U.S. patent number RE46,504 [Application Number 15/088,702] was granted by the patent office on 2017-08-08 for light delivery system.
This patent grant is currently assigned to PURDUE PHARMACEUTICAL PRODUCTS L.P.. The grantee listed for this patent is PURDUE PHARMACEUTICAL PRODUCTS L.P.. Invention is credited to William Louis Barnard, James C. Chen, Jonathan S. Dahm, David B. Shine.
United States Patent |
RE46,504 |
Dahm , et al. |
August 8, 2017 |
Light delivery system
Abstract
A light delivery system to provide light treatment to a patient
includes a catheter assembly having a plurality of light sources
that transmit light towards a target site within a patient. In one
embodiment, the light delivery system has a plurality of light
sources mounted to a flexible transparent base that extends at
least partially through a distal tip of the catheter assembly. The
light sources can be wire bonded or mounted in a flip chip
arrangement onto the base. In one embodiment to produce the distal
tip, an array of light energy sources can be held by an array of
holders of a fixture device. A vacuum is applied to secure each
light energy source in a corresponding holder. While the vacuum is
applied, the energy sources are electrically connected by wire
bonding. The vacuum can be reduced or stopped thereby permitting
removal of the light energy sources from the fixture device.
Inventors: |
Dahm; Jonathan S. (Key Largo,
FL), Barnard; William Louis (Maple Valley, WA), Chen;
James C. (Clyde Hill, WA), Shine; David B. (Littleton,
CO) |
Applicant: |
Name |
City |
State |
Country |
Type |
PURDUE PHARMACEUTICAL PRODUCTS L.P. |
Stamford |
CT |
US |
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Assignee: |
PURDUE PHARMACEUTICAL PRODUCTS
L.P. (Stamford, CT)
|
Family
ID: |
39105914 |
Appl.
No.: |
15/088,702 |
Filed: |
April 1, 2016 |
PCT
Filed: |
October 11, 2007 |
PCT No.: |
PCT/US2007/081131 |
371(c)(1),(2),(4) Date: |
February 05, 2010 |
PCT
Pub. No.: |
WO2008/046015 |
PCT
Pub. Date: |
April 17, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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60851141 |
Oct 11, 2006 |
|
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Reissue of: |
12445061 |
Oct 11, 2007 |
8685005 |
Apr 1, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N
5/062 (20130101); A61N 5/062 (20130101); A61N
5/0601 (20130101); A61N 5/0601 (20130101); A61N
2005/0652 (20130101); A61B 18/24 (20130101); A61N
2005/0652 (20130101); A61B 18/24 (20130101) |
Current International
Class: |
A61B
18/18 (20060101); A61N 5/06 (20060101); A61N
1/30 (20060101); A61B 18/24 (20060101) |
Field of
Search: |
;606/2-19 ;604/4,21
;600/156-183 ;607/88-94 ;128/898 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0266038 |
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May 1988 |
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EP |
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0755697 |
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Jan 1997 |
|
EP |
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08-505803 |
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Jun 1996 |
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JP |
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11-186590 |
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Jul 1999 |
|
JP |
|
11-242451 |
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Sep 1999 |
|
JP |
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2002-222998 |
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Aug 2002 |
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JP |
|
2005-129821 |
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May 2005 |
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JP |
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WO-9505214 |
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Feb 1995 |
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WO |
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9743965 |
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Nov 1997 |
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WO |
|
0207629 |
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Jan 2002 |
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WO |
|
0241364 |
|
May 2002 |
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WO |
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2004082736 |
|
Sep 2004 |
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WO |
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2006031934 |
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May 2006 |
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WO |
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WO-2008046015 |
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Apr 2008 |
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WO |
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Other References
Jonathan S. Dahm, "Flexible Intra-Body Photo-Therapy Device
Containing Transparent Substrate LED's on a Transparent Polymetric
Substrate," U.S. Appl. No. 60/581,167, filed Jun. 17, 2004, 7
pages. cited by applicant .
Phillip Burwell, "Flexible LED Arrays for Phototherapeutic
Procedures," U.S. Appl. No. 60/640,382, filed Dec. 30, 2004, 13
pages. cited by applicant .
PCT International Search Report, mailed Mar. 19, 2008, for
PCT/US2007/081131, 13 pages. cited by applicant .
Japan Patent Office, Official Office Action, counterpart JP Patent
Application 2009-532583, mailed Sep. 5, 2012, 12 pages (includes
English Translation). cited by applicant .
International Searching Authority, Written Opinion, PCT Application
PCT/US2007/081131, Apr. 11, 2009, 6 pages. cited by applicant .
Noguchi, H., "The Photodynamic Action of Eosin and Erythrosin upon
Snake Venom," Journal of Experimental Medicine, 1906, vol. 8, pp.
252-266. cited by applicant .
Bolande et al., "Photodynamic Action," Archives of Pathology, 1963,
vol. 75, pp. 115-122. cited by applicant .
Ballio et al., "Research Progress in Organic-Biological and
Medicinal Chemistry," Societa Editoriale Farmaceutica, 1964, vol.
I, pp. 260-336. cited by applicant .
Tapper et al., "Photosensitivity from Chlorophyll-Derived
Pigments," Journal of the Science of Food and Agriculture, 1975,
vol. 26, pp. 277-284. cited by applicant .
Ison et al., "Phototoxicity of Quinoline Methanols and Other Drugs
in Mice and Yeast," The Jounral of Investigative Dermatology, 1969,
vol. 52, No. 2, pp. 193-198. cited by applicant .
Eskins et al., "Sensitized Photodegradation of Cellulose and
Cellulosic Wastes," Photochemistry and Photobiology, 1973, vol. 18,
pp. 195-200. cited by applicant .
Krinsky, N., "Cellular Damage Initiated by Visible Light," Symposia
of Society for General Microbiology, 1976, pp. 209-239. cited by
applicant .
Song et al., "Photochemistry and Photobiology of Psoralens,"
Photochemistry and Photobiology, 1979, vol. 29, pp. 1177-1197.
cited by applicant .
Haas et al., "Photodynamic Effects of Dyes on Bacteria," Mutation
Research, 1979, vol. 60, pp. 1-11. cited by applicant .
Webb et al., "Photodynamic Effects of Dyes on Bacteria," Mutation
Research, 1979, vol. 59, pp. 1-13. cited by applicant .
Barltrop et al., "Potential Management of Florida Red Tide Through
Selective Photodynamic Action," Journal of Environmental Science
and Health, 1980, AI5(2), pp. 163-171. cited by applicant .
Parrish, J., "Photobiologic Considerations in Photoradiation
Therapy," Proceedings of a Porphyrin Photosensitization Workshop,
Sep. 28-29, 1981, pp. 91-108. cited by applicant .
Bertoloni et al., "Photosensitizing Activity of Water- and
Lipid-Soluble Phthalocyanines on Escherichia coli," FEMS
Microbiology Letters 71, 1990, pp. 149-156. cited by applicant
.
Gulliya et al., "Tumor Cell Specific Dark Cytotoxicity of
Light-Exposed Merocyanine 540: Implications for Systematic Therapy
Without Light," Photochemistry and Photobiology, 1990, vol. 52, No.
4, pp. 831-838. cited by applicant .
Kennedy et al., "Photodynamic Therapy with Endogenous
Protoporphyrin," Journal of Photochemistry and Photobiology, B:
Biology, 1990, No. 6, pp. 143-148. cited by applicant .
Gilliya et al., "Preactivation--A Novel Antitumor and Antiviral
Approach," European Journal of Cancer, 1990, vol. 26, No. 5, pp.
551-553. cited by applicant .
Chang et al., "Synegy between Preactivated Photofrin II and
Tamoxifin in Killing Retrofibroma, Pseudomyxoma and Breast Cancer
Cells," European Journal of Cancer, 1991, vol. 27, No. 8, pp.
1034-1038. cited by applicant .
Doiron, D., "Instrumentation for Photodynamic Therapy," Laser
Systems for Photobiology and Photomedicine, 1991, pp. 229-230.
cited by applicant .
Chanh et al., "Preactivated Merocyanin 540 Inactives HIV-1 and SIV:
Potential Therapeutic and Blood Banking Application," Journal of
Acquired Immune Deficiency Syndrome, 1992, pp. 188-195. cited by
applicant .
Gulliya et al., "Preactivation: A New Concept for Generation of
Photoproducts for Potential Therapeutic Applications," Seminars in
Surgical Oncology, Jul./Aug. 1992, vol. 8, No. 4, pp. 250-253.
cited by applicant .
Ma et al., "Effects of Light Exposure on the Uptake of Photofrin II
in Tumors and Normal Tissues," International Journal of Cancer,
1992, vol. 52, pp. 120-123. cited by applicant .
Pervaiz et al., "Protein Damage by Photoproducts of Merocyanine
540," Free Radical Biology & Medicine, 1992, vol. 12, pp.
389-396. cited by applicant .
Labrousse et al., "Photodynamic Killing of Dictyostelium disoideum,
Amoebae Mediated by 4', 5'-Diiodofluorescein Isothiocyanate
Dextran. A Strategy for the Isolation of Thermoconditional
Endocytosis Mutans," Photochemistry and Photobiology, 1993, vol.
67, No. 3, pp. 531-537. cited by applicant .
