U.S. patent application number 16/840136 was filed with the patent office on 2021-03-18 for systems, compositions, and methods for local imaging and treatment of pain.
This patent application is currently assigned to THE REGETNS OF THE UNIVERSITY OF CALIFORNIA. The applicant listed for this patent is THE REGENTS OF THE UNIVERSITY OF CALIFORNA. Invention is credited to David S. Bradford, Jeffrey C. Lotz.
Application Number | 20210077048 16/840136 |
Document ID | / |
Family ID | 1000005239921 |
Filed Date | 2021-03-18 |
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United States Patent
Application |
20210077048 |
Kind Code |
A1 |
Bradford; David S. ; et
al. |
March 18, 2021 |
SYSTEMS, COMPOSITIONS, AND METHODS FOR LOCAL IMAGING AND TREATMENT
OF PAIN
Abstract
Pain factors are labeled with targeted agents or markers
delivered into the body. The labeled pain factors are imaged with
appropriate imaging tools in a manner allowing selective
identification and localization of areas of pain source or
transmission. The labeled pain factors allow spatial
differentiation in the imaging sufficient to specify the location
of the pain so as to drive therapeutic decisions and techniques in
order to treat the pain. Pain factors labeled and imaged in this
manner may include one or more of nerve factors, blood vessel
factors, cellular factors, and inflammation factors. Labeled
markers may include for example radioactive materials (e.g.
tritiated or iodinated molecules) or other materials such as metal
(e.g. gold) nanoparticles. Intermediary binding materials may be
used, such as for example bi-specific antibodies. Therapeutic
components of the system and method include for example localized
energy delivery or ablation treatments, or local drug or other
chemical delivery. Locations containing pain factor selectively
bound by targeted agents are selectively treated with directed
energy into a region containing the targeted agent bound to the
pain factor.
Inventors: |
Bradford; David S.;
(Sausalito, CA) ; Lotz; Jeffrey C.; (San Mateo,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THE REGENTS OF THE UNIVERSITY OF CALIFORNA |
Oakland |
CA |
US |
|
|
Assignee: |
THE REGETNS OF THE UNIVERSITY OF
CALIFORNIA
Oakland
CA
|
Family ID: |
1000005239921 |
Appl. No.: |
16/840136 |
Filed: |
April 3, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16158610 |
Oct 12, 2018 |
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16840136 |
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14850945 |
Sep 10, 2015 |
10123759 |
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16158610 |
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12053379 |
Mar 21, 2008 |
9161735 |
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14850945 |
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PCT/US2006/036943 |
Sep 21, 2006 |
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12053379 |
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60719670 |
Sep 21, 2005 |
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60750990 |
Dec 15, 2005 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 6/506 20130101;
A61B 18/14 20130101; A61B 2018/00577 20130101; A61M 5/1723
20130101; A61N 7/02 20130101; A61B 2018/00339 20130101; A61B 5/4824
20130101; A61B 2018/00642 20130101; A61M 5/007 20130101; A61K
51/1096 20130101; A61B 5/4041 20130101; A61M 2230/005 20130101;
A61K 49/0002 20130101 |
International
Class: |
A61B 6/00 20060101
A61B006/00; A61B 5/00 20060101 A61B005/00; A61K 49/00 20060101
A61K049/00; A61N 7/02 20060101 A61N007/02; A61B 18/14 20060101
A61B018/14; A61K 51/10 20060101 A61K051/10; A61M 5/00 20060101
A61M005/00; A61M 5/172 20060101 A61M005/172 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0003] This invention was made with Government support under
AG017762, awarded by the National Institutes of Health (NIH). The
Government has certain rights in the invention
Claims
1. (canceled)
2. A method of treating back pain of a patient, the method
comprising: delivering a substantially targeted agent that is
adapted to differentially bind to a pain factor into or adjacent a
vertebral endplate of a vertebra of the patient; wherein the
targeted agent is conjugated with an imaging contrast label to
thereby form a targeted label configured to artificially label the
pain factor in a manner substantially increasing an ability to
image the pain factor with a magnetic resonance imaging ("MRI")
tool; imaging, with the MRI tool, the targeted label coupled to the
pain factor; determining whether the vertebral endplate is a pain
source based on the imaging; channeling a path toward a target
treatment location within bone of a vertebral body of the vertebra
using an introducer; delivering a therapeutic device through the
introducer to the target treatment location within the bone of the
vertebral body; wherein the therapeutic device comprises a delivery
probe with an elongated body; wherein the therapeutic device is
adapted to ablate nerve tissue; and using the therapeutic device,
ablating a basivertebral nerve at the target treatment location
within the bone of the vertebral body.
3. The method of claim 2, wherein the delivery probe comprises an
ultrasound probe configured to deliver ultrasound energy.
4. The method of claim 2, wherein the delivery probe comprises a
radiofrequency probe configured to deliver electrical energy.
5. The method of claim 4, wherein the radiofrequency probe
comprises first and second electrodes in a bipolar lead assembly
arrangement.
6. The method of claim 2, wherein the delivery probe is configured
to deliver microwave energy.
7. The method of claim 2, wherein the delivery probe is configured
to deliver at least one therapeutic chemical.
8. The method of claim 2, wherein the therapeutic device is
configured to deliver thermal energy.
