytic RNA's or ribozymes which
can specifically degrade RNA sequences, by preparing mutant
transcripts lacking a domain for activation, or over express
recombinant proteins which antagonize the expression or function of
other activities. Advances in biochemistry and molecular biology in
recent years have led to the construction of recombinant vectors in
which, for example, retroviruses and plasmids are made to contain
exogenous RNA or DNA respectively. In particular instances the
recombinant vector can include heterologous RNA or DNA by which is
meant RNA or DNA which codes for a polypeptide not produced by the
organism susceptible to transformation by the recombinant vector.
The production of recombinant RNA and DNA vectors is well
understood and need not be described in detail. Such gene therapy
preparations could be delivered in a variety of fluid agents, one
of which is phosphate buffered saline.
[0018] Details on microencapsulated cells are described in U.S.
Pat. No. 5,698,531 and additional details on the delivery of
genetic material are described in U.S. Pat. No. 5,704,910. Both of
these patents describe the potential of delivering such agents
endoluminally within a blood vessel. Neither of these provides a
means to deliver such agents at a depth within the heart muscle,
and neither of them recognizes the potential of this approach. U.S.
Pat. No. 5,661,133 does recognize the potential for delivering
genes to the heart, but does not describe the means of delivery
other than by injection.
[0019] U.S. Pat. No. 5,244,460 issued to Unger describes a method
of introducing growth factors over time by delivering them through
fluid catheters into the coronary arteries, but this does not
result in efficient delivery of these agents to the ischemic
tissue. If these or other agents are delivered to the coronary, a
region of tissue that is equivalent to that supplied by the artery
will receive the therapeutic agents. This may be substantially more
tissue than is in need of local drug delivery therapy. Further, if
a vessel is occluded, the growth factors will act in the tissue
which the coronary arteries successfully perfuse. As the underlying
problem of ischemic tissue is poor perfusion, excess growth factor
must be delivered in order to obtain the desired effects in the
poorly perfused tissue. Further, growth factors may cause unwanted
angiogenesis in tissues where inappropriately delivered. The cornea
is described by Unger as such a location, but perhaps more critical
is inappropriate delivery of these factors to the brain. Further,
placement of delivery devices within these coronary arteries as
Unger describes will tend to obstruct these arteries and may
augment occlusive thrombosis formation. There is a significant need
for a means and method of minimizing the amount of growth factors
for introducing angiogenesis by delivering these agents only to the
site where they are most needed.
[0020] In addition to a device for delivering growth factors, there
are complications with clinically acceptable procedures where
special devices for delivering agents to ischemic tissue will be
useful. After opening vessels using PTCA, the vessels often lose
patency over time. This loss of patency due to re-stenosis may be
reduced by appropriate pharmacological therapy in the region of the
artery. There is a need for new techniques that will enable
pharmacological therapy to reduce the incidence of restenosis.
Arrhythmogenic Sites
[0021] Cardiac arrhythmias are abnormal rhythmic contractions of
the myocardial muscle, often introduced by electrical
abnormalities, or irregularities in the heart tissue, and not
necessarily from ischemic tissue.
[0022] In a cardiac ablation procedure, the arrhythmogenic region
is isolated or the inappropriate pathway is disrupted by destroying
the cells in the regions of interest. Using catheter techniques to
gain venous and arterial access to the chambers of the heart, and
possibly trans septal techniques, necrotic regions can be generated
by destroying the tissue locally. These necrotic regions
effectively introduce electrical barriers to problematic conduction
pathways.
[0023] U.S. Pat. No. 5,385,148 issued to Lesh describes a cardiac
imaging and ablation catheter in which a helical needle may be used
to deliver fluid ablative agents, such as ethanol, at a depth
within the tissue to achieve ablation. Lesh further describes a
method of delivering a pharmacological agent to the tissue just
before performing the chemical ablation procedure to temporarily
alter the conduction of the tissue prior to performing the
ablation. Such temporary alteration of tissue has the advantage of
allowing the physician to evaluate the results of destructive
ablation in that region prior to actually performing the ablation.
This method of ablation has the advantage that the ablative fluid
agents are delivered to essentially the same tissue as the
temporary modifying agents. However, with ablative fluid agents it
is difficult to control the amount of tissue which is
destroyed--especially in a beating heart, and ablative RF energy is
in common use because of its reproducible lesions and ease of
control. There is a need for an ablation catheter that provides for
both temporary modification of tissue conductivity by delivery of
therapeutic agents at a depth within the tissue and delivery of RF
energy from the same structure within the heart wall that was used
to deliver the therapeutic agents.
[0024] U.S. Pat. No. 5,527,344 issued to Arzbaecher describes a
pharmacological atrial defibrillator and method for automatically
delivering a defibrillating drug into the bloodstream of a patient
upon detection of the onset of atrial arrhythmias in order to
terminate the atrial arrhythmias, and is herein incorporated by
reference. By delivering agents to a blood vessel, Arzbaecher
requires systemic effects to be achieved in order to terminate the
atrial arrhythmias. The advantages of local drug delivery are
completely absent from the system described. There is a need for a
system and method to transiently treat atrial arrhythmias by local
delivery of pharmacological agents which will effect the excitation
of the cardiac tissue locally.
[0025] There have been many patents describing systems for
delivering anti inflammatory agents to the endocardial surface of
the heart. Such surface delivery is less viable for regions at a
depth within the tissue. Further, because of the volume of fluid
moving by the inner surfaces of the heart, higher concentrations
may be required at the surface to counteract the effects of
dilution. These higher doses result in greater likelihood of
problematic systemic effects from the therapeutic agents.
Delivering agents within the tissue will minimize the dilution of
agents, and decrease the possibility of the agents being delivered
to inappropriate sites. This is particularly important with growth
factors whose systemic affects are not well documented, just as it
is important for antiarrhythmic agents whose pro-arrhythmia
systemic effects have been recognized. There is a need for a means
to deliver agents to ischemic and arrhythmogenic sites within the
myocardium.
[0026] The prior art of devices to deliver substances at a depth
within the heart is not extensive. U.S. Pat. Nos. 5,447,533 and
5,531,780 issued to Vachon describe pacing leads having a stylet
introduced anti inflammatory drug delivery dart and needle which is
advanceable from the distal tip of the electrode. U.S. Pat. No.
5,002,067 issued to Berthelson describes a helical fixation device
with a groove to provide a path to introduce anti-inflammatory drug
to a depth within the tissue. U.S. Pat. No. 5,324,325 issued to
Moaddeb describes a myocardial steroid releasing lead whose tip of
the rigid helix has an axial bore which is filled with a
therapeutic medication such as a steroid or steroid based drug.
None of these patents provide a means for site specific delivery of
agents as all applications of the drug delivery systems are at the
location selected for pacing. None of these has provided a means or
method for delivering agents to ischemic or infarcted tissues. Of
these, only Vachon and Moaddeb provide a means for effectively
delivering the anti-inflammatory agents to a depth within the
myocardium. U.S. Pat. No. 5,551,427 issued to Altman describes a
catheter system capable of delivering drugs to the heart at a depth
within the heart tissue.
[0027] U.S. Pat. No. 5,431,649 issued to Mulier describes a hollow
helical delivery needle to infuse the heart tissue with a
conductive fluid prior to ablation to control the lesion size
produced. The system does not have drug delivery capabilities.
[0028] None of the prior art provides controlled release matrix
delivery down a needle or helix to a depth within the heart tissue.
None of the prior art provides for a distally located osmotic pump
to deliver agents to a depth within the heart tissue. None of the
prior art provides a means of delivering agents transiently to a
depth within the heart tissue upon demand. None of the prior art
provides a means to clear the catheter system of one drug and
effectively replace it with a second drug. None of the prior art
provides a low impedance conductor to the drug delivery structure
for performing ablation after the delivery of a drug. None of the
prior art includes the use of macromolecular controlled release
matrices such as ethylene vinyl acetate co-polymer to deliver
agents with large molecular weights to a depth within the heart
tissue.
[0029] Local drug delivery provides many advantages. Approaches for
local delivery of agents at a depth within a tissue enables the
delivery of drugs to sites where they are most needed, reduces the
amount of drugs required, increases the therapeutic index of the
particular dosing regime, and increases the control over the time
course of agent delivery. These, in turn, improve the viability of
the drugs, lower the amount (and cost) of agents, reduce systemic
effects, reduce the chance of drug-drug interactions, lower the
risk to patients, and allow the physician to more precisely control
the effects induced. Such local delivery may mimic endogenous modes
of release, and address the issues of agent toxicity and short half
lives. Approaches for local drug delivery using a catheter based
system with a distally located tissue penetrating element have
applications in organs such as the heart, pancreas, esophagus,
stomach, colon, large intestine, or other tissue structure to be
accessed via a controllable catheter.
[0030] Local drug delivery to the heart is known. In U.S. Pat. No.
5,551,427, issued to Altman, implantable local drug delivery at a
depth within the heart is described. The patent shows an
implantable helically coiled injection needle which can be screwed
into the heart wall and connected to an implanted drug reservoir
outside the heart. This system allows injection of drugs directly
into the wall of the heart acutely by injection from the proximal
end, or on an ongoing basis by a proximally located implantable
subcutaneous port reservoir, or pumping mechanism. The patent also
describes implantable structures coated with coating which releases
bioactive agents into the myocardium. This drug delivery may be
performed by a number of techniques, among them infusion through a
fluid pathway, and delivery from controlled release matrices at a
depth within the heart. Controlled release matrices are drug
polymer composites in which a pharmacological agent is dispersed
throughout a pharmacologically inert polymer substrate. Sustained
drug release takes place via particle dissolution and slowed
diffusion through the pores of the base polymer. Pending
application Ser. Nos. 08/816,850 by Altman and Altman, and
09/131,968 by Altman and 09/177,765 by Altman describe and
09/257,887 by Altman and Altman describe some additional techniques
for delivering pharmacological agents locally to the heart. The
techniques described herein are all incorporated by reference.
[0031] Recently, local delivery to the heart has been reported of
therapeutic macromolecular biological agents by Lazarous [94
Circulation, 1074-1082 (1996)], plasmids by Lin [82 Circulation
2217-2221 (1990)], and viral vectors by French [90 Circulation
2414-2424 (November 1994)] and Muhlhauser [3 Gene Therapy 145-153
(1996)]. March [89 Circulation 1929-1933 (May 1994)] describes the
potential for microsphere delivery to the vessels of the heart,
such as to limit restenosis.
[0032] U.S. Pat. No. 4,296,100 issued to Franco describes direct
injection of FGF into the heart but specifically does not call out
catheter techniques. U.S. Pat. No. 5,693,622 issued to Wolff
describes promoters for gene therapy to the heart, but does not
enable the delivery of DNA sequences through either vascular or
cardiac catheter, or by the injection into the interstitial spaces
of the heart.
[0033] U.S. Pat. Nos. 5,807,395; 5,431,649 and 5,405,376 issued to
Mulier and U.S. Pat. No. 5,385,148 issued to Lesh describe helical
needles for use during an ablation procedure, and are limited to
ablation catheter uses. They also require the presence of high
conductors capable of carrying energy to perform ablation, and do
not provide for instruction on how to access different regions of
the myocardium and confirm the placement of a device prior to the
delivery of fluid agent, nor do they describe a means for
guaranteeing that a precise dose is delivered of a particular fluid
agent. U.S. Pat. No. 5,840,059 issued to March describes a means of
delivering therapeutic agents into a channel within the heart, but
suffers the serious limitation in that the material will likely not
be retained in the channels. The viscous carrier suggested by March
to help retain the material within the channels poses substantial
risk as embolic material should it escape from the channels and be
released into the endocardial chamber.
SUMMARY
[0034] The devices and methods described below provide for the
delivery of small doses of therapeutic agents within the body, in
particular the heart. The catheters described below include a
distal helical coil or other fixation and penetrating element which
can be operated from the proximal end of the catheter to engage and
penetrate the myocardium. Once delivered to the inside of the
heart, the catheter can be used to inject small doses of
therapeutic agents to the myocardium. The drug delivery system of
the catheter allows for precise control of the dose injected into
the heart wall.
[0035] The devices may be used to administer a number of
therapeutic agents followed by additional therapeutic agents or
passive agents intended to ensure that the intended dose is
delivered notwithstanding the dead space of the catheter.
Therapeutic agent in the catheter dead space is flushed from the
dead space into the heart. Calibrated therapeutic agent reservoirs
account for the dead space, and passive agent reservoirs provide a
ready source for flushing fluid. The reservoirs may be filled prior
to a catheterization, and inserted into a catheter proximal handle
so that they are easily operated during the catheterization. The
reservoirs are connected to the drug delivery lumen of the infusion
catheter through a valve which may be selectively operated to align
one or the other reservoir to the drug delivery lumen of the
catheter. Additionally, the drug reservoirs may be connected to the
valve through flexible distensible lengths of tubing, permitting
easy manipulation of the reservoirs for filling and placement in
the proximal handle.
[0036] The catheter described herein can be used for a number of
procedures, including local delivery of angiogenic agents,
controlling heart rate during heart procedures and transmyocardial
revascularization.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIG. 1a shows a partial cross sectional view of a drug
delivery catheter.
[0038] FIG. 1b shows a cross sectional view of the proximal portion
of a dual lumen drug delivery catheter.
[0039] FIG. 1c shows a partial cross sectional view of a distal
portion of drug delivery catheter with a hollow fixation helix.
[0040] FIG. 2 shows a partial cross sectional view of a distal
portion of a drug delivery catheter with a short needle located in
the axis of the helical fixation device.
[0041] FIG. 3a shows a partial cross sectional view of the distal
portion of a drug delivery catheter which incorporates an osmotic
pump.
[0042] FIG. 3b shows a partial cross sectional view of the distal
portion of a drug delivery catheter which incorporates an osmotic
pump.
[0043] FIG. 4 shows a partial sectional view of a distal portion of
a drug delivery catheter.
[0044] FIG. 5a shows a partially sectional view of the distal
portion of a drug delivery catheter with a rate control
barrier.
[0045] FIG. 5b shows a partially sectioned view of the distal
portion of a drug delivery catheter with a second lumen for stylet
use during implantation.
[0046] FIG. 5c is a cross sectional view of bi-lumen catheter of
FIG. 5b.
[0047] FIG. 6 shows a partially sectional view of a subcutaneous
injection port, and a drug delivery catheter.
[0048] FIG. 7 shows a partially sectional view of the distal end of
a drug delivery catheter.
[0049] FIG. 8 shows a partially sectional view of a filled helical
drug delivery fixation means.
[0050] FIG. 9 shows a partially sectioned view of the distal end of
a drug delivery catheter.
[0051] FIG. 10a shows a partially sectioned view of a drug delivery
catheter with a nitinol transient delivery means.
[0052] FIG. 10b shows a partial cross sectional view of a distal
portion of drug delivery catheter with a vapor pressure transient
delivery means.
[0053] FIG. 11 shows a sectional view of a drug delivery catheter
placed through a guide catheter into the left ventricle of a human
heart.
[0054] FIG. 12 shows an infusion catheter.
[0055] FIG. 13 shows a handle of an infusion catheter.
[0056] FIG. 14 shows a handle of a steerable guide catheter.
[0057] FIG. 15a through FIG. 15f shows a distal end of a steerable
guide catheter with a coaxial infusion catheter system.
[0058] FIG. 16 shows a steerable guide catheter with a slotted
torque tube bending element.
[0059] FIGS. 16a, 16b and 16c are cross sections of the steerable
guide catheter of FIG. 16.
[0060] FIG. 17 shows a distal end of a steerable guide catheter
with centrally located infusion catheter.
[0061] FIG. 18 shows a schematic of a preferred technique for
performing percutaneous transmyocardial revascularization and
therapeutic delivery with a helical needle catheter system.
[0062] FIG. 19 shows one embodiment of the distal end of an
infusion and guide catheter pair.
[0063] FIG. 20 shows the distal end of a catheter with pincher
fixation means.
[0064] FIG. 20a is a cross section of the catheter illustrated in
FIG. 20.
[0065] FIG. 21 shows a distal end of a helical needle infusion
catheter.
[0066] FIGS. 22a through FIG. 22c show preformed shapes of guide
catheters for accessing different regions in the left ventricle of
a heart.
[0067] FIG. 23 shows a handpiece for a catheter system.
DETAILED DESCRIPTION OF THE INVENTIONS
[0068] New concepts for delivering agents for the treatment of
heart failure, ischemia, arrhythmias, and restenosis are disclosed.
The main embodiment consists of transvenous or transarterial
catheter delivery techniques for delivering agents directly to a
chosen site within the heart at a depth within the heart tissue.
Hollow helical delivery devices, needle delivery devices, and
implantable controlled release matrices may be inserted such that
metabolic agents, anti ischemic agents, growth factors,
antiarrhythmic agents, anti-inflammatory agents, gene therapy
preparations, and combinations of these agents may be delivered
directly to the tissue that can benefit most from these agents.
These systems have applicability in many areas of the body,
particularly those which may be accessed via a body duct or
vessel.
[0069] These drug delivery structures may be made from drastically
different materials depending upon whether the device is to be used
chronically or acutely. For example, metal components in the
implantable embodiments which are formed of a Platinum Iridium
alloy consisting of ninety percent Platinum and ten percent Iridium
will typically be replaced with 316L surgical stainless steels in
the acute embodiments. Likewise implantable grades of silicone and
polyurethane will be replaced with polyurethanes, polyolefins,
fluoropolymers, nylon, and the like in the acute uses of the
devices. As a means of addressing this, the term catheter is used
to describe both chronically and acutely implantable systems.
[0070] FIG. 1a shows a first cardiac drug delivery catheter with a
sectional view of the proximal end. Pin 2 is shown mechanically
crimped at crimp 6 to electrically conductive helical coil 8. Crimp
6 is typically covered by compliant polymer molding 4 which may
form a seal with a catheter port on a drug delivery reservoir or
pumping means (not shown). Further molding 4 and catheter body 14
may have external sealing rings to provide fluid tight seals with
such ports. Pin 2 connects to internal tubing 10 with lumen 12
which travels the entire length of the catheter to the distal end
22 and allows for fluid agents to be delivered through a fluid
pathway in the fixation end 24. The catheter body 14, 20, and 22
covers the coil 8 along the entire length of the delivery system
distal to crimp 4 such that rotation of pin 2 or crimp 4 relative
to proximal catheter body 14 will result in rotation of coil 8
within catheter body 14, 20, and 22 and deploy fixation mechanisms
at fixation end 24. The central lumen 12 in some embodiments may
also be used to pass a stylet for use during implantation to
facilitate the implantation procedure.
[0071] The catheter shown in FIG. 1a differs from those in the
prior art in that it is made of permanently implantable materials,
it has electrical continuity from end to end for sensing cardiac
activity, it has a lumen for conveying fluidic agents along its
length, and a hollow fixation means for delivering fluidic agents
to a depth within the heart tissue. The materials selected must be
able to be implanted for a period on the order of a week without
rejection by the patient in order to deliver growth factors over an
extended period of time to the patient, or for permanent
implantation to provide for transient drug delivery driven by a
proximal reservoir and energy source. The catheter body 14, 20, and
22 would be an implant grade polyurethane or silicone, and the
distal fixation mechanism at fixation end 24 would be a platinum
iridium alloy. The catheter has a single electrode to facilitate
implantation by sensing the electrical potential at the implant
site. None of the prior art contains this combination which is
necessary to achieve the advantages of ease of implantation, and
delivery of fluidic agents to a depth within the heart from a
proximally located reservoir.
[0072] FIG. 1b shows another embodiment of the proximal end of a
catheter delivery system in which a second stylet lumen 66 is
provided for insertion of a stylet. Such an additional lumen may be
useful to prevent contamination of the inner drug delivery tubing
62 during implantation. Inner tubing 62 is connected to pin 52 at
connection 56, which may be performed simply by pulling tubing 62
over pin 52 at connection 56. Electrically conductive coil 60
surrounds tubing 62 and may be rotated relative to outer jacket or
catheter body 58 of the delivery system. After implantation using a
stylet in stylet lumen 66, pharmacological agents may be delivered
to the heart by a fluid pathway defined by delivery system lumen
64. The different tubing barriers are shown more clearly in tubing
cross section 68. In this specific embodiment, crimp 54 which
connects pin 52 and coil 60 is not overmolded, and a single set of
seals 70 are shown molded over the proximal end of catheter body
58. Seals 70 prevent migration of fluids into the catheter after
connection with a catheter port in a drug delivery reservoir or
pumping means. In one embodiment, the distal end of the drug
delivery catheter shown in FIG. 1b would be the distal embodiment
shown in FIG. 5b. The use of such a second lumen with a drug
delivery system for delivery of agents to a depth within the heart
does not appear in the prior art.
[0073] FIG. 1c shows a partial cross sectional view of a distal
portion of a delivery catheter which is to be implanted
endocardially by the appropriate venous or arterial access. Here, a
simple pathway for fluid to pass from a subcutaneous reservoir or
delivery pump (not shown) through a deployable helical needle is
provided. Helical coil 102 is shown here as being multifilar, but
could be single filar as well. Varying the number of filars allows
the flexibility of the catheter as well as the coils ability to
transmit torque to the helical fixation structure 114 which is
formed of a radio opaque material such as Pt/Ir 90/10. The helical
fixation structure is screwed into the heart by turning the coil
102 inside the outer catheter body 106. A fixed structure 130, on
the inner wall of the catheter body 106, for advancement and
retraction of the helical fixation structure 114, forces the
helical fixation structure 114 to advance from the distal end of
the catheter when the central helical coil 102 and tube for drug
delivery 104 are rotated counterclockwise. Fixed structure 130 is
typically formed from a radio opaque material to assist the
implanting physician in identifying when helical fixation structure
114 has been deployed. Fixed structure 130 also will retract the
helical fixation structure 114 from the heart wall when the coil
102 is rotated clockwise. These directions could easily be reversed
by varying the direction of the winding of the helical fixation
structure 114. The helical coil 102 which provides torque to
implant the helical fixation structure 114 is welded or crimped to
the torque delivery structure 110 at the coil to torque delivery
structure connection 128. Here, the coil cross section 108 is shown
crimped at connection 128. Proximal stop 124, and distal stop 112
are raised portions on the inside of the catheter body 106, and
prevent the helical fixation structure 114 from being too far
extended or retracted. A fluid path is provided from the proximal
end of the catheter (not shown) by tube for drug delivery 104 which
connects to the tube fitting 126 of the hollow helical fixation
structure 114. The hollow helical fixation structure 114 may have a
number of small holes or helix apertures 116, 118, 120, 122 along
its length where it is penetrated into the heart tissue. These
holes provide a means for delivering agents into the heart tissue
at a depth within the tissue. Helix tip 132 is sharp to facilitate
penetration of the heart tissue, and acts as a further opening for
the agents to migrate from the tissue. In some embodiments the
helix apertures may be on only the distal portion of the helix to
minimize the possibility of agents being delivered within the heart
chambers. In other embodiments, the helix apertures are not present
to maximize the structural integrity of the fixation helix. Where
this is the case, all agents would be delivered to the heart from
the aperture at the hollow helix tip 132. The fixation helix 114 is
rigidly attached to the torque delivery structure 110 to provide
means for advancement when coil 102 is rotated.