Lytle et al., "Light Emitting Diode Source for Photodynamic
Therapy," SPIE, 1993, vol. 1881, pp. 180-188. cited by applicant
.
Schlager et al., "Immunophototherapy for the Treatment of Cancer of
the Larynx," SPIE, 1993, vol. 1881, pp. 148-158. cited by applicant
.
Nagae, T. et al., "Endovascular Photodynamic Therapy Using
Mono-L-Aspartyl-Chlorin e6 to Inhibit Intimal Hyperplasi in
Balloon-Injured Rabbit Arteries," Lasers in Surgery and Medicine
28: 381-388, 2001, Wiley-Liss, Inc. cited by applicant .
Japan Patent Office, Official Office Action, counterpart JP Patent
Application No. 2009-532583, mailed Jun. 26, 2013, 10 pages. cited
by applicant.
|
Primary Examiner: Wehner; Cary
Attorney, Agent or Firm: Troutman Sanders LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit under 35 U.S.C. .sctn.119(e) of
U.S. Provisional Patent Application No. 60/851,141 filed Oct. 11,
2006. This provisional application is incorporated herein by
reference in its entirety.
Claims
What is claimed is:
1. A catheter assembly for performing light therapy on a subject,
the assembly comprising: a control system adapted to be operated by
a user; a catheter body extending from the control system, the
catheter body dimensioned for placement within the subject; and a
distal tip at an end of the catheter body, the distal tip including
a transparent substrate having a plurality of locking features,
wherein the transparent substrate is a substantially flat strip,
wherein the entire flat strip comprises a transparent material, an
array of spaced apart light sources for emitting light mounted on
the flat strip and controlled by the control system, and a flexible
outer member encapsulating both the substrate and the light
sources, wherein portions of the flexible outer member pass through
the locking features to lock the flexible outer member to the
substrate, wherein the substantially flat strip carries a
conductive connector adapted to provide power to the array of light
sources and transmits most of the light emitted from the array of
light sources towards the substrate such that a sufficient amount
of light is transmitted through the substrate and the outer member
to activate a therapeutically effective amount of treatment agent
in the subject.
2. The catheter assembly of claim 1 wherein the outer member has a
cross-sectional width that is less than about 1.25 mm.
3. The catheter assembly of claim 1 wherein the substrate has a
substantially rectangular cross-sectional shape.
4. A .[.device.]. .Iadd.kit .Iaddend.for performing a medical
treatment, the .[.device.]. .Iadd.kit .Iaddend.comprising: .Iadd.a
photoreactive agent comprising talaporfin sodium; .Iaddend. a
plurality of light sources capable of emitting light .[.for
treating a patient.]. .Iadd.to activate the photoreactive
agent.Iaddend.; a distal tip having a substantially flat strip and
being dimensioned for placement within a patient, wherein the light
sources are coupled to a section of the substantially flat strip,
wherein substantially all of the section comprises a transmissive
material such that a substantial portion of the light emitted from
the plurality of light sources directed towards the strip is
transmitted through the strip when the light sources are energized;
and an outer member surrounding and encapsulating the strip and the
plurality of light sources.
5. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the
plurality of light sources is coupled to a flat surface of the
strip.
6. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the outer
member is dimensioned for percutaneous delivery to a target region
within the patient.
7. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the outer
member is made of plastic and encapsulates the strip and the
plurality of light sources.
8. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the outer
member has a cross-sectional width that is less than about 1.25
mm.
9. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the outer
member has a cross-sectional width that is less than about 1
mm.
10. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the
outer member has a cross-sectional width that is less than about
0.75 mm.
11. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein one pair
of leads electrically connects each adjacent pair of light
sources.
12. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the
plurality of light sources are LEDs mounted to the strip in a flip
chip arrangement.
13. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the
strip comprises a plurality of locking structures, at least one of
the locking structures positioned between each adjacent pair of
light sources.
14. The .[.device.]. .Iadd.kit .Iaddend.of claim 13, wherein the
outer member is an encapsulant surrounding the strip and light
sources, wherein each locking structure is a through hole that
receives a portion of the encapsulant.
15. The .[.device.]. .Iadd.kit .Iaddend.of claim 4, further
comprising: means for electrically connecting the plurality of
light sources.
16. The .[.device.]. .Iadd.kit .Iaddend.of claim 15 wherein the
means for electrically connecting the plurality of light sources
comprises traces in communication with the light sources, the
traces arranged to provide activation of a selected number of the
light sources.
17. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the
outer member physically contacts the plurality of light sources and
the substrate.
18. The .[.device.]. .Iadd.kit .Iaddend.of claim 4, further
comprising a conductive connector that provides power to the
plurality of light sources, the conductive connector being carried
by the strip.
19. The .[.device.]. .Iadd.kit .Iaddend.of claim 18 wherein the
conductive connector and the light sources are directly connected
to the strip.
20. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the
light sources output light through portions of the distal tip on
opposite sides of the strip.
21. The .[.device.]. .Iadd.kit .Iaddend.of claim 4 wherein the
light sources emit light in different direction such that light is
emitted away from an upper face of the strip and an opposing lower
face of the strip.
22. The .[.device.]. .Iadd.kit .Iaddend.of claim 4, further
comprising an optically transparent adhesive that couples the light
sources to the section of the substantially flat, transparent
support.
23. The .[.device.]. .Iadd.kit .Iaddend.of claim 4, further
comprising connectors that electrically connect the light sources
together, wherein the connectors are spaced apart from the
strip.
24. A method of producing a catheter for treating a patient, the
method comprising: coupling a plurality of light sources onto a
substantially flat strip, the light sources being spaced from one
another with respect to a longitudinal length of the substantially
flat strip and mounted on a longitudinal section of the flat strip,
wherein substantially all of the longitudinal section of the flat
strip comprises a transparent material such that light from the
light sources passes through the flat strip; connecting the
plurality of light sources to a power source for energizing the
plurality of light sources; and placing an outer body around the
flat strip and plurality of light sources coupled thereto, the
outer body configured for positioning with a patient at a selected
treatment location.
25. The method of claim 24 wherein the coupling of the plurality of
light sources comprises mounting a series of LEDs upon the flat
strip with a bonding material.
26. The method of claim 24 wherein the connecting of the plurality
of light sources comprises connecting adjacent light sources with a
pair of leads.
27. The method of claim 26 wherein each light source has a first
side and an opposing second side, the first side is mounted to the
flat strip and the leads are connected to the second side.
28. The method of claim 24 wherein the coupling of the plurality of
light sources to the flat strip comprises: coupling a pair of
electrodes of each light source to a corresponding pair of mounting
pads on the flat strip.
29. The method of claim 24, further comprising: placing the light
sources in an array of holders of a fixture device; electrically
coupling the light sources together while the light sources are
retained in the holders; after coupling the light sources together,
removing the light sources from the fixture device.
30. The method of claim 29, further comprising applying a vacuum
such that the light sources are pulled into corresponding
holders.
31. A method of manufacturing a catheter for treating a patient,
the method comprising: placing a light transmission assembly in a
lumen of an outer member, the light transmission assembly
comprising a plurality of light sources coupled to a transparent
flat section of a substantially flat strip positioned in the outer
member, wherein the light sources are positioned to output light
that travels through the transparent flat section of the flat
strip; and after the light transmission assembly is in the outer
member, thermally encapsulating the light transmission assembly in
the outer member.
32. The method of claim 31 wherein the thermal encapsulation of the
light transmission assembly includes melting the outer member onto
the light transmission assembly.
33. The method of claim 31 wherein the thermal encapsulation of the
light transmission assembly includes placing flowable material into
the lumen of the outer member between the light transmission
assembly and the outer member, and reflowing at least one of the
flowable material and the outer member after placing the flowable
material into the lumen of the outer member.
34. The method of claim 31 wherein the entire strip comprises an
optically transparent material.
35. The method of claim 31 wherein the strip comprises windows
positioned beneath the light sources.
36. A method of treating .[.visceral adipose.]. tissue, the method
comprising: .Iadd.providing a photoreactive agent comprising
talaporfin sodium to a patient;.Iaddend. providing a catheter
having a distal end with a plurality of light sources, a
substantially flat and transparent strip, and an outer member,
wherein the distal end is sufficiently flexible for placement
within .[.a.]. .Iadd.the .Iaddend.patient, the light sources are
carried by transparent material of the transparent strip, the
transparent strip and the light sources are positioned within the
outer member; advancing the distal end of the catheter through the
patient until the distal end is proximate to the .[.visceral
adipose.]. tissue; and illuminating the .[.visceral adipose.].
tissue using the plurality of light sources such that light from
the light sources travels through portions of the transparent strip
carrying the light sources.
37. The method of claim 36 wherein illuminating the .[.visceral
adipose.]. tissue with the plurality of light sources comprises
activating .[.a treatment.]. .Iadd.the photoreactive .Iaddend.agent
in the .[.visceral adipose.]. tissue so as to destroy at least a
portion of the .[.adipose.]. tissue.
38. A catheter for treating visceral adipose tissue, the catheter
comprising: a distal tip dimensioned for delivery through a
patient, the distal tip being adapted to emit a sufficient amount
of light to activate treatment agent in the visceral adipose tissue
when the distal tip is in a treatment position, which is proximate
to the adipose tissue, the distal tip including a cover, a
substantially flat transparent strip carrying a conductive
connector, a plurality of light sources coupled to a substantially
flat and transparent section of the transparent strip such that the
conductive connector delivers power to the plurality of light
sources, the cover surrounding the light sources and the
transparent section of the transparent strip, wherein substantially
all of the transparent section of the transparent strip comprises a
transparent material; and a main body extending from the distal
tip, the main body dimensioned for percutaneous delivery of the
distal tip to the treatment position.