9. The method of claim 2, wherein the imaging contrast label
comprises an MRI contrast agent.
10. The method of claim 2, wherein the pain factor comprises a
nerve factor.
11. The method of claim 2, wherein the pain factor comprises an
inflammatory factor.
12. The method of claim 2, wherein the pain factor comprises a
cellular factor.
13. A method of treating back pain of a patient, the method
comprising: delivering a substantially targeted agent that is
adapted to differentially bind to a pain factor into or adjacent a
vertebral endplate of a vertebra of the patient; wherein the
targeted agent is conjugated with an imaging contrast label to
thereby form a targeted label configured to artificially label the
pain factor in a manner substantially increasing an ability to
image the pain factor with an imaging tool; imaging, with the
imaging tool, the targeted label coupled to the pain factor;
determining whether the vertebral endplate is a pain source based
on the imaging; channeling a path toward a target treatment
location within bone of a vertebral body of the vertebra using an
introducer; delivering an energy delivery assembly through the
introducer to a position at or adjacent the target treatment
location within the bone of the vertebral body; wherein the energy
delivery assembly is adapted to deliver a therapeutic dose of
energy in a substantially localized manner that is substantially
isolated to the target treatment location; and wherein the
therapeutic dose of energy is sufficient to ablate nerve tissue;
and using the energy delivery assembly, ablating an intraosseous
nerve at the target treatment location within the bone of the
vertebral body.
14. The method of claim 13, wherein the energy delivery assembly
comprises a radiofrequency probe configured to deliver the
therapeutic dose of energy.
15. The method of claim 14, wherein the radiofrequency probe
comprises first and second electrodes in a bipolar lead assembly
arrangement.
16. The method of claim 13, wherein the therapeutic dose of energy
is thermal energy.
17. The method of claim 13, wherein the imaging tool is a magnetic
resonance imaging ("MRI") tool and wherein the imaging contrast
label comprises an MRI contrast agent.
18. The method of claim 13, wherein the pain factor comprises an
inflammatory factor.
19. A method of treating back pain of a patient, the method
comprising: delivering a substantially targeted agent that is
adapted to differentially bind to a pain factor into or adjacent a
vertebral endplate of a vertebra of the patient; wherein the
targeted agent is conjugated with an imaging contrast label to
thereby form a targeted label configured to artificially label the
pain factor in a manner substantially increasing an ability to
image the pain factor with an imaging tool; imaging, with the
imaging tool, the targeted label coupled to the pain factor;
determining a pain source based on the imaging; channeling a path
toward a target treatment location within bone of a vertebral body
of the vertebra using an introducer; delivering a therapeutic
device through the introducer to the target treatment location
within the bone of the vertebral body; wherein the therapeutic
device is adapted to deliver a therapeutic dose of energy to the
target treatment location; wherein the target treatment location
comprises an intraosseous nerve.
20. The method of claim 19: wherein the therapeutic device
comprises a radiofrequency probe having first and second electrodes
in a bipolar lead assembly arrangement; wherein the therapeutic
dose of energy comprises electrical energy or thermal energy;
wherein the imaging tool comprises a magnetic resonance imaging
("MRI") tool; and wherein the imaging contrast label comprises an
MRI contrast agent.
21. The method of claim 19, wherein the pain factor comprises an
inflammatory factor.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/158,610 filed on Oct. 12, 2018, which is a
continuation of U.S. patent application Ser. No. 14/850,945 filed
on Sep. 10, 2015, incorporated herein by reference in its entirety,
which is a continuation of U.S. patent application Ser. No.
12/053,379 filed on Mar. 21, 2008, now U.S. Pat. No. 9,161,735,
incorporated herein by reference in its entirety, which is a 35
U.S.C. .sctn. 111(a) continuation of PCT international application
number PCT/US2006/036943 filed on Sep. 21, 2006, incorporated
herein by reference in its entirety, which claims priority to, and
the benefit of, U.S. provisional patent application Ser. No.
60/719,670 filed on Sep. 21, 2005, incorporated herein by reference
in its entirety, and which claims priority to, and the benefit of,
U.S. provisional patent application Ser. No. 60/750,990 filed on
Dec. 15, 2005, incorporated herein by reference in its entirety.
Priority is claimed to each of the foregoing applications.
[0002] The above-referenced PCT international application was
published as PCT International Publication No. WO 2007/035906 on
Mar. 29, 2007, which publication is incorporated herein by
reference in its entirety.
NOTICE OF MATERIAL SUBJECT TO COPYRIGHT PROTECTION
[0004] A portion of the material in this patent document is subject
to copyright protection under the copyright laws of the United
States and of other countries. The owner of the copyright rights
has no objection to the facsimile reproduction by anyone of the
patent document or the patent disclosure, as it appears in the
United States Patent and Trademark Office publicly available file
or records, but otherwise reserves all copyright rights whatsoever.
The copyright owner does not hereby waive any of its rights to have
this patent document maintained in secrecy, including without
limitation its rights pursuant to 37 C.F.R. .sctn. 1.14.
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0005] This invention pertains generally to imaging of tissues
associated with skeletal joints. More particularly, it relates to
identification and/or characterization of localized factors
associated with musculoskeletal pain using labeled markers and
related imaging tools.