[0074] FIG. 1c shows a means for delivering agents by a fluid path
to a depth within the heart tissue, and is novel in that it
delivers a wide variety of agents by way of a fluid pathway to a
depth within the tissue from a proximally located reservoir and is
able to transmit electrical energy along helical coil 102 to and
from helical fixation structure 114 by way of electrically
conductive torque delivery structure 110. It can be viewed as the
distal end of the implantable catheter whose proximal end is
described in FIG. 10a or FIG. 10b. In one embodiment, the device of
FIG. 1 could be used for chronic delivery of antiarrhythmic agents
to alter local conduction either continuously, or dynamically on
demand based upon the signals sensed through helical fixation means
structure 114. Such algorithms have been described for
pharmacological atrial defibrillation by Arzbaecher in U.S. Pat.
No. 5,527,344. In other embodiments agents for a variety of disease
states may be continuously infused by the fluid pathway presented
such that they are delivered to a specific site within the
myocardium. The proximal end of the catheter may be connected to a
drug pumping mechanism or to a proximally located reservoir. Such
proximal devices may be implantable or exist outside the patient.
Access to implantable proximal devices for refilling agents is
easily achieved with a subcutaneous port.
[0075] Transient delivery of pharmacological agents based upon
demand requires the presence of electrical conductors along the
length of the drug delivery catheter to monitor the electrical
action of the heart. Delivering of agents upon demand will alter
the local conduction or automaticity of the cardiac tissue and
allow for the arrhythmia to be treated. A very small amount of drug
will be required to treat a specific location within the tissue,
which has substantial benefits. A small doses of antiarrhythmic
agents will minimize the need to refill the proximally located
reservoir; and reduce the systemic effects that result from large
drug doses as well as the effects that the agents will have on
normally functioning cardiac tissue. In one application of this
embodiment, the device would be implanted in the right atrium at a
location determined to be most likely to terminate a patients
supraventricular arrhythmia. A subcutaneous infusion pump could be
triggered by the electrical activity of the heart, and a very small
region of tissue would receive local drug delivery for a
preprogrammed duration. A small region of heart would then be
modified such that cardiac excitation wavefronts would be altered
by the tissue treated. This will provide substantial advantages to
patients, even if not 100 percent effective. Typical drugs
delivered would be antiarrhythmic agents such as those described by
in U.S. Pat. No. 5,551,427 issued to Altman.
[0076] In a separate embodiment, the device described in FIG. 1c
could be an acute catheter made of non-implantable materials.
Catheter body 106 would be formed of polyurethane or a
fluoropolymer such as ETFE or PTFE; helical fixation structure 114,
and torque delivery structure 110 would likely be made of Titanium
or 316L stainless steel. Such a catheter would be used for acute
ablation procedures in which antiarrhythmic agents are delivered to
temporarily alter the conduction of the heart at the site of the
implanted helix. Electrical mapping and stimulation measurements
may then be made to determine if the region is appropriate to be
ablated. If the region is not appropriate the device may be removed
and repositioned. If the region affected by the anti arrhythmic
agents which effect tissue conduction is desired to be ablated, RF
energy may be delivered from the electrically active helix to a
large surface electrode, such as that used in electro-cautery. The
first region ablated will be that equivalent to the surface of the
implanted helix. The helical coil 102 is highly conductive to
enable RF energy to be conducted to the distal fixation structure
to allow ablation of the region immediately at the fixation
structure. Such a high conductivity coil could be formed from a
number of wires wrapped in parallel in which each wire has a high
conductivity silver core jacketed by an MP35N non corrosive alloy.
This catheter provides for both temporary modification of tissue
conductivity by delivery of therapeutic agents to a depth within
the tissue, and delivery of RF energy from the structure within the
heart wall that was used to deliver the therapeutic agents. The
ablation catheters described in the prior art do not simultaneously
provide for drug delivery and ablation from the same structure.
[0077] FIG. 2 shows another distal portion of a delivery catheter
for endocardial placement. The operation is similar to that shown
in FIG. 1, and is applicable to all embodiments described. However,
here the solid fixation structure 202 does not provide a fluid path
for delivery of agents. The fluid pathway is instead provided by a
centrally located hollow needle 204. Apertures could also be made
along the needle to provide more exposure to the tissue within the
heart wall. Fluid agents may flow down the inside of a connecting
tube 104, inside the hollow needle 204, and out through apertures
in the surface (not shown) and the needle tip 206. Agents are
delivered via the needle to a depth within the tissue. The solid
fixation structure advances in the same manner as described in FIG.
1, and may be rigidly attached to the torque delivery structure 110
by a weld 208. Other methods of connection are also possible. The
primary advantage of this design is that the solid helical fixation
structure 202 is structurally more robust than that of the hollow
structure shown in FIG. 1c. This will facilitate implantation of
the structure.
[0078] Other embodiments which incorporate osmotic pumps,
controlled release matrices, membrane barriers, and catheter based
transient delivery means increase the ability to control the
delivery of agents to a depth within the heart tissue. They have
substantial advantages in delivering agents such as growth factors
and gene therapy preparations in that very small amounts of the
agents are required, the delivery is controlled over time, and the
agents are delivered to a depth within the heat.
[0079] FIG. 3 shows an osmotic pump located at distal end of a
catheter to drive therapeutic agent into heart tissue using a
needle 318 or hollow helix (not shown) fluid transport system as
described. Agents may be delivered via the fluid pathway previously
described, through the check valve 302, and into the drug volume or
drug reservoir 304. After the drug volume 304 is full, agents will
migrate out the needle tip 320, and apertures 322. In this way, the
drug volume 304 may be loaded before, during, or after implantation
from the proximal end of the drug delivery catheter. Once advanced
into the heart tissue, diffusion of water across the semipermeable
membrane 312 will occur because of the presence of the osmotic salt
310. As this salt expands with hydration, pressure will be exerted
against the flexible barrier 306 and the rigid osmotic pump housing
308. The expansion of the osmotic salt 310 is tantamount to a
constriction of the drug volume 304 and as the check valve 302 is
closed to reverse flow, the agents are forced through the delivery
structure and into the heart wall. Here, the pathway to the needle
tip 320 is by way of proximal needle apertures 316 and proximal
needle opening 324 within the drug volume 304. The rigid support
314 provides means of supporting the helical fixation means and the
needle delivery structure.
[0080] Placing an osmotic pump directly at the site where agents
are delivered has the benefit of limiting the amount of agent in
the system. In devices where the agent in the filling tube can be
removed, the site-specific osmotic pump does not require a long
length of tubing filled with pharmacological agent. This may be
particularly useful for agents whose systemic effects are
undesirable or unknown. To deliver agents by a fluid pathway along
the length of a catheter system will require a length of tubing to
be filled with the appropriate agent. Although minimizing the cross
sectional area of such a tube will result in a reduction of the
problem of excessive agents, putting the pump at the site for
delivery completely eliminates the problem. Placing the osmotic
device at the end of the catheter tube provides the advantageous
means for follow-up delivery after the pump has delivered all of
the agents in the drug volume 304. Further, a very small amount of
agent may be all that is required and the osmotic pump may be small
enough to be placed on a catheter at the site for delivery.
Although catheter based osmotic pumps have been described for
steroid elution to the surface of the endocardium, there is no
prior art for such catheter based osmotic pumps capable of
delivering pharmacological agents at a depth within a tissue with
the means disclosed here. Further, there have been no descriptions
of catheter based osmotic pumps which may be filled proximally
after implant and whose agents may be altered during delivery. Such
delivery techniques have substantial advantages for macromolecules
such as growth factors and genetic material. Further, they may
allow for very controlled delivery of microsphere or micelle
encapsulated agents such as may be required for gene therapy.
[0081] The drug reservoir can be either a solution or a solid
formulation contained in a semipermeable housing with controlled
water permeability. The drug is activated to release in solution
form at a constant rate through a special delivery orifice. The
release of drug molecules or encapsulated drug molecules from this
type of controlled release drug delivery system is activated by
osmotic pressure and controlled at a rate determined by the water
permeability and the effective surface area of the semipermeable
housing as well as the osmotic pressure gradient. Devices which use
hydrodynamic pressure gradients are similar except the
semipermeable membrane is replaced by an opening, and the osmotic
salt is replaced by an absorbent and swellable hydrophilic
laminate.
[0082] FIG. 3b shows a partially sectional view of another
embodiment of the distally located osmotic pump. Here check valve
402 is located at the proximal end of the needle structure 404
which is continuous through the drug volume 304. This needle
structure 404 provides more structural stability to the drug
delivery device and guarantees that there will be a fluid pathway
even after the osmotic action has driven all of the agent out of
the drug volume 304. Further, a section of seal 406 is shown
attached to the inside of the catheter body. Osmotic pump housing
308 moves within seal 406 which acts to prevent migration of fluids
into the catheter body.
[0083] FIG. 4 shows another embodiment of a cardiac drug delivery
system. Here fixation mechanism consists of a needle 484 with
apertures 486 that penetrates the myocardium and is held in place
by barbs 466. In a chronic implant barb 466 may be composed of
either a rigid metallic alloy or a biodegradable polymer. If a
biodegradable material is used, long term tissue attachments will
maintain fixation with the heart, and the barb 466 will not cause
undue trauma should the drug delivery system need to be
explanted.
[0084] In addition, FIG. 4 shows a multilumen catheter and valve
system for the filling of reservoir 462. Agents may be delivered
down the fluid path defined by filling lumen 452 in bilumen tubing
450 such that unidirectional check valve 456, shown here as a ball
check valve, is opened allowing agents to flow through lumen 458 of
tube 460 and out the distal end of tube 480. The ball check valve
has a sphere in a generally conical tube which allows
unidirectional flow by obstructing the smaller diameter fluid
pathway to reverse flow and not obstructing the larger diameter
circular pathway of the open flow direction. In various embodiments
it could be replaced with a reed check valve, a hinged plate check
valve, or the equivalent. After the reservoir is filled, the fluid
will open check valve 472 and flow out clearing lumen 468 in
bilumen tube 450. This filling action will force ball check valve
470 closed. After filling, the remaining agent in the bilumen tube
may be cleared by delivering sterile distilled water, which may
contain anticoagulants such as heparin to assure long term patency
of the catheter lumens, down clearing lumen 468. This clearing
fluid will force check valve 472 closed, and check valve 470 open
such that agents may be flushed from the bilumen tube and replaced
with the distilled water or other flushing agents. If the system is
chronically implanted, such a bilumen tube and series of valves
would allow one to fill the reservoir 462 and clear the bilumen
tube 450 after implant. Further, because the distal end of the tube
480 allows for filling of the reservoir 462 from the distal end,
agents may be changed merely by filling via filling lumen 452 which
will force the existing agents out through proximal reservoir exit
474, through valve 472 and clearing lumen 468. If the proximal end
of such a bilumen delivery system were connected to a dual port
subcutaneous reservoir (not shown) agents would be injected into
one port while withdrawn from the second port.
[0085] In this delivery catheter, the distal housing also acts as
an osmotic delivery system with semi permeable membrane 496,
hydrophilic salt or agent 476, and flexible polymer barrier 464
allowing for controlled delivery of agents over a period of time.
After the expiration of the osmotic energy source, agents may be
delivered via the fluid pathway by an external pumping means if
desired. The valve housing 454 houses the three unidirectional
valves 456, 470, and 472, and provides tube fittings 488 and 490
for connection to the bilumen tubing. This valve housing 454 is
also attached by a crimp 494 to the coil 492. This complicated
structure would be assembled from the separate components and
combined. Separate valves could be fit into openings in a simpler
metallic form, and the whole could be mechanically and hermetically
attached to the rigid osmotic pump housing 478. Rigid support 482
is rigidly attached to needle 484, and may also have structural
elements which enter into the region of the hydrophilic salt, and
possibly attach to the valve housing 454. It should be clear that
many variations are possible.
[0086] FIG. 5a shows a partially sectional view of an embodiment
where a membrane or rate controlling barrier 506 stands between the
agent reservoir 502 and the apertures 518 in the proximal end of
the delivery needle 520 which would allow the agents to be
delivered to the distal end of the delivery needle 524, and through
the apertures 522. It is clear that the needle could be replaced
with a hollow helical delivery device as shown in FIG. 1c if so
desired. Included here is optional controlled release structure 508
for providing chronic delivery of agents to the implant site. As
this agent diminishes, new agents can be provided through the
connecting tube and check valve 402, such that rate of release is
governed by control barrier 506. Barrier 506 is shown here with
substantial thickness, but it could be formed of a simple membrane,
a membrane reinforced with a substantially porous structure, such
as a laminate of expanded polytetrafluoroethylene (ePTFE), or any
other structure which could be used to govern the rate of drug
delivery to the side of the barrier connected by a fluid pathway to
the tissue to be treated. The design of the control release barrier
would be customized for the agents to be delivered and may be
intentionally designed to specify a rate of delivery substantially
different from that which the optional control release structure
508. Needle plug 516 prevents flow through the needle lumen, while
maintaining a rigid axial support, and could be formed of an inert
polymer or metallic material. Rigid support 510 acts to support
axial location of needle 524 and may be a mechanical base for the
helical fixation means. Controlled release structure 508 could be
composed of a macromolecular controlled release matrix such as EVAC
housing a growth factor such as TAF, bFGF, or aFGF.
[0087] In another preferred embodiment of FIG. 5A, controlled
release structure 508 would be left out and the space would be
filled with pharmacological agents and act as a reservoir for acute
delivery immediately after implantation. The fluid path for
subsequent agents would then pass through tubing 104, through check
valve 402, through proximal needle 512 and through proximal
apertures 514 into agent reservoir 502, contained by drug reservoir
housing 504. The fluid agent must then pass through rate control
barrier 506 to be in contact with acute fluid reservoir 508.
[0088] In other embodiments of FIG. 5, the control barrier 506
could be electrically activated to allow rapid delivery of positive
pressure and agent delivery from one side to the other. In this
electrically activated embodiment, the optional control release
structure or acute reservoir 508 could merely deliver agents
acutely to preserve the viability of the fluid pathway for the time
when therapy is deemed necessary. Acute delivery of
antithrombolytics and anti-inflammatory agents would limit
blockages and tissue inflammation resulting from the implantation
of the structure in the heart wall and improve the ability of a
transient system to deliver agents quickly and effectively to the
region within the tissue. An electrically controlled barrier could
be fashioned much like any electrically controlled microvalve.
[0089] FIG. 5b shows a partially sectional view of the drug
delivery system described in FIG. 5 which incorporates a separate
stylet lumen 552 within the same catheter body 550. Such a stylet
lumen will allow for a removable wire element that will allow the
implanting physician to control the shape of the device to guide it
to the appropriate site. This additional lumen 552 allows the drug
delivery tubing to travel the length of the coil in its own lumen
554. Although shown here as a continuous part of catheter body 550,
stylet end stop 556 would most likely be attached as a separate
component. FIG. 5c is a cross sectional view of bi-lumen catheter
body 550 which shows the diameter of stylet lumen 552 to be
substantially smaller than lumen 554. These lumens may change
depending upon the requirements for different applications. Such an
additional lumen for stylet use could easily be combined with any
of the drug delivery systems presented here. This additional lumen
will prevent the lumen of the drug delivery tubing 104 shown in
these drawings from getting obstructed with body fluids during
stylet use, prevent damage to tubing 104 by the stylet, and allow
the materials of both stylet and tubing 104 to be chosen without
regard to the requirements of the other.
[0090] FIG. 6 shows a partially sectional view of one preferred
embodiment of a subcutaneous reservoir 626 and a drug delivery
catheter 628 which may be connected to the proximal end of the
delivery catheters shown. Subcutaneous reservoir 601 consists of a
housing 602 whose reservoir 606 may be filled with a fluid
pharmacological agent. The agent is introduced into the
subcutaneous reservoir 601 by transcutaneous injection into the
reservoir 606 through the polymer injection barrier 604. This
barrier is typically composed of silicone rubber such that it
creates a seal after removal of the filling needle. In addition,
the housing 602 is typically constructed of titanium, polyurethane,
or other known rigid biocompatible and non-reactive materials.
[0091] FIG. 6 provides a means for connecting the drug delivery
catheter to a subcutaneous reservoir, constant pressure pumping
means, or transient delivery automatic infusion pumps. Subcutaneous
reservoir 626 has a port 610 which accepts the proximal end of
delivery catheter 628 such that the region of separation 622
between the crimp structure 620 and proximal end of the jacket body
614 is completely within port 610. This will prevent fluids from
entering the separation 622 which allows the coil and inner tubing
624 to rotate relative to the jacket body 614 for advancement of
fixation structure 616 and needle delivery system 618. After the
proximal end is inserted into port 610 of subcutaneous reservoir
626, a set screw may be advanced within threads 608 to secure the
catheter in position by applying force to pin 612. This set screw
connection to the pin is common in devices used to deliver
electrical therapy to the heart, and could be used to perform an
electrical connection to the fixation means 616 or needle 618 in
order to sense the electrical activity of the tissue. This
electrical signal could be monitored by devices with algorithms
similar to those designed to deliver electrical therapy to the
heart, accept that instead of electrical therapy they introduce
pharmacological therapy.
[0092] FIG. 7 shows another embodiment of an acute drug delivery
system. The catheter body 702 houses a lumen 704 for fluid
transport of therapeutic agents and a lumen 706 for stylet use
during implantation. Lumen 704 travels the length of the delivery
catheter and connects to needle delivery structure 714. During
implantation through the vasculature, blood soluble coating 710
completely protects the vasculature from the sharp elements of the
helical fixation means 712 and the needle delivery structure 714.
Blood soluble coatings such as sugars may be used. After the
appropriate heart chamber is accessed, the physician must wait for
the coating 710 to dissolve. The coating may be combined with a
radio opaque material such as barium sulfate to identify better
when this has been accomplished. After the coating 710 has
dissolved, the physician implants the helical fixation means 712 by
rotating the entire catheter about its own axis. Torque is
delivered from the catheter body 702 to the helical fixation means
712 by the embedded portion of the helical fixation means 708. This
embedded region can easily be manufactured using molding and
bonding technology. The principle advantage of this device is the
small cost of manufacturing such a simple design with no moving
parts.
[0093] FIG. 8 shows a hollow helical fixation means 802 with
apertures 804 along its length. Sectional view of FIG. 8A shows the
hollow cross section 812 to be filled with a second material 810.
Second material in the preferred embodiment is a controlled release
polymer matrix filled with a therapeutic agent for extended
delivery of agents through apertures 804 in helical fixation means
802. In one embodiment controlled release matrix is comprised of
silicone rubber and the agent to be delivered is lidocaine. In
another embodiment the agent may be amiodarone HCL. In another
embodiment, the controlled release matrix is EVAC and the agent is
aFGF. Other variations are also possible. After implantation of the
structure within the heart wall by penetration of helix tip 808,
the rest of the helix is rotated such that all apertures 804 are
within the tissue. Agents then migrate from the controlled release
matrix to the tissue in which it is implanted. Such a controlled
release matrix filling of the hollow core which penetrates the
heart could be pursued with other penetrating structures as
well.
[0094] FIG. 9 shows a drug delivery system with VEGF in an EVAC
matrix 908 housed in a reservoir defined by cylinder 906, and ends
904 and 914. In the preferred embodiment, these are non-permeable,
although in other embodiments permeability may be desirable. End
904 acts both to transmit torque to helical fixation means 916, but
also as a stop for a stylet (not shown) which may be used during
implantation down the coil lumen 902. After implantation of the
drug delivery catheter, body fluids migrate through apertures in
distal needle 920 and into reservoir through proximal needle 912
and dissolve pharmacological agents in acute dosage 910 which may
be present to counter inflammation associated with implantation.
Over time, growth factors are delivered via needle 920 to a depth
within the heart. Note that the absence of a tube for agent
delivery enables stylet use during implantation. In variations on
this embodiment, other controlled release means could be housed
within a semi permeable structure that would allow increased fluid
transport to assist in delivery of agents through needle 920 to a
depth within the heart wall.
[0095] FIG. 10a shows another drug delivery catheter in which
agents may be delivered transiently to a depth within the tissue.
Here, helical coil consists of four co-radial wires 1000a, 1000b,
1000c, and 1000d which are electrically isolated from one another
by a layer of insulation. The electrical insulation allows a
current pathway to be defined which allows current to flow through
electrical connection 1018 of wires 1000c and 1000d and into
Nitinol thermally activated shape memory ribbon 1020, which wraps
around flexible polymer barrier 1010 and is also shown in cross
sections 1006, 1024, and 1008. Current flowing through Nitinol
ribbon 1020 completes its circuit to wires 1000a and 1000b at
electrical connection 1002 to torque delivery structure 1004 via
conduction through connection to support structure 1012 which is
electrically connected to needle 1028. Insulating structure 1032
separates the two electrical connection regions on structure torque
delivery structure 1004 and allows current to pass through ribbon
1020. If the electrical resistance of the nitinol is relatively
high, ohmic heating may prove to be sufficient to cause a
constricting shape change upon the flexible polymer barrier 1010.
Contained within flexible polymer barrier 1010 is a partially
porous polymer controlled release matrix structure 1022 such as
silicone rubber containing lidocaine, which upon compression by the
nitinol ribbon, will force agents out of the controlled release
matrix 1022 and through the needle 1028 within the reservoir 1026
and out the needle 1016 into the heart.
[0096] FIG. 10b shows another transient drug delivery structure in
which a reservoir contains a fluid whose vapor pressure provides
the energy to deliver therapeutic agents. As in FIG. 10a, the
different filars in the helical coil, such as filar cross section
1068, are electrically insulated from one another such that two
independent electrical connections may be made at crimp 1050 and
crimp 1072 which are separated from each other by electrically
insulating barrier 1070. The electrical connections made at crimp
1050 and 1072 have an electrical path between them which is defined
by resistive heating element 1052 which passes through reservoir
1056. Within reservoir 1056 is a fluid gas mixture which provides a
constant pressure at human body temperature via plate 1058 to the
drug matrix 1060. If drug matrix 1060 is a substantially porous
controlled release matrix, the pores surrounding the matrix will be
filled with relatively high concentration of agents in fluids. As
electrical energy is delivered down the two independent electrical
conductors to resistive heating element 1052 and increase the
temperature of the fluid within reservoir 1056. As reservoir
housing 1066 and support structure 1064 are rigid and
non-compliant, this will increase the pressure within reservoir
1056, cause expansion of bellows 1054 and apply pressure to the
controlled release matrix 1060. This will force the concentrated
fluid from within the porous controlled release matrix into
proximal end of needle delivery system 1074 and out through the
distal needle into the heart wall. Such vapor pressure energy
sources have been used in infusion pumps such as Infusaid's
infusion pump (Norwood, Ma). However, it is not known if such a
system has ever been implanted on a catheter, or whether the vapor
pressure system has provided for a thermal element to increase the
temperature within the charging fluid and thus the pressure
delivered transiently. In addition to the porous matrix, there is a
soluble anti-thrombogenic and anti inflammatory agent for acute in
acute dosage form 1062 which surrounds proximal length of needle
1074, while still leaving the end free for agent administration.
Such acute dosage forms may be very useful for guaranteeing the
long term outcome of such controlled delivery systems by minimizing
the response of the tissue to the trauma of implantation.
[0097] A method for delivering therapy using a combined drug
delivery ablation catheter proceeds as follows. Initially the
arrhythmogenic site is located using techniques common to those in
the field of cardiac electrophysiology. The delivery system is
inserted into the appropriate site within the heart by the internal
or external jugulars, cephalic vein, subclavian vein, femoral
artery or other vascular delivery routes. Then, the drug delivery
structure is implanted at the arrhythmogenic site to supply an
appropriate agent for altering the local conduction properties.
After implantation, agents are delivered and the effect on the
arrhythmogenic site is evaluated by electrical techniques such as
mapping. If the location is appropriate, and the agents appear to
terminate the critical arrhythmia, RF energy is delivered to the
tissue by way of the same structure used to deliver the agents to
the heart. If the position is inappropriate and the local
pharmacological agents do not correct for the arrhythmia, the
device is repositioned, and the procedure is repeated.
[0098] A method for transient treatment of supraventricular
arrhythmias using a chronically implantable transient drug delivery
catheter proceeds as follows. After electrophysiologists have
specified the appropriate region for implantation based upon the
patient's cardiac electrical action, a catheter is implanted at
this site to deliver antiarrhythmic agents at a depth within the
heart transiently, as well as to sense the electrical activity near
the device. The catheter is then connected to an external
controller and power source, which determines suitability of
therapy and delivers energy to a device such as those described in
FIGS. 10a and 10b for transient delivery of pharmacological agents,
or to a device such as that shown in FIG. 1c coupled to a
proximally located pumping means. The device then senses cardiac
activity through the surface of the drug delivery structure. When
the heart experiences an arrhythmic event, the controller
identifies the event and activates the energy source which delivers
the drug to the heart. This drug modifies the selected area of
tissue and either terminates the arrhythmia, or substantially
reduces the magnitude of the required electrical therapy. If the
arrhythmia does not terminate, the pump may deliver a secondary
dosage, or trigger an external electrical therapy device. If no
arrhythmia is sensed. The device is maintained in monitoring
mode.
[0099] FIG. 11 shows a sectional view of the heart 1101 with a
triple catheter system passed retrograde across the aorta 1105 and
into the left ventricular chamber 1115. Guide catheter 1120 is
placed across the tricuspid valve and a steerable guide catheter
1125 is advanced through its lumen in order to target a region of
the heart wall 1110 for delivery. Within the steerable guide
catheter 1125 is drug delivery catheter 1130. Once oriented towards
a region of the heart wall 1110 such as the septal region 1140
shown, the centrally located drug delivery catheter 1130 is
advanced into the heart wall 1110 and fixed to the heart tissue by
means of the fixation element 1135. In the case of the hollow
helical fixation structure 1135 shown, an element in the centrally
located drug delivery catheter 1130 must be rotated in order to
advance the fixation helix into the heart wall. The catheter system
used to implement the inventions described herein can be provided
in a variety of configurations permitting delivery and deployment
of the fixation tip within the heart. In one alternative
embodiment, the outer guide catheter is not used, and only the
steerable guide catheter and drug delivery catheter are used. The
drug delivery catheter may be a non-steerable catheter within a
steerable guide catheter. In a third embodiment, a single steerable
drug delivery catheter is used, which also allows for deployment of
a distally located penetrating structure such as the helix 1135
shown, with or without a guide catheter. In a fourth embodiment,
the single catheter system may be preformed to effect a particular
shape within the heart, while allowing deployment of the distally
located penetrating structure which is directed to the desired site
in the heart by the preformed shape of the preformed distal tip of
the drug delivery catheter. In a fifth embodiment, a dual catheter
system is used in which the guide catheter is pre-shaped to effect
delivery to a certain location, and the drug delivery catheter is
delivered from within the pre-shaped system. The preformed shapes
are chosen to facilitate preferred orientation of the distal tip of
the catheter system in apposition to a desired site of treatment
(i.e., the distal opening 1136 is facing treatment site 1137 in the
septal wall) when the catheter distal tip is at rest within the
heart.
[0100] The use of these various systems is similar, but there are
subtle differences. For example, in the case where there is an
outer guide catheter which is separate from the centrally located
drug delivery catheter, the catheter will likely be passed over
either a guidewire, or other pre-placed catheter system to gain
access to the ventricle. In the case where the system is a single
catheter with a deployable infusion element, the catheter can be
designed such that the distal curve enables the catheter system to
be prolapsed across the aortic valve or steered through and
eliminates the need for guiding wires and guiding catheters to
access the heart chamber for some physicians. In the cases where
concentric catheters are used, there will be concern that blood may
enter the very thin space between the catheters, and catheters
would be designed with infusion ports to enable the continuous
flushing of the space between these catheter systems. Further,
these catheter surfaces may be coated with heparin to reduce their
thrombogenicity and potential for embolic thrombus formation.
[0101] Although ultrasound, radio-opacity, electromagnetic signals,
and the like may be used to position the system within the
myocardium with techniques described elsewhere, the location of the
infusion system once fixed to the tissue is preferentially
confirmed visually by flushing the heart chamber with a contrast
medium and viewing the radio-opaque penetrating element and
catheter body relative to the boundaries of the heart wall. In many
cases this will be performed by delivering contrast through a guide
catheter, but adjacent separate catheters, as well as distally
located contrast lumens within the drug delivery catheter are
viable routes for contrast medium to egress into the heart chamber
where delivery is desired. Contrast could also be delivered down a
drug delivery lumen and into the myocardium to confirm device
position, evaluate pharmacokinetics, or visually observe the
lymphatic transport away from the region.
[0102] The drug delivery catheters with distal fixation devices are
beneficially combined with the features described in the following
figures, which enable confirmation of position of the catheter and
controlled injection of a desired dose of therapeutic agent into
the heart wall. The catheter system that has its drug lumen
pre-filled with a passive agent such as saline or Ringer's solution
to be positioned prior to delivering the therapeutic agents. Once
positioned, the therapeutic agent is delivered, and is then
followed by a small volume of the passive agent. This subsequent
delivery of passive agent will clear the dead space in the
catheter, ensuring injection of the entire dose (as measured by the
catheter fluid volume) and promote advancement of the therapeutic
agent into the myocardium.
[0103] FIG. 12 shows a drug delivery catheter with fixed distal
penetrating element for implantation within the heart. Catheter
handle 1202 is shown with its outer casing removed to illustrate
the position of the two syringes 1204 and 1206 within the handle.
The syringe plungers 1230 are slidably disposed within the
syringes, and are operable from outside the catheter handle with
the thumb-slides illustrated in FIG. 13. Prior to delivery of the
catheter distal tip 1231 into the heart, the small syringe 1206 is
filled with therapeutic agent and large syringe 1204 is filled with
passive agent. Syringes 1204 and 1206 are filled in the traditional
manner and are then connected attached to distensible tubing 1208
and 1207 with luer fittings 1213 and laid into position within the
catheter handle 1202. Prior to insertion of the catheter into the
body, the therapeutic agent syringe 1206 is flushed, with stopcock
1210 rotated such that therapeutic agent syringe may flush any air
within the syringe into distal drug delivery tubing 1212. Then,
also prior to delivery into the body, the stopcock 1210 is turned
so that passive agent syringe and its distensible tubing 1208 are
aligned in fluid communication with the drug delivery tubing 1212.
The drug delivery tubing may be flushed for a full measure of the
catheter drug delivery tubing, until the entire tubing length and
the distal penetrating element's dead space has been flushed of any
air within. The dead space is the volume of the fluid pathway
between the reservoir of therapeutic agent and the discharge point
at the distal tip of the catheter.
[0104] The dead space in many catheters will be equivalent to the
amount of drug in a proximally located reservoir that is not
effectively delivered to the tissue. This dead volume will cause
inaccuracy in dosing, which can be important when small volumes are
delivered. It is desirable to have the dead space be small, and the
preferred inner diameter of the drug delivery tubing is preferably
less than 0.03 cm (0.012''). (In a catheter of 100 cm length, this
amounts to a dead space volume of 0.07 milliliters, and in a
catheter of 135 cm length, it results in a dead space of about 0.09
milliliters. Preferably, the volume of the dead space is in the
range of 0.05 ml and 0.25 ml.) Control of the dead space volume is
important to provide good control of the drug dosage into the
heart.
[0105] One way to eliminate the issue of dead space and dosing
errors is to have a post delivery flushing method. Syringe 1204 is
larger in diameter than syringe 1206 such that an equivalent
displacement of each syringe will result in more fluid being
dispersed from the larger syringe. In this way, therapeutic agents
may be delivered in volumes less than that of the dead space and
followed up by a flushing infusion that will fully clear the
remaining therapeutic from the catheter body. This flushing
procedure has the advantage that it enables small volumes of agents
to be redistributed to some degree by a passive flushing medium
such as buffered saline. Additionally, the system may be flushed
and filled with the flushing fluid from the second syringe prior to
injection of therapeutic agent from the first syringe, so that
doses of therapeutic agent which are smaller than the volume of the
dead space may be accurately delivered, and expensive therapeutic
agent need not be used merely for flushing the system of air
bubbles. After the system is initially flushed and filled with the
fluid from the second syringe, a predetermined dose of the
therapeutic agent may be injected from the first syringe into the
dead space of the tube 1212. The injected therapeutic agent is then
fully delivered upon being flushed from the dead space by a second
injection of the flushing fluid from the second syringe.
[0106] The components of the fluids stored in each syringe may be
adjusted to provide additional benefits. Dual syringes, coupled to
the secure fixation element, provide means to infuse the tissue
with one agent, and follow it with delivery of a second potentially
synergistic agent without having interaction between these two
agents occur before delivery. The second syringe can be loaded with
an agent which activates components of the therapeutic agent stored
in the first syringe by altering the physical and chemical
properties of the first agent. Delivery of the activating agent to
exact site is thereby accomplished without manipulation of the
catheter system. One example of such a use would be to deliver
liposomal preparations from the first syringe, in which liposomes
encapsulate a therapeutic compound and protect the therapeutic
compound from degrading interaction with the catheter tubing. The
liposomes are typically stable within a narrow range of pH, but
which are unstable exposed to a different pH. The second syringe
can then be loaded with a fluid having a liposome destabilizing pH.
When this liposome destabilizing fluid is injected, it serves to
clear the dead space of the therapeutic agent and interacts with
the liposomes in the first agent to break down the liposomes and
release the encapsulated therapeutic compounds simultaneously or
shortly after the injection of the therapeutic agent into the
heart. In this way, the encapsulated agents are released only after
they have been deposited into the tissue and have been flushed with
a destabilizing solution which destabilizes and breaks down the
liposomes which encapsulate the therapeutic agent. Also, a contrast
medium may be used as the flushing medium provided in the second
syringe, so that flushing will also serve to mark the location at
which the therapeutic agents were delivered. Marking the injection
site with contrast agent injected into the wall of the heart
facilitates subsequent placement of the infusion needle for
additional injections of therapeutic agents.
[0107] A luer adapter 1201 for delivering contrast medium is
present on the back of the catheter system in this design so that
contrast may be delivered through the catheter body tubing 1214 in
the space 1230 surrounding the drug delivery tubing 1212. This luer
fitting is connected to contrast tubing 1203 which communicates
into the Y-adapter 1205 with a suitable bonding or potting agent.
The Y-adapter also is bonded to drug delivery tubing 1212 at the
proximal end of the drug delivery tubing and to catheter body
tubing 1214 at its proximal end. When contrast agent is injected
into the luer fitting 1201, it flows through the space between the
drug delivery tubing and the catheter body 1214. Small holes may be
provided at the distal end of the catheter to enable the contrast
to escape, or the penetrating element such as helix 1224 may be
fixed over a hollow cylinder 1218 attached to catheter body 1214 by
adhesive or other bonding material 1226. Here therapeutic or
passive agents are delivered through hollow helical needle 1224
from drug delivery tubing 1212 and contrast is delivered through
the annular lumen 1252 between the catheter body 1214 and the drug
delivery tubing 1212, then through cylinder 1218. A pressurized
source of passive agent, such as saline solution, may be connected
to the luer fitting 1201 with a Y-adapter 1251 so that the catheter
body may be flushed continuously to prevent the possibility of
blood entering between the drug delivery catheter and the catheter
body catheters, clotting, and thereafter becoming dislodged into
the blood stream. Infusion solutions such as heparinized saline are
preferred for this. In one embodiment the inter-catheter space
(that is, the annular space or lumen 1215 between tube 1212 and
catheter body 1214) could be connected to a gravity fed or pump fed
fluid source such that the infusion would be continuous during the
procedure. Additional branches could be used such that the catheter
could be continually flushed and contrast could be delivered
transiently for performing ventriculograms and the like to confirm
catheter position.
[0108] FIG. 13 shows an enlarged view of the catheter handle shown
in FIG. 12 with the cover 1301 in place and the syringe plungers in
place on thumb-slides 1306 and 1302. Stops or detents 1312a, 1312b,
and 1312c are provided on the outer surface of the cover, in
partially obstructing relationship to the thumb slides so that,
when the thumb-slides are pushed distally, they encounter
noticeable resistance upon meeting any one of the detents, but may
be pushed past the detents with additional force applied by the
operator of the device. This enables the operator to inject
predetermined volumes of fluid (corresponding to the volume of the
syringe cleared by movement of the syringe plunger between the
detents) by pushing the thumb-slides between detents. These stops
may be either visual marks, or they may be physical barriers
requiring more force to overcome, or an adjustment to be made
before passing. Prior to injection, the stops may be moved along
track 1314 such that they can be varied and effect a different
dosing regime for a different patient or different agents, if so
desired. Slides 1306 and 1302 advance in tracks 1308 and 1304 and
engage the plungers, so that the plungers move with the
thumb-slides, thereby displacing fluid from the syringes and into
the drug delivery tubing. (The cover 1301 may be snapped in place
after positioning the syringes internally, and may be hinged as
shown schematically along line 1318 so that it lifts for syringe
placement. A hole 1316 is shown to allow access to the stopcock
within, but an alternative structure on the cover 1301 could be
placed to engage the stopcock.)
[0109] FIG. 14 shows the two piece proximal handling mechanism for
drug injection and manipulation of the helical coil attached to
drug delivery tube 1212 and steerable guide catheter 1412. FIG. 14
shows the drug delivery catheter handle 1202 and steering handle
1450 in an elevational view. The drug delivery handle has a
cylindrical distal end 1404 to facilitate engagement with the
cylindrical bore 1451 of catheter handle 1406. The drug delivery
catheter may be rotated relative the steering catheter handle, and
can be longitudinally advanced and retracted several centimeters
while the cylindrical distal end is engaged inside the cylindrical
bore. The guide catheter 1412 is steerable, and has at least one
pull wire 1416 which is pulled around pulley 1414 and over rotation
knob 1410 where it is attached by block 1418. The pull wire is
disposed within the side wall of the guide catheter and secured to
the guide catheter body at the distal end of the guide catheter,
such that rotation of knob 1410 will pull the pull wire 1416 and
effect a deflection of the distal tip of guide catheter 1412 (not
shown). An additional pullwire 1417 may be provided on the opposite
side of the catheter body to provide positive control of the distal
tip curvature, rather than relying on the resilience of the
catheter tip to effect straightening. In one embodiment, the drug
delivery catheter 1408 is placed in the guide catheter prior to
steering the guide catheter within the heart in order to prevent
the localized bending on the hollow guide structure from causing a
kink to form in the distal tip of the hollow catheter. The drug
infusion catheter acts to support the guide catheter during the
steering process. Such a system may be steered across the aortic
valve, or deflected 180 degrees upon itself to prolapse across the
valve. The more traditional approach of advancing the steerable
guide over a preplaced guide wire, and then following it with the
infusion system is also appropriate.
[0110] FIG. 15A shows a means for stabilizing the distal portion of
the guide catheter to prevent localized buckling. To control
steering, it is desirable to have a catheter that will not buckle
and which also has a lower bending rigidity in the plane in which
the distal structure is to bend. It is also desirable that the
distal region of the catheter not be substantially stiff. Braided
catheter body 1502 is bonded to the bendable region through
standard catheter joining techniques such as an overmolded lap
joint. The deflecting region of the guide catheter 1530 comprises a
flexible and easily bendable tube 1504 with a coil 1506 disposed
coaxially within the tube shown in cross section in FIG. 15a 15A
and in an elevational view in FIG. 15B. Coil 1506 will prevent the
structure from buckling locally. The pullwires 1416 and 1417 are
fixed at their distal ends to the distal end of the coil 1506, or
to a point in the bending section wall, so that proximal tension on
either pullwire bends the bending section. An alternative solution
would be to place a number of hoops in the distal portion of the
catheter that can move relative to one another. To create the
lowest bending rigidity in the desired plane of bending, bending
ribbons 1508, 1510, 1520, and 1522 are placed such that their long
axes are in the plane perpendicular to the desired plane of bending
as defined by the plane in which both pull wires lie. The ribbons
may be fixed to the helical coil 1506, or they may rely on
adhesives to secure and define their positions within the catheter
body. The ribbon and helical coil may also be formed simultaneously
by molding them out of higher durometer polymer materials, although
they are metallic in their preferred embodiments. FIG. 15B shows
that the two pull wires 1416 and 1417 may be attached to the distal
portion of these ribbons or even to the distal portion of the
helical coil. Again, connecting means are likely to involve
crimping, brazing, welding, and combinations of these. Pull wire
may also be replaced with a pull cable in embodiments where
multiple flexures of the bending element may introduce fatigue.
FIG. 15C is a distal end view of the catheter which shows the two
ribbons 1508 and 1510 positioned adjacent to the two pull wire
lumens 1512 and 1514 (which house pull-wires 1416 and 1417), being
disposed within the catheter within the plane established by the
two pullwires. FIG. 15D shows a modification of the placement of
the bending elements in relation to the pull-wires. The two pull
wires 1416 and 1417 are again located in the catheter body wall,
defining a plane in which the two pull wires lie, with ribbons 1520
and 1522 being disposed in the plane intersecting the pullwire
plane at an angle of about 90 degrees and intersecting the center
of the catheter. The preferred bending plane 1530 of the ribbons is
parallel with the plane 1531 in which the pullwires lie. FIG. 15E
illustrates another embodiment in which four ribbons are placed
within the catheter body wall, distributed at 90 degree intervals
around the circumference of the catheter body wall, with the
preferred bending planes 1530 of each ribbon parallel to each
other, and two pull wires are disposed within the catheter body
wall, 180 degrees apart from each other and within the plane 1531.
FIG. 15F shows the cross section 15F of FIG. 15A, illustrating the
braided catheter body tubing 1502 and showing lumens 1514 and 1512
which enable the pull wires and cables to be pulled by the hand
piece with minimal friction.
[0111] FIG. 16 shows a steerable guide catheter with two distally
located bending segments 1602 and 1604. Bending segments 1604 and
1602 are formed of a slotted hypodermic tube such as that described
in U.S. Pat. No. 5,322,064. These two bending elements are formed
from the same piece of hypotube with the slots of segment 1602 made
at 90 degrees angle from the slots in segment 1604, thereby
comprising two sets of slots orthogonally arranged on the
circumference of the tube. The hypodermic tubing is covered with
thin walled polyolefin material (not shown) and tipped with a soft
tip low durometer Pebax or silicone material 1650 at the distal
tip. Pull wires are affixed to the tubing by wrapping them around
small pins and passing the pull wires through holes in the distal
regions of each bending element. Bending segment 1602 has a single
wire, shown in the cross section of FIG. 16a, disposed within the
lumen 1619 in underlying catheter body 1616 with the slotted
hypodermic tubing 1618 coaxially overlying the catheter body 1616.
The pullwire is anchored at the distal end of the ending segment so
that proximal movement of the pull wire causes bending of the
segment. The pullwire lumen is oriented at the circumferential
center of the cutaway slots, so the bending force is applied along
the plane in which the slots have created a bending preference,
(that is, the slots are perpendicular to the plane of bending, and
establish the preferential bending plane, and the pullwire is
located in the preferential bending plane, on the same side of the
catheter as the slots. Segment 1604 has an additional pull wire
lumen 1621, shown in the cross section of FIG. 16b, the pull wire
(not shown) which affixes to the hypodermic tubing near the distal
end of segment 1604 and enters through the hypodermic tubing 1618
to enter in lumen 1621 in Pebax tubing 1616. The pullwire 1621 is
operable from the proximal end, and translates tension on the
pullwire into bending of segment 1614 in the plane perpendicular to
the length of the slots. The lumen 1621 is orthogonal, or located
90.degree. from the lumen 1619 relative to the circumference of the
tube, so the tip of the catheter can be bent to different degrees
in two planes established by the pull wires and the central axis of
the catheter. The tubing 1616 runs the length of the catheter and
passes within proximal braided catheter shaft 1624, as shown in the
cross section of FIG. 16c. Pebax may also be lined with PTFE for
lubricity in advancing catheter elements down its length. The
catheter shaft 1624 may be formed with a number of sections such
that the durometer changes from high durometer to low durometer
resin near the distal end of the catheter. The braid can also be
varied to affect stiffness and torqueability and in the preferred
embodiment is made with 0.0025 inch (0.06 mm) diameter stainless
wire with 45 Pics per inch (20 pics per cm). Pull wires connect to
proximal pull wire knobs 1614 and 1610 which are disposed one atop
another to facilitate ergonomic control of dual axis bending at the
distal end. This guide catheter is molded with luer 1612 in place
in proximal handle 1612 such that this guide catheter can be used
for performing coronary angiograms, left ventricular angiograms,
and as a guide for placing other devices and fluid agents within
body lumens. In addition to its ability to access the heart, this
dual axis steerable guide catheter has many advantages as it may
also be slightly modified to enable docking of an infusion catheter
handpiece.
[0112] FIG. 17 shows a steerable guide catheter similar to the
device of FIG. 16 modified by the addition of a docking infusion
catheter. Here, infusion catheter handpiece 1710 enters the
proximal handle 1714 of the steerable guide which has a narrowing
channel 1716 for enabling the advancement of an infusion catheter
after the guide has been advanced to its appropriate location
within the body over a guidewire. The funnel-shaped narrowing
channel 1716 prevents the infusion catheter 1718 from catching and
buckling during its advancement into the lumen of the guide
catheter. The cylindrical body of the infusion catheter proximal
handle 1202 fits into the cylindrical bore of the steering catheter
handle. The dual syringe system of this figure is similar to the
system of FIG. 12, but has been modified so that each syringe
connects to a separate lumen in a dual lumen tube 1750 which
traverses the entire catheter length. This bi-lumen tubing connects
directly to the fixation helix 1704, as shown in FIG. 4. Here the
dead space for each tubing length remains, but precision of the
interaction of the two agents may be controlled at the distal end
of the catheter, to achieve the advantages of flushing and
interaction already described. In FIG. 17, the distal helix
infusion element is shown to be larger than the lumen available
within the catheter body, and to taper to a smaller diameter within
the catheter body. Such a system cannot be passed from one end of
the catheter to the other, but enables the diameter of the catheter
to be kept to a minimum. In such a system, the larger fixation
structure is essentially garaged in the larger body tubing of the
guide catheter tip 1650 or distal bending segment 1602, and can be
advanced and rotated by advancing and rotating the cylindrical
infusion handpiece 1710 within the guide handpiece 1714. Once
advanced just a bit from its garage, space exists between the guide
catheter inner lumen and the infusion catheter outer diameter for
flushing of contrast agents to improve visualization of the
catheter position. Such infusions enable very clear visual
confirmation of the engagement of a fixation element with any
region desired within the heart when viewed under bi-planar
fluoroscopy.
[0113] FIG. 18 shows a schematic of the helical infusion system
being used for percutaneous transmyocardial revascularization
(TMR). The helix 1804, which may be delivered to the endocardial
spaces of the heart with any of the previously described catheters
and methods, is advanced to a depth within the heart tissue, for
example the left ventricle wall 1816, is used to create helical
pathways of damage within the heart tissue. Cross-section of the
helix path in the heart tissue would reveal areas 1808 of damage
that corresponds to the needle track. These areas of damage may be
beneficial in that these small injuries will trigger endogenous
repair mechanisms and reduce angina. Although others are creating
straight channels in the heart using lasers, radiofrequency energy,
or mechanical coring techniques these systems are less desirable.
The helical system shown has the distinct advantage that it
maximizes the volume of tissue effected, while minimizing the
damage that is introduced (particularly limiting damaged to the
endocardium for any given amount of myocardial damage).
Simultaneously, damaged tissue 1808 is interleaved with undamaged
tissue 1810 through the penetration process. This allows more
interaction of healthy tissue with the factors involved in the
tissues response to injury. Further, because the helical pathway
through the tissue is more quickly self-sealing than the straight
puncturing devices currently used, it has large benefits as well.
The helical pathway and screw-action required for TMR wounding
prevents puncture of the heart and bleeding into the pericardium.
The self-sealing helical pathway greatly reduces the risk of life
threatening pericardial tamponade being caused by blood entering
the pericardium, and also greatly reduces the potential of
therapeutic agents 1818 previously or subsequently deposited in the
myocardium from leaking into the heart chamber and entering the
systemic circulation. Reduced leakage is important to ensure that
dosing is appropriately delivered, and critical to prevent the
possibility of embolic events occurring when controlled release
structures larger than 8 microns in diameter are delivered to the
tissue. Agents 1818 in the preferred embodiment are microspheres
containing angiogenic agents with a minimum diameter of 30 um in
diameter.
[0114] A cardiac surgeon performs TMR according to FIG. 18 by
inserting the helical needle into a chamber of the heart, for
example the left ventricle, and then operating the helical coil to
screw it into the heart wall. The surgeon may then inject a small
volume of contrast agent through the helical coil into the heart
wall to mark the position of the wound. The contrast agent may be
incorporated into degradable macromolecules, microspheres or other
large molecules described herein to inhibit quick migration within
the myocardium and back-leakage from the wound or needle track. The
surgeon may then inject a therapeutic agent into the wound, through
the helical coil. Again, the therapeutic agent may be incorporated
into macromolecules, microspheres or other large molecules to
prevent excessively quick migration and back-leakage into the heart
chambers. The therapeutic agent may include the patient's own
blood, which carries endogenous angiogenic agents. The surgeon may
then remove the helical coil by unscrewing it (through operation of
the proximal end of the catheter), and perform the penetration on
another site within the heart wall. The surgeon will be guided in
selection of subsequent sites by the appearance of the contrast
agent in the fluoroscopic image of the heart which clearly
illustrates areas previously treated. Typically, the process is
repeated to create 4 to 30 wounds in the myocardium.
[0115] FIG. 19 shows the distal end of another fixation infusion
catheter. The helix 1902 is larger than lumen 1904 in catheter body
1906 and cannot be passed from end to end. However, helix 1902 can
be retracted and parked in enlarged distal portion 1916 of lumen
1904 to prevent its being caught on tissue during insertion and
manipulation prior to engagement with the heart. Parallel lumen
1912 in the wall of catheter body 1906 provides both a means of
infusing contrast adjacent to distally located helix to improve
visualization of structures adjacent to the helix as well as the
fixation of the helix, and a means of advancing the catheter system
over a guide wire. Drug delivery lumen 1910 passes through
torqueable pushable catheter body 1908 and connects up to distally
located drug infusion helix 1902.
[0116] FIG. 20 shows a distal end of an infusion catheter system
with pincher fixation element. Here, catheter body 2002 houses
pincer fixation lumen 2003, straight needle drug delivery lumen
2012, and utility lumen 2010 which may be used for passing the
system over a guidewire (the lumens are visible in the cross
section of FIG. 20a), or for infusing contrast near the distal end
of the catheter system. The pincer fixation jaws 2006 are opened by
pushing on the stylet 2008 and applying tension on the coil element
2004. As the coil 2004 is sized such that it stretches slightly
with this force, the jaws will exit the tubing 2002 as they open.
Releasing the force on stylet mechanism 2008 allows the jaws to
close under a spring action not shown. Once secured to tissue such
as the endomyocardium in a fashion similar to a cardiac biopsy,
contrast can be infused down utility lumen 2010, to confirm the
fixation of the jaws to the endocardium, and a needle can be
advanced out of needle lumen 2012. Tubing 2002 may be formed of
braiding reinforced Pebax or the equivalent, and the durometer of
the tubing resin would be reduced from proximal end to the distal
end to optimize the pushability, and torqueability with the
flexibility in the heart chamber. For example in a 54 inch length
(137 cm) of catheter body tubing, six sections from proximal to
distal could be specified: 25 inch (63.5 cm) length of Nylon
Vestamid, 1 inch (2.54 cm) section of Pebax 72D, 20 inch (50.8 cm)
section of Pebax 63D, 1 inch (2.5 cm) section of Pebax 55D, 1 inch
(2.5 cm) section of Pebax 40D, and a 25 inch (63.5 cm) section of
Pebax 35D. The entire length would be reinforced with 0.0025'', 45
pics Per Inch (20 pics per centimeter) stainless steel
braiding.
[0117] Similar fixation mechanisms can be envisioned that involve
dual intersecting precurved needles, dual needles that are hinged
to become trapped in trabeculae, polymer tine structures, and the
like.
[0118] FIG. 21 shows a distal end of a fixation catheter. Here, the
flexibility of the distal end is optimized by incorporating a
helical spring with the distal helical infusion element.
Approximately six French diameter braided Pebax distal end of
infusion catheter body 2102 houses a braided polyamide drive shaft
2104 with an interior diameter of 0.025 inches (0.63 mm) and an
outer diameter of 0.045 inches (1.14 mm). Polyamide drive shaft
2104 is connected to helical coil 2106 with an interior diameter of
0.030 inches (0.76 mm) and an outer diameter of 0.039 inch (0.99
mm), the coil being a four filar right hand wound structure with
0.004 inch (0.10 mm) diameter wire. Coil 2106 and polyamide drive
shaft 2104 are connected over a Pebax support with an interior
diameter of 0.024 inches (0.61 mm) and an outer diameter of 0.030
inches (0.76 mm). A very thin wall 35D Pebax tubing 2105 is melted
over the junction of the drive shaft 2104 and the helical coil 2106
and pressure is applied using a appropriately sized heat shrink
tubing which is subsequently removed. Drug delivery tubing 2110,
shown here to be single lumen tubing having an interior diameter of
0.010 inches (0.25 mm) and an outer diameter of 0.016 inches (0.41
mm) passes within Pebax tubing 2108 and connects to the stainless
steel fixation and infusion helix formed of hypodermic tubing
having an interior diameter of 0.008 inches (0.20 mm) and an outer
diameter of 0.016 inches (0.41 mm) and wound into a helix geometry
that has an interior diameter of 0.030 inches (0.97 mm) and an
outer diameter of 0.058 inches (1.47 mm). Between the helical coil
2106 and the drug delivery tubing 2110 is a Pebax tube with an
interior diameter of 0.016 inches (0.41 mm) and an outer diameter
of 0.030 inch (0.76 mm) which adds mechanical support. The use of
adhesives, epoxies, and molten polymer resin to adhere these
structures together is achieved using standard techniques. In one
embodiment, the straight most proximal region of the fixation helix
is actually given a slight undulating bend such that it can be
embedded in a Pebax material with a mechanical lock to prevent its
detachment. This structure altogether provides a means to fix a
structure to the heart through a guide catheter and provide
substantial flexibility to the distal end.
[0119] FIG. 22A through FIG. 22C show different preformed guide
catheter shapes for accessing different regions of the myocardium.
They can be formed in these shapes by placing them over a preformed
steel mandrel and placing them in an oven to allow the
thermoplastic to reflow. Guide catheters are typically used for
accessing the coronary arteries, and these shapes are novel in that
they have been designed to access different regions of the left
ventricle from a retrograde trans-aortic technique. Guide catheters
are typically made of co-extruded or pull-truded stainless steel
braiding and PTFE inner layer with an outer liner selected from
polyester, blended nylon, Pebax, and the like as has already been
described in the description of FIG. 21.
[0120] FIG. 22A shows a catheter 2201 with a 90 degree bend 2202
located two centimeters from the distal end 2203 of the guide
catheter with the bend radius being around 2 centimeters for
accessing the postero-lateral ventricular wall and adjacent
regions. FIG. 22B shows a catheter 2211 with a bend 2212 located 1
cm from distal end 2203 of the catheter and deflected off axis
(i.e., the long axis of the catheter body when at rest in a
straight line) by about 30 degrees for accessing regions adjacent
to the inferior left ventricular apex. FIG. 22C shows a catheter
2231 with four bends 2232 each with a radius of curvature of 1.5
cm. They are located 2 cm, 4 cm, 6 cm and 8 cm from distal end of
the guide catheter and are all 90 degree bends but in opposite
directions as shown. The bend geometry is defined in relation to
the long axis of the guide catheter, labeled as item 2210. The
distal end of the guide catheter thus is formed with a first 90
degree bend away from the long axis of the catheter at a point
about 8 cm from the distal tip, creating a segment of guide
catheter running perpendicular to the long axis of the guide
catheter, a second 90 degree bend toward the long axis of the guide
catheter (bend located 6 cm from the distal tip of the catheter),
creating a segment of guide catheter running parallel to the long
axis of the catheter, a third 90 degree bend toward the long axis
of the guide catheter (bend located 4 cm from the distal tip of the
guide catheter), creating a second segment running perpendicular to
the long axis of the guide catheter, and a fourth 90 degree bend
distally in line with the long axis of the guide catheter (bend
located about 2 cm from the distal end of the guide catheter),
creating a fourth segment running parallel and co-linearly with the
long axis of the catheter, with all bend segments and the proximal
segment of the guide catheter lying in the same plane. This
catheter is useful for delivering agents adjacent to the anterior
wall of the left ventricle as well as the anterior apical
regions.
[0121] FIG. 23 shows a handle for a steerable infusion catheter
system. The handle is comprised of two matching halves, the lower
half 2318 and an upper half that is removed to illustrate the
internal components of the handle. One or more steering knobs
connect to wheel 2308, which is provided to pull on one or more
pull wires in order to effect deflection of the distal end of a
steerable catheter. Set screw knob 2304 is attached to wheel 2308
with a screw extension that penetrates the hand-piece, so that the
position of the wheel (and thus the deflection of the catheter) may
be locked into place with set screw knob 2304 which tightens upon
the hand-piece 2318. The wheel 2308 is preferably constructed to
allow passage of the infusion catheter either through or past the
wheel without interference. The wheel may be disposed against the
wall of the hand-piece, leaving sufficient space in the center of
the hand piece for passage of the infusion catheter, or it may have
longitudinal passageway 2350, as shown, which permits passage of
the infusion catheter through the wheel (although it may cause
slight bend in the portion of the infusion catheter housed within
the wheel), in which case the wheel must have a diameter sufficient
to cause the desired deflection of the guide catheter with wheel
rotation limited by the deflection of the infusion catheter within
the wheel passageway. The infusion catheter is slidably disposed in
the guide catheter and wheel bypass region, and fixable to the
advancement slide 2310. Advancement slide 2310 is slidable within
the hand-piece channel, and operable by a thumb slide on the
outside of the hand-piece connected to the slide through a slot in
the outer surface of the hand-piece. The advancement slide is
fixable (though not always fixed) to the infusion catheter so that
movement of the slide causes longitudinal movement of the infusion
catheter. The travel of the slide is sufficient to allow the distal
end of the catheter, including the helical needle, to advance to a
desired extent, and may be limited to prevent the possibility that
the penetrating element can be extended completely through the
myocardium. Once the position of the deflection is fixed by the
operator, the infusion catheter is advanced by advancing
advancement slide 2310 in channel hand piece channel. (This slide
has a spring element 2312 between its two halves to enable the
infusion catheter body to pass between fixation clamps in the
hand-piece body which is provided in halves (lower half 2318 is
shown, and the upper half is not shown in order to illustrate the
internal parts of the hand-piece). The two halves of the hand-piece
are held together by screws 2306 and 2314. Slide 2310 slides
axially within the handle advancing the catheter through a hollow
wheel bypass region. Thumb screw 2316 is rotationally fixed to the
infusion catheter, so that rotation of the thumb screw causes
rotation of the infusion catheter and the helical needle at the
distal end of the infusion catheter. The infusion catheter proximal
end which lies within the thumb screw region of the hand-piece is
longitudinal slidable within the thumbscrews (to permit the sliding
controlled by the side 2310), but rotationally fixed to the thumb
screw 2316. This may be accomplished by providing the proximal end
of the infusion catheter with longitudinally oriented ribs, and
providing the internal bore of the thumbscrew 2316 with teeth or
cogs which engage the ribs. Once advanced out of the distal end of
the catheter, the penetrating helical needle of the infusion
catheter is quickly advanced into the heart wall by rotation of
thumb drum 2316 which is locked to the catheter body when rotated.
Space in the most proximal end of the catheter hand piece is set
aside for placement of the coiled tubing and luers that connect to
the drug infusion catheter and the outer steerable guide body (not
shown). Strain release 2302 prevents damage to the outer guide
body. Within the outer catheter body there is also an O-ring seal
which is proximal to an outer side port for accessing the outer
catheter body lumen. This O-ring is sized to prevent leakage of
fluids from the space between the outer guide catheter and the
infusing catheter. The location of the O-ring is distal to the
longitudinal passageway and proximal to the distal end of the
strain relief. Thus, a simple handpiece that provides steerability
for the outer catheter body, extension of an inner catheter body
with a distal helical infusion element, and rotation of said
infusion element is provided.
[0122] In use, a surgeon or operator such as an interventional
cardiologist inserts the catheter into the body at the femoral
artery, using a cut-down or the Seldinger technique to gain access
to the artery. The operator then inserts a guidewire into the
vasculature and advances a guidewire across the aortic valve into
the heart. The operator then inserts the steerable guide catheter
system over the guidewire, slides it over the guidewire until the
distal tip of the steerable guide catheter is in the heart, and
then removes the guidewire. After the guide wire is removed, the
infusion catheter system is advanced through the steerable guide
catheter, and the patient's own blood is infused through the drug
delivery lumen of the infusion catheter system so that albumin will
bind to the polymer surface of the catheter lumen (thereby
preventing the drugs to be delivered through the lumen from binding
to the lumen). Following infusion of blood down the drug delivery
lumen, an appropriate medium such as saline or ringers solution is
promptly delivered. (Alternatively, saline or ringers containing
albumin could be delivered. Likewise, for agents where binding to
the polymer walls of the catheter is not an issue, this step would
be skipped.) After the lumen of the infusion catheter has been so
prepared, the helical infusion needle is screwed into appropriate
regions of the heart wall. Contrast is infused through the annular
lumen or space between the guide catheter and the infusion catheter
to confirm the position of the system under fluoroscopy, and the
system is used to inject therapeutic agents, such as microspheres
larger than 15 um in diameter, to a depth within the myocardium.
The operator forces the plunger of syringe 1206 (FIG. 12) of the
therapeutic agent reservoir to force the therapeutic agents into
the heart. The amount displaced from the syringe should be equal to
the desired dose minus the dead space downstream of valve 1210.
Following operation of the therapeutic reservoir syringe, the
operator forces passive agent by operation of the plunger of
syringe 1204, forcing an amount of passive agent into the drug
delivery lumen that is equal to the dead space, to ensure that the
entire dead space is cleared of the desired dose of therapeutic
agent and that the desired dose is actually delivered to the heart
tissue. The catheter is maintained engaged with the heart for a
period of time sufficient to ensure that the injected therapeutic
agent is absorbed by the heart tissue and does not merely leak out
of wound caused by the penetrating helical needle. The catheter is
then carefully disengaged from the heart tissue by unscrewing the
helix through rotation of the appropriate portion of the proximal
handling mechanism. If appropriate, the procedure may be repeated
at different locations within the heart.
[0123] Fixation infusion systems provide time to confirm the
position of the helical needle or other fixation device within the
heart during an interventional procedure using electrical signals
within the heart tissue, standard fluoroscopic imaging techniques,
fluoroscopic techniques in which contrast is infused adjacent to
the penetrating element and/or at a depth within the tissue,
ultrasound imaging techniques, or even electromagnetic imaging
techniques such as those developed by Johnson and Johnson BioSense.
Where fluoroscopy is used, contrast agent may be injected through
the steerable guide catheter 1624 (FIGS. 16 and 17, or through the
annular lumen 1252 of the infusion catheter system. Additionally,
contrast agent may be injected into the heart wall through the
helical needle after it has been driven into the myocardium, so
that the depth of helical needle within the heart wall can be
confirmed.
[0124] Fixating infusion systems for delivery of therapeutic agents
optimizes the control over dosing. Certainty as to the position of
the injecting needle eliminates the potential for delivering agents
inappropriately, and assures the operator that agents have been
delivered to a depth within the tissue. The fixation approach
provides the ability to flush the deadspace of the catheter after a
procedure to eliminate this potential dosing error, and allows for
control over redistribution of the infused agent by controlling the
volume and time course of the agent infused. In the case of the
helical fixation means, the long path length of the penetrating
element (i.e., the needle track) adds the added advantage that
agents delivered to a depth within the myocardium will not leak
back into the heart chambers, and more dose will reach the target
tissue. This has huge advantages in intra-myocardial delivery of
microsphere controlled release systems which have been sized so
that they will not migrate within the myocardium, but which are
large enough to cause adverse embolic events should they escape
into the left ventricle, but is advantageous also for conservation
of all injected therapeutic agents. Typically, when therapeutic
agents are injected into the heart wall with a straight needle,
much of the therapeutic agent leaks backward, out of the
penetration wound (the needle track), and into the endocardial
space (and subsequently into the vascular system to impose systemic
pharmacological and thrombotic/embolic effects on the patient).
When injecting therapeutic agents with a helical needle, and
maintaining the helical needle in place during injection, the rate
of back-leakage is diminished. Thus, for a given desired resident
dose (the dose remaining in the myocardium after back-leakage of
the leaking volume of the therapeutic agent), the necessary
injected dose need only be about 2 to 10 times the desired resident
dose. Where the therapeutic agent is comprised of macromolecules 10
kilo Daltons and above, and 0.5 cc of therapeutic agent was slowly
injected over 30 seconds, followed by injection of 0.2 cc of
passive agent injected over 30 seconds, followed by continued
retention of the helical needle in the needle track for about 30
seconds, 25% of the dose was retained in the myocardium 1.5 hours
after injection. In this case, injection of a dose no larger than
about 3-4 times the volume of the desired resident dose is
sufficient to provide the desired resident dose.
[0125] The fixation means improves physician control of delivering
therapeutic agents, genes, and cells for molecular and cellular
therapeutic cardiology. The physician can confirm that delivery is
appropriate, can infuse agents over any specified time course to a
depth within the target tissue, and the physician can deliver other
agents at the same sites without fear that the catheter system has
moved.
[0126] These same systems are useful for a new type of diagnostic
procedure in which a fluid agent is infused to a depth within a
particular tissue and the fluid is then withdrawn through the same
infusion element. In this way a type of fluid biopsy may be
performed and the mileau within the tissue may be assessed for the
presence of markers of different disease states.
[0127] Further the devices described wherein the guide catheter is
designed to have a space between it and the fixation systems may be
used as a left ventricular angiography catheter with controlled
fixation for improved visualization of specific regions of interest
within the heart. In use, the endocardial space is accessed as
described above, through the vascular system, and the helical
needle is driven into the heart wall near the site which is to be
visualized in angiography. After the catheter is anchored to the
heart wall, angiographic contrast agent is delivered through the
guide catheter or through the infusion catheter body (1214 and
1750, for example). The contrast fluid may be injected at high
pressure without whipping within the heart and wandering away from
the target to be imaged.
[0128] Catheters with a straight cylindrical lumen from one end to
the other could be used with a thin bundle of optical fibers passed
through the lumen to create channels within the heart for improving
the flow of pharmacological agents within the heart. In other
variations, the thin optical fiber could be replaced with a thin RF
electrode structure which could literally burn channels within the
tissue. Such procedures could be viewed as a combined
transmyocardial revascularization (TMR) and drug delivery. For
example, after a catheter is implanted and agents are delivered to
minimize re-flow damage to the heart, simple TMR could be
introduced with a centrally placed optical fiber. Subsequent to the
TMR, angiogenic growth factors could be introduced
[0129] Thus, while the preferred embodiments of the devices and
methods have been described in reference to the environment in
which they were developed, they are merely illustrative of the
principles of the inventions. Other embodiments and configurations
may be devised without departing from the spirit of the inventions
and the scope of the appended claims.
* * * * *