U.S. patent application number 14/023015 was filed with the patent office on 2014-01-09 for implant delivery catheter system and methods for its use.
This patent application is currently assigned to BioCardia, Inc.. The applicant listed for this patent is BioCardia, Inc.. Invention is credited to Peter A. Altman, Mark A. Lovich, Aaron J. Miller, Daniel C. Rosenman, Michael A. Schwartz.
Application Number | 20140012189 14/023015 |
Document ID | / |
Family ID | 24166681 |
Filed Date | 2014-01-09 |
United States Patent
Application |
20140012189 |
Kind Code |
A1 |
Rosenman; Daniel C. ; et
al. |
January 9, 2014 |
Implant Delivery Catheter System And Methods For Its Use
Abstract
Catheter systems and methods for implanting helical or dart-like
implants into the myocardium or other body tissue. The catheter
system includes a helix for fixing the distal end of the catheter
to the myocardium, an implant held by the helix, mechanisms for
driving the fixation helix into the myocardium, and mechanisms for
driving the implant into the myocardium, removing the fixation
helix and leaving the implant behind. The implant may be coated,
filled, or made of a drug or drug eluting compound, or drug
delivery matrix of any composition.
Inventors: |
Rosenman; Daniel C.; (San
Carlos, CA) ; Altman; Peter A.; (San Carlos, CA)
; Lovich; Mark A.; (San Carlos, CA) ; Schwartz;
Michael A.; (San Carlos, CA) ; Miller; Aaron J.;
(San Carlos, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BioCardia, Inc. |
San Carlos |
CA |
US |
|
|
Assignee: |
BioCardia, Inc.
San Carlos
CA
|
Family ID: |
24166681 |
Appl. No.: |
14/023015 |
Filed: |
September 10, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11295412 |
Dec 6, 2005 |
8529550 |
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14023015 |
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10292667 |
Nov 12, 2002 |
6971998 |
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11295412 |
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09543127 |
Apr 5, 2000 |
6478776 |
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10292667 |
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Current U.S.
Class: |
604/60 |
Current CPC
Class: |
A61B 17/3478 20130101;
A61M 37/0069 20130101; A61F 2/2493 20130101; A61B 2018/00392
20130101; A61B 2017/00247 20130101; A61K 9/0024 20130101; A61B
17/3468 20130101; A61N 1/0568 20130101; A61N 2001/0578 20130101;
A61M 2025/0089 20130101 |
Class at
Publication: |
604/60 |
International
Class: |
A61M 37/00 20060101
A61M037/00; A61B 17/34 20060101 A61B017/34 |
Claims
1. A catheter system for delivering a helical implant into tissue
including: a helical implant; a steerable catheter; and a central
holder disposed within the steerable catheter, said central holder
releasably attached to the helical implant.
2. The catheter system of claim 1 wherein the central holder is
releasably attached to the helical implant through a detent
system.
3. The catheter system of claim 1 wherein the helical implant
further comprises a plurality of detent receiving ports, and the
central holder further comprises a plurality of detents configured
to engage the detent ports.
4. The catheter system of claim 3, wherein the detents of the
central holder comprise outwardly biased fingers with inwardly
facing detents which mate with the detent receiving ports.
5. The catheter system of claim 4, wherein the steerable catheter
is longitudinally translatable relative to the central holder, and
operable to hold the detents of the outwardly biased fingers in
engagement with the detent receiving ports when disposed about the
detent fingers, and operable to translate relative to the holder to
allow the fingers to open to an unrestrained position to release
the helical implant.
6. The catheter system of claim 4 wherein the helical implant is
characterized by a proximal end and a distal end, and the central
holder is characterized by a proximal end and a distal end, and the
detent receiving ports are disposed at the proximal end of the
helical implant, and the helical implant is releasably attached to
the distal end of the central holder.
7. The catheter system of claim 1 wherein the helical implant
comprises a drug delivery helix, said drug delivery helix loaded
with therapeutic agents.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 11/295,412, filed Dec. 6, 2005, now U.S. Pat. No. 8,529,550,
which is a continuation of U.S. application Ser. No. 10/292,667
filed Nov. 12, 2002, now U.S. Pat. No. 6,971,998 which is a
continuation of U.S. application Ser. No. 09/543,127 filed Apr. 5,
2000, now U.S. Pat. No. 6,478,776.
FIELD OF THE INVENTIONS
[0002] The inventions described below relate to site-specific
delivery of therapeutic agents, devices, structures and catheter
systems, means for implanting and using these systems to enable
delivery of therapeutic agents to the body, and methods for
manufacturing these devices.
BACKGROUND OF THE INVENTIONS
[0003] Cardiovascular disease is the leading cause of death in the
United States and many other developed countries. A major
contributing factor to cardiovascular disease is atherosclerosis,
or the hardening of the arteries due to plaque formation. As
atherosclerosis progresses, the blood vessels narrow and may close
entirely. As a result, ischemia, or inadequate blood flow to
tissues, can result and damage the affected tissue. In patients
with coronary artery disease, ischemia in the heart can lead to
severe chest pain, impaired cardiac function or, if very severe,
heart attacks. Approximately 50% of deaths attributable to
cardiovascular disease are due to coronary artery disease.
[0004] Treatment alternatives for coronary artery disease range
from risk factor modification and exercise programs for patients
with limited disease to major surgical procedures in severely
diseased patients. Drug therapy is a mainstay of treatment for
coronary artery disease. Surgical intervention such as angioplasty
and/or stent placement are often used to open occluded vessels for
patients with severe disease. Angioplasty procedures typically use
an inflatable balloon catheter to physically open a narrowed blood
vessel. Studies have shown that 30% to 40% of the time the artery
narrows again, or undergoes restenosis within seven months
following angioplasty. The procedure is difficult or impossible to
perform on certain patients with multiple vessel disease, diffuse
disease, calcified vessels or vessels that are too small to access.
Stent placement has become a good alternative to angioplasty, but
the challenges of re-occlusion of the stent have not been
completely solved, and stents are not generally used to treat
multiple occlusions. For patients with severe coronary artery
blockages, the preferred treatment is still the coronary artery
bypass graft surgery, in which the occluded coronary arteries are
replaced with the patient's saphenous vein. The conventional CABG
procedure requires cutting through the sternum of the chest and
placing the patient on cardiopulmonary bypass, both of which
involve significant risk of morbidity and mortality. In addition,
it is difficult or impossible to perform CABG on certain patients
with diffuse atherosclerotic disease or severe small vessel disease
or patients who have previously undergone a CABG procedure.
[0005] Pacemakers provide another treatment for heart disease.
Pacemakers with helical tipped active fixation leads have been in
clinical use for greater than 25 years. Often when implantable
leads become infected or fail due to fatigue, physicians will
extract the entire body of the lead and leave behind the active
fixation element which is buried in the myocardium. Furman S.;
Hayes, D.; Holmes, D.: A Practice of Cardiac Pacing, Futura, Mount
Kisco, New York, 3.sup.rd ed., 1993 shows an image of a patient
with four separate abandoned intramyocardial electrodes in addition
to two more additional electrodes for dual chamber pacing left
behind in the heart with no apparent effect. It is well recognized
that a helical intramyocardial implant remnant resulting from the
extraction of a lead system poses no known risk to the patient.
[0006] Restoring blood flow to areas of ischemia through
angiogenesis offers one of the most promising therapeutic options
for treatment of coronary artery disease. Angiogenesis, or the
formation of new blood vessels, is the body's natural response to
ischemia. It also occurs as a normal physiological process during
periods of tissue growth, such as an increase in muscle or fat,
during the menstrual cycle and pregnancy, and during healing of
wounds. Under ischemic conditions, expression of certain genes
leads to the production of growth factors and other proteins
involved in angiogenesis. The endothelial cells, which line blood
vessels, contain receptors that bind to growth factors. Binding of
the growth factors to these receptors triggers a complex series of
events, including the replication and migration of endothelial
cells to ischemic sites, as well as their formation into new blood
vessels. However, in ischemic conditions, the growth factor genes
often may not produce sufficient amounts of the corresponding
proteins to generate an adequate number of new blood vessels. A
logical therapeutic approach to this problem is to enhance the
body's own response by temporarily providing higher concentrations
of growth factors at the disease site. For cardiac disease, this
will require a cardiovascular delivery system. Current delivery
systems however are undesirable for a number of reasons.
[0007] One delivery system that has been proposed is the delivery
of angiogenic agents through the coronary arteries. However, the
extent of collateralization (growth of blood vessels elsewhere in
the body, like the brain and lenses of the eye) observed is
undesirable, so the dose provided must be less than desired.
Delivery of recombinant growth factors bFGF and VEGF to the
coronary arteries has entered Phase II human clinical trials, but
the route of administration does not appear to be optimal. This is
best shown by the recently completed VIVA phase II clinical trial
in which rhVEGF 165 was delivered to both the coronary arteries and
intravenously over periods of time, and yet did not show a
statistically significant improvement in the patients who received
the drug versus the placebo.
[0008] Additionally, arterial delivery treats the tissue subtended
by the vessel with agents delivered to the most highly perfused
tissue and rapidly washing away from the tissue. If agents are
delivered to the coronary artery, the coronary artery bed, which
includes richly and poorly perfused regions, will receive the drug
therapy. Due to the nature of the restenosis or flow restriction,
poorly perfused (ischemic) areas will receive less angiogenic
agents, and healthy tissue will receive more. 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. Because of the high flow in the arteries,
growth factor that is not bound by receptors in the vessels is
quickly distributed to the rest of the body.
[0009] The pharmacokinetics of these clinical studies has not been
discussed scientifically, yet it has been shown that sustained
delivery is important to promote optimal angiogenesis. Gene therapy
preparations are being used in the clinic to provide for sustained
delivery of different forms of angiogenic agents VEGF and FGF to
increase the magnitude of the therapeutic effect. Gene therapy
currently suffers the difficulty that agents must be (1) delivered
to the site, (2) gain access to the targeted cell cytosol, (3)
become incorporated in the host cell's DNA, (4) be transcribed to
produce mRNA, (5) the mRNA must be translated to produce the
protein, and then (6) the protein must find a means of egress from
the cytosol to the extracellular space in order to have its
intended endogenous effects of promoting angiogenesis. At each of
these six steps there are substantial efficiency issues that are
difficult to control. There are currently three clinical trials
entering Phase II studies in which the effective dose (step 6 of
the cascade) of therapeutic protein that is being delivered to the
tissue is not well understood.
[0010] Implantation of local drug delivery depots is an alternative
to poorly controllable injection of gene therapy preparations.
However, currently proposed depots pose difficulties. The
processing steps needed to make them can render the therapeutic
agent to be delivered biologically inactive. Nugent, M. A., Chen O.
S., and Edelman, E. R., Controlled release of fibroblast growth
factor: activity in cell culture. 252 Mat. Res. Soc. Symp. Proc.:
273 (1992) illustrates the difficulties in producing useful depots.
They identified the problem with Ethylene Vinyl Acetate Copolymer
(EVAC) delivery of bFGF as being attributable to the denaturation
of nearly 95% of the protein by the organic solvents necessary to
fabricate EVAC matrices. This means that for a desired dose, about
20 times the desired dose must be used to end up with an implant
that carries the desired dose. Recently, these issues have been
resolved for surgical delivery of bFGF by the successful surgical
implantation through the epicardium of alginate encapsulated
heparin sepharose controlled release depots in a phase I clinical
trial. Sellke, et al., Therapeutic Angiogenesis with Basic
Fibroblast Growth Factor: Technique and Early Results, 65 Annals
Thoracic Surgery, 1540 (1998). Although this is by far the most
advanced work done to date, the controlled release depots are too
large (0.5 cm to 1.0 cm in diameter) to be delivered percutaneously
by a catheter system. Their placement requires surgical access to
the surface of the heart. It is also unlikely that the desired
target area for these devices is epicardial or even endomyocardial
as ischemic zones tend to be localized to the subendocardium. These
issues limit this delivery approach, add risks to the patients who
receive it, and increase the procedural costs of this delivery
method.
[0011] Our own catheter systems with helical infusion needles for
interstitial delivery provide for delivery of small controlled
release structures such as microspheres (diameter=15 to 150 um) by
transporting them through a fluid slurry to a depth within the
heart with high efficiency. Our system reduces the potential of
"back leak" or "squeeze out" of controlled release microsphere
slurry or gel materials into the left ventricular chamber. These
small controlled release systems have a very large
surface-area-to-volume ratio, thus making it difficult to provide
optimal release kinetics for many known microsphere systems, such
as the Alkermes Prolease system. It can be difficult to achieve
zero order release kinetics in which the dose is delivered at a
constant rate over time. In addition, polymeric microspheres
require formulation specific issues to be addressed for each agent
that is to be delivered, and these can cause additional problems as
already discussed.
[0012] If the drug releasing structure is implanted in the left
ventricle from the endocardial surface, there is a danger that
solid particles can escape into the arterial blood system and be
pumped out to the body. These embolic particles could end up lodged
in a vessel and occlude it, causing ischemia or necrosis to tissue
elsewhere in the body. Another danger is that a proliferative
agent, such as a growth factor, could embolize and be delivered to
an unintended area of the body, such as the brain or the retina,
where new uncontrolled blood vessel growth (angiogenesis) could
damage healthy tissue. Therefore, there is a need for a structure
that can deliver solid or degradable forms of therapeutic to a
depth of the myocardium while lowering the risk for embolic
events.