2. Description of Related Art
[0006] Chronic back pain (i.e. generally persisting longer than 12
weeks) is among the most prevalent and expensive non-lethal
conditions in the United States, and is believed to be the most
common cause of disability in persons under 45 years old. The
number of people suffering from chronic back pain is estimated to
exceed 25% of the overall population. Every year, about 3-4% of the
U.S. population is estimated to be disabled temporarily, and about
1% of the working age population is estimated to be disabled
totally and permanently, due to intractable back pain. An estimated
11.7 Million patients present medically with chronic back pain.
National disability expenses for this prevalent condition range
from $30-$70 billion per year. Effectively treating this prevalent
condition remains among the largest unmet clinical needs in
medicine. Properly diagnosing and localizing the source of pain
also remains a significant shortcoming on the critical path toward
providing such therapy in a targeted manner with predictably
successful outcomes.
[0007] Diagnosis of the location, mode, and extent of disc
degeneration is often used as a precursor tool to drive therapy for
treating back pain. However, such measures are often not specific
enough to localize the exact site in or around a degenerating disc
where pain is being experienced. Also, a direct correspondence is
not always found between disc degeneration and back pain.
Consequently, existing imaging modalities that identify (and even
quantify) disc anatomy, such as CT or MRI, are not always helpful
at localizing sources of back pain in many cases.
[0008] Accordingly, there is still a substantial need for new
imaging modalities to objectively, accurately, and specifically
identify and localize source(s) of pain, and in particular back
pain, and still more particularly lower lumbar back pain. There is
in particular such a need with respect to identifying painful discs
in an improved way, and to localize within or around those discs
the specific site of injury or source of pain in an improved,
predictable, dependable manner.
BRIEF SUMMARY OF THE INVENTION
[0009] Accordingly, certain aspects of the present invention
provide a system, composition of matter, and method that better
describe, diagnose, and localize of the sources of pain in and
around musculoskeletal joints, and in particular beneficial modes
in and around spinal discs in relation to back pain.
[0010] Among the various modes employed according to this aspect,
one particular beneficial mode involves artificially labeling
substances locally in the area of back pain, such as in a
particular beneficial example the spinal motion segment, that are
known suspects to pain generation and transmission, such as for
example disc, facet joints, and vertebral bodies.
[0011] Two particularly beneficial embodiments according to this
mode, useful either alone or in combination, include: (a) labeling
nerves, and in particular beneficial embodiments nociceptors, and
(b) labeling chemical factors that irritate nerves, (c) labeling
cells that produce chemical factors that irritate nerves; and (d)
labeling blood vessels that are typically in close approximation to
nerves.
[0012] In addition to the significant benefit provided by these
approaches for clinical diagnosis, they are also considered highly
beneficial in providing new avenues to drive choices for
therapeutic approaches.
[0013] One aspect of the invention is a method for conducting a
medical procedure related to a localized, active source of pain at
a location within a patient. This method includes artificially
labeling a pain factor at the location in a manner substantially
increasing the ability to image the pain factor with an imaging
tool. The labeled pain factor is then labeled in a manner
sufficient to selectively differentiate a first concentration of
the labeled pain factor at the location versus a second
concentration of the labeled pain factor in tissue adjacent to the
location.
[0014] According to one highly beneficial mode, the location is
associated with a skeletal joint.
[0015] Another mode of this aspect further includes delivering a
substantially targeted label into the patient that is adapted to
differentially bind to and label a pain factor associated with the
source of pain at the location. The pain factor at the location is
artificially labeled by binding the pain factor with the targeted
label.
[0016] According to one embodiment, the differential binding
comprises specific binding to the pain factor.
[0017] According to another embodiment, the differential binding
comprises non-specific binding to the pain factor.
[0018] According to another mode, the pain factor comprises at
least one of a nerve factor, an inflammatory factor, a cellular
factor, or a blood vessel factor, or a combination thereof.
[0019] In one more particular mode, the pain factor comprises a
nerve factor.
[0020] According to one embodiment of this mode, the nerve factor
comprises at least one substance associated with at least one of a
nerve fiber or a cellular structure associated with the nerve
fiber.
[0021] In another embodiment, the nerve factor comprises a
substance associated with a nerve fiber. According to one
particularly beneficial embodiment, the substance is in particular
associated with nociceptors.
[0022] In another more particular mode, the pain factor comprises a
blood vessel factor.
[0023] According to one embodiment of this mode, the blood vessel
factor comprises at least one of a blood vessel or a substance or
structure associated with the blood vessel.
[0024] In another embodiment of this mode, the blood vessel factor
comprises a substance or structure associated with
microvessels.
[0025] According to another more particular mode, the pain factor
comprises a cellular factor.
[0026] According to one embodiment of this particular mode, the
cellular factor is associated with a cell that produces at least
one inflammatory factor.
[0027] In another embodiment, the cellular factor is associated
with at least one inflammatory factor.
[0028] In another embodiment, the cellular factor is associated
with cells actively producing inflammatory factors.
[0029] In another embodiment, the cellular factor is associated
with an inflammatory cell of a type that is attracted to a second
pain factor at the location. According to one particular variation
of this embodiment, the inflammatory cell comprises a leukocyte or
macrophage.
