U.S. patent application number 14/198497 was filed with the patent office on 2014-07-03 for methods and devices for in vivo targeted light therapy.
This patent application is currently assigned to Abbott Cardiovascular Systems, Inc.. The applicant listed for this patent is Abbott Cardiovascular Systems, Inc.. Invention is credited to Kevin J. Ehrenreich, Kyle Klein, John Stankus.
Application Number | 20140188035 14/198497 |
Document ID | / |
Family ID | 51018019 |
Filed Date | 2014-07-03 |
United States Patent
Application |
20140188035 |
Kind Code |
A1 |
Ehrenreich; Kevin J. ; et
al. |
July 3, 2014 |
METHODS AND DEVICES FOR IN VIVO TARGETED LIGHT THERAPY
Abstract
Catheter-based systems for in-vivo targeted light therapy
include a first type of catheter configured for photo-activating
photosensitive substances in tissue, and a second type of catheter
configured for photo-degrading photosensitive substances in tissue.
The catheters may be configured to produce light using a variety of
light sources, such as light emitting diodes (LEDs) and fiber
optics. The light transmission is directed to tissue in such a way
that only portions of tissue in a treatment area are exposed to
light, depending upon whether the tissue is diseased or
healthy.
Inventors: |
Ehrenreich; Kevin J.; (San
Francisco, CA) ; Klein; Kyle; (San Jose, CA) ;
Stankus; John; (Campbell, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems, Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
Abbott Cardiovascular Systems,
Inc.
Santa Clara
CA
|
Family ID: |
51018019 |
Appl. No.: |
14/198497 |
Filed: |
March 5, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12191200 |
Aug 13, 2008 |
|
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|
14198497 |
|
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Current U.S.
Class: |
604/21 |
Current CPC
Class: |
A61B 2017/00057
20130101; A61N 2005/0602 20130101; A61N 5/062 20130101; A61B
2562/0233 20130101; A61B 5/0084 20130101; A61B 5/1459 20130101;
A61N 2005/0652 20130101; A61N 5/0603 20130101; A61B 2018/00904
20130101; A61B 18/1492 20130101 |
Class at
Publication: |
604/21 |
International
Class: |
A61N 5/06 20060101
A61N005/06 |
Claims
1-13. (canceled)
14. A therapeutic method, comprising the steps of: providing a
catheter having a balloon and light member located at a distal end
of the catheter, the light member including a plurality of
light-emitters and light detectors; locating the balloon and light
member at a treatment area; locating abnormal tissue by detecting
among the light detectors a variation in reflected light intensity;
and initiating photodynamic therapy (PDT) including activating a
portion of the light emitters based on the detected variation in
reflected light intensity.
15. The method of claim 21, further including the controller
receiving a signal from a light detector, and the controller
initiating PDT if the signal is equal to a first value and not
emitting light if the signal is equal to a second value, or if the
signal is between a third value and a fourth value.
16. The method of claim 14, wherein the activating a portion of the
light emitters includes activating light emitters that oppose
abnormal tissue.
17. The method of claim 16, wherein the activating a portion of the
light emitters includes activating light emitters that do not
oppose abnormal tissue.
18. The method of claim 14, further including the step of inflating
the balloon so as to press the balloon against tissue, wherein the
balloon provides a line of site from the light member to the
tissue.
19. The method of claim 18, wherein the initiating PDT includes
adjusting from the proximal portion of the catheter the light
energy for PDT, and delivering the light energy for PDT through
light emitters selected during the detecting step.
20. The method of claim 19, wherein the light emitters include a
light guide portion of the catheter coupled to an extracorporeal
light source.
21. The method of claim 14, the catheter including a controller
disposed at the distal end, wherein the controller performs the
initiating and detecting steps.
22. The method of claim 14, wherein the detecting a variation in
reflected light intensity further includes the steps of, for each
of a plurality of light emitters and light detectors, receiving a
signal generated from a light detector in response to reflected
light from a light emitter, and if the signal is less than a
predetermined value or within a predetermined range, using the
light emitter for PDT.
23. The method of claim 14, wherein the light emitters are light
emitting diodes (LEDs) and the light detectors are photodiodes.
24. The method of claim 14, wherein after PDT is initiated, further
including repeating the detecting a variation in reflected light
intensity after a predetermined amount of time has elapsed,
followed by initiating the PDT a second time.
25. The method of claim 14, further including a calibrating step
performed prior to the detecting step, the calibrating step
including, for each of the light emitters, activating the light
emitter, and detecting an intensity of reflected light received for
each of a plurality of nearby light detectors, wherein a nearby
light detector has a highest intensity of reflected light for the
activated light emitter, and the detecting step further including
activating a first light emitter and determining whether the first
light emitter opposes the abnormal tissue based on the magnitude of
signal received at the nearby light detector for the first light
emitter.
26. A therapeutic method, comprising the steps of: providing a
catheter having a balloon and light member located at a distal end
of the catheter, and a first drug eluting stent (DES) mounted on
the balloon, the first DES having a first overlapping portion and
the drug includes a photo-sensitive drug; locating the first DES at
the treatment area, wherein the treatment area includes a second
DES having a second overlapping portion; placing the first DES at
the treatment area such that the first overlapping area overlaps
the second overlapping area; and activating the light member such
that the light member emits light only upon the first overlapping
area to thereby affect only the photo-sensitive drug at the
overlapping area.
27. A catheter having distal and proximal portions, comprising: a
balloon, or a balloon and stent, and a light member located at the
distal portion, the balloon or stent, respectively, configured for
being placed in contact with tissue; and the light emitting member
including a plurality of light-emitters and light detectors,
wherein the light-emitters and detectors are arranged in pairs of
light-emitters and light detectors such that a light detector is
capable of detecting the light that is reflected from tissue
receiving light emitted from an adjacent light-emitters; and a
controller disposed at the distal portion and configured to perform
the following steps: detect a variation in reflected light
intensity among a plurality of light detectors, wherein the
variation in reflected light intensity indicates locations where
abnormal tissue opposes light-emitters; and initiate a photodynamic
therapy (PDT) including activating a portion of the light emitters
based on the detected variation in reflected light intensity.
28. The catheter of claim 27, wherein the light emitters are light
emitting diodes (LEDs) and the light detectors are photodiodes.
29. The catheter of claim 28, wherein light emitting member
includes a plurality of semiconductor substrates arranged in an
array of LED and photodiode pairs.
30. The catheter of claim 27, wherein the controller includes a
circuit formed on a polyimide substrate and located at the distal
portion.
Description
[0001] This is a divisional application of U.S. application Ser.
No. 12/191,200 filed Aug. 13, 2008, the contents of which are
hereby incorporated by reference in its entirety for all
purposes.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to methods and devices for using
light energy and photo-sensitive substances during the course of a
drug therapy.
[0004] 2. Description of the State of the Art
[0005] Photodynamic therapy (PDT) involves the delivery of chemical
compound drugs called photosensitizers into tissue and then
exciting the photosensitizer in order to enable an energy transfer
from the photosensitizer to a nearby oxygen molecule. This produces
an excited singlet state oxygen molecule that reacts with nearby
bio-molecules. With respect to typical cardiovascular applications
of PDT, this reaction causes localized damage in the target
atherosclerotic tissue, thereby providing a beneficial effect to
the patient.
[0006] Photochemical degradation occurs when a compound is exposed
to high amounts of light which correspond to the absorbance band of
the compound. The general mechanism for this degradation involves
the absorption of light energy by electrons in chemical bonds. This
energy causes the electrons to move to a higher energy state, which
can produce a reactive region in the molecule. These reactive
regions are more likely to interact with other compounds, notably
oxygen, which can break or alter the chemical bond in the compound,
resulting in an overall degradation of the chemical.
SUMMARY OF THE INVENTION
[0007] The invention is directed to methods and devices for drug
delivery using light to activate one or more drugs and/or to
degrade a drug's potency. In either case, the invention teaches
various devices and methods for performing targeted drug therapy
for various types of anatomy. Among the benefits, devices are
provided that can reduce the complexity of a procedure associated
with light-based drug therapy, such as PDT, photo-chemical
degradation, and activation of a photo-cross-linkable therapeutic
loaded hydrogel. Features of the invention provide a safer working
environment for light-based drug therapy, improve the ability to
deliver light energy sufficient to activate or degrade a drug in
tissue, improve the ability to activate or degrade a drug's potency
at an intended location, but not elsewhere, reduce a patient's
"dark time", which is intended to mean the period when a patient
administered with a photo-activated substance must not be exposed
to light, and/or enable more precise targeting of tissue for drug
therapy.
[0008] In accordance with one or more of the foregoing objectives,
a device configured to perform light-based therapy, e.g., PDT, may
integrate flexible electronics at a distal portion thereof,
including light emitters and light detectors. In some embodiments,
one or more arrays of light emitting diodes (LEDs) are positioned
near a working end of a medical device, e.g. a balloon catheter.
The LEDs generate light that excites a photosensitizer and
initiates PDT of adjacent tissue. Photodiodes may be used in
combination with the LEDs to detect reflected light from the
anatomy. Depending on the magnitude of the detected light, the
photodiodes may transmit a signal that causes the LEDs to either be
powered on or off. In this way, a closed loop control system may be
used to perform light therapy, e.g., PDT, in a safe and efficient
manner. The closed-loop system may be entirely located at the
distal portion of the device.
[0009] In accordance with one or more of the foregoing objectives,
embodiments of the invention include a catheter configured such
that a power supply provides electrical power to a distal portion
of a catheter, which is safer and easier to implement than Class
III lasers that are sometimes used for light therapy, e.g., PDT. In
addition, electrical power leads may be more flexible, and thus
more deliverable, than fiber optics that are sometimes used for
light therapy, e.g., PDT. Additionally, a closed loop control
design according to embodiments of the invention may reduce damage
of healthy tissue by deactivating LEDs adjacent to healthy tissue.
Additionally, a closed loop control design improves power
consumption and optimizes light delivery of a diode array to
improve efficiency and efficacy of PDT.
[0010] According to one aspect of the invention, there are methods
and devices for activating photosensitizers in order to initiate a
light therapy, e.g., PDT, photochemical degradation, activation of
a photo-cross-linkable therapeutic loaded hydrogel. It is
particularly useful in bodily vessels since the disclosed methods
and devices enable tracking through small diameter vessels such as
cardiovascular vessels.
[0011] The invention includes the recognition that with the
emergence of drug eluting stents (DES) for the treatment of
cardiovascular disease, there exists a potential for drug
interactions that may not have been considered in a stent's
original design or drug elution profile. For example, if a DES of
one drug was used in close proximity to a DES of a different drug,
there would exist a potential for a drug interaction which may not
have been characterized by either producer of the stents. In
another example, if two drug eluting stents were placed overlapping
in vasculature, the overlapping region would effectively contain
twice the designed dose of drug. This dose may cause a sub-optimal
clinical outcome. In another example, the diffusion of a drug away
from the drug-eluting source could be reduced to a very local
region by exposing the proximal and distal ends of the drug-elution
device to a degrading light source.
[0012] In accordance with one or more of the foregoing objectives,
methods and devices are provided that enable an operator to
selectively degrade unwanted drug in blood vessels or other anatomy
using light. This is useful in such cases as when a DES or drug
coated balloon with a specific active agent, e.g., Everolimus, is
placed near a DES with a different active agent, e.g., Paclitaxel.
In such cases, an operator may degrade the drug proximal to a prior
implanted stent to prevent possible drug interaction. Drug
interaction may occur due to drug diffusion into adjacent tissue,
one DES overlaps another implanted DES etc. In other embodiments
selective degrading of drugs can allow an operator to degrade an
excess of the same DES drug, e.g., if two DES stents overlapped,
the operator can reduce the possibility of introducing a doubling
of the dosage by degrading the drug present in an overlapping
region of two DES using light therapy. Other embodiments would
allow an operator to focus drug exposure to a very specific region
of interest by preventing a diffusion of the drug away from the
site of delivery.
[0013] In accordance with one or more of the foregoing objectives,
a catheter-based system contains two components. One component is a
drug delivery device. This device can be in the form of a DES, drug
coated balloon, bio-absorbable drug eluting stent, a double balloon
with drug perfusion, or any other drug delivering device used in
vasculature. The second component would be a light source capable
of delivering a specific wavelength or wavelengths of light
radiation in a targeted manner. The light source may include light
emitting diodes, a fiber optic cable with diffuser, a fiber optic
cable with a microlens, thin-film diodes, organic light emitting
diodes, or any other light source capable of specific, targeted
light dosing. The wavelength(s) of light chosen for treatment may
depend on the absorbance band of the drug intended to be degraded.
Multiple light wavelengths could be utilized to optimize drug
degradation and also the penetration depth of exposure. For
instance, longer wavelengths of light, although having less energy,
are able to penetrate further into body tissue than shorter
wavelengths. Light wavelength and intensity may be optimized in
this sense, e.g., longer wavelengths for deeper penetration,
shorter wavelengths for high energy, to improve the effectiveness
of a treatment. For example, optimized wavelength and intensity can
promote efficacy towards reduction of restenosis and improve
re-endothelialization and long term DES safety. Both stent and
balloon coatings can be chosen for optimal degradation.
[0014] A drug coated region could be any drug eluting source, e.g.,
a stent or balloon coated surface. Tissue would be exposed to light
energy by way of windows formed as part of a balloon membrane.
Select wavelengths may be allowed to pass through the membrane's
windows, while other wavelengths are blocked. In other embodiments,
the windows may be transparent, thereby allowing all light to pass
through the membrane (in this case the light source may only emit
certain bands of light). The grating of the window and/or
wavelength of light may be chosen based on the absorbance band for
the substance being used. The window(s) or light-blocking
location(s) on the membrane would determine the effective area the
drug would be allowed to expose at full strength. In one respect, a
balloon membrane may be constructed with combinations of light
filters, e.g., UV, near infra red (NIR), white light, all light,
etc. Diffused light may be used in these embodiments. A distal or
proximal light source may be used. It will be appreciated that a
broad spectrum of light wavelengths may be delivered toward the
tissue in accordance with this invention; however, this may not be
ideal since it is generally desirable to limit the energy that is
delivered into the tissue to prevent excessive heating, for
example.
[0015] According to one embodiment, a balloon catheter having a
window would be used as a DES delivery device. The window can allow
for a certain portion of the drug on the stent length to be
deactivated in order to prevent the vessel from being exposed to a
double dose of drug.
[0016] According to another embodiment, windows may be replaced
with light sources attached distally, proximally, or both relative
to the balloon. One advantage of this design would be a greater
exposure as compared to a light source confined to a pressurized
balloon chamber. In these embodiments, a degrading light source can
expose larger portions of adjacent to tissue to degrade drug that
may have diffused quickly after being deposited at a target
tissue.
[0017] "Target tissue" refers to the tissue that is diseased or
abnormal that will be, or is intended to be, treated by a medical
device according to the disclosure. In some embodiments, the
medical device is configured to expose the target tissue to light
energy, e.g., for photo-activation of a substance present in the
target tissue. In other embodiments, a medical device is configured
for light exposing healthy tissue that may be present adjacent to a
treatment area. A "treatment area" refers to the general location
of the target tissue. A treatment area includes, in addition to the
target tissue, healthy or normal tissue that is adjacent the target
tissue.
[0018] In other embodiments, a targeted drug therapy as taught by
the invention may be used in vasculature, as well as in cancer
treatment for a variety of anatomy. For example, tumors may be
treated with a potent compound and the regions proximal to the
tumor could be exposed to light of a specific wavelength to
decrease the spread of the potent compound to other tissues. For
tissues that diffuse drugs rapidly, light could be used to slow or
control the diffusion of the drug, limiting its effects to the
targeted region.
[0019] Most light-activation therapies require a patient to spend
many hours without exposure to light due to the reactivity of the
photosensitizer used in these therapies. The disclosed methods and
devices provide ways in which to expose a patient to a wavelength
of light that would degrade, as opposed to activate, a
photosensitizer. This feature provides an approach for reducing the
amount of photosensitizer in unwanted areas, e.g., skin, and may
even reduce the overall half-life of a drug in the body. This can
also reduce the "dark time" for the patient, i.e., the amount of
time the patient cannot be exposed to light due to the presence of
light-activated substances in his/her body.
[0020] According to another embodiment, a device may provide both a
drug activating wavelength and a degrading wavelength. The drug
activating wavelength could be focused on a region requiring
therapy, while the degrading wavelength could be used to prevent
the spread of a drug to adjacent tissue. This technique may be
especially useful during the treatment of a cancerous tumor, as
discussed above. For example, a balloon membrane may be configured
with multiple light filters (drug-activating and drug-degrading
light filters). In another example, a drug-activating light source
may be emitted from the balloon and drug-degradation light source
emitted from a catheter shaft at distal and/or proximal locations
relative to the balloon.
[0021] Methods and devices disclosed herein may also be utilized in
combination with a delivery of a photo-cross-linkable therapeutic
loaded hydrogel (e.g. gel paving or needle injection) via double
balloon infusion or coated balloon that is later exposed and
polymer gelled.
[0022] According to another aspect of the invention, the methods
and devices disclosed herein may be utilized for a combined
delivery of multiple therapeutics such as an anti-inflammatory drug
(e.g. dexamethasone) or -olimus drug in combination with a
photosensitizer. For example, "end effects" are known to be
especially troublesome in terms of restenosis. It may not be
desirable to activate a photosensitizer along an entire length of a
stent, since the damage to the vessel may be unwarranted given the
therapeutic effect that the stent will provide. However,
light-activation at the end regions of the stent may contribute to
an overall improvement in therapy, and specifically, to a decrease
in restenosis at the stent ends. A stent may therefore be
photo-activated by directing light of a select wavelength towards a
portion of the tissue in a treatment area, so as to activate a
previously delivered photosensitizer at the ends.
[0023] According to one embodiment, a catheter having distal and
proximal portions includes a balloon, or a balloon and stent,
located at the distal portion, and a light emitting member located
adjacent the balloon. The balloon and light emitting member are
configured such that a first portion of the tissue is prevented
from receiving light while a second portion of the tissue is
exposed to light. The light emitting member may include a plurality
of light-emitters and light detectors, and a control system
disposed at the distal portion and configured for activating the
light-emitters based on signals received from the light-detectors.
The light-emitters are light-emitting-diodes (LEDs) and the
light-detectors are photodiodes. In other embodiments the balloon
has a membrane formed from balloon material, such that the balloon
material forms a first balloon portion configured to block all
light transmission or allow transmission of light at a first
wavelength, and the balloon material forms a second balloon portion
configured to allow transmission of light at a second wavelength.
The first and second wavelengths may correspond to near infra red,
IR, visible and/or UV light wavelengths.
[0024] According to another embodiment a catheter having distal and
proximal portions and configured for treating tissue in a treatment
area, means for producing light at the distal portion, and means
for exposing only a portion of the tissue in the treatment area to
the light. The means for exposing only a portion of the tissue in
the treatment area to the light may include logic located at the
distal portion of the catheter and configured for selective
illumination of tissue. The means for producing light may include
light emitters and light detectors, and the means for exposing only
a portion of the tissue in the treatment area to the light may
include turning a portion of the light detectors on or off
depending on one or more signals received from the light detectors.
The means for exposing only a portion of the tissue in the
treatment area to the light may include a balloon having a light
blocking portion and a light admitting portion. The means for
exposing only a portion of the tissue in the treatment area to the
light may also include a balloon and light guides disposed distally
and/or proximally of the balloon.
[0025] According to another embodiment, a method of in vivo light
therapy using a catheter includes the steps of locating a balloon
of the catheter at a treatment area, wherein at least a portion of
the balloon is located opposite a target tissue, and exposing only
a portion of tissue in the treatment area to light energy using a
light member, wherein the remaining tissue in the treatment area is
not exposed to light energy either because the tissue is not
opposite activated portions of the light member or the remaining
tissue is shielded from the light energy. This method may further
include the step of producing a signal in response to light emitted
from the light member, and initiating light therapy including
emitting light from the light member if the signal is equal to a
first value and not emitting light if the signal is equal to a
second value. The locating step may include placing a surface of
the balloon having a drug disposed thereon in contact with a target
tissue, and then exposing only the tissue adjacent the target
tissue to light energy. The method of in-vivo light therapy may
also include illuminating tissue adjacent the target tissue
including transmitting light from a first balloon portion, or
transmitting light from a light emitting member located distally
and/or proximally of the balloon.
[0026] The method of in vivo light therapy may include deploying a
first drug eluting stent (DES) mounted to the balloon, and then
exposing to light energy only the tissue that is opposite an end of
the implanted first DES. The DES may be deployed adjacent a second,
previously implanted DES. The second DES may place a first drug in
tissue and the first DES may place a second drug in the tissue. In
this embodiment, the exposing to light energy step degrades one of
the first and second drugs.
[0027] According to another embodiment, a catheter's balloon has a
membrane wall including a first wall portion formed from a material
that transmits light of a first wavelength and a second wall
portion that transmits light of a second wavelength or
substantially prevents all light transmission; and the catheter
includes a light emitting membrane disposed within the membrane.
The catheter may further include a stent mounted on the
balloon.
[0028] According to another embodiment, a method for treating
tissue using a drug eluting stent (DES) includes the steps of
deploying the DES in a vasculature containing a target tissue and
exposing tissue located opposite an end of the deployed stent to
light energy. The exposing tissue step may include exposing tissue
to drug-degrading light energy. The deploying step may include
deploying the DES adjacent a second DES.
[0029] One or more of the foregoing features of invention may also
be practiced in the context of other in vivo procedures that rely
on a targeted, local delivery of a drug in a blood vessel or other
anatomy.
INCORPORATION BY REFERENCE
[0030] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 is side, partial cross-sectional view of one
embodiment of a balloon catheter according to the disclosure.
[0032] FIG. 2 is a front cross-sectional view of the balloon
catheter taken at Section II-II in FIG. 1.
[0033] FIGS. 3A-3B are schematic illustrations of features
associated with an array of light emitters (e.g., LEDs) and array
of light detectors (e.g., photodiodes) located at a distal portion
of the balloon catheter of FIG. 1. FIG. 3A depicts the light
emitted from the LEDs and reflected towards the photodiodes when
the balloon catheter's distal portion is positioned at a treatment
area that has both abnormal and healthy tissue. FIG. 3B depicts a
distribution of lighting corresponding to the locations of abnormal
tissue and healthy tissue.
[0034] FIG. 4 is a flow diagram relating to a procedure for
performing light therapy on a target tissue.
[0035] FIG. 5 is a partial view of a balloon catheter located at a
treatment area according to another aspect of the disclosure.
[0036] FIG. 6 is a side view of a distal portion of a second
embodiment of a balloon catheter located at a treatment area
according to the disclosure.
[0037] FIG. 7 is a side view of is a side view of a distal portion
of a third embodiment of a stent delivery catheter and prior
implanted stent located at a treatment area according to the
disclosure.
[0038] FIG. 8 is a bar-chart showing the effectiveness of drug
degradation using light for Everolimus combined with a
photosensitizer in a solution of methanol.
DETAILED DESCRIPTION OF THE INVENTION
[0039] According to one aspect of the disclosure a catheter
includes on-board electronics including an array of light-emitters
and light-detectors. The electronics may be located at a distal
portion such that a substantial amount of control of the
light-emitters and light-detectors resides at the distal portion of
the catheter. In some embodiments, the electronics are configured
to provide closed-loop control of the light-emitters. In this way,
the catheter may determine the desired light distribution on tissue
that contains photo-degraded and/or photo-activated substances. In
a preferred embodiment, the catheter's on-board electronics decide
whether to turn on, or turn-off a light-emitting diode (LED) based
on the differences between the magnitude of reflected light between
healthy and abnormal tissue.
[0040] FIG. 1 depicts a side, partial view of a balloon catheter 1
shown in partial cross-section. FIG. 2 depicts a frontal
cross-section of the catheter 1 taken at section II-II in FIG. 1.
The catheter 1 has a distal portion 12 and a proximal portion 14. A
balloon assembly 6 resides at the distal portion 12. A shaft 2,
which may be a composite shaft constructed to achieve a desired
flexibility, rigidity, deliverability, etc. extends from the distal
portion 12 to the proximal portion 14 of the catheter 1.
[0041] Various lumens are formed by the shaft 2. These lumens,
which are formed over a portion or approximately the length of the
catheter shall generally be referred to as aspects of shaft 2,
e.g., shaft body portion 2a, 2b, etc (see below). However, the
disclosure is intended to encompass any catheter known in the art
that is capable of providing the required lumens and performing the
specified functions of those lumens in accordance with the
disclosure. As such, the disclosure is not limited to a particular
type of catheter. Rather, it applies to, e.g., a unitary or
composite-type catheter, Over-The-Wire (OTW) or Rapid-Exchange (RX)
type catheter, etc. Examples of balloon catheters are described in
U.S. Pat. No. 7,131,963 and US Pub. No. 2008/0025943. A guide wire
11 is used to guide the catheter 1 to a treatment area that
includes the target tissue. In an alternative embodiment, catheter
1 may be a fixed-wire type catheter that does not require guide
wire 11 for guidance through a patient anatomy.
[0042] Referring to the cross-sectional views in FIGS. 1 and 2, at
the distal portion 12 a tubular body portion 2b of shaft 2 extends
from a proximal end 6b of the balloon portion 6 to a distal end 6a
thereof. Body 2b defines the portion of the balloon's inflation
lumen between ends 6a and 6b. The outer surface of body 2b may have
a multi-sided face, e.g., 8-sided, for purposes of mounting
electronics as will be discussed shortly. Body 2a defines the
portion of the catheter's guide wire lumen between ends 6a and 6b.
Bodies 2a, 2b may be portions of a composite or integral shaft.
[0043] The balloon 7 may be made of material that can transmit
broadband or narrow-band light. Hence, the balloon membrane may be
constructed from a transparent-type balloon material so that very
little light energy is reflected or absorbed by the membrane; or
the balloon material may be constructed from a material that
absorbs or reflects light of certain wavelengths, while allowing
light of other wavelengths to pass through. Balloon material
possessing a combination of light filtering properties may also be
desirable. Preferably, a folded or pleated balloon type is used.
This is primarily to ensure that light transmissive and opaque
segments are accurately placed during inflation, since the balloon
of this invention need not be a high pressure balloon. Thus,
compliant balloons may also be used, which may not require folding
or pleating but instead will be configured significantly
circumferentially at all operational diameters. The ends of the
balloon 7 are secured at ends 6a, 6b to shaft 2 by, e.g., an
adhesive; however, in an alternative embodiment, the balloon ends
6a, 6b may be secured to the shaft using other chemical or thermal
welding processes The balloon 7 is inflated by a fluid delivered to
the balloon via the inflation lumen (formed in-part by body 2b).
Body 2b includes an aperture 6c which puts the inflation lumen in
fluid communication with balloon chamber 7a. Thus, as a fluid (gas
or liquid) is passed through the inflation lumen the fluid exits
through aperture 6c to pressurize the balloon 7. The balloon 7 is
shown in a fully expanded state in FIG. 1.
[0044] Referring to FIG. 1, the catheter 1 includes arrays of light
emitters (e.g., light emitter 28) and light detectors (e.g., light
detector 26) disposed on substrates 30. These light emitters and
detectors are used to selectively photo-activate agents in tissue.
One aspect of the catheter 1 according to the disclosure is the
on-board ability at the distal portion 12 to selectively turn on or
off light emitters as the catheter 1 is positioned near the
treatment area. In this way, the catheter 1 can produce an energy
flux only at, e.g., the target tissue, based on a distribution of
light received over the body 2b of the catheter 1. This light is
detected by the light detectors.
[0045] Referring to FIGS. 1 and 2, a plurality of semiconductor
substrates 30 are arranged on the exterior surface of the body 2b
or integral with the outer surface of body 2b. Each of the
substrates 30, e.g., substrate 31a, preferably contain several
Light-Emitting-Diodes (LEDs) for emitting light and photodiodes for
detecting light. In other embodiments, the light source may include
thin-film diodes, organic light emitting diodes, or any other light
source capable of specific, targeted light dosing and disposed on a
circuit board meeting the footprint requirements of a catheter
intended for in vivo light therapy. The wavelength(s) of light
chosen for treatment may depend on the absorbance band of the drug
intended to be activated or degraded.
[0046] The LEDs and photodiodes are arranged in longitudinally
extending strips so as to provide an LED array light emitting and
photodiode light-detecting capability over the catheter length
extending between ends 6A and 6B. These LEDs and photodiodes may be
operated by a controller unit 34 disposed at the distal portion 12.
The catheter 1 may include a power cord 38 that provides power to a
controller 34 and circuitry associated with LED and photodiode
chips. The controller 34 may be formed by depositing material onto
a plastic substrate in order to form a flex circuit. Since the
substrate is flexible, it may be formed radially about the catheter
body. One example of material that is suitable for a flex circuit
substrate is Polyimide. The power cord 38 may pass through the
inflation lumen. At the distal portion 14 the power cord 38 exits
through a port 14a. A connector 42 may be provided to connect the
power cord to a power source. As depicted, the catheter may include
eight longitudinally extending substrates, i.e., 31a-31h, that are
disposed on eight sides of body 2b (FIG. 2). Each substrate has an
array of photodiode-LED pairs. For instance, in the cross-sectional
view of FIG. 2 LED-photodiode pairs 22a-22h correspond to one of
the LED-photodiodes disposed on each of the respective substrates
31a-31h. The substrates 31 may be integrated into the body 2b or
adhered, attached, etc. to the body 2b. The substrates 31 and/or
body 2b may include heat sinks that transfer heat generated by the
LEDs to an inner lumen, e.g., inflation lumen, by way of metallic
heat paths extending radially through body 2b. Transfer or heat
isolation may also be achieved by a circulating fluid, e.g.,
inflation fluid, or flushing fluid passed through, e.g. the lumen
formed by body 2b.
[0047] A substrate such as substrate 31a may correspond to a
portion of a circuit board including other substrates, e.g.,
adjacent substrates 31b and 31 h, or an individual circuit board
having its own input/output for electrically communicating with the
controller 34. In a preferred embodiment, a circuit board may
contain several tightly packed LED/photodiodes manufactured by
Stocker Yale, Inc., 32 Hampshire Road, Salem, N.H. 03079
(http://www.stockeryale.com/i/leds/). Each array 31a-31g may
correspond to such a circuit board.
[0048] As was just recently mentioned, each LED may be paired with
a photodiode as in, e.g., LED-photodiode pairs 22a, 22b, and 22c
(LEDs are distinguished from photodiodes in the drawings by
hash-marks over photodiodes). The pair may be designed to operate
as follows. The LED portion emits light towards adjacent tissue.
Light reflected, emitted or scattered from the tissue is detected
by the adjacent photodiode. The amplitude of this light energy is
then communicated to the controller 34 from the photodiode by an
electrical signal that is proportional to the magnitude of the
detected light energy. The controller 34 may then be programmed to
turn the LED "on" or "off" based on the magnitude of electrical
signal received from the photodiode. By placing the LED and
photodiode in pairs, the controller 34 may need only simple logic
since it may in some cases be assumed that light detected at a
photodiode originated substantially from the adjacent or closest
LED. For example, the controller 34 logic may assume that whenever
a signal above a certain threshold is produced by the photodiode
portion of LED-photodiode pair 22a, the signal was caused
substantially by the LED portion of this pair, i.e., the closest
LED. Other logic may be used to determine which LED lights were the
cause of a signal produced by a photodiode.
[0049] A catheter according to the disclosure need not assume that
the majority of light received by a photodiode was the result of
light emitted from the adjacent LED. For instance, the catheter 1
may execute an on-board diagnostic or calibration routine before
reaching a treatment area to determine how LED light is reflected
from tissue when the catheter is placed in similar anatomy, e.g.,
similar vasculature, as the treatment area (absent the abnormal
tissue). The controller 34 would initiate an on-off cycle over all
LEDs, recording the magnitude of the signal produced at a
photodiode during the brief time that each individual LED is the
only LED emitting light. Then, the LED corresponding to the highest
magnitude electric signal produced by the photodiode is designated
as the LED that will be turned on/off based on the signal received
from this photodiode. This procedure may then be repeated for all
photodiodes. At the end of this calibration, the controller has
assigned or cross-referenced one or more LEDs with a signal
produced at each of the photodiodes. Accordingly, when the catheter
arrives at the treatment area, the controller determines which
LED(s) to turn on or off by cross-referencing the photodiode
signals with the corresponding LED(s).
[0050] The logic according to the disclosure may therefore be used
to determine which LEDs to de-energized or turn off when the
electrical signal produced by a photodiode is above a certain
threshold. "On/off" signal commands to LEDs may be produced by the
controller 34 by opening/closing switches, and the photodiode
signals communicated to the controller 34 in order to decide which
LEDs should be turned on or off. In some embodiments the controller
34 may have programmable logic or hard-wired (i.e.,
non-programmable) logic.
[0051] In other embodiments a controller may not be needed.
According to these embodiments, a substrate may include circuits
that have their own logic built-in for deciding whether an LED
remains on or off. For example, for an embodiment that has
LED-photodiode pairs, a signal produced by the photodiode may turn
off the adjacent LED if the signal magnitude reaches a threshold
level. Again, this design assumes that the light detected by the
photodiode is always due in substantial part to the light emitted
by the adjacent LED. Under these embodiments the LED-Photodiode
pairs on a substrate may operate as autonomous units.
[0052] The catheter may have a 1:1 ratio of LED chips to photodiode
chips, e.g., as in the embodiments of arrays of LED-photodiode
pairs. In other embodiments the ratio may be 2:1 (meaning two LED
to every photodiode), 3:1, 4:1. The selected ratio and logic used
to determine which LEDs to turn on/off may depend on the type of
anatomy being treated. For example, irregular or unpredictable
light scatter or reflection properties due to the geometry of the
anatomy may require more sophisticated logic. When the walls of an
anatomy are smooth, and cylindrical like (as in the illustrated
example), then a more simple logic may be the preferred choice.
[0053] FIGS. 3A-3B illustrate schematically aspects of embodiments
just described. FIG. 3A depict the light intensities of the emitted
and reflected light for LED-photodiode array 31c from FIG. 1. For
ease of illustration, the balloon 7 of the catheter 1 is not drawn
in FIG. 3A. Here the LEDs for array 31c are designed by clear boxes
and referred to as L1, L2, L3, L4 . . . L10. The photodiodes are
designated by hash boxes and referred to as P1, P2, P3, . . . P10.
Opposing the array 31c is a section of tissue. The intensity of
emitted light from each of the LEDs is E1 and the intensity of the
reflected light is R1, R2 or R3.
[0054] A section of tissue opposing LEDs L4, L5, L6 and L7 contains
abnormal tissue, whereas the section of tissue opposing LEDs L1-L3
and L8-L10 is healthy. Because a tumorous tissue can have different
light reflecting properties from healthy tissue, the reflected
light for P4-P7 is significantly different in magnitude from P1-P3
and P8-P10. In particular, the healthy tissue will tend to reflect
more light than the abnormal tissue. As such, there is a higher
return energy flux detected by photodiodes that receive light
reflected from healthy tissue. This is depicted in FIG. 3A by the
different intensities of reflected light R1, R2 and R3 in FIG. 3A.
The light emitted from the LEDs is depicted by E1.
[0055] Distinguishing light characteristic of tissue may be used as
the criteria to selectively turn on or off LEDs. Thus, a local
presence of a tissue type, or transition between tissue types may
be inferred based on the signals produced by photodiodes in
response to the variation in reflect light intensity. FIG. 3B
depicts the distribution of LEDs turned "on" verses those turned
"off" as a result of the reflected light distribution depicted in
FIG. 3A. Since photodiodes P4-P7 received an amount of reflected
light resulting in an electrical signal having a magnitude less
than some predetermined amount (call it "X"), the LEDs associated
with these photodiodes were turned on to photo-activate a
photo-sensitive substance in the tissue, i.e., the abnormal tissue
opposing LEDS P4-P7. The LEDs associated with P1-P3 and P8-P10 are
turned off since the magnitude of the light energy detected by
these photodiodes resulted in an electrical signal above the
threshold X (indicating the presence of healthy tissue).
[0056] In other embodiments, a detected magnitude of light energy
above a threshold may instead cause an LED to turn on, rather than
off. For example, when light energy is desirable for purposes of
degrading a drug's potency in healthy tissue that is adjacent to
cancerous tissue, but without affecting the drug's potency in the
cancerous tissue, LEDs would be turned on if the magnitude of the
electrical signal at the corresponding photodiode is greater than
X.
[0057] As depicted in FIG. 3A, the LED-photodiode pair (L7, P7) is
located at a transition zone between healthy and abnormal tissue.
In this area, the reflected light R3 may produce an electrical
signal much greater than the signal corresponding to R1 yet still
less be less than the threshold X. In the examples described above,
L7 would be turned on since the magnitude of the signal is less
than X. In other embodiments a criterion for turning on/off an LED
may instead be based on whether the signal falls within a range of
values, as opposed to whether it is above or below a single value.
In still other embodiments, a mean of several received electrical
signals may be compared to a value. These signals may be obtained
from changes in the light distribution resulting from slight
perturbations in the catheter's placement. Related criteria for
turning an LED on/off would be to protect healthy tissue as the
priority over ensuring that the substance in the abnormal tissue is
everywhere photo-activated, in which case L7 may instead be turned
off since it appears to cover healthy as well as abnormal tissue
(or, in the case of when healthy tissue is being protected by
supplying a drug-degrading light energy, L7 would be turned on).
Other criteria for turning LEDs on or off would be the optimization
of the available power. When less LEDs are used, the available
energy flux per LED goes up for a constant source of available
power supplied to the distal portion 12. It may be more effective
to deliver a higher energy flux per LED by turning off LEDs that
may be positioned opposite both healthy and abnormal tissue (rather
than turning on LEDs that illuminate both abnormal and healthy
tissue) so as to ensure photo-activation (or photo-degradation, as
the case may be) of at least some of the photo-sensitive
substance.
[0058] A method for activating photosensitizers absorbed in
abnormal tissue, but not adjacent, healthy tissue is depicted in
the flow diagram of FIG. 4. A photosensitizer is deposited,
injected, etc. into the body such that tissue at the treatment area
absorbs this photo-sensitive substance. Next, the catheter 1 is
delivered to the treatment area, e.g., percutaneously. The balloon
7 is then inflated and pressed against the tissue. This provides a
light path from/to the light detectors and emitters. As such, the
balloon 7 may be thought of as a blood-displacement feature for
displacing blood from the treatment area so that there is a clear
line of sight between a LED/photodiode and opposing tissue.
Preferably, neither the inflation fluid nor the balloon membrane
diffuse, refract or reflect any appreciable amount of light.
[0059] The operator may then initiate the on-board control, e.g.,
supply power to controller 34. When on-board control begins, a
determination is made as to which LEDs are positioned opposite
healthy tissue and/or which LEDs are positioned opposite abnormal
tissue, e.g., lipid-rich tissue such as atheroma which tends to
absorb and scatter more light than healthy tissue. LEDs may
thereafter be controlled by a closed-loop electronic control system
residing at the catheter distal portion 12. The program may be
initiated by communicating a "start" signal from the proximal
portion 14 to the controller 34 or simply energizing a circuit
located at the distal portion 12. Once initiated, LEDs may be
controlled autonomously by the controller 34. According to these
embodiments the operator need not monitor or decide which
individual LEDs are turned on/off during the therapy. For example,
any of the examples of logic and circuit architecture disclosed
earlier, including the controller 34, circuit board 30 (or both)
may be programmed to decide which LEDS should be turned on to
photo-activate the substance in tissue and/or which LED should be
turned off based on, e.g., an electrical signal corresponding to a
threshold reflected light intensity "X", on-off cycling of LEDs,
etc. (as discussed earlier). Further examples follow.
[0060] As depicted in FIG. 4, after initiating the controller 34 a
timer "t" is initially set to a constant T. The controller 34 then
performs a calibration routine 34a because "t=T". This calibration
routine may first turn "on" all LEDs then decide which LEDs to turn
"off". For example, the controller 34 activates all LEDs and then
turns off any LED where the signal produced at the corresponding
photodiode (e.g., photodiode P1 of the LED-photodiode pair (L1, P1)
depicted in FIG. 3A) exceeds a maximum value X (as depicted in
block 34b of FIG. 4). For embodiments of a medical device intended
to supply light energy for purposes of drug degradation (as opposed
to drug-activation), block 34b would instead turn on an LED if the
electrical signal exceeded the value X.
[0061] After this initialization routine, the LEDs that were set to
"ON" are used to photo-activate substance in the tissue while the
remaining LEDs are left off. After a period of time has elapsed
equal to, or exceeding T (as depicted schematically by the counter
"t=t+1" and decision point "t=T?") the calibration routine 34a is
repeated. Preferably, the calibration routine is repeated on a
regular basis to automatically account for any intentional or
unintentional movement of the catheter in the body. Further, it is
contemplated that the calibration routine may be sufficiently brief
to avoid significant unintentional activation or degradation of
photosensitizer should there be intentional or unintentional
movement of the catheter in the body. As such, the light
distribution may automatically update without requiring direct
operator involvement.
[0062] The bandwidth of light used to photo-activate may be NIR,
IR, visible or UV. The catheter 1 may also include a circuit for
communicating a control signal to the operator that indicates the
number of LEDs that the controller has decided should be used to
treat tissue (transmitted over cable 38). From this information the
operator may control/monitor the energy flux per unit area being
supplied to tissue. In other embodiments the controller 34 may be
programmed to control the power supplied to the LEDs to ensure that
the energy flux does not exceed a maximum, or to optimize the LEDs
turned on/off as a function of the range of energy flux needed to
treat tissue, e.g., between 15-50 J/cm.sup.2.
[0063] According to others aspect of the disclosure, a catheter
includes a light source, or is coupled to an extracorporeal light
source. The light emitted from the catheter at its distal portion
may be filtered by a filter provided by the balloon membrane
according to some embodiments. In other embodiments a catheter has
a light emitting member at a location distal and/or proximal of a
balloon. A catheter according to these embodiments may be used to
achieve a desired activation or degradation of a photo-sensitive
substance using light energy. Methods according to these
embodiments include the delivery of a drug coated balloon or DES to
a target tissue.
[0064] Referring to FIG. 5, a balloon catheter 100 is depicted
within a vessel with its balloon in the expanded state. The
catheter 100 is guided to this treatment area along the guide wire
11 (as before). Unless noted below explicitly or implied by the
context of the discussion, as will be appreciated, the catheter 100
possesses the same features as embodiments of catheter 1 discussed
earlier.
[0065] Catheter 100 includes a light source that is capable of
emitting light 120 from body 2b, which as before may extend between
ends 6b, 6a and within the balloon chamber 7a (see FIG. 1). Light
may emit over the entire length of the body 2b, or only at select
portions, such as nearest ends 6a, 6b. The light source may
correspond to an LED array (as described earlier) or fiber optics.
In the later case, a fiber optic bundle may be configured to
transmit light originating at the proximal portion 14 of the
catheter to a location near end 6b, e.g., by passing the fiber
optic bundle through the inflation lumen. From this point, the body
2b may be configured to transmit light from its outer surface.
Light collectors and/or diffusers may be incorporated into body 2b
to improve/enhance the light distribution as it exits the fiber
optics. For example, a focusing lens can first collect light
exiting from the fiber optics, followed by a diffusion lens, which
forms the outer surface of 2b. A diffusion lens can provide uniform
illumination of the surrounding tissue. An LED array may instead be
chosen over fiber optics so that, e.g., light transmission losses
from the proximal portion 14 to the distal portion 12 are reduced.
This LED array may be constructed on the same type of circuit as
discussed earlier in connection with FIGS. 1-3. Additionally, for
embodiments of catheter 100 the array(s) may contain only LEDs,
i.e., the circuit board(s) need not also include photodiode chips;
although in some embodiments photodiodes may be used as this can
provide additional advantages in view of the disclosure. Examples
of suitable light sources for light-emitting catheters are
described in U.S. Pat. No. 7,344,528, U.S. Pat. No. 5,800,478, U.S.
Pat. No. 7,252,677 and U.S. Pat. No. 6,749,623.
[0066] According to embodiments of the catheter 100, the membrane
61 of balloon 60 may have a combination of balloon membrane
material (i.e., the portions 62 and 66b, 66a) that substantially
prevent all wavelengths of light from passing through the membrane
walls, and membrane material, or windows 64b, 64a that permit a
wide or narrow bandwidth of light to pass. As such, tissue may be
exposed to light energy at locations where windows, e.g., 64b and
64a, are present while portion 62 prevents light energy within the
balloon from reaching tissue. Portions 66 may be opaque.
[0067] According to the following example (depicted in FIG. 5), the
catheter 100 is used to supply drug-degrading light energy to
healthy tissue. As such, the light-blocking portion of the balloon
membrane (portion 62) is placed opposite the target tissue and the
windows 64 opposite the healthy tissue. In other embodiments, the
catheter 100 may be configured to provide drug-activating light
energy to a target tissue. For these embodiments, portion 62 may be
made from transparent balloon material and portions 64 from
light-blocking balloon material.
[0068] In the case of supplying drug-degrading light energy
according to some embodiments, a drug, e.g., Everolimus, is
combined with a photosensitizer and deposited on portion 62. The
objective is to deposit a full dosage of active drug to the target
tissue but not the surrounding tissue (designated "adjacent tissue"
in FIG. 5). This is achieved by exposing the adjacent tissue to
light that degrades the drug's potency (due to the activation of a
photosensitizer) should any drug diffuse or otherwise come in
contact with the adjacent, healthy tissue. By this approach an
undesirable presence of the drug at the adjacent tissue can be
dealt with by degrading the drug's effectiveness using light, e.g.,
UV light.
[0069] According to one method the catheter 100 is positioned so
that portion 62 is located at the target tissue. The balloon is
expanded to place the drug (deposited on the surface 62) in contact
with the target tissue. The light source is then activated and
light 120 emits from body 2b. The tissue on each side of the target
tissue is exposed to light since in this case windows 64 are
located near ends 6b, 6a. The target tissue is opposite the
light-blocking membrane portion 62. Therefore, the target tissue
does not receive the drug degrading light whereas the adjacent
tissue does receive this light. After an energy flux has been
achieved sufficient to activate photosensitive material in the
adjacent tissue, the drug's potency in the adjacent tissue is
reduced.
[0070] FIG. 8 is a bar-chart showing the effectiveness of drug
degradation using light. The tests were conducted on Everolimus
combined with a photosensitizer in a solution of methanol. After a
sufficient number of trials were conducted, a mean and standard
deviation of the percent recovery for Everolimus was computed for
each of two cases (as shown). The first case corresponds to the
percent recovery of Everolimus without exposing the solution to UV
light energy (referred to as "EV+Sensitizer+Dark") and the second
case corresponds to the percent recovery of Everolimus when the
solution is exposed to UV light energy (referred to as
"EV+Sensitizer+Light"). As can be seen, there is more than a 3%
reduction in the potency of Everolimus after the solution was
exposed to UV light.
[0071] In some embodiments it may be important or at least
desirable to achieve a 100% degradation, so that one has absolute
control over what tissue is exposed to the drug and which is not.
However, depending on the rate of drug degradation, the toxicity of
the degradation products, light penetration into the tissue, etc.,
it may be difficult or even undesirable to achieve 100%. In other
embodiments, one may attempt to reduce the amount of drug to a
level out of its beneficial therapeutic range, or specifically to a
level below that which produces the undesirable effects we would
like to prevent with this technique. The percent degradation would
depend on the original drug dosing (amount of drug in the tissue)
and the therapeutic window of the drug.
[0072] In one example, a sample available drug was used, which can
be Everolimus. The drug was mixed with a photosensitizer in
methanol, and exposed to a low intensity laser light source at the
wavelength used to activate the photosensitizer. The dark and light
samples were then sent for analysis of total drug concentration via
HPLC (total content assay), which gives how much drug is contained
in a specific volume of solution. The percent recovery is measured
as the concentration of drug recovered divided by the original
concentration of the solution. A low (3%) difference, as depicted
in the illustrative example, may be due to a multitude of factors.
For example, the amount of drug used in the experiment may be so
great as to not reflect a noticeable difference between the exposed
and unexposed. A concentration of 1.5 mg/ml of Everolimus was used
in 18 ml of methanol, which means a total drug content of 27 mg . .
. a typical 28 mm stent contains about 130 ug of Everolimus, which
would be much more sensitive for a small change in drug content.
The laser light source used was of a much lower power (25 mW) than
one that would be used in clinical practice (500 mW), but which was
compensated for by applying a longer exposure time to equal the
comparable light dose that would be used in the clinic. The long
experiment time may lead to a greater amount of natural degradation
in the control (dark) sample, and when considering that the laser
is of a low power to cause any additional degradation, a difference
between the two in the illustrated example may not be as
significant.
[0073] An ideal drug for use would contain a linkage which would
make it more sensitive to either to degradation via light exposure
or a degradation reaction with a reactive oxygen species triggered
by light exposure to the photosensitizer.
[0074] A catheter adapted for being used in a manner consistent
with the disclosure may also be configured with light-emitting
members located proximal, distal or proximal and distal of a
balloon assembly. For example, a catheter 200 depicted in FIG. 6
includes light emitting members 220a and 220b located proximal and
distal of balloon assembly 60. Light emitting members 220a, 220b
may be used to degrade drug that is diffused into, or otherwise
comes in contact with the adjacent tissue. The target tissue is
treated with the drug at full potency when the balloon places
surface 62 (containing the drug-sensitizer combination) against the
target tissue. When the light emitting members (e.g., respective
distal and proximal portion(s) 220a, 220b of catheter shaft, which
may include diffusion lenses coupled to fiber optics or one or more
LED array(s)) are activated, the light, e.g., UV light, degrades
the potency of the drug that is present in the adjacent tissue. One
benefit of a catheter constructed in accordance with the
embodiments relating to FIG. 6 is that a greater amount of adjacent
tissue may be treated with light.
[0075] In other embodiments, a balloon catheter according to the
disclosure may be used in connection with the delivery of Drug
Eluting Stents (DES). For example, a catheter may be configured to
prevent or mitigate the mixing of drugs carried by two DES, or
reduce instances of double-dosing of the same drug when a DES is
placed adjacent to another, previously implanted DES, or when
portions of these stents overlap each other. Referring to the
example depicted in FIG. 7, a catheter 300 delivers DES B to a
treatment area. DES B carries a DRUG B on its outer surface and
will be implanted adjacent a previously implanted DES A. This stent
carried a DRUG A which has begun to perfuse into the tissue (as
shown).
[0076] A balloon assembly 60 portion of catheter 300, which carries
DES B to the treatment site, may include a light-blocking portion
66 of the balloon membrane 61 and a filter, light admitting or
window 64 located at the proximal end, distal end or both ends of
the balloon (also corresponding to ends of DES B). The length of
the window(s) 64 may correspond to the amount of overlap intended
between the two stents, or the expected amount (or rate) of
diffusion of DRUG A and/or DRUG B after the second stent has been
implanted. DES B may span over the window or light emitting portion
of the balloon, or the catheter may have a second light emitting
portion adjacent one or both ends of DES B for illuminating areas
adjacent DES A. In some embodiments DES A may be provided from the
same stent provider as DRUG B, or a different provider. DRUG A may
be the same as DRUG B or different. In some embodiments a stent
delivery catheter may include windows at both ends to reduce the
appearance of "end effects" as discussed earlier.
[0077] Referring again to the balloon catheter of FIG. 5, in some
embodiments the portion 62 may permit a first wavelength of light
to pass through the membrane walls to reach the target tissue,
while portions 64 permit a second wavelength to pass through the
membrane walls to reach adjacent, healthy tissue. For example, a
first portion of a balloon membrane may permit only NIR light to
pass through the walls whereas a second portion allows all light to
reach tissue. Referring again to FIG. 6, in a variation of the
catheter 200, one or more light sources produce light at light
member(s) 220 and within the balloon chamber 7a (see FIG. 1). The
light emitted from light member(s) 220 and from within the balloon
chamber 7a may be broad band light. The balloon membrane, however,
permits only a narrow band of light from passing through its walls,
e.g., NIR. In these examples a drug-coated balloon catheter (or
DES) may use light to both activate a photosensitive drug in target
tissue and degrade that drug's potency in adjacent healthy tissue.
These embodiments may be especially useful when treating
tumors.
[0078] In accordance with the foregoing embodiments, a treatment
agent can include, but is not limited to, an anti-proliferative, an
anti-inflammatory or immune modulating agent, an anti-migratory, an
anti-thrombotic or other pro-healing agent or a combination
thereof.
[0079] The anti-proliferative agent can be a natural proteineous
agent such as cytotoxin or a synthetic molecule or other substances
such as actinomycin D, or derivatives and analogs thereof
(manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue,
Milwaukee, Wis. 53233; or COSMEGEN available from Merck) (synonyms
of actinomycin C1); all taxoids such as taxols, docetaxel, and
paclitaxel, and paclitaxel derivatives; all olimus drugs including
macrolide antibiotics such as tacrolimus, rapamycin (i.e.,
sirolimus) derivatives of which include
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-(3-hydroxy)propyl-rapamycin, 40-O-tetrazole-rapamycin,
40-epi-(N-1-tetrazolyl)-rapamycin (ABT-578 manufactured by Abbott
Laboratories, Abbott Park, Ill.); everolimus (i.e., RAD-001);
FKBP-12 mediated mTOR inhibitors, perfenidone and prodrugs,
co-drugs and combinations thereof.
[0080] The anti-inflammatory agent can be a steroidal
anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, or
a combination thereof. In some embodiments, anti-inflammatory drugs
include, but are not limited to, alclofenac, alclometasone
diproprionate, algestone acetonide, alpha amylase, amcinafal,
amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra,
anirolac, anitrazafen, apazone, balsalazide disodium, bendazac,
benoxaprofen, benzydamine hydrochloride, bromelains, broperamole,
budesonide, carprofen, cicloprofen, cintazone, cliprofen,
clobetasol propionate, clobetasone butyrate, clopirac, cloticasone
propionate, cormethasone acetate, cortodoxone, deflazacort,
desonide, desoximetasone, dexamethasone dipropionate, diclofenac
potassium, diclofenac sodium, diflorasone diacetate, diflumidone
sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide,
drocinonide, endrysone, enlimomab, enolicam sodium, epirizole,
etodolac, etofenamate, felbinac, fenamole, fenbufen fenclofenac,
fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazocort,
flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin
meglumine, fluocortin butyl, fluorometholone acetate, fluquazone,
flurbiprofen, fluretofen, fluticasone propionate, furaprofen,
furobufen, halcinonide, halobetasol propionate, halopredone
acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen
piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen,
indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam,
ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol
etabonate, meclofenamate sodium, meclofenamic acid, meclorisone
dibutyrate, mefenamic acid, mesalamine, meseclazone,
methylprednisolone suleptanate, morniflumate, nabumetone, naproxen,
naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,
orpanoxin, oxaprozin, oxyphenbutazone sodium glycerate,
perfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine,
pirprofen, prednazate, prifelone, prodolic acid, proquazone,
proxazole, proxazole citrate, rimexolone, romazarit, salcolex,
salnacedin, salsalate, sanguinarium chloride, seclazone,
sermetacin, sudoxicam, sulindac, suprofen, talmetacin,
talniflumate, talosalate, tebufelone, tenidap, tenidap sodium,
tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol
pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate,
zidometacin, zomepirac sodium, aspirin (acetylsalicyclic acid),
salicyclic acid, corticosteroids, glucocorticoids, tacrolimus,
pimecorlimus, prodrugs thereof, co-drugs thereof, and combinations
thereof.
[0081] These agents can also have anti-proliferative and/or
anti-inflammatory properties or can have other properties such as
antineoplastic, antiplatelet, anti-coagulant, anti-fibrin,
antithrombonic, antimitotic, antibiotic, antiallergic, antioxidant
and/or cytostatic (i.e. cell-suppressing) properties. Examples of
suitable treatment and prophylactic agents include synthetic
inorganic and organic compounds, proteins and peptides,
polysaccharides and other sugars, lipids, and DNA and RNA nucleic
acid sequences having therapeutic, prophylactic or diagnostic
activities. Nucleic acid sequences include genes, antisense
molecules which bind to complementary DNA to inhibit transcription,
and ribozymes. Some other examples of other bioactive agents
include antibodies, receptor ligands, enzymes, adhesion peptides,
blood clotting factors, inhibitors or clot dissolving agents such
as streptokinase and tissue plasminogen activator, antigens for
immunization, hormones and growth factors, oligonucleotides such as
antisense oligonucleotides and ribozymes and retroviral vectors for
use in gene therapy. Examples of antineoplastics and/or
antimitotics include methotrexate, azathioprine, vincristine,
vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.,
Adriamycin.RTM. from Pharmacia & Upjohn, Peapack, N.J.), and
mitomycin (e.g., Mutamycin.RTM. from Bristol Myers Squibb Co,
Stamford, Conn.). Examples of such antiplatelets, anticoagulants,
antifebrin, antithrombins include sodium heparin, low molecular
weight heparins, heparinoids, hirudin, argatroban, forskolin,
vapiprost, prostacyclin, and prostacyclin analogues, dextran,
D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist antibody, recombinant hirudin, thrombin inhibitors such
as Angiomax a (Biogen, Inc. Cambridge, Mass.), calcium channel
blockers (such as nifedipine), colchicine, fibroblast growth factor
(FGF) antagonists, fish oil (omega 3-fatty acid), histamine
antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a
cholesterol lowering drug, brand name Mevacor.RTM. from Merck &
Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such
as those specific for Platelet-Derived Growth Factor (PDGF)
receptors), nitroprusside, phosphodiesterase inhibitors,
prostaglandin inhibitors, suramin, serotonin blockers, steroids,
thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist),
nitric oxide or nitric oxide donors, super oxide dismutases, super
oxide dismutase mimetic,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
estradiol, dietary supplements such as various vitamins, and a
combination thereof. Examples of cytostatic substances include
angiopeptin, angiotensin converting enzyme inhibitors such as
captopril (e.g., Capoten.RTM. and Capozide.RTM. from Bristol Myers
Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g.
Prinivil.RTM. and Prinzide.RTM. from Merck & Co., Inc.,
Whitehouse Station, N.J.). An example of an antiallergic agent is
permirolast potassium. Other therapeutic substances or agents which
may be appropriate include .alpha.-interferon, and genetically
engineered epithelial cells. The foregoing substances are listed by
way of example and are not meant to be limiting. Other treatment
agents which are currently available or that may be developed in
the future are equally applicable.
[0082] In accordance with the foregoing embodiments, the reactive
oxygen producing and light emitting photosensitizers include, but
are no limited to: Pyrrole-derived macrocyclic compounds, naturally
occurring or synthetic porphyrins or derivatives thereof, naturally
occurring or synthetic chlorines and derivatives thereof, naturally
occurring or synthetic bacteriochlorins and derivatives thereof,
synthetic isobacteriochlorins and derivatives thereof,
phthalocyanines and derivatives thereof, naphthalocyamines and
derivatives thereof, porphycenes and derivatives thereof,
naphthalocyanines and derivatives thereof, porphycyanines and
derivatives thereof, pentaphyrin and derivatives thereof,
sapphyrins and derivatives thereof, texaphyrins and derivatives
thereof, phenoxazine dyes and derivatives thereof, phenothiazines
and derivatives thereof, chalcoorganapyrylium dyes and derivatives
thereof, triarylmethanes and derivatives thereof, rhodamines and
derivatives thereof, fluorescenes and derivatives thereof,
azaporphyrins and derivatives thereof, benzochlorins and
derivatives thereof, purpurins and derivatives thereof,
chlorophylls and derivatives thereof, squaraines and derivatives
thereof, hypericin and derivatives thereof, verdins and derivatives
thereof, xanthenes and derivative thereof, etc.
[0083] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
* * * * *
References