SUMMARY
[0013] The devices and methods described below provide for new
treatments for heart disease. The treatment includes permanent
placement of a drug-carrying coil or dart into the center of the
myocardium, isolated from the internal chambers of the heart and
pericardial space outside the heart. The coil or dart can be pushed
into the heart wall from a catheter that is navigated through the
patient's arteries and into the patient's heart, so that the device
is inserted into the heart wall from inside the heart. The coils
and darts are made in various embodiments allowing them to be
loaded with a drug which, after implantation, slowly seeps into the
heart wall and delivers minute amounts of drugs steadily over
several weeks. The device designed to deliver coils includes the
coil and comprises a catheter used to deliver the coil and a
releasable connector connects the coil to the catheter. In one
embodiment, the catheter has a second coil, which we refer to as
the fixation coil, securely fixed to the distal end of the
catheter. The drug delivery coil nests inside the coils of the
fixation coil, and can be helically rotated distally to detach
itself from the fixation coil, but the catheter prevents its
rotation proximally. Thus, when the surgeon screws the fixation
coil into the heart wall, the drug delivery coil is driven in along
with the fixation coil, but when the surgeon unscrews the fixation
coil from the heart wall, the drug delivery coil remains in place.
In an embodiment designed to deliver darts into the heart wall, the
catheter includes the fixation coil fixed to the distal tip and the
dart releasably attached to the distal tip. The surgeon screws the
fixation coil into the heart wall, and then drives the dart into
the heart wall through the center of the helix. When the surgeon
unscrews the fixation helix from the heart wall, the dart is left
behind. Various embodiments of the drug delivery coils and dart are
also disclosed, as well as methods for making them.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 shows a sectional view of a patient's heart with an
implant delivery catheter with a deployable element placed through
a guide catheter into the left ventricle wall.
[0015] FIG. 2 shows an enlarged view of the patient's heart in
section, with the implant delivery catheter in the left ventricle,
and the helical drug delivery structure implanted in the left
ventricle wall.
[0016] FIG. 3 shows an isometric view of the deployable helix
catheter with the sheath retracted and the controlled release
structure ready to be deployed.
[0017] FIG. 4 is an enlarged view of the distal end of the
deployable helix catheter with the sheath covering the distal end
partially retracted to expose the dual helices.
[0018] FIG. 5 is an enlarged cross sectional view of the distal end
of the deployable helix catheter with the sheath retracted and the
controlled release structure ready to be deployed.
[0019] FIG. 6 is a schematic of the tamping method used to
incorporate solid therapeutic material into the drug delivery depot
tube, prior to creating the drug delivery structure.
[0020] FIG. 7 is a schematic side view of the method used to
manufacture the fixed and deployable helical elements of the
implant delivery catheter.
[0021] FIG. 8 is a schematic side view of the process of loading
the helically shaped deployable controlled release structure onto
the distal end of the deploying catheter.
[0022] FIG. 9 is a detailed side view of a drug delivery structure
that may be deployed by the invention.
[0023] FIG. 10 is a cross sectional view of a drug delivery
structure that may be deployed by the invention.
[0024] FIG. 11 is a detailed side view of an alternate construction
of the drug delivery structure that may be deployed by the
invention.
[0025] FIG. 12 is a cross sectional of the drug delivery structure
of FIG. 11.
[0026] FIGS. 13, 14, and 15 are detailed views of alternate
constructions of drug delivery structures that may be deployed by
the invention.
[0027] FIG. 16 is a schematic and cross-sectional view of a
helically shaped controlled release structure embedded in the wall
of the myocardium, to a depth within the myocardium.
[0028] FIG. 17 is a schematic and cross-sectional view of an
alternately constructed helically shaped controlled release
structure embedded in the wall of the myocardium to a depth within
the myocardium
[0029] FIGS. 18 and 19 are detailed side views of an alternative
method to deploy a helically shaped controlled release structure
from a catheter.
[0030] FIG. 20 is a side view of the another deployable drug
delivery structure catheter.
[0031] FIG. 21 is a detailed side view of the distal end of the
deployable implant delivery catheter in FIG. 20, with the drug
delivery structure partially deployed.
[0032] FIG. 22 is a cross sectional of the detailed side view of
the distal end of the deployable implant delivery catheter shown in
FIG. 21.
[0033] FIGS. 23 and 24 are alternative embodiments of the drug
delivery structure.
[0034] FIG. 25 is a detailed side view of an embodiment of the drug
delivery structure that can be delivered by the catheter of this
invention.
[0035] FIG. 26 is a cross sectional view of the drug delivery
structure shown in FIG. 25.
[0036] FIG. 27 is a view of the drug delivery structure shown in
FIG. 25 embedded in the wall of the myocardium, to a depth within
the myocardium.
DETAILED DESCRIPTION OF THE INVENTIONS
[0037] FIG. 1 shows a sectional view of the heart 1 within a
patient 2. A steerable guide catheter system 3 is placed within the
patient, having been percutaneously inserted into an artery such as
the femoral artery, and passed retrograde across the aorta 4 and
into the left ventricular chamber 5. Steerable guide catheter 3 is
advanced through the patient's vasculature into the left ventricle
in order to target a region of the heart wall 6 for delivery. An
implant delivery catheter 7 with a fixation element 8 has been
inserted through the guide catheter, so that the distal tip of the
implant delivery catheter and the fixation element are proximate
the target region of the heart. Once oriented toward a region of
the heart wall 6 within, for example, the left ventricle wall 9,
the centrally located implant delivery catheter 7 is advanced into
the heart wall 9 and fixed to the heart tissue by means of the
fixation element 8. As described below, the catheter shown in FIG.
1 is different from the prior art in that it can deliver a
helically shaped controlled release drug reservoir to a depth
within the intended tissue, so that the reservoir is below the
surface of the tissue.
[0038] FIG. 2 shows an enlarged view of the patient's heart with
the distal end 10 of the implant delivery catheter 7 and the distal
end 11 of the guide catheter 3 within the left ventricle chamber.
The surgeon has deployed the helical drug delivery structure 12
into the wall of the left ventricle 9. The implant delivery
catheter resides within a lumen of the guide catheter, and is
rotatable within the guide catheter. To place the helical drug
delivery structure 12 into the myocardium, the surgeon has rotated
the implant delivery catheter 7 to screw it into the myocardium.
After the drug delivery helix is screwed into the heart wall, the
helix is left in place. If the helix is comprised of metal or other
non-biodegradeable material, it may remain in place permanently,
allowing the drugs carried by the helix to have their desired
effect on the heart, while the metal portions of the helix remain
in place without harm to the patient. The helix may also be made of
a rigid biodegradable material such as polyurethane as described in
Leong, U.S. Pat. No. 5,167,907 (Jan. 5, 1993).
[0039] As shown in FIG. 3, the implant delivery catheter 7
comprises an outer sheath 13 that slides over an inner core 14 and
the tip of the device in the distal tip area 10. The outer sheath
is connected to proximal handle 15 and may include braided
reinforcement. The fixation element 8, which in this case is a
helix or corkscrew with a sharp tip is mounted at the distal tip of
the implant delivery catheter, and is operably connected to the
proximal handle 16 through the inner core 14. (The outer sheath,
though desirable, may be dispensed with, and the guide catheter
alone may be used to protect the vascular access pathway from
injury due to rotation of the inner core. The implant delivery
catheter may be a non-steerable catheter within a steerable guide
catheter.
[0040] In a third embodiment, a single steerable implant delivery
catheter is used, which also allows for deployment of a distally
located penetrating structure such as helix 8 shown in FIG. 3 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
implant 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 implant 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 when the catheter distal tip is at rest within the heart.
A sixth embodiment uses a trans-septal approach to the left side of
the heart from the right side of the heart. In this embodiment, the
guide catheter is routed up the venous side of the patient's
vasculature to the right atrium or ventricle. Then a septal
crossing device, such as a Brockenbrough needle is used to cross
into the left side of the heart through the septum. The
helix-deploying catheter is then guided into the left side of the
heart within this guide catheter. A seventh embodiment enters the
heart through the coronary sinus and delivers the deployable helix
from the coronary veins into the myocardium. An eighth embodiment
approaches the heart from a transthoracic direction, through the
chest wall. In this embodiment, the deployment device is shortened
and stiffened so that it reaches the heart through the small spaces
between the chest ribs and is stiff enough to support its own
weight and the stresses of being passed between the ribs. Of course
standard transvascular techniques could be used to implant the
device in the right ventricle and the right atria of the heart as
well.
[0041] FIG. 4 shows a detailed side view of the distal end of the
drug delivery structure catheter. The sheath 13 is shown in the
pulled back position so that it reveals two helical structures. The
anchoring helix 17 is securely fastened to the implant delivery
catheter and the inner core 14 (shown in FIG. 5) so that it rotates
with the core when the core is rotated by the operator. The
deployable helical drug delivery structure 12 is releasably secured
to the catheter inner core such that after it is screwed into the
myocardium, it may be released from the inner core and remain in
place. The two helices are wrapped in parallel around a common
longitudinal axis that coincides with the longitudinal axis of the
catheter inner core. A centrally located hollow straight needle 18
is extended through the central axis of the helices and penetrates
the myocardium when the helices are screwed in.
[0042] FIG. 5 is a cross sectional view of the detailed view in
FIG. 4 showing more of the internal details in the catheter. The
centrally located hollow straight needle 18 is constructed of
sharpened stainless steel. The proximal winds of the helix are
wrapped coaxially around the distal tip of the catheter inner core
14 and attached securely by gluing, crimping, heat shrinking or
other bonding technologies. The catheter inner core has an infusion
tube 21 with a lumen 22 aligned in fluid communication with the
lumen of the needle 18. The infusion tube 21 is typically thin
walled FEP, PTFE, Pebax, PEO, polyethylene, polyolefin, nylon, or
other polymer material that can contain a fluid. The proximal end
of the infusion tube 21 is bonded to the proximal handle 16 (shown
in FIG. 3) through gluing or other joinery. This creates a fluid
path from the proximal handle 16 to the distal straight needle 18
that can be used by the physician to infuse diagnostic or
therapeutic fluids during the procedure. The infusion tube is
located within the torque transmitting rotational drive shaft 23.
The torque transmitting shaft may be separate from the infusion
tube or integral with the infusion tube. The extreme distal tip 24
of the torque transmitting shaft forms, with the infusion tube, a
distally facing shoulder 25 or protuberance which prevents proximal
movement of the helically rotatable drug delivery structure.
(Clearly, the rotational drive shaft and the infusion tube can be
provided as a single piece, providing a unitary inner core. In this
case, an annular flange, boss or protuberance on the inner core
will act as the shoulder to prevent proximal movement of the
helical drug delivery structure.) The centrally located straight
needle 18 also serves to constrain the helical drug delivery
structure 12 to the fixed helical anchoring structure 17 during use
of the device. The sharp point of the straight needle 18 serves to
pierce the tissue and center the device in the myocardium while the
operator rotates the helices into the tissue. The fixed helical
anchoring structure is attached to the infusion tubing 21, but can
be attached to the rotational drive shaft 23. The drive shaft 23 is
designed to be flexible in bending but able to transmit torque in
either clockwise or counterclockwise directions. The torque
transmitting shaft may of various designs of available torque
transmitting shafts, including braided shafts, cross-wound drive
shafts and coil-reinforced tubing. The reinforcement typically
increases the shaft's ability to transmit torque while not
significantly increasing it's bending stiffness. The proximal end
of the rotational drive shaft 23 is bonded into the proximal handle
16. The proximal handle 16 transmits torque, tension, and
compression to the distal fixed helical anchoring structure 17
through this drive shaft 23. The outer sheath distal segment 13d is
sized so that it can slide longitudinally over the fixed and
helical drug delivery structure 12 and 17 by a clearance or slight
friction fit. The sheath material is typically a 35 D durometer
soft Pebax polymer. It may be provided with radiopaque loading
agents such as barium sulfate or a platinum iridium marker band to
make the end of the catheter more evident on x-ray fluoroscopy.
This outer sheath distal segment is heat fused to the catheter
outer sheath proximal segment 26. The catheter outer sheath
proximal segment 26 is typically a braided or reinforced Pebax
polymer of varying durometers, usually between 72 D and 40 D. The
proximal end of the outer sheath proximal segment 26 is bonded to
the outer sheath proximal handle 15 (shown in FIG. 3) such that
when the proximal handle 15 (which is fixed to the outer sheath) is
longitudinally translated relative to the catheter inner core
proximal handle 16 by the operator, the sheath covers or uncovers
the distal parts of the catheter including the fixed anchoring
helix 17, deployable helical drug delivery structure 12 and
straight hollow needle 18. The outer sheath distal segment 13d and
outer sheath proximal segment 26 are sized to provide a clearance
fit over the torque transmission drive shaft 23.
[0043] FIG. 6 shows one method of filling the hollow implantable
tubing with a powdered therapeutic with or without excipients or
fillers such as dextrum by tamping the tube into a reservoir of
therapeutic agent (the tubing is later wound into the deployable
helical drug delivery structure shown in the previous figures). The
method may be accomplished by hand or by machine. A reservoir of
powder 27 such as lyophilized protein is held in a container 28
such as a glass beaker. The powder is of such a depth that the
hollow stainless steel hypo tube 29 can be submerged for a fraction
of its length into the powder. The tube is repeatedly tamped into
the powder, driving the powder up the tube where it is held by
friction. The tubing typically used in this stage is 0.016 inch
outside diameter and 0.008 inch inside diameter implant grade 316L
or 316 LVM stainless steel. Once enough therapeutic powder is
driven into the tube, the tube is made into the deployable helix
structure. The ends of the tube are crimped or capped after the
tube has been filled as described. One end of the tube may be
sharpened before the tamping stage or after the winding stage. If
the tube is provided with perforations or apertures communicating
from the lumen of the tube through the wall to the exterior (as
shown in FIG. 17, for example), the holes may be covered by a
temporary and removable polymer sleeve for filling through tamping
and then removed either before winding or before implantation,
depending upon the consistency of the packed material.
Alternatively, the polymer sleeve that covers the apertures in the
tubing before packing could be made of a thin bioerodable or
biodegradable material such as a polysaccharide, PVA or other known
degradable material that is left in place even after the device has
been implanted. This polymer sleeve degrades to expose the
apertures for delivery. Additionally, the slots or apertures can be
potted or filled with the degradable material without coating the
entire helix outer surface with the degradable material.
[0044] As the drug delivery coil is essentially stuffed with
lyophilized protein powder there is no processing required that is
agent specific. No chemical interactions other than those that
result from the relevantly gentle mechanical tamping techniques
required to fill the device will result. No protein goes into
solution, interacts with solvent, or has to go through temperature
extremes associated with forming cast controlled release devices or
spraying of microspheres. This results in a device that should work
well for nearly any lyophilized protein that is stable at storage
temperature for an extended period of time and body temperature of
37 degrees for the intended duration of delivery.
[0045] This approach should provide an easy method to achieve zero
order release kinetics in which there is a constant rate of
therapeutic delivery from the implanted depot. Delivery of
hydrophobic molecules from a reservoir of lyophilized molecules
results in a maximum concentration at the interface between the
protein exposed to the surrounding fluid milieu and the fluid
milieu itself. This concentration will not change at the interface
as the fluid milieu becomes saturated at physiological pH and
temperature, as there is a reservoir of protein ready to go into
solution. Thus it is the effective surface area of the exposed
protein-fluid milieu interface that will govern the rate of device
release. Since this surface area is fixed and does not change, and
the concentration at the interface does not change for a given
protein while the depot is active, the release kinetics are
governed entirely by the transport in the milieu adjacent to the
interface of the device.
[0046] FIG. 7 shows an apparatus for winding the fixed and
deployable helices used in the construction of the catheter. Two
stainless steel tubes or rods 30 and 31 are clamped in a chuck 32
over mandrel 33. The chuck 32 is mounted in block 34. The diameter
of mandrel 33 controls the inside pitch diameter of the helices.
The stainless steel rods or tubes 30 and 31 are held closely spaced
together and at an angle offset from the long axis of the mandrel
33, while chuck 32 is turned either by hand or by an electric motor
(one of these rods has preferably been loaded with a therapeutic
agent as described above). As the chuck turns, the rods or tubes 30
and 31 are plastically deformed and wound into a helical pattern
with the windings of the two helices created arranged parallel to
each other and tightly spaced, so that there is little or no gap
between the turn of one helix and the surrounding turns of the
other helix. The winding spacing controls the pitch of the finished
device. When enough length is wound on the mandrel, the chuck is
opened and the wound helices are removed from mandrel 33. The
helices are then separated, cut to length, and sharpened. One wound
helix is bonded into the catheter to become the fixed helical
anchoring member, and the other becomes the helical implantable
drug delivery structure. Because they are wound at the same time,
with the coils touching, they have the same pitch and pitch
diameter and therefore nest within one another with a sliding fit.
The preferred dimensions of the deployed helical controlled release
structure are an outer diameter of between 0.300'' and 0.100'',
with a more preferred range of 0.040'' and 0.060''. The helix is
preferably composed of between 2 and 4 coils, with an inter-coil
spacing (pitch) of between 0.020'' and 0.060'' and a total length
of approximately 0.200''. The proximal end of the helix is closed.
The distal end of the helix is sharpened into a point that easily
pierces tissue and remains open to allow the therapeutic agent to
diffuse into the tissue. The helix is preferably filled with a
volume of between 1.times.10-5 cubic centimeters and 9.times.10-3
cubic centimeters of therapeutic agent and further preferably
around 3.times.10-4 cubic centimeters of lyophilized therapeutic
agent with or without powdered excipients such as dextrum. The time
course of diffusion of therapeutic from a reservoir of this size
and length is computed to be on the order of several days depending
on molecular size, temperature and diffusion conditions in the
tissue in which the structure is placed. The size of the deployable
helix and the length of the diffusion path can be modified to
shorten or lengthen the path of diffusion as needed for the desired
therapeutic.
[0047] FIG. 8 shows the process of loading the deployable helical
drug delivery structure 12 onto the end of the catheter. The loader
turns the helical drug delivery structure 12 onto the fixed helical
anchoring structure 17 until it is fully seated, having been
screwed as far into the catheter sheath 13 as it will go (this will
be limited by the distal shoulder of the catheter inner core). When
fully seated, the helices are locked together longitudinally and
radially (that is, movement along the radius of their radial cross
section is not possible), but they may slide along the helical
rotational pathway defined by the spaced between successive turns
of each helix (and thereby translate longitudinally relative to
each other). After seating, the catheter sheath 13 can be advanced
to cover both helices by actuating the proximal handles illustrated
in the previous figures. The catheter sheath 13 prevents the
helical drug delivery structure 12 from working loose of the fixed
helical anchoring structure 17 until the device is in use in a
patient and operated appropriately by the surgeon. (Not shown in
this view is the optional central needle that further stabilizes
the two helices and helps with tissue penetration in use. In the
preferred embodiment this needle is used.)
[0048] FIG. 9 is a detailed side view of a deployable helical drug
delivery structure and FIG. 10 is a cross sectional view of the
body of the structure. As illustrated in FIG. 10, the helical drug
delivery structure is comprised along its helix length of an outer
tube 35 that may be made of an implantable grade stainless steel,
platinum, platinum-iridium, polymer, glass or ceramic. The outer
tube provides the structural strength for the helix, and includes a
lumen within the tube for storage of a therapeutic agent reservoir
36. The distal tip 37 of helical drug delivery structure 12 has
been sharpened for tissue penetration. The proximal cap 38 of the
helical drug delivery structure has been capped with cap 38 to
allow only one exit from the reservoir for the therapeutic agent
reservoir 36 to escape.
[0049] FIG. 11 shows an alternative construction for the deployable
drug delivery structure. FIG. 12 shows a cross sectional view of
the body of the alternative construction. In this construction, the
helix comprises a rigid helix coated with an outer coating 40 made
up of the therapeutic agent (the therapeutic agent may be
encapsulated in a biocompatible polymer controlled release polymer
such as EVAC, 1, or a bioabsorbable polymer such as polyurethane).
The core material 41 of the helix is the structural element and may
be constructed of metal, ceramic, glass, or polymer. The coating is
intended to allow the therapeutic agent to leach, dissolve, or
degrade into the myocardium to deliver therapeutic agents (although
non-degradable agents that remain firmly attached to the core helix
may be used). In this embodiment, the therapeutic begins to escape
in all directions as soon as the structure is inserted into the
tissue.
[0050] FIGS. 13, 14 and 15 show alternative constructions for the
deployable drug delivery structure. In FIG. 13 the proximal end 38
and the distal end 37 of the helical drug delivery structure are
both open (the cap 38 shown in FIGS. 9 and 11 is not used). This
allows two paths of diffusion for the therapeutic in the center of
the device to reach the tissue. In FIG. 14 the helical drug
delivery structure has been machined to provide slots or apertures
42 in the wall of the helix, providing for migration of therapeutic
agent from the helix over its entire length. In this embodiment,
distal end 37 may be closed or open. The slots are sized to allow a
controllable rate of drug delivery along the entire length of the
helical drug delivery structure. The slots can be created in the
helical tube after winding or in the raw material straight tubing
used to construct the helix either before or after filling the tube
with therapeutic. The slots can be created in the stainless steel
tubes by laser cutting, electro-discharge machining, conventional
machining, electrochemical etching or other methods. FIG. 15 shows
another construction of the deployable drug delivery structure.
This construction has a series of circular holes 43. These holes
can be sized and positioned to control the rate of therapeutic
diffusion from the structure. These holes can also be created by
the machining methods use to construct the structure shown in FIG.
14.
[0051] FIG. 16 shows helical drug delivery structure 12 implanted
in the myocardium 6 in the left ventricle. The drug delivery
structure 12 has been advanced so that its proximal tip 38 is at a
depth below the endocardial surface 44. This allows the endocardium
to heal over the small helical needle track wound created by
turning the device into the tissue. Eventually, the healing
response within the myocardium will seal the drug delivery
structure off from the circulating blood within the heart chamber
(indicated at item 45). In this figure, the drug delivery depot
only has one opening on its distal tip 37 that is located in the
ischemic target area 46 of the myocardium. The drug delivery
structure is placed at a depth within the myocardium, ensuring that
the distal tip of the structure does not penetrate all the way
through the heart wall and enter the pericardium or pericardial
space 47.
[0052] FIG. 17 shows the alternative helical drug delivery
structure 12, as illustrated in FIG. 15, implanted in the
myocardium 6 of the left ventricle. This helical drug delivery
structure has multiple holes for faster diffusion of the
therapeutic agent into the tissue to be treated. The therapeutic
agent will diffuse into the myocardium over the entire length 48 of
the helix.
[0053] FIG. 18 shows another structure for a delivery catheter
distal end and the mating portion of the drug delivery helix. The
central holder 52 has resiliently outwardly biased fingers 53 with
inwardly facing detents 54 which interact with mating detent
receiving ports 55 on the head 56 of the deployable helix 12. In
use, after navigation through the vasculature to the target site
within the myocardium, the surgeon will first screw the helix into
the myocardium to the desired depth, and then retract the catheter
outer sheath 13 (that is, slide it proximally) while holding the
central holder 52 in place to translate it relative to the holder.
(The catheter outer sheath and the inner core are actuated by
moving the proximal handles longitudinally relative to one
another.) Retraction of the catheter outer sheath allows the spring
fingers to open to their open, unrestrained position and release
the head of the deployable helix 12 and release the helix from the
delivery catheter, as shown in FIG. 19. For removal of the delivery
catheter, the proximal handles are operated to retract the central
holder 52 into the catheter outer sheath 13, and the outer shaft
bends the elastic fingers back to their closed position. The
elastic fingers may be formed of resilient material such as 316L
stainless steel, spring steel, or shape memory super alloys.
[0054] In use, the devices shown in FIGS. 1 and 2 are relatively
simple to operate. The surgeon performing the implantation
procedure inserts the implant delivery catheter into the patient's
vasculature through the skin, typically entering the femoral artery
through the thigh, and navigates the catheter into the heart. The
surgeon places the distal tip of the catheter, including the
fixation coil, in close proximity to the target site within the
heart wall, and then rotates the catheter inner core (by turning
the proximal handle 16 on the catheter inner core) to screw the
fixation coil in to the heart wall. The drug delivery coil, which
is nested in the coils of the fixation coil, is forced into the
myocardium along with the fixation coil. The surgeon screws the
fixation coil into the heart wall until the drug delivery coil is
disposed completely within the myocardium, typically ensuring that
the proximal tip of the drug delivery coil is below the level of
the endocardium, while also ensuring that neither the fixation coil
or the drug delivery coil penetrate the heart wall and poke through
into the pericardium or pericardial space. When the drug delivery
coil is properly located, the surgeon unscrews the fixation coil.
The drug delivery coil remains in place within the myocardium
because it is not restrained from distal helical rotation relative
to the fixation coil. The surgeon may choose to implant a several
implants throughout a region of the heart. Thus, the method
comprises deploying a series of drug delivery coils loaded with
therapeutic agents into the myocardium, and leaving them in place
permanently. The therapeutic agents are released over time by
diffusion, elution, osmosis, or hydrolysis to have long lasting
effect on the heart.
[0055] As an adjunct to coil placement, the centrally located
hollow straight needle 18 shown in FIGS. 4 and 5 can be used to
transiently infuse an additional therapeutic agent to a depth
within the heart tissue at the time that the drug delivery coil is
implanted. It could also be used to deliver contrast material to
confirm penetration of the myocardium. The additional therapeutic
agent can be used to ameliorate the immediate effect of the
implant, or it can be used to jump start the therapy with a small,
quickly absorbable dose of the therapeutic agent or a fast acting
analog (that is, having immediate effect relative to the implant).
Thus the additional therapeutic agent can be an anti-inflammatory
agent, an anti-hypotensive agent, another growth factor or other
drug. The transiently delivered fluid agent may start the cascade
of healing that the diffusion from the controlled release matrix
can continue over time. The transiently delivered fluid could be a
heparin binding agent that has a tendency to stick to the
interstitial matrix in the myocardium and work over time when given
in a single dose. The growth factor in the implanted controlled
release matrix could be a non-heparin binding molecule that moves
through the interstitial tissue more rapidly, i.e. is easier to
clear from the heart, and therefore should be delivered over a
period of time.
[0056] FIG. 20 illustrates an embodiment of the implant delivery
catheter. The implant delivery catheter 7 comprises the two handles
the proximal handle 16 which is secured to the catheter inner core
14 and a distal handle 15 which is secured to the catheter outer
sheath 13. The drug delivery dart 59 and anchor helix 17 are
disposed on the distal end 10 of the catheter inner core. One or
both of the handles has features on it such as ribs or grooves to
make gripping more secure or flat on one side so that rotational
position can be sensed by feel. The handles can be rotated with
respect to one another and can translate longitudinally relative to
one another. For the preferred embodiment, the catheter outer
sheath 13 is between 0.5 and 3 mm in outer diameter and more
preferably between 1 and 2.5 mm in outer diameter. The wall
thickness of the catheter outer sheath is between 0.1 and 0.5 mm in
thickness. The catheter inner core 14 is preferably between 0.2 and
1 mm in diameter with a wall thickness of 0.1 to 0.3 mm.
[0057] FIG. 21 shows the distal end of the catheter shown in FIG.
20. Here catheter outer sheath 13 is shown with distal soft tip 58
with fixation element 8 disposed coaxially around implantable dart
59. Dart 59 may protrude from the catheter outer sheath 13 before
insertion into the tissue if so desired, but in its preferred
embodiment it is housed in the outer sheath during navigation of
the catheter through the vasculature. The dart has a sharpened
distal tip 60 to aid tissue penetration and a proximal end 61 with
a mating structure for releasably mating with the catheter inner
core. The dart is releasably attached to the catheter inner core 14
as illustrated in FIG. 22.
[0058] FIG. 22 shows a cross sectional view of the distal portion
of the catheter shown in FIG. 21. The catheter inner core 14 has a
threaded segment 62 located just proximal of the distal tip 63 of
the catheter inner core. This segment is fitted with external screw
threads. This threaded rod portion 62 may be a polymer or metallic
rod or tube. The threading is preferably eighty to ninety threads
per inch, but can be adjusted to control the amount of travel
generated by one rotation. The proximal end of the threaded segment
62 is turned down to a diameter that fits into the distal end of
catheter inner core proximal section 65. This joint can be a force
fit, or the threaded portion may be glued in with cyanoacrylate,
epoxy, or ultraviolet cured adhesives. Alternatively, this joint
can be reinforced with an external sheath, heat shrink, crimp or
covering. The distal end of the threaded segment 62 is also turned
down to a smaller diameter and is inserted into and joined with
distal segment 66 of the catheter inner core 14, also constructed
of stainless steel braid reinforced polyimide with thin walls. The
outer diameter of the distal segment 66 may be the same as the
proximal segment 65, or may be larger to more closely match the
inside diameter of the catheter outer sheath 13. This portion of
distal segment 66 has a distal internal diameter sized to receive
the proximal end 61 and mating structure 67 (in this case the
necked down area) of the implantable dart 59.
[0059] The catheter outer sheath 13 has an internally threaded
segment 72 which may be formed with a nut embedded at a distance
proximal from the distal end and corresponding to the externally
threaded segment of the catheter inner core. This nut 73 is
internally threaded with the same pitch as the threaded portion 62
of the catheter inner core. The nut 73 is bonded into the internal
section of the outer sheath 13 by gluing, crimping, or heat fusing.
The distal portion of the catheter inner core proximal section 65
is sized such that it is larger than the opening in nut 73, and the
extreme distal tip of the inner core proximal section forms the
distal facing shoulder 74 with a diameter exceeding the inner
diameter of the nut.
[0060] The outer sheath 13 can be composed of one or more sections
that are split at the nut location to make assembly easier. The
outer sheath portions are heat bonded, glued or welded together
after the nut is bonded inside the outer shaft and the drive shaft
threaded through the nut. The outer sheath 13 terminates in a soft
tip 58 at its distal end. This soft tip is typically 35 durometer
Pebax and serves to protect the tissue that the tip of the catheter
touches. The soft tip is either heat fused, glued, or otherwise
bonded to the end of the remainder of the outer sheath. The soft
tip may be loaded with a radiopaque material such as barium
sulfate, or have an embedded radiopaque marker band constructed of
gold, platinum, platinum/iridium or stainless steel to increase its
visibility under x-ray fluoroscopy. Inside the distal part of the
outer sheath 13 is the fixation element 8. In this embodiment, the
fixation element 8 is a helical structure. This helical structure
is made from solid stainless steel rod or hollow wire or tube. The
helix is wound such that its outer diameter closely matches the
inner diameter of the outer sheath 13. The proximal portion of the
helix is preferably encased in a soft Pebax sheath 75. This soft
Pebax sheath 75 encapsulation allows the helix to be heat fused
with the soft tip 58, making a unitary construction that can
transmit torque, tension and compression. This encapsulation sheath
75 may have an internal diameter that is closely mated to the
diameter of the dart, to help retain the implantable dart until it
is deployed. The fixation element 8 can be constructed of hollow
tubing that is connected with a tube that connects up to a luer
fitting on the proximal end of the catheter. This tube can be used
to inject or infuse diagnostic or therapeutic materials from the
proximal end of the catheter to the myocardial tissue in which the
catheter is lodged. The fixation element 8 preferably terminates in
a sharp point to aid tissue penetration.
[0061] In operation, the surgeon first navigates the distal end of
the implant delivery catheter through the patients vasculature and
in to a heart chamber, so that the dart and fixation element are
proximate a target site of heart tissue. The surgeon then rotates
the catheter outer sheath while urging it distally, to screw the
fixation element into the myocardium. As the fixation element is
driven into the myocardium, the surgeon may view the fixation
element position to ensure that it is screwed into the desired
target site. With the correct positioning ensured, the surgeon
rotates the inner core to drive the dart into the myocardium.
Rotation of the inner core proximal section 65 turns the threaded
segment inside nut 73 and urges the entire catheter inner core
forward and drives distal segment 66 forward into the implant dart
59, thereby forcing the dart out of the device. The catheter inner
core proximal section 65 may be pulled forward until the distal
facing shoulder 74 contacts nut 73 and limits the travel of
driveshafts. (Alternatively, this motion can be limited by the
distance between the two handles on the proximal end of the
device.) This limits the depth to which the dart may be driven, to
ensure that it is not driven through the heart wall. The distance
76, which is the distance between the proximal face of the nut (or
other inwardly intruding boss on the inner wall of the catheter
outer sheath) and the distal face of the shoulder (or other
outwardly protruding boss on the catheter inner core) in the ready
condition should be chosen such that the maximum possible travel of
the dart from the outlet of the catheter is less than the expected
thickness of the heart wall.
[0062] The dart used in the embodiments of FIG. 22 can be provided
in various configurations. As illustrated in FIG. 22, the proximal
portion 61 of the dart 59 is turned down to fit into the distal
opening in the catheter inner core distal segment 66. The joint is
a sliding or loose friction fit between the distal segment shaft
and the implant. The dart is constructed of metal, glass, ceramic,
polymer or biologic material or a combination thereof. It may or
may not have external features to aid its retention in tissue such
as barbs, threads or wings. FIG. 23 illustrates the dart 59 fitted
with screw threads 77 which enhance retention in the myocardium and
increase the surface are of interface between the dart and the
myocardium. FIG. 24 illustrates the dart 59 fitted with outwardly
biased, radially extending barbs 78 which also enhance retention in
the myocardium and increase the surface are of interface between
the dart and the myocardium. FIG. 25 shows the dart with a porous
or perforated exterior, which may be filled with a fluid
therapeutic agent. The porosity or apertures in the exterior permit
fluid within the dart to move out of its internal cavity and into
the region of the myocardium in which the dart is implanted. The
darts may be constructed of a polymer that has been loaded with a
therapeutic agent and injection molded into its final form. As
shown in FIG. 26, the dart may be constructed of a shell 79 of
polymer, ceramic, glass, elastomer and metal that encases a central
portion 80 containing therapeutic material such as lyophilized
therapeutic protein. The central portion may be a cast, compression
molded or extruded reservoir of therapeutic substance or
therapeutic substance encapsulated in bioabsorbable polymers or
bioabsorbable polymer microspheres. The distal portion 60 of the
dart is typically sharpened to a point to ease its insertion into
tissue. The point may be multifaceted or conical or beveled. In the
preferred embodiment, the diameter of the dart implant is typically
0.5 to 1 mm. The length of the implant is typically 1-10 mm, and
more preferably 3-6 mm. The inside edges of the active fixation
helix serve to support and guide the implant into the tissue during
implantation. FIG. 27 shows the dart-like drug delivery structure
implanted in the myocardium 6 in the left ventricle. The drug
delivery dart 59 has been advanced so that its proximal end 61 is
at a depth below the endocardial surface 44. This allows the
endocardium to heal over the small helical needle track wound
created by turning the device into the tissue. Eventually, the
healing response within the myocardium will seal the drug delivery
structure off from the circulating blood within the heart chamber
(indicated at item 45). In this figure, the drug delivery depot has
several openings 81 on near its distal tip 60 that is located in
the ischemic target area 46 of the myocardium. The drug delivery
structure is placed at a depth within the myocardium, ensuring that
the distal tip of the structure does not penetrate all the way
through the heart wall and enter the pericardium or pericardial
space 47.
[0063] The screw threads 77, the barbs 78, and the helical turns of
helical drug delivery structure 12 provide fixation means for each
drug delivery structure, and any equivalent means may be used to
enhance retention of the drug delivery structure within the body
tissue in which it is placed.
[0064] The helix can be loaded with therapeutic agents using many
methods. The tubing can be filled with the powder by pouring the
powder into the top of the hollow tube through a funnel. This
filling process can be aided by agitating the supply or receiving
tubes with mechanical or ultrasonic vibration. After filling, one
or both ends of the hollow tube may be closed by crimping or
capping or plugging. The process may take place in a controlled
environment, such as under dry nitrogen gas at 0 degrees Celsius,
to keep the protein dry, loose, and stable. The lyophilized protein
can be made into a paste or suspension and driven into the hollow
helical tube by pressure exerted by a syringe, fluid dispenser,
pump, or compressed gas source. The suspension liquid would be
non-reactive with the protein and would later be evaporated or
driven off by elevated temperature storage. Multiple therapeutic
agents can be mixed in their dry form and the mixture can be
installed in the controlled release structure. In addition to
powdered lyophilized therapeutic, the deployable helix structure
can be filled with microspheres that have been loaded with the
therapeutic agent. Spheres in diameter up to the inside diameter of
the helical tubing can be used, 0.008''. These spheres could be
constructed of bioabsorbable polymers that bulk erode,
bioabsorbable polymers that surface erode, or nonabsorbable
biocompatible polymers with diffusion paths and pores depending on
the desired time course of elution. Another means of filling the
hollow helix or helical tube with therapeutic protein is to dip the
tubes into a solution of solvent and therapeutic protein. The tube
is then air dried or placed in an oven to drive off the solvent. A
coating of therapeutic powder is left behind. This process can be
repeated to deposit more therapeutic agent until the desired
quantity is achieved. Another means of filling the hollow helical
tube with therapeutic agent is to insert mold or overmold the tube
or finished helix with a polymer, either bioabsorbable or
biocompatible, that has been loaded with the therapeutic. These
polymers may be urethanes, polylactides, polyglycolides,
polycaprolactones, polyanhydrides, acrylics, polyesters, epoxies
and the like. If the therapeutic agent is only stable at low
temperatures, this filling or coating can be completed with a low
temperature casting material such as urethane, epoxy or acrylic.
Another means of filling the hollow helix with therapeutic agent is
to cast, mold, or extrude the therapeutic agent and a polymer
carrier into a rod or thread form. This thread or rod can be
inserted into the hollow helix tube and locked in place before the
tube is bent into the helical shape around the mandrel. The
fixation may be by a mechanical interference, or crimping, or
melting to constrain the thread relative to the tube.
[0065] Alternatively, the hollow helix can be filled with the
therapeutic agent intraoperatively. If the tube contains a
hydrophilic biocompatible polymer core or coating, such as ethylene
vinyl acetate copolymer (EVA), the surgeon would dip or soak the
deployable helix in a reconstituted solution of therapeutic agent
and saline or ringer's lactate. The hydrophilic medium in or around
the helix would take up the therapeutic by capillary action and
wicking, thereby loading the deployable helix device.
Alternatively, the doctor could fill the helix with therapeutic
solution by coupling the helix to a syringe and injecting the
solution into the lumen of the helix before attaching the helix to
the catheter. Another method of constructing a deployable helix is
to sinter a metal or ceramic into the final shape. The sintered
helix would have a porous construction that could wick up the
therapeutic fluid through capillary action as described above.
[0066] While the devices and methods have been described in
relation to the treatment of the heart and treatments for ischemia
with implantation of a helix or dart loaded with an angiogenic
agent, they may be adapted to treat other conditions within the
heart, other organs of the body, and conditions such as tumor and
cancers. For example, the coils or darts or implants of other
shapes can be adapted for implant into a tumor and loaded with a
tumor necrosis factor. Many compounds may be loaded into the
implants. "Angiogenic agents" and "endothelial agents" including
the following may be used: insulin like growth factor -I (IGF-I),
VEGF, VIGF, PDGF, epidermal growth factor
[0067] (EGF), CTGF and members of its family, FGF, TGF-a and TGF B;
the widely recognized angiogenic agents VEGF-165, VEGF-121,
VEGF-145, FGF-1, FGF-2, Transforming Growth Factor (TGF-B), Tumor
Necrosis Factor a (TNF-a), Tumor Necrosis Factor B (TNF-B),
Angiogenin, Interleukin-8, Proliferin, Prostaglandins (PGE),
[0068] Placental Growth factor, Granulocyte Growth Factor, Platelet
Derived Endothelial Cell Growth Factor, Hepatocyte Growth Factor,
DEL-1, Angiostatin -1 and Pleiotrophin.
[0069] For treatment of cancers and tumors, angiostatic agents may
be used including antibodies or other antagonists to angiogenic
agents as defined above, such as antibodies to VEGF or Angiotensin
2 and 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, paclitaxel, cisplatin, and other bioactive and organic
chemical agents.
[0070] 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.
* * * * *