39. The catheter of claim 38 wherein the energized distal tip emits
sufficient amount of light to activate treatment agent in the
visceral adipose tissue to destroy the visceral adipose tissue
illuminated by the distal tip.
40. A method of manufacturing a catheter for treating a patient,
the method comprising: coupling a plurality of light sources to a
portion of a substantially flat transmissive strip, the entire
portion of the strip carrying the light sources comprises a
transmissive material; electrically coupling together the plurality
of light sources using a conductive connector coupled to the
portion of the strip such that a power source can energize the
plurality of light sources; and forming an outer body about the
strip and plurality of light sources coupled thereto, the strip of
transmissive material extending longitudinally along the outer body
and between the plurality of light sources, the outer body
dimensioned for placement within a patient.
41. The method of claim 40 wherein electrically coupling together
the plurality of light sources comprises connecting adjacent light
sources with a pair of leads of the conductive connector.
42. The method of claim 40, further comprising: coupling a power
source to the plurality of light sources, the power source capable
of simultaneously energizing a substantial number of the light
sources.
43. A .[.device.]. .Iadd.kit .Iaddend.for performing a medical
treatment, the device comprising: .Iadd.a photoreactive agent
comprising talaporfin sodium;.Iaddend. a plurality of light sources
capable of emitting light .[.for treating a patient.]. .Iadd.to
activate the photoreactive agent.Iaddend.; a substantially flat and
transparent support made of a transmissive material, the support
carrying the plurality of light sources such that light emitted
from the plurality of light sources directed towards the support is
transmitted through portions of the support carrying the light
sources when the light sources are energized; and an outer member
dimensioned for placement in .[.the.]. .Iadd.a .Iaddend.patient and
encapsulating the plurality of light sources and the support, the
plurality of light sources physically contacting and being embedded
in the outer member.
44. The .[.device.]. .Iadd.kit .Iaddend.of claim 43 wherein at
least one of the light sources extends across most of a width of
the transparent support.
45. The .[.device.]. .Iadd.kit .Iaddend.of claim 43, further
comprising an optically transparent adhesive that couples the light
sources to the support.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to a light delivery system
useable for medical treatment, such as light therapy for the
treatment of proliferative diseases.
2. Description of the Related Art
Light therapy includes photodynamic therapy (PDT) which is a
process whereby light of a specific wavelength or waveband is
directed toward a target cell or cells that have been rendered
photosensitive through the administration of a photo-reactive,
photo-initiating, or photosensitizing agent. This photo-reactive
agent has a characteristic light absorption waveband and is
commonly administered to a patient via intravenous injection, oral
administration, or by local delivery to the treatment site. It is
known that abnormal cells in the body may selectively absorb
certain photo-reactive agents to a greater extent than normal for
healthy cells. Once the abnormal cells have absorbed and/or
molecularly joined with the photo-reactive agent, the abnormal
cells can then be treated by exposing those cells to light of an
appropriate wavelength or waveband that substantially corresponds
to the absorption wavelength or waveband of the photo-reactive
agent.
The objective of PDT may be either diagnostic or therapeutic. In
diagnostic applications, the wavelength of light is selected to
cause the photo-reactive agent to fluoresce as a means to acquire
information about the targeted cells without damaging the targeted
cells. In therapeutic applications, the wavelength of light
delivered to the targeted cells treated with the photo-reactive
agent causes the agent to undergo a photochemical reaction with
oxygen in the localized targeted cells, to yield free radical
species (such as singlet oxygen), which cause localized cell lysis
or necrosis.
PDT has therefore proven to be an effective oncology treatment for
destroying targeted cancerous cells. In addition, PDT has been
proposed as a treatment for other ailments, some of which are
described in Applicant's co-pending patent application U.S.
Publication No. 2005/0228260 (U.S. patent application Ser. No.
10/799,357, which is hereinafter referred to as the '357 patent
application).
One type of light delivery system used for PDT treatments comprises
the delivery of light from a light source, such as a laser, to the
targeted cells using a single optical fiber delivery system with
special light-diffusing tips. This type of light delivery system
may further include single optical fiber cylindrical diffusers,
spherical diffusers, micro-lensing systems, an over-the-wire
cylindrical diffusing multi-optical fiber catheter, and a
light-diffusing optical fiber guidewire. This light delivery system
generally employs a remotely disposed high-powered laser or solid
state laser diode array, coupled to optical fibers for delivery of
the light to the targeted cells. However, the use of laser light
sources has several drawbacks, such as relatively high capital
costs, relatively large size equipment, complex operating
procedures, and safety issues in working with and around
high-powered lasers.
The '357 patent application addresses some of these concerns and
also addresses the desire to develop a light-generating apparatus
that can be secured within a blood vessel or other orifice. The
securing mechanism of such an apparatus would also be capable of
removing light absorbent or light blocking materials, such as
blood, tissue, or another object from the light path between the
targeted cells and the light transmitters. Securing the apparatus
within a blood vessel, for example, can be achieved with an
inflatable balloon catheter that matches the diameter of the blood
vessel when the balloon is inflated.
An introducing sheath having a lumen extending therethrough to
create a passageway for insertion of other instruments into a
patient's body through the sheath may be used with the light
delivery system. One type of introducing sheath is described in
another one of Applicant's co-pending patent applications, PCT
Application No. PCT/US2005/032851. In general, this type of
introducing sheath surrounds a penetrating device, which is
introduced into the body and then removed, leaving the sheath
behind as a passageway. One such instrument that can be inserted
through the sheath is a light catheter for PDT treatment.
The light source for the light system used for PDT treatments may
also be light emitting diodes (LEDs). Arranged LEDs form a light
bar for the light system, where the LEDs may be either wire bonded
or electrically coupled utilizing a "flip chip" technique that is
used in arranging other types of semiconductor chips on a
conductive substrate. Various arrangements and configurations of
LEDs are described in U.S. Pat. Nos. 6,958,498; 6,784,460; and
6,445,011; and also in the '357 patent application.
BRIEF SUMMARY OF THE INVENTION
The embodiments described herein are generally related to a light
delivery system usable for treating a patient by light therapy. As
used herein, the term "light therapy" is to be construed broadly to
include, without limitation, methods of treating a patient with
light applied externally and/or internally. Light therapy can be
used to treat various types of medical conditions, such as
proliferative diseases including cancer. The light delivery system
can have a relatively simple construction to reduce production time
and fabrication costs. In some embodiments, the light delivery
system comprises a catheter having a light bar, which is formed by
a series of light sources positioned along a mounting base. The
light bar is capable of delivering a sufficient amount of light to
effectively treat target tissue. In one embodiment, the light bar
is positioned within a distal tip of the catheter.
The distal tip is preferably flexible such that the distal tip can
be twisted, bent, rolled or otherwise distorted. Thus, the distal
tip can assume various positions during treatment without adversely
affecting performance of the catheter or traumatizing the patient.
In other embodiments, the distal tip is semi-rigid or rigid and is
particularly well suited for delivery along somewhat linear
delivery paths. The semi rigid or rigid distal tip can maintain its
shape throughout the entire delivery process.
In some embodiments, a light delivery system for treating a patient
includes a catheter having one or more light sources capable of
transmitting light. The light sources can be energized in situ so
as to output radiative energy. In some embodiments, the light
sources are LEDs that form a light bar. The LEDs can be linearly
spaced along a distal end of the catheter. In some variations, the
LEDs are mounted to a mounting member which is sufficiently
flexible to bend through an angle of at least 180.degree.,
160.degree., 140.degree., 100.degree., 90.degree., 80.degree., or
ranges encompassing such angles. In some variations, the mounting
member is substantially optically transparent for transmitting
light emitted by the LEDs.
In some embodiments, the light delivery system is a low profile
catheter that is used to treat remote target region(s) of a
patient. The catheter is sufficiently flexible so as to permit
delivery along a tortuous path through the patient in order to
locate a distal end of the catheter at the desired remote target
region.
In some embodiments, a device for performing a medical treatment
comprises a plurality of light sources capable of emitting light
for treating a patient and a distal tip. The distal tip has an
elongate base and is dimensioned for placement within a patient.
The base can comprise a transmissive material. In some embodiments,
the device can be flexible, semi rigid, and/or rigid.
In other embodiments, a device for performing a medical treatment
is provided. The device comprises a plurality of light sources
capable of emitting light for treating a patient; and a distal tip
has an elongate base and is sufficiently flexible for placement
within a patient, the base comprises a transmissive material such
that a substantial portion of the light emitted from the plurality
of light sources directed towards the base is transmitted through
the base when the light sources are energized, the plurality of
light sources being mounted upon the base.
In some embodiments, a method of producing a catheter for treating
a patient is provided. The method comprises coupling a plurality of
light sources onto a transparent elongate support, the light
sources being spaced from one another; connecting the plurality of
light sources such that a power source energizes the plurality of
light sources; and placing an outer body around the elongate
support and plurality of light sources mounted thereto, the outer
body configured for positioning with a patient at a selected
treatment location.
In some embodiments, a method of forming a light delivery system
for treating a patient is provided. The method comprises placing an
array of light energy sources in an array of holders of a fixture
device, the light energy sources configured to treat a patient when
energized in situ; electrically coupling the light energy sources
together while the light energy sources are retained in the
holders; after coupling the light energy sources together, removing
the light energy sources from the fixture device; and encapsulating
the array of light energy sources within an outer body, the outer
body dimensioned for placement within a patient.
The light delivery systems described herein are well suited for
other uses. For example, the light delivery systems can be used to
improve lighting conditions during manufacturing processes,
installation processes, repair processes, and the like. In some
embodiments, the light delivery system can be used in combination
with a viewing system (e.g., a camera, optical fibers, etc.).
During operation of the viewing system, the light delivery system
can provide adequate illumination for proper viewing. As such, the
light delivery system can be used in the aerospace industry,
electronics industry, construction, and other industries or
settings that may require viewing in relatively small and/or remote
locations having limited access, for example.
The light delivery systems can be snaked through conduits, piping,
electrical components, walls, lumens, body vessels (e.g., the
vascular system), and the like to provide flexibility in gaining
access to regions of interest. For the sake of convenience, the
light delivery systems will be discussed primarily with respect to
medical uses.
In some embodiments, a light delivery apparatus can be used to
treat a target site of tissue to promote tissue growth (e.g., cell
division, cell growth or enlargement, etc.), increase the rate of
healing, improve circulation, reduce or minimize pain, relieve
stiffness, and the like. The light delivery apparatus can
illuminate different types of tissue, such as muscle, bone,
cartilage, or other suitable tissue, without using a treatment
agent. One or more light sources of the light delivery apparatus
can be configured to emit light with near-infrared or infrared
wavelengths. This light itself can cause tissue growth.
Alternatively, the light delivery apparatus can be used in
combination with growth enhancers, growth factors, and the
like.
The light delivery apparatus can also be used to destroy tissue by
emitting energy that causes cell destruction. One or more energy
sources of the light delivery apparatus can be activated to
generate enough heat for cell destruction. If the energy sources
are LEDs, the LEDs, when activated, can generate a sufficient
amount of heat to cause tissue damage. In other embodiments, the
energy sources can emit ultraviolet light that destroys the target
cells. Such embodiments are especially well suited for destroying a
thin layer of tissue without using a treatment agent or damaging an
underlying layer of tissue.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
In the drawings, identical reference numbers identify similar
elements or acts. The sizes and relative positions of elements in
the drawings are not necessarily drawn to scale. For example, the
shapes of various elements and angles may not be drawn to scale,
and some of these elements may be arbitrarily enlarged and
positioned to improve drawing legibility.
FIG. 1 is a side elevational view of a light delivery system having
a catheter assembly and control system, according to one
illustrated embodiment.
FIG. 2A is a side elevational view of a distal end of the catheter
assembly of FIG. 1, where the distal end includes an array of light
sources mounted to an elongate base. Internal components are shown
in dashed line.
FIG. 2B is a top schematic view of the distal end of the catheter
assembly of FIG. 1.
FIG. 3A is a side elevational view of the elongate base of FIG.
2A.
FIG. 3B is a top elevational view of the elongate base of FIG.
3A.
FIGS. 3C to 3E are axial cross-sectional views of different
embodiments of bases suitable for carrying an array of light
sources.
FIG. 4 is a side elevational view of an array of light sources
mounted to the base of FIGS. 3A and 3B.
FIGS. 5A and 5B are side and top elevational views, respectively,
of a light transmission system, where wires connect adjacent light
sources.
FIG. 6 is a side schematic view of a distal end of a catheter
assembly having light sources which are flip chip mounted to an
elongate base, according to one illustrated embodiment.
FIG. 7 is a top elevational view of the base of FIG. 6.
FIG. 8A is a side elevational view of one light source positioned
above the base of FIG. 7.
FIG. 8B is a side elevational view of the light source of FIG. 8A
after the light source has been assembled with the base.
FIG. 9 is a top elevational view of an array of light sources
linearly mounted to an upper face of the base.
FIG. 10 is a side elevational view of a light source mounted above
an aperture extending through a base, according to one illustrated
embodiment.
FIG. 11 is a side schematic view of a distal end of a catheter,
where an array of light sources is within an encapsulant.
FIG. 12A is a top elevational view of a portion of a light
transmission system, according to one illustrated embodiment.
FIG. 12B is a cross-sectional view of the light transmission system
of FIG. 12A taken along line 12B-12B.
FIG. 13 is an axial cross-sectional view of the light transmission
system of FIG. 12A, where the light transmission system is within
an encapsulant.
FIG. 14A is a top elevational view of a circuit having traces
coupled to a base.
FIG. 14B is a bottom elevational view of the circuit of FIG.
14A.
FIG. 15A is a top elevational view of circuit having traces coupled
to a base, according to another illustrated embodiment.
FIG. 15B is a bottom elevational view of the circuit of FIG.
15A.
FIG. 16A is a top elevational view of a circuit having traces
coupled to a base, in accordance with another illustrated
embodiment.
FIG. 16B is a distal portion of the circuit of FIG. 16A.
FIG. 16C is a central portion of the circuit of FIG. 16A.
FIG. 16D is a proximal portion of the circuit of FIG. 16A.
FIG. 17 is a cross-sectional view of a pair of light sources
mounted to a multilayer circuit.
FIG. 18A is a circuit diagram of one embodiment of a light bar
circuit.
FIG. 18B is a circuit diagram of another embodiment of a light bar
circuit.
FIG. 19 is a perspective view of an empty manufacturing tool for
holding the light sources of FIG. 11.
FIG. 20 is a perspective view of the manufacturing tool of FIG. 19,
where the manufacturing tool is holding an array of light sources
connected by wires.
FIG. 21 is an enlarged perspective view of the light sources,
wires, and manufacturing tool illustrated in FIG. 20.
FIG. 22 is a side elevational schematic view of a distal tip having
a two-sided light source array in accordance with one
embodiment.
FIG. 23 is a schematic cross-sectional view of a distal tip having
a two-sided light source array in accordance with another
embodiment.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 is a side elevational view of a light delivery system 100
including a control system 106 and a catheter assembly 110
extending distally from and coupled to the control system 106,
according to one embodiment. The light delivery system 100 can be
used to perform various types of light therapy. Light therapy is
broadly construed to include photo-activating or photo-exciting one
or more target cells by subjecting the one or more target cells to
one or more wavelengths of light that are approximately close to,
if not equivalent to, at least one excitation wavelength of the
target cells. This photo-excitation process can be used during an
oncology treatment program, for example, to treat diseased or
otherwise undesirable and/or cancerous target cells. It is
understood that even if one cell is "targeted," it is possible that
other cells in a vicinity of the targeted cell may also be
subjected to light. The light delivery system 100 can be used to
treat other types of abnormal cells.
The catheter assembly 110 includes a distal tip 114 and a catheter
body 116 extending between the distal tip 114 and the control
system 106. The distal tip 114 includes a transmission system 120
(shown in phantom) configured to output energy, such as radiant
energy, suitable for treating a target region in the patient. Once
the distal tip 114 is positioned at the target site, the control
system 106 can be utilized for selectively controlling the output
from the distal tip 114.
The control system 106 can include a controller 124 and a power
supply 126 (shown in phantom in FIG. 1) in communication with the
transmission system 120. The controller 124 can be operated to
select the amount of radiant energy emitted by the light
transmission system 120.
The illustrated internal power supply 126 is a battery, such as a
lithium battery. In other embodiments, the light delivery system
100 is powered by an AC power source, such as an electrical outlet
typically found at a hospital, medical facility, or other suitable
location for performing light therapy. The control system 106 can
include a power cord that can be connected to the AC power source.
Accordingly, various types of internal and/or external power
sources can be utilized to power the light delivery system 100.
The catheter assembly 110 of FIG. 1 has a low profile configuration
suitable for percutaneous advancement and navigation within a
patient. Such a construction allows convenient delivery and
placement of the distal tip 114 at remote locations within a
patient, unlike catheters with larger light bars. The catheter
assembly 110 can also be dimensioned for other means of delivery
and placement. For example, the catheter assembly 110 can be
configured for external light delivery (e.g., transcutaneous or
transdermal delivery). This external catheter assembly can be
larger than the percutaneously delivered catheter assembly
described above. Accordingly, the dimensions (e.g., the axial
length, cross-sectional width, etc.) the catheter assembly 110 can
be selected based upon the accessibility of the target tissue.
The catheter assembly 110 can have a cross-sectional width that is
less than about 1.25 mm. In some embodiments, the catheter assembly
110 has a cross-sectional width that is less than about 1 mm. In
some embodiments, the catheter assembly 110 has a cross-sectional
width that is less than about 0.80 mm. In some embodiments, the
catheter assembly 110 has a cross-sectional width that is less than
about 0.75 mm. In some embodiments, the catheter assembly 110 has a
cross-sectional width that is less than about 0.70 mm. The distal
tip can have a cross-sectional width less than about 10 mm, 5 mm,
1.5 mm, 1.25 mm, 1.0 mm, 0.75 mm, 0.5 mm, and ranges encompassing
such widths. Other dimensions are also possible.
In some embodiments, the light delivery system 100 can be used as
an adjunct during another medical procedure, such as minimally
invasive procedures, open procedures, semi-open procedures, or
other surgical procedures that preferably provide access to a
desired target region. Many times, the access techniques and
procedures used to provide access to a target region can be
performed by a surgeon and/or a robotic device, such as robotic
systems used for performing minimally invasive surgeries. Those
skilled in the art recognize that there are many different ways
that a target region can be accessed. Optionally, the light
delivery system 100 is used with guidewires, delivery sheaths,
delivery devices (e.g., endoscopes, bronchoscopes, optical
instruments, etc.), introducers, trocars, biopsy needle, or other
suitable medical equipment. If the target treatment site is at a
distant location in the patient, delivery devices should be used
for convenient navigation through tortuous body lumens or other
anatomical structures in the patient. The flexible light delivery
system 100 can be easily positioned within the patient using, for
example, steerable devices, such as endoscopes, bronchoscopes, and
the like. Semi-rigid or rigid light delivery systems 100 can be
delivered using trocars, access ports, rigid delivery sheaths using
semi-open procedures, open procedures, or other delivery
tools/procedures that provide a somewhat straight delivery path,
for example. Advantageously, the semi-rigid or rigid system 100 can
be sufficiently rigid to displace internal tissue to help
facilitate light delivery to the target tissue. When inserted in
the patient, the system 100 can be easily rotated and advanced
axially while maintaining its configuration.
FIGS. 2A and 2B show the distal tip 114 including the transmission
system 120 encapsulated in a protective outer body 136. When the
transmission system 120 is activated, radiant energy is delivered
from the transmission system 120 through the outer body 136 to the
desired target region, preferably tissue near the outer body 136
such that an effective amount of radiant energy reaches the target
region.
The transmission system 120 includes one or more energy sources 138
mounted onto a base 142. As used herein, the term "energy source"
is a broad term and includes, but is not limited to, energy sources
capable of emitting radiant energy, such as electromagnetic energy.
Non-limiting exemplary energy sources can be light sources capable
of emitting visible light waves, non-visible light waves, and
combinations thereof. The energy sources can be LEDs (such as edge
emitting LEDs, surface emitting LEDs, super luminescent LEDs),
laser diodes, or other suitable energy sources.
FIGS. 2A and 2B illustrate a linear array of LEDs 138 spaced apart
along the length of the distal tip 114. In the illustrated
embodiment, the LEDs 138 are coupled upon a longitudinally
extending upper face 200 of the elongate base 142. A conductive
connector 148 interconnects the LEDs 138 so as to distribute
electrical energy between the LEDs. The term "conductive connector"
is a broad term and includes, without limitation, lead(s), wire(s)
(preferably flexible wires), bus bar(s), a conductive film or ink
applied to a substrate, or other conductor suitable for
electronically coupling the LEDs 138 to the control system 106. In
the illustrated embodiment of FIGS. 2A and 2B, the conductive
connector 148 is a plurality of leads 150 formed by a pair of wires
160, 162 extending above and coupled to the LEDs 138, thereby
forming a complete circuit.
The LEDs 138 can be arranged in parallel, series, or combinations
thereof. For example, some LEDs 138 can be arranged in series while
other LEDs are arranged in parallel. As such, various circuit
configurations can be used when mounting the LEDs 138 to the base
142. Exemplary non-limiting embodiments of circuits are discussed
below in detail.
With continued reference to FIG. 2B, each LED 138 has electrodes
170, 172 coupled to the wires 160, 162, respectively. Each LED 138
can also include one or more layers .Iadd.180 .Iaddend.(e.g., GaN
layers, AlGaN layers, InGaN layers, .[.AlInGap.]. .Iadd.AlInGaP
.Iaddend.layers and/or AlInGaN layers) disposed between the
electrodes 170, 172 and a substrate 182, as shown in FIG. 2A. In
the illustrated embodiment, the substrate 182 is a transmissive
substrate. For example, the substrate 182 can be optically
transparent to the light emitted from the layer(s) described
above.
The illustrated LEDs 138 can emit appropriate wavelength(s) or
waveband(s) suitable for treating the patient, with or without
using a treatment agent. If a treatment agent (e.g., a
photo-reactive or photosensitive agent) is utilized, the LEDs 138
preferably emit radiation wavelength(s) or waveband(s) that
corresponds with, or at least overlap with, the wavelength(s) or
waveband(s) that excite or otherwise activate the agent.
Photosensitive agents can often have one or more absorption
wavelengths or wavebands that excite them to produce substances
which damage, destroy, or otherwise treat target tissue of the
patient. For example, the LEDs 138 can be configured to emit light
having a wavelength or waveband in the range from about 400
nanometers to 1,000 nanometers. In some embodiments, the LEDs 138
emit a wavelength or waveband in the range from about 600
nanometers to about 800 nanometers. In some embodiments, the LEDs
138 emit a wavelength or waveband in the range from about 600
nanometers to about 700 nanometers. In one embodiment, for example,
the LEDs 138 emit radiation with a peak wavelength of 664
nanometers plus or minus 5 nanometers.
Each LED 138 of the distal tip 114 can be configured be to emit the
same wavelength or waveband. However, LEDs having different
wavelengths or wavebands can be used to provide varying outputs.
These LEDs 138 can be activated simultaneously or at different
times depending on the desired treatment. The various LEDs 138 can
also be activated and deactivated in a pulsed sequence. For
example, the LEDs 138 may form two halves of the light array which
are alternately turned on and off. Alternately, the system may be
programmed to selectively activate and deactivate different
selected segments of LEDs 138 along the length of the light bar. In
this manner, a treatment protocol, for example causing the LEDs to
be lit in a certain sequence, at a particular power level for a
selected period of time, may be programmed into the control system
106.
The distal tip 114 can have any number of LEDs 138. In the
illustrated embodiment, five LEDs are positioned generally along
the longitudinal axis of the distal tip 114. However, a higher or
lower number of LEDs can be selected based on the desired energy
output, emitted wavelength(s) and/or waveband(s), surface area of
target site, desired level of energy penetration, and other
treatment parameters. In some embodiments, for example, about 60
LEDs are spaced along the distal tip 114 at a 1 mm pitch. In other
embodiments, the LEDs can be at a pitch in the range of about 1.5
mm to about 0.5 mm. In some embodiments, less than 70 LEDs are
spaced along the distal tip 114. In other embodiments, less than 50
LEDs are spaced along the distal tip 114. In yet other embodiments,
less than 40 LEDs are spaced along the distal tip 114. The
illustrated LEDs 138 are evenly spaced and form a single row;
however, other LEDs arrangements are possible. For example, the
distal tip 114 can include a matrix of LEDs 138.
As described above in connection with FIGS. 2A and 2B, the LEDs 138
are mounted upon the upper face 200 of the base 142. Any suitable
mounting means can be employed to temporarily or permanently couple
the LEDs 138 onto the base 142. For example, adhesives, bonding
material, fasteners, solder, or other coupling means can securely
couple the LEDs 138 to the base 142. The mounting means can be
optically transparent in order to transmit light generated by the
LEDs 138 to the base 142 which, in turn, transmits light that
ultimately reaches the patient. In the illustrated embodiment of
FIGS. 2A and 2B, optically transparent epoxy permanently couples
the linearly spaced LEDs 138 to the upper face 200.
With continued reference to FIGS. 2A and 2B, the base 142 is an
elongate member that extends longitudinally along the distal tip
114, and provides a relatively large mounting area on the upper
face 200 for convenient placement of the LEDs 138. The base can be
a support substrate sized to hold any number of LEDs.
The base 142 is preferably sufficiently flexible so as to permit
enough distortion of the distal tip 114 for delivery along a
tortuous path. The base 142 can be twisted, bent, rolled, and/or
otherwise distorted, preferably without any appreciable damage to
the base 142 and/or LEDs 138 mounted thereto. In some embodiments,
the base 142 can be moved through an angle of 220.degree.,
180.degree., 150.degree., 130.degree., 90.degree., 70.degree.,
50.degree., and ranges encompassing such angles.
In some embodiments, the base 142 is a thin, flat strip of a
flexible material. The thin base 142 helps reduce the profile of
the light transmission system 120 and, consequently, the overall
cross-sectional width of the distal tip 114. Furthermore, the base
142 can be easily bent and twisted to allow navigation along
tortuous paths within the patient, thus permitting flexibility in
selecting treatment protocols.
The base 142 can have a polygonal axial cross-section (e.g., a
rectangular cross-section), elliptical cross-section, or other
suitable axial cross-section. FIGS. 3C to 3E illustrate various
axial cross-sections of the base 142.
Various materials can be used to construct the base 142. Flexible,
semi-rigid, and/or rigid bases 142 can be made of rubber, composite
materials, thermoplastics, polymers (e.g., polyester, polyethylene
terephthalate (PET), polypropylene, polyethylene naphthalate (PEN),
and combinations thereof. In one embodiment, the base 142 comprises
a somewhat transparent material, preferably an optically
transparent polyester. At least one wavelength of light emitted by
the LEDs can pass through the base 142, as discussed in more detail
below.
The material(s) forming the base 142 can be selected to achieve the
desired structural properties, thermal properties, electrical
properties, optical properties, and durability. For example, to
dissipate heat generated by the LEDs 138, the base 142 can comprise
a heat conductive material that can act as a heat sink for
conducting heat away from the LEDs in order to maintain the light
transmission system 120 at an appropriate operating temperature.
Additionally, one or more ribs, stiffeners, joints, reinforcement
members, strain relief elements, or other structural elements can
be added to the base 142 to achieve the desired properties. As
noted above, the base 142 may be somewhat rigid for some medical
applications. For example, a base 142 in distal tip 114 for
applying light externally to the patient may be a rigid member
comprised of metal, rigid plastic, or other suitably stiff
material.
As mentioned above, the base 142 can comprise a transmissive
material to allow light emitted from the LEDs to pass therethrough.
Thus, the base 142 advantageously supports the LEDs 138 while also
permitting the passage of light therethrough to increase the
efficacy of the light treatment and decrease power consumption.
Further, the base 142 can be relatively large for an enlarged LED
mounting zone without appreciably reducing the amount of light
reaching the target tissue. This results in easy placement of the
LEDs.
Suitable transmissive materials include, but are not limited to,
polymers such as polyester, PET, polypropylene, combinations
thereof and the like. One or more layers of material can form the
base 142. Preferably, a substantial amount of the light directed
from the LEDs 138 towards the base 142 is transmitted through the
base 142. In some embodiments, at least 40% of the light emitted
towards the base 142 is transmitted therethrough. In some
embodiments, at least 50% of the light directed towards the base
142 is transmitted therethrough. In some embodiments, at least 60%
of the light directed towards the base 142 is transmitted
therethrough. In some embodiments, at least 70% of the light
directed towards the base 142 is transmitted therethrough. In some
embodiments, at least 80% of the light directed towards the base
142 is transmitted therethrough. In some embodiments, at least 90%
of the light directed towards the base 142 is transmitted
therethrough. Additionally, one or more light passageways,
through-holes, windows, or other structures can be formed in the
base 142 to increase the amount of light passing through the base
142.
The base 142 can optionally include one or more opaque materials
that can inhibit or prevent one or more wavelengths or wavebands
from passing therethrough. Opacification agents, additives,
coatings, or combinations thereof can be utilized to render the
base 142 (or portion thereof) somewhat opaque. In some embodiments,
the opacification agents include, but are not limited to, dyes,
pigments, metal particulates or powder, or other materials that can
be coated onto, disbursed throughout, or otherwise disposed in the
base 142. If desired, the base 142 can function as a filter so as
to inhibit or prevent one or more wavelengths or wavebands from
reaching the patient's tissue.
In some embodiments, the base 142 extends proximally from the
distal tip 114 along the entire length of the catheter body 116. In
other embodiments, a proximal end of the base 142 is positioned
distally of the proximal end of the catheter assembly 110. For
example, the proximal end of the base 142 can be positioned at some
point along the catheter body 116, or within the distal tip
114.
As shown in FIGS. 2A and 2B, the light transmission system 120 is
housed within the outer body 136, as discussed above. The outer
body 136 is preferably transmissive so as to transmit radiation
emitted from the light transmission system 120. For example, the
outer body 136 can be made of the same material(s) forming the base
142. During advancement through the patient's body and placement at
the target site, external forces may be applied to the distal tip
114. Accordingly, the outer body 136 can be made of a material
suitable for limiting or preventing undesirable damage to the light
transmission system 120.
The outer body 136 can define a chamber 206 sized to accommodate
the light transmission system 120. In some embodiments, an
encapsulate (e.g., a polymer) can be used to fill the chamber 206
in order to minimize or prevent movement of the light transmission
system 120 relative to the outer body 136. Alternatively, the outer
body 136 can define a hollow chamber 206 which can increase the
overall flexibility of the distal tip 114. Optionally, the outer
body 136 can be an expandable member, such as those disclosed in
the '357 patent application, which is hereby incorporated by
reference in its entirety. The chamber 206 can be filled with an
inflation fluid to inflate the outer body 136. In other
embodiments, the outer body 136 is a monolithic protective outer
member, such as a member molded over the light transmission system.
Accordingly, the outer body 136 can have a one-piece or multi-piece
construction.
FIGS. 3A, 3B, and 4-5B illustrate one embodiment of a process to
produce a distal tip 114 using wire bonding techniques. FIGS. 3A to
3E show the base 142 which is the starting material for forming the
distal tip 114. LEDs 138 are attached to the upper surface 200 of
the base 142, as shown in FIG. 4. The base 142 maintains the
desired spacing between the mounted LEDs 138 while the wire bonds
150 are formed. In this manner, the base 142 helps to improve the
tolerances between the LEDs, even though the LEDs may be subjected
to subsequent processing. In the illustrated embodiment of FIG. 5A,
for example, the pair of wires 160, 162 are connected to the
electrodes 170, 172, respectively, with solder while the LEDs 138
remain securely mounted to the base 142. Accordingly, the base 142
can function as a LED holder thus reducing fabrication time and
improving tolerances. Additionally, the base 142 can be made of a
low cost material (e.g., polyester) that is ultimately integrated
into the distal tip assembly 114 thereby reducing material waste
and cost.
After assembling the transmission system 120 (as shown in FIGS. 5A
and 5B), the outer body 136 can be formed by various molding
techniques. For example, the outer body 136 can be formed through a
molding process (e.g., an injection molding process, compression
molding process, etc.), thermoforming, machining process, or
combinations thereof. In some embodiments, the light transmission
system 120 can be placed in a mold cavity corresponding to the
desired shape of the outer body 136. To oversold the light
transmission system 120, a molten polymer can be injected into the
mold cavity. Alternatively, the outer body 136 can be a preformed
hollow member. The light transmission system 120 can be inserted
into the member until the distal tip 114 is fully assembled.
FIG. 6 shows another embodiment of a distal tip that can be
incorporated into the light delivery system 100 of FIG. 1. The
distal tip 300 of FIG. 6 may be generally similar to the distal tip
114 illustrated in FIG. 1, except as further detailed below.
The distal tip 300 of FIG. 6 has an array of LEDs 304 that are
mounted in a flip chip arrangement. A flip chip is one type of
integrated circuit (IC) chip mounting arrangement that does not
require wire bonding between chips (e.g., the chip mounting
arrangement described above in connection with FIGS. 1-5B). Thus,
wires or leads that typically connect a chip/substrate having
connective elements can be eliminated to further reduce the profile
of the distal tip. That is, the distal tip 300 can have a lower
profile than the distal tip 114 and is well suited for delivery
along narrow passageways. By way of example, the distal tip 114 of
FIG. 1 can have a diameter in the range of about 1.5 mm to about
1.2 mm, although other diameters are also possible. The flip chip
mounted distal tip 300 of FIG. 6 has a diameter in the range of
about 0.8 mm to about 0.7 mm. In some embodiments, the distal tip
300 has a diameter of about 0.74 mm. Thus, the distal tip 300 can
be delivered along relatively narrow delivery paths, while
providing the same output as the wire bonded distal tip 114.
FIGS. 7-10 illustrate one embodiment of a process to produce a
distal tip 300 of FIG. 6 having flip chip mounted LEDs. Generally,
instead of wire bonding described above, solder beads or other
elements can be positioned or deposited on chip pads such that when
the chip is mounted upside-down in/on the substrate, electrical
connections are established between conductive traces of the
substrate and the chip.
FIG. 7 illustrates a circuit 309 including a base 310 and an array
of conducting traces or electrodes 314, 316 suitable for flip chip
mounting. As shown in FIG. 8A, an LED 304 can be positioned above
the pair of the traces 314, 316. Solder beads 320 are formed on the
electrodes 324 of the LED 304 such that when the LED 304 is lowered
onto the circuit 309, preformed solder beads can electrically and
mechanically connect the LED to the traces 314, 316 of the base
310. After one or more of the LEDs 304 are placed upon the base
310, the solder beads 320 can be heated or thermally treated until
the solder securely couples the LEDs 304 to the base 310, as shown
in FIG. 8B. After the LEDs 304 are mounted onto the base 310, an
outer body 330 can be formed in the manner described above.
The base 310 of FIG. 7 can comprise the same materials as the base
142 of FIGS. 2A and 2B. However, the base 310 can also be formed of
other materials. For example, the base 310 can be formed of a
polyamide material (e.g., polyimide flex) that is especially
well-suited for flip chip mounting arrangements. To increase the
amount of light passing through the base 310, one or more light
passageways can be formed in the base 310. A light passageway can
be a through-hole, window, transmissive material(s), or other
suitable element for increasing the amount of light traveling
through the base 310. The number and/or size of the light
passageways can be increased or decreased to increase or decrease,
respectively, the amount of transmitted light.
FIG. 10 shows a light passageway 334 (shown in phantom) in the form
of a through-hole in the base 310. As such, light emitted from the
LED 304 can pass easily through the base 310 via the light
passageway 334. The light passageway 334 can be formed before,
during, or after the LED 304 is mounted to the base 310. For
example, the LED 304 can be mounted onto a pre-formed perforated
base 310. Preferably, the light passageways 334 are positioned so
as to effectively transmit light from the LED through the base
310.
FIG. 11 shows another distal tip that can be incorporated into the
light delivery system 100 of FIG. 1. The distal tip 400 may be
generally similar to the distal tip 114 illustrated in FIG. 1,
except as further detailed below.
The distal tip 400 of FIG. 11 has a light transmission system
including a plurality of light sources 410 that are wire bonded
together by a plurality of conductive elements 412 in the form of
leads. Advantageously, the distal tip 400 can be formed without
utilizing the support bases as described above. The light
transmission system can be directly mounted in the outer body 406,
so as to reduce the number of components forming the tip.
Additionally, the support bases described above may inhibit the
passage of light therethrough thereby limiting the illumination of
the tissue. Thus, the distal tip 400 can be used to deliver an
increased amount of light.
The stress on the leads 412 of FIG. 11 may be less than the stress
experienced by the leads 150 of FIGS. 2A and 2B because the base
142 of FIG. 2A may help define the bend axis of distal tip 114. As
such, the base 142 can cause the bend axis to be spaced an
undesirable distance from the leads resulting in increased axial
stresses in the leads when the distal tip 114 is bent. In FIG. 11,
however, a support base does not move the bend axis away from the
leads 412. Accordingly, the leads 412 can be positioned near or at
the neutral axis of the distal tip 400, thereby reducing or
eliminating axial stresses on the leads. In some embodiments, leads
412 can act as pivot points defining the bending axis of the distal
tip 400, if desired.
FIGS. 12A and 12B illustrate a light transmission system 340 having
a plurality of flip chip mounted light sources 352A, 352B coupled
to a circuit 353. A base 354 of the circuit 353 defines one or more
locking structures 360 for enhancing coupling between an
encapsulant and the light transmission system 340. As shown in FIG.
13, an encapsulant 362 can surround the light transmission system
340, and a portion 363 of the encapsulant 362 can pass through the
locking structure 360 extending through the base 354. As such, the
locking structure 360 can minimize, limit, or prevent movement
between the light transmission system 340 and encapsulant 362.
Additionally, the locking structure 360 can advantageously inhibit
or prevent delamination of the encapsulant 362 from the base
354.
The illustrated locking structure 360 of FIGS. 12A to 13 is a
through-hole having an elongated axial cross-section. In some
non-limiting exemplary embodiments, the locking structure 360 has a
width of about 0.005 inch (0.127 mm) and a length of about 0.011
inch (0.28 mm) and is located between two light sources 352A, 352B,
each having a length and width of about 0.014 inch (0.356 mm). The
size of the locking structure 360 can be increased or decreased to
increase or decrease, respectively, the amount of the encapsulant
363 extending through the base 354. In other embodiments, the
locking structure 360 can have a polygonal (including rounded
polygonal), elliptical, circular, or any other suitable
cross-section. A drilling process, machining process, or other
suitable process can be used to form the structure 360.
With reference again to FIG. 12A, the light transmission system 340
includes a pair of generally longitudinally-extending traces 364,
366 interposed between the light sources 352A, 352B and base 354.
The traces 364, 366 interconnect adjacent pairs of light sources
352A, 352B. To accommodate an enlarged locking structure 360, the
distance between portions of the traces 364, 366 can be increased,
as shown in FIG. 12A. In the illustrated embodiment of FIG. 12A,
the distance D1 between the traces 364, 366 is greater than the
distance D2 between the portions of the traces 364, 366 adjacent or
beneath the light sources 352A, 352B. The spacing between the
traces 364, 366 can be selected based on the size, position, and/or
configuration of the locking structure 360.
The other light transmission systems disclosed herein can also
include one or more locking structures. For example, the base 142
of FIG. 2A can include one or more locking structures interposed
between adjacent pairs of wire bonded LEDs. Thus, locking
structures can be used with wire bonded LEDs, flip chip LEDs, and
other chip mounting arrangements.
With continued reference to FIGS. 12A and 12B, the traces 364, 366
are delivery traces connecting the light sources 352A, 352B. The
base 354 is interposed between the delivery traces 364, 366 and
return traces 368, 370. A coverlay 361 (shown removed in FIG. 12A)
can overlay at least a portion of both the base 354 and the traces
364, 366, 368, 370, as shown in FIG. 12B.
The light delivery systems described herein can have circuits with
different configurations. The configurations of the circuits can be
selected to achieve the desired output from each light source.
FIGS. 14A to 16D illustrate circuits that can be used in the light
delivery systems disclosed herein. FIG. 14A illustrates a circuit
371 including a trace system 369 having a plurality of traces 372,
373, 374 coupled to a base 375. Bonding pads 376 are positioned to
receive the light sources 377 (shown in phantom).
At least one of the traces 372, 373, 374 can be a cross-over trace.
In the illustrated embodiment of FIG. 14A, the trace 374 is a
cross-over trace and includes a pair of opposing
longitudinally-extending side portions 374A, 374B and a cross-over
trace 374C extending laterally between the side portions 374A,
374B. In this manner, the trace 374 can connect opposing connectors
of adjacent light sources 377. The circuit 371 can have any number
of traces as desired.
A pair of return traces 378, 379 of FIG. 14B is coupled to the
bottom surface of the base 375 and can increase the current
carrying capability of the light delivery system without blocking a
substantial amount of light emitted from the light sources 377. The
return traces 378, 379 can be positioned directly opposite portions
of the traces 372, 373, 374 such that the traces 378, 379 do not
increase the amount of blocked light. In some embodiments, the
width of the traces 378, 379 can be generally equal to or less than
the width of the opposing portions of the corresponding traces 372,
373, 374.
FIGS. 15A and 15B illustrate another circuit for a light delivery
system. A trace system 380 has segments that provide independent
activation of one or more groups of light sources. The illustrated
trace system 380 includes a plurality of traces 381A-D mounted to
the base 382. A controller or switch 384 for selectively
controlling current flow is positioned between the traces 381B,
381C. The controller 384 can thus determine the current flow to
distal light sources (not shown). The illustrated trace system 380
has a single controller 384; however, any desired number of
controllers can be used to separate one or more light sources.
FIGS. 16A to 16D show a light transmission system in accordance
with one embodiment. The illustrated light transmission system 385
of FIG. 16A has a distal portion 386 (FIG. 16B), proximal portion
387 (FIG. 16D), and central portion 388 (FIG. 16C) extending
therebetween. A pair of traces 389A, 389B extend along the length
of the transmission system 385. A base 413 is positioned between
the traces 389A, 389B. As shown in FIGS. 16B to 16D, light sources
415 (shown in phantom) can be spaced from each other along the
light transmission system 385. The traces 389A, 389B are preferably
spaced laterally from the light sources 415 for improved
transmission through the base 413. In one embodiment, the base 413
is transparent.
The illustrated light transmission system 385 can have a single or
double sided mounting arrangement. The material of the base 413 can
be removed to improve the optical properties of the base 413. Laser
and/or mechanical muting techniques can be used to remove a portion
(e.g., a substantial portion) of the material of the base 413
positioned adjacent and/or beneath a plurality of light sources
415. Other types of material removal techniques, such as etching,
can also be used.
The circuits of FIGS. 14A to 16D can be used for a one-sided or
two-sided flip chip mounting arrangement. FIG. 17 shows a two-sided
arrangement having light sources 390A, 390B mounted to opposing
sides of a multilayer board 391. The board 391 includes the light
source 390A mounted to traces 392, 393 via solder 394. The traces
392, 393 are mounted to an upper surface of an upper base 395. A
return trace 396 is interposed between the upper base 395 and a
lower base 397. The light source 390B is mounted to traces 398, 399
via solder 400. Upper and lower coverlays 401A, 401B can cover and
protect the traces 392, 393 and traces 398, 399, respectively. Of
course, the board 391 can be transparent to allow the passage of
light therethrough.
As noted above, the light transmission systems disclosed herein can
have various types of circuit arrangements. FIG. 18A is a circuit
diagram 403 showing light sources 404A-D. The light sources 404A,
404B are in a parallel arrangement. The light sources 404C and 404D
are likewise in a parallel arrangement. Any desired number of light
sources can be arranged in a parallel arrangement. The light
sources 404A, 404B and light sources 404C, 404D form groups 405,
406, respectively, that are arranged in series. Any number of light
source groups can be arranged in series. FIG. 18B illustrates a
plurality of light sources 407A-C in a series arrangement.
FIGS. 19 and 23 show methods of producing distal tips for light
delivery systems. FIGS. 19 to 21 illustrate one embodiment of a
process to produce a distal tip, such as the distal tip 400 of FIG.
11 as detailed below.
FIG. 19 shows a fixture device 440 that is configured to receive
and hold the LEDs 410 during assembling. The illustrated fixture
device 440 includes an array of holders 442 and a pair of elongated
slots 448 extending along inwardly from one side of the fixture
device 440. The holders 442 are sized and configured to receive at
least a portion of the LEDs 410. The pattern of the holders 442
corresponds to the desired pattern of the LEDs. Each holder 442
comprises a mounting portion 444 and a through hole 446. The
mounting portion 444 can be a recess configured to receive at least
a portion of the LEDs. Alternatively, the mounting portions 444 can
be one or more protrusions, keying structures, or other suitable
structure for engaging and holding an LED.
In the illustrated embodiment, to place the LEDs 410 within a
corresponding holder 442, the bottom portion of each LED 410 is
placed within a corresponding mounting portion 444 such that the
electrodes of the LED are facing outwardly, as shown in FIG. 20. To
ensure that the LEDs are properly retained in their corresponding
holders 442, a vacuum can be applied via the through hole 446.
Optionally, the mounting portions 444 can have sealing members
(e.g., rubber inserts, compliant flanges, etc.) to form a seal
between the LEDs and holders 442. Preferably, the vacuum is
continuously applied while wire leads are attached to the
electrodes of the LEDs.
As shown in FIG. 20, wires extending from the outermost LED can
pass through the slots 448 which function as wire holders. In this
manner, the fixture device 440 can effectively hold the LEDs and
wires in desired locations to ensure proper positioning and
alignment. Once the light transmission system 450 is assembled (as
shown in FIG. 20), the light transmission system 450 can be removed
from the fixture device 440 for subsequent processing. If a vacuum
was applied during assembling, the vacuum can be reduced or
eliminated to permit easy removal of the LEDs from the fixture
device 440. In some embodiments, a positive pressure is applied to
release the LEDs from the tool. The assembled LEDs can then be
place in a mold and encapsulated with material to the desired final
dimensions, as discussed in connection with FIG. 23.
The distal tips described above can be modified to have light
sources facing any number of directions. FIG. 22 shows a distal tip
500 having a two-sided light transmission system 510. The light
transmission system 510 is interposed between a first array of
light sources 524 and second array of light sources 528. In the
illustrated embodiment, the wire bonded light sources 524, 528 are
mounted to upper and lower faces 532, 536, respectively, of the
base 510. The light sources 524, 528 can advantageously directly
light in different directions, preferably in substantially opposite
directions. The illustrated light sources 524, 528 can be applied
to the base 510 by using the process illustrated in FIGS. 3A to 5B.
In other embodiments, a two-sided light transmission system
includes flip chip mounted light sources mounted to upper and lower
faces of a base, preferably formed by the process illustrated in
FIGS. 7 to 9. Thus, light sources can be applied to any number of
faces of a mounting substrate.
FIG. 23 shows a distal portion of a light transmission system 600
having a two-side chip mounting arrangement. The light sources 602,
604 are encapsulated in an inner portion 606. An outer portion 608
is disposed over the inner portion 606.
The inner portion 606 can be formed through a casting or molding
process, such as an injection molding process. The inner portion
606 and light sources 602, 604 can then be inserted into the outer
portion 608. In one embodiment, the outer portion 608 is in the
form of a tube. The outer portion 608 can be processed to bond,
adhere, or otherwise couple the outer portion 608 to the inner
portion 606. In some embodiments, the outer portion 608 is a
thermoplastic elastomer tube (e.g., a polyether block amide tube,
PEBAX.RTM. tube, etc.) that receives the inner portion 606. After
assembling the inner and outer portions 606, 608, the assembly is
heated to a reflow temperature to cause at least one of the inner
portion 606 and outer portion 608 to flow, thereby coupling the
inner and outer portions 606, 608. This reflow encapsulation
process results in a strong bond formed between the inner and outer
portions 606, 608.
In another embodiment, the light transmission system 600 is
inserted into the outer portion 608. Material is injected into the
lumen 613 of the outer portion 608 to form the inner portion 606.
In some embodiments, molten polymer is injected into the lumen 613
and flows between the outer portion 608 and light transmission
system 600. The polymer preferably fills the spaces with the lumen
613.
The thickness T of the outer portion 608 can be selected based on
the desired overall axial width of the catheter. In the illustrated
embodiment of FIG. 23, the inner portion 606 has a diameter in the
range of about 0.015 inch (0.381 mm) to about 0.025 inch (0.635
mm). In some embodiments, the diameter of the inner portion 606 is
about 0.020 inches (0.508 mm). The thickness T of the outer portion
608 can be in the range of about 0.002 inch (0.051 mm) to about
0.007 inch (0.178 mm). In some embodiments, the thickness T is
about 0.005 inch (0.127 mm).
Generally, the light delivery systems can be positioned relative to
a target site and then activated to deliver light to the target
site. The light delivery systems can be used to treat organs,
vasculature, tissue (e.g., epithelial tissue, connective tissue,
muscle tissue and nerve tissue), and various systems including, but
not limited to, organ systems, circulatory systems, and other
suitable systems in the patient.
In some embodiments, the light delivery systems are used to treat
adipose tissue, such as subcutaneous adipose tissue located
directly beneath the skin or adipose tissue (e.g., visceral fat or
intra-abdominal fat) located proximate internal organs. After
administering a treatment agent, the light delivery systems can be
used to remove or otherwise alter these types of adipose tissue.
U.S. Patent Publication No. 2005-0085455, which is hereby
incorporated by reference in its entirety, discloses various
methods, treatment agents, and the like that can be used in
combination with the light delivery systems described herein to
treat visceral fat.
Visceral fat, such as panniculus adipose tissue, may have a
contributory role in medical conditions, such as type II diabetes.
The reduction of this visceral fat may improve a patient's
condition. If a person is suffering from type II diabetes, for
example, the reduction of visceral fat may reverse or improve
insulin resistance, diabetes syndrome, and/or metabolic syndrome.
This can lead to reduced medical costs associated with diabetes.
The frequency and likelihood of complications (e.g., heart disease,
renal failure, foot ulcers, and diabetic retinopathy, and the like)
of diabetes can also be reduced or eliminated.
In some embodiments, the light delivery system 100 of FIG. 1 has
the catheter assembly 110 dimensioned for insertion (e.g.,
percutaneous delivery) into and through a patient. The distal tip
114 can be moved into operative engagement with the patient's
visceral fat. Once positioned, the distal tip 114 can illuminate
the visceral fat for a desired period of time. In some non-limiting
embodiments, for example, the catheter assembly 110 has an outer
diameter less than about 1 mm for convenient placement within the
patient.
Various delivery techniques can provide access to the visceral fat.
A delivery device, such as an introducer or biopsy needle, can be
used to access the visceral fat. The light delivery system 100 can
be placed while utilizing a visualization technique (e.g.,
ultrasound, fluoroscopy, CT, and MRI) to facilitate proper
positioning. One or more visualization aids can be provided on the
system 100 to allow easy visualization in situ.
The treatment agent, such as talaporfin sodium, can be administered
to the patient by a suitable delivery means. To deliver a
therapeutically effective amount of the agent, the agent can be
administered intravenously, or by any other suitable means. After
the agent is adequately dispersed at the target site, the
transmission system 120 is activated to illuminate the target site.
For example, the transmission system 120 can be activated for about
1 hour and then removed from the patient. The transmission system
120 can be stopped automatically or by user input.
The treated adipose cells may break down (e.g., immediately or
gradually over an extended period of time) and are subsequently
absorbed by the patient's body. In this manner, the amount of
visceral fat can be reduced in a controller manner. This procedure
can be performed any number of times at different locations until
the desired amount of fat has been eliminated. For example,
visceral fat can be removed until achieving a noticeable
improvement in insulin resistance. Of course, fat at other target
sites can also be treated in a similar manner. Thus, fat deposits
can be precisely destroyed or eliminated for health or cosmetic
reasons. Moreover, because the system 100 has a low profile, the
distal tip 114 can be delivered to remote locations using minimally
invasive techniques.
The light delivery systems can also be dimensioned to fit within
the vasculature system, such as within lumens of veins or arteries,
or other anatomical lumens in the respiratory system, for example.
The size of the light delivery system can be selected based the
target treatment site and delivery path to the treatment site.
All of the above U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification and/or listed in the Application Data Sheet, to
include U.S. Pat. Nos. 6,958,498; 6,784,460; 6,661,167; and
6,445,011; U.S. Publication No. 2005/0228260; International Patent
Application Nos. PCT/US2005/032851 and PCT/US01/44046; and U.S.
Provisional Patent Application No. 60/640,382 are incorporated
herein by reference, in their entirety. Except as described herein,
the embodiments, features, systems, devices, materials, methods and
techniques described herein may, in some embodiments, be similar to
any one or more of the embodiments, features, systems, devices,
materials, methods and techniques described in the incorporated
references. In addition, the embodiments, features, systems,
devices, materials, methods and techniques described herein may, in
certain embodiments, be applied to or used in connection with any
one or more of the embodiments, features, systems, devices,
materials, methods and techniques disclosed in the above-mentioned
incorporated references.
The various methods and techniques described above provide a number
of ways to carry out the invention. Of course, it is to be
understood that not necessarily all objectives or advantages
described may be achieved in accordance with any particular
embodiment described herein. Thus, for example, those skilled in
the art will recognize that the methods may be performed in a
manner that achieves or optimizes one advantage or group of
advantages as taught herein without necessarily achieving other
objectives or advantages as may be taught or suggested herein.
Furthermore, the skilled artisan will recognize the
interchangeability of various features from different embodiments
disclosed herein. Similarly, the various features and steps
discussed above, as well as other known equivalents for each such
feature or step, can be mixed and matched by one of ordinary skill
in this art to perform methods in accordance with principles
described herein. Additionally, the methods which are described and
illustrated herein are not limited to the exact sequence of acts
described, nor are they necessarily limited to the practice of all
of the acts set forth. Other sequences of events or acts, or less
than all of the events, or simultaneous occurrence of the events,
may be utilized in practicing the embodiments of the invention.
Although the invention has been disclosed in the context of certain
embodiments and examples, it will be understood by those skilled in
the art that the invention extends beyond the specifically
disclosed embodiments to other alternative embodiments and/or uses
and obvious modifications and equivalents thereof. The materials,
methods, ranges, and embodiments disclosed herein are given by way
of example only and are not intended to limit the scope of the
disclosure in any way. Accordingly, the invention is not intended
to be limited by the specific disclosures of preferred embodiments
disclosed herein.
* * * * *