[0030] According to another more particular mode, the pain factor
comprises an inflammatory factor.
[0031] According to another mode, the pain factor comprises a
cytokine.
[0032] According to another mode of the present aspect, the pain
factor comprises substance P or an analog or derivative or binding
agent or antibody thereof.
[0033] According to another mode, the pain factor comprises CGRP or
an analog or derivative or binding agent or antibody thereof.
[0034] According to another mode, the pain factor comprises
receptor tyrosine kinase A (TrkA) or an analog or derivative
thereof.
[0035] According to another mode, the pain factor comprises a TrkA
binding agent or antibody.
[0036] According to another mode, the pain factor comprises a TrkA
receptor or a binding agent or antibody thereof.
[0037] According to another mode, the pain factor comprises nerve
growth factor (NGF) or an analog or derivative thereof.
[0038] According to another mode, the pain factor comprises an NGF
binding agent or antibody.
[0039] According to another mode, the pain factor comprises an NGF
antagonist or an analog or derivative thereof.
[0040] According to another mode, the pain factor comprises an
NGF-antagonist binding agent or anti-NGF antagonist antibody.
[0041] According to another mode, the pain factor comprises a nerve
binding agent or antibody or an analog or derivative thereof.
[0042] According to another mode, the pain factor comprises protein
gene product 9.5 (PGP 9.5) or an analog or derivative or binding
agent or antibody thereof.
[0043] According to another mode, the pain factor comprises SYN or
an analog or derivative or binding agent or antibody thereof.
[0044] According to another mode, the pain factor comprises
peripherin or an analog or derivative or binding agent or antibody
thereof.
[0045] According to another mode, the pain factor comprises
Neurofilament 200 kD (NF200) or an analog or derivative or binding
agent or antibody thereof.
[0046] According to another mode, the pain factor comprises tissue
necrosis factor alpha (TNF-.alpha. or an analog or derivative or
binding agent or antibody thereof.
[0047] According to another mode, the pain factor comprises a
TNF-.alpha. blocker or binding agent or antibody thereof.
[0048] According to another mode, the pain factor comprises
macrophage migration inhibitory factor (MIF or an analog or
derivative or binding agent or antibody thereof.
[0049] According to another mode, the pain factor comprises
infliximab, or an analog or derivative thereof, or a binding agent
or an antibody thereof.
[0050] According to another mode, the pain factor comprises PECAM
or an analog or derivative or binding agent or antibody
thereof.
[0051] According to another mode, the pain factor comprises CD34 or
an analog or derivative or binding agent or antibody thereof.
[0052] According to another mode, the pain factor comprises
vascular cell adhesion molecule-1 (VCAM-1) or an analog or
derivative or binding agent or antibody thereof.
[0053] According to another mode, the pain factor comprises an
interleukin or an analog or derivative or binding agent or antibody
thereof.
[0054] According to one embodiment of this mode, the interleukin
comprises IL-1 or an analog or derivative or binding agent or
antibody thereof.
[0055] According to another embodiment, the interleukin comprises
IL-6 or an analog or derivative or binding agent or antibody
thereof.
[0056] According to another embodiment, the interleukin comprises
IL-8 or an analog or derivative or binding agent or antibody
thereof.
[0057] According to another mode of the present aspect, the pain
factor comprises prostaglandin E2 (PGE.sub.2) or an analog or
derivative or binding agent or antibody thereof.
[0058] According to another mode, the pain factor comprises a
factor associated with pH in tissue or a binding agent or an
antibody thereof.
[0059] According to one embodiment of this mode, the labeled pain
factor is indicative of a relatively low pH below a predetermined
threshold at the location.
[0060] According to another mode, the pain factor comprises a
factor associated with pO2 in tissue or a binding agent or an
antibody thereof.
[0061] In one embodiment according to this mode, the labeled pain
factor is indicative of a relatively low pO2 at the location.
[0062] According to another mode, the pain factor comprises glial
fibrillary acidic protein (GFAP) or an analog or derivative or
binding agent or antibody thereof.
[0063] According to another mode, the pain factor comprises
synuclein (SYN) or an analog or derivative or binding agent or
antibody thereof.
[0064] According to another mode of the present aspect, the
targeted label comprises at least one of a nerve factor, a blood
vessel factor, a cellular factor, an inflammatory factor, or an
antibody thereof.
[0065] According to one embodiment of this mode, the targeted label
comprises a nerve factor or a binding agent or an antibody
thereof.
[0066] In one variation according to this embodiment, the nerve
factor comprises at least one substance associated with at least
one of a nerve fiber or a cellular structure associated with the
nerve fiber or an antibody thereof.
[0067] In another variation, the nerve factor comprises a substance
associated with a nerve fiber or a binding agent or an antibody
thereof.
[0068] In another embodiment, the targeted label comprises a blood
vessel factor or a binding agent or an antibody thereof.
[0069] In one variation of this embodiment, the blood vessel factor
comprises a substance associated with a structure of a blood vessel
or a binding agent or an antibody thereof.
[0070] In another variation, the blood vessel factor comprises a
substance associated with a structure of a microvessel or a binding
agent or an antibody thereof.
[0071] According to another embodiment, the targeted label
comprises a cellular factor or a binding agent or an antibody
thereof.
[0072] In one variation, the cellular factor is associated with a
cell that produces at least one inflammatory factor, or a binding
agent or an antibody thereof.
[0073] In another variation, the cellular factor is associated with
at least one inflammatory factor or a binding agent or an antibody
thereof.
[0074] In another variation, the cellular factor is associated with
an intervertebral disc cell that is actively producing inflammatory
factors, or a binding agent or an antibody thereof.
[0075] In another variation, the cellular factor is associated with
an inflammatory cell of a type that is attracted to the pain factor
at the location, or a binding agent or an antibody thereof.
[0076] According to one feature of this variation, the inflammatory
cell comprises a leukocyte, or a binding agent or an antibody
thereof.
[0077] According to another embodiment, the targeted label
comprises an inflammatory factor, or a binding agent or an antibody
thereof.
[0078] In one variation of this embodiment, the inflammatory factor
comprises a cytokine, or an analog or derivative thereof, or a
binding agent or an antibody thereof.
[0079] According to another mode of the present aspect, the
targeted label comprises a binding agent or antibody to substance
P.
[0080] According to another mode, the targeted label comprises a
binding agent or antibody to calcitonin gene-related peptide
(CGRP).
[0081] According to another mode, the targeted label comprises a
TrkA antibody or binding agent.
[0082] According to another mode, the targeted label comprises
nerve growth factor (NGF), or an analog or derivative thereof.
[0083] According to another mode, the targeted label comprises a
NGF binding agent or an anti-NGF antibody.
[0084] According to another mode, the targeted label comprises a
NGF antagonist or a binding agent or an antibody thereof.
[0085] According to another mode, the targeted label comprises an
anti-NGF antagonist antibody or binding agent.
[0086] According to another mode, the targeted label comprises a
nerve antibody or binding agent.
[0087] According to another mode, the targeted label comprises PGP
9.5, or an analog or derivative thereof, or a binding agent or an
antibody thereof.
[0088] According to another mode, the targeted label comprises a
binding agent or antibody to peripherin.
[0089] According to another mode, the targeted label comprises
Neurofilament 200 kD (NF200), or an analog or derivative thereof,
or a binding agent or an antibody thereof.
[0090] According to another mode, the targeted label comprises
TNF-.alpha., or an analog or derivative thereof, or a binding agent
or an antibody thereof.
[0091] According to another mode, the targeted label comprises a
TNF-.alpha. blocker.
[0092] According to another mode, the targeted label comprises
infliximab, or an analog or derivative thereof, or a binding agent
or an antibody thereof.
[0093] According to another mode, the targeted label comprises a
PECAM binding agent or antibody.
[0094] According to another mode, the targeted label comprises a
binding agent or antibody to CD34.
[0095] According to another mode, the targeted label comprises an
interleukin binding agent or antibody.
[0096] In one embodiment of this mode, the interleukin binding
agent or antibody comprises an IL-1 binding agent or antibody.
[0097] In another embodiment of this mode, the interleukin binding
agent or antibody comprises an IL-6 binding agent or antibody.
[0098] In another embodiment of this mode, the interleukin binding
agent or antibody comprises an IL-8 binding agent or antibody.
[0099] According to another mode of the present aspect, the
targeted label comprises a binding agent or antibody to
PGE.sub.2.
[0100] According to another mode, the targeted label comprises a
binding agent or antibody to MIF.
[0101] According to another mode, the targeted label comprises an
antibody or binding agent to a factor associated with pH in
tissue.
[0102] According to one embodiment of this mode, the labeled pain
factor is indicative of a relatively low pH below a predetermined
threshold at the location.
[0103] According to another mode, the targeted label comprises an
antibody or binding agent to a factor associated with pO2 in
tissue.
[0104] According to one embodiment of this mode, the labeled pain
factor is indicative of a relatively low pO2 at the location.
[0105] According to another mode, the targeted label comprises a
radioactive material.
[0106] According to one embodiment of this mode, the targeted label
comprises a radio-labeled TNF-.alpha. antibody, or an analog or
derivative thereof.
[0107] According to another embodiment, the targeted label
comprises radiolabeled iodine. In one variation of this embodiment,
the radiolabeled iodine comprises I-125.
[0108] According to another mode, the targeted label comprises a
nanoparticle.
[0109] According to another mode, the targeted label comprises
gold.
[0110] According to another mode, the targeted label comprises iron
oxide.
[0111] According to another mode, the targeted label comprises
gadolinium.
[0112] According to another mode of the present aspect, the method
further includes imaging the labeled pain factor using an imaging
tool that comprises a phosphor imaging plate.
[0113] According to another mode, the method includes imaging the
labeled pain factor using MRI.
[0114] According to another mode, a first binding agent is
delivered into the body that is adapted to bind to a first pain
factor. The targeted label is delivered into the patient's body
after the first binding agent is bound to the first pain factor.
The targeted label is adapted to bind to a site located on the
bound combination of the first binding agent and the first pain
factor.
[0115] According to one embodiment, the first binding agent
comprises a bi-specific antibody with a first binding site adapted
to bind to the first pain factor and a second binding site adapted
to bind to the targeted label.
[0116] According to another mode, the targeted label comprises a
cell bound to an antibody having an exposed binding site that is
adapted to bind to the pain factor.
[0117] According to another mode, the method further includes
conducting a therapeutic procedure in a substantially localized
manner to the location where the targeted labeled pain factor is
locally imaged.
[0118] In one embodiment of this mode, the therapeutic procedure is
adapted to substantially alleviate generation or transmission of
pain at the location.
[0119] According to another embodiment, the therapeutic procedure
is adapted to substantially ablate at least one nerve at the
location.
[0120] In another embodiment, the therapeutic procedure comprises
delivering at least one therapeutic chemical in a substantially
localized manner to the location.
[0121] In another embodiment, the therapeutic procedure comprises
delivering a therapeutic dose of energy in a substantially
localized manner to the location.
[0122] In one variation of this embodiment, the therapeutic
procedure further comprises ablating at least one nerve at the
location with the therapeutic dose of energy.
[0123] In another variation, the therapeutic procedure further
comprises delivering ultrasound energy to the location. In a
further variation, the method further includes delivering the
ultrasound energy in a directed manner locally into the location
from a second location. In still a further variation, the second
location is outside of the patient, and the ultrasound energy is
delivered via high intensity focused ultrasound (HIFU) that is
adapted to focus the ultrasound energy to the location. In yet
another variation, the second location is adjacent to the location
within the patient, and the ultrasound energy is delivered via a
directional ultrasound probe. In still a further feature of this
variation, the second location is adjacent to an intervertebral
disc and the location receiving the directional ultrasound therapy
is within the intervertebral disc.
[0124] According to another variation of the present embodiment,
the therapeutic dose of energy comprises thermal energy.
[0125] According to another variation, the therapeutic dose of
energy comprises electrical energy. In one further variation, the
method involves delivering the electrical energy via a
radiofrequency (RF) probe.
[0126] According to another variation, the therapeutic dose of
energy comprises microwave energy.
[0127] According to another variation, the therapeutic dose of
energy comprises light energy.
[0128] According to another mode of the present aspect, the
location comprises at least a portion of an intervertebral
disc.
[0129] According to another mode, the location comprises a region
of tissue located within only a portion that is equal to less than
an entire circumference of an intervertebral disc.
[0130] In one embodiment of this mode, the portion comprises a
region of tissue located within less than or equal to one-half of
the circumference of the intervertebral disc.
[0131] In one variation of this embodiment, the portion comprises a
region of tissue located within less than or equal to one-quarter
of a circumference of the intervertebral disc.
[0132] According to another mode of the present aspect of the
invention, the location comprises an end-plate associated with a
vertebral body.
[0133] According to another mode, the location comprises a facet
joint.
[0134] The method of the present aspect according to another mode
includes delivering the targeted label in a localized manner to the
location.
[0135] One embodiment of this mode further includes injecting the
targeted label into a region of tissue associated with the location
using a local injection assembly.
[0136] Another embodiment includes delivering the targeted label
systemically to the patient.
[0137] One further embodiment includes injecting the targeted label
into the patient's systemic blood circulation.
[0138] Another further embodiment includes delivering the targeted
label into the patient's gastrointestinal system.
[0139] Another mode includes artificially labeling the pain factor
at multiple said locations by binding the pain factor with the
targeted label delivered into the patient. The labeled pain factor
is then imaged with an imaging tool adapted to image at least one
of the targeted label or the labeled pain factor and in a manner
sufficient to differentiate a first concentration of the labeled
pain factor at the multiple said locations versus a second
concentration of the labeled pain factor in tissue adjacent to the
multiple said locations.
[0140] According to one embodiment of this mode, the method further
includes conducting at least one therapeutic procedure in a
substantially localized manner to each of the locations where the
targeted labeled pain factor is locally and selectively imaged.
[0141] According to another mode of this present aspect, the pain
factor comprises MIF or a binding agent or antibody thereof.
[0142] According to another mode of this aspect, the targeted agent
comprises an MIF binding agent or antibody.
[0143] According to another mode of the present aspect, the
targeted agent comprises a nanoparticle.
[0144] According to another mode of the present aspect, the
targeted agent comprises at least one of gold or iron oxide.
[0145] According to another mode of the present aspect, the
targeted agent comprises an MRI contrast agent.
[0146] According to one embodiment of the preceding mode, the MRI
contrast agent comprises gadolinium.
[0147] According to another embodiment of the present mode, the
method further comprises MRI imaging an area of increased
concentration of the MRI contrast agent bound to the pain
factor.
[0148] According to another mode of the present aspect, the
targeted agent comprises an ultrasound contrast agent.
[0149] According to one embodiment of this mode, the method further
comprises ultrasonically imaging an area of increased concentration
of the ultrasound contrast agent bound to the pain factor.
[0150] According to another mode of the present aspect, the
targeted agent comprises a radiographic contrast agent.
[0151] According to one embodiment of this mode, the method further
comprises imaging an area of increased concentration of the
radiographic contrast agent bound to the pain factor using
X-ray.
[0152] According to another mode of the present aspect, the method
further comprises imaging a location of the targeted agent bound to
the pain factor in a manner allowing for enhanced localized therapy
to the location.
[0153] According to another mode of the present aspect, the method
further comprises delivering the targeted agent into the patient
via the patient's respiratory system.
[0154] Another aspect of the invention involves a system for
treating pain at a location within a body of a patient. This aspect
includes a targeted agent that comprises a targeted label that is
adapted to bind to and label a pain factor associated with a source
of pain at the location. Also included is a delivery assembly that
is adapted to deliver the targeted label into the patient. An
imaging system also included in the system is adapted to image at
least one of the targeted label or the labeled pain factor and in a
manner sufficient to selectively differentiate a first
concentration of the labeled pain factor at the location versus a
second concentration of the labeled pain factor in tissue adjacent
to the location. A therapeutic device assembly is also included,
and is adapted to provide therapy in a substantially localized
manner that is substantially isolated to the location.
[0155] According to one mode of this aspect, the targeted label is
adapted to bind and label a pain factor associated musculoskeletal
joint pain, and the location is associated with at least one
musculoskeletal joint.
[0156] According to one embodiment, the therapeutic device assembly
comprises an energy delivery assembly that is adapted to deliver a
therapeutic dose of energy in a substantially localized manner that
is substantially isolated to the location associated with the
musculoskeletal joint.
[0157] According to one further embodiment, the energy delivery
assembly is adapted to be delivered into the patient to a position
at or adjacent to the location.
[0158] According to another further embodiment, an introducer is
provided in the system and is adapted to deliver the energy
delivery assembly to the location.
[0159] In one variation of this embodiment, the introducer
comprises a needle assembly. This may provide the additional
feature in that the needle assembly is adapted to be advanced
through bone and to deliver the therapeutic device assembly to a
position within the bone. According to another further feature, the
therapeutic device assembly may be adapted to ablate an
intraosseous nerve within the bone and that is associated with pain
related to the labeled pain factor visualized at the location. In
another further beneficial feature, the needle assembly is adapted
to be advanced through bone of a vertebral body and to deliver the
therapeutic device assembly to a position within the vertebral body
associated with a basivertebral nerve, and the therapeutic device
assembly is adapted to ablate the basivertebral nerve from the
position.
[0160] According to another mode of the present aspect, the
therapeutic device assembly comprises a radiofrequency (RF) current
ablation assembly.
[0161] In one embodiment, the RF current ablation assembly
comprises a first electrode and a second electrode adapted to be
positioned at first and second positions adapted to straddle at
least a portion of the basivertebral nerve. The RF current ablation
assembly is adapted to deliver the RF current between the first and
second electrodes sufficient to ablate nerve tissue between the
first and second positions.
[0162] According to one variation of this embodiment, the RF
current ablation assembly comprises a delivery probe with an
elongated body that carries the first and second electrodes in a
bipolar lead assembly arrangement.
[0163] According to another mode of the present embodiment, the
targeted label is adapted to bind and label a pain factor
comprising at least one of a nerve factor, a blood vessel factor, a
cellular factor, an inflammatory factor, or an antibody
thereof.
[0164] It is to be appreciated that further more detailed
particularly beneficial modes provided hereunder are contemplated
with respect to the present aspect described. In particular,
further modes of the present aspect include the various beneficial
examples for pain factors and targeted labels described for use
under the method aspect of the invention described above.
[0165] According to one further mode of the present aspect, the
targeted label is adapted to selectively bind and label a pain
factor that comprises at least one of Substance P, CGRP, trkA, NGF,
an NGF antagonist, PGP 9.5, SYN, peripherin, Neurofilament 200 kD
(NF200), PECAM, CD34, GFAP, an interleukin, a leukocyte, a
cytokine, TNF-.alpha., MIF, an analog or derivative thereof, or a
binding agent or antibody thereof.
[0166] According to another mode of the present aspect, the
targeted label comprises a binding agent or antibody of at least
one of Substance P, CGRP, trkA, NGF, an NGF antagonist, PGP 9.5,
SYN, peripherin, Neurofilament 200 kD (NF200), PECAM, CD34, GFAP
for endothelial cells, an interleukin, a leukocyte, a cytokine,
TNF-.alpha. or MIF, or comprises NGF, NF200, PGP 9.5, or an analog
or derivative thereof.
[0167] According to another mode of the present aspect, the
targeted label is adapted to bind and label TNF-.alpha. or a
binding agent or an antibody thereof.
[0168] According to another mode of the present aspect, the
targeted label comprises a labeled TNF-.alpha. antibody or binding
agent.
[0169] According to another mode of the present aspect, the
targeted label comprises infliximab, or an analog or derivative
thereof, or a binding agent or antibody thereof.
[0170] According to another mode of the present aspect, the
targeted label comprises a radioactive material. According to one
embodiment of this mode, the targeted label comprises a
radio-labeled TNF-.alpha. antibody, or an analog or derivative
thereof. According to another embodiment of this mode, the targeted
label comprises radiolabeled iodine. According to one variation of
this embodiment, the radiolabeled iodine comprises 1-125.
[0171] According to another mode, the system further includes an
imaging tool that is adapted to image the labeled pain factor in a
manner sufficient to differentiate a first concentration at the
location associated with pain versus a second concentration at a
second location adjacent to the location and associated with less
pain that at the location.
[0172] According to another mode of the present aspect, the pain
factor comprises MIF or a binding agent or antibody thereof.
According to another mode, the targeted agent comprises an MIF
binding agent or antibody. According to still another mode, the
targeted agent comprises a nanoparticle. According to yet still
another mode, the targeted agent comprises at least one of gold or
iron oxide.
[0173] According to another mode of the present aspect, the
targeted agent comprises an MRI contrast agent. According to one
embodiment of this mode, the MRI contrast agent comprises
gadolinium. According to another embodiment, the system further
comprises an MRI system configured for MRI imaging an area of
increased concentration of the MRI contrast agent bound to the pain
factor.
[0174] According to another mode of the present aspect, the
targeted agent comprises an ultrasound contrast agent. According to
one embodiment of this mode, the system further comprises an
ultrasound imaging system configured for ultrasonically imaging an
area of increased concentration of the ultrasound contrast agent
bound to the pain factor.
[0175] According to still another mode of the present aspect, the
targeted agent comprises a radiographic contrast agent. In one
embodiment of this mode, the system further comprises an X-ray
imaging system configured for X-ray imaging an area of increased
concentration of the radiographic contrast agent bound to the pain
factor.
[0176] Another aspect of the invention is a method for imaging and
identifying a localized, active source of pain at a location
associated with a region of tissue in a patient, such as in
particular beneficial further modes a skeletal joint in a patient,
and in still further beneficial more detailed modes spinal joints
in a patient. This method includes delivering a substantially
targeted label into the patient that is adapted to differentially
bind to and label a pain factor. A pain factor that is resident at
the location is artificially labeled by binding the pain factor
with the targeted label delivered into the patient. The labeled
pain factor is imaged with an imaging tool adapted to image at
least one of the label or the labeled pain factor and in a manner
sufficient to differentiate a first concentration of the labeled
pain factor at the location versus a second concentration of the
labeled pain factor in tissue adjacent to the location.
[0177] According to various modes of this aspect, the pain factor
may be related to at least one of a nerve fiber, a substance
associated with a nerve fiber, a blood vessel, a substance
associated with a blood vessel, a cell actively producing at least
one inflammatory factor, a cell attracted to inflammation or other
pain factors, or a chemo-inflammatory factor, or a combination
thereof.
[0178] Another aspect of the invention is a system for identifying
or characterizing a property of tissue associated with a skeletal
joint. Such aspect may further include any one or more of the
various aspects, modes, embodiments, variations, or features herein
shown or described, or combinations thereof.
[0179] According to one mode of this aspect, the system is adapted
to provide information indicative of a degree of a property of at
least a portion of an intervertebral disc.
[0180] Another aspect is a system for identifying or characterizing
a property of tissue associated with a skeletal joint in a patient.
This includes labeling at least one of: pain factors, nerve
factors, blood vessel factors, cellular factors, or inflammation
factors. Or, the system may include a combination of one or more of
the foregoing.
[0181] According to one mode of this aspect, the information is
related to a degree of a property of at least a portion of an
intervertebral disc.
[0182] Another aspect of the invention is a system for
characterizing at least a portion of an intervertebral disc with
respect to a degree of a property of that disc, such as in
particular related to pain or degeneration. This system includes a
labeled marker delivery system and a labeled marker imaging system.
The labeled marker imaging system provides information that is
useful to indicate at least in part the degree of the property.
[0183] According to one further embodiment of the foregoing aspects
and modes, the respective system is adapted to produce the
information based on either or both of an annular portion or a
nucleus portion of the intervertebral disc.
[0184] According to another embodiment, the system is adapted to
display a geographical representation related to the spatial
concentration of the labeled factor, and a portion of the
geographical representation provides the information.
[0185] According to another embodiment, the information is adapted
to distinguish a degree of degradation of the disc. According to
one highly beneficial further embodiment, the information is
adapted to distinguish as to the degree of degradation by reference
to a Thompson scale.
[0186] According to another embodiment, the property comprises at
least one of pain, or at least one factor that correlates with
pain.
[0187] According to another embodiment, the information is related
to ratios of concentration of one or more pain factors.
[0188] According to another embodiment, the information is related
to presence of secondary or other indirect materials that
generally, though indirectly, correlate well with presence of other
more direct pain factors.
[0189] According to another embodiment, the information relates to
at least one chemical constituent of an intervertebral disc.
[0190] According to another embodiment, the property comprises at
least one of a degree of dehydration of the disc, a degree of
breakdown of a proteoglycan matrix of the disc, and a degree in a
breakdown of a collagen matrix.
[0191] According to another embodiment, the system further includes
a radiolabel imaging system that is adapted to produce the
information.
[0192] Another aspect of the invention is a method for identifying
or characterizing a property of tissue associated with a skeletal
joint. One or more of the foregoing method aspects, modes,
embodiments, variations, or features herein described, or
combinations thereof, may be employed to advance this method.
[0193] One further mode of this aspect further includes providing
information indicative of a degree of a property of at least a
portion of an intervertebral disc.
[0194] Another aspect is a method for identifying or characterizing
a property of tissue associated with a skeletal joint in a patient,
and includes at least one of the following steps: labeling a pain
factor in the tissue; imaging the labeled pain factor in the
tissue; comparing different imaged regions having different
concentrations of the labeled pain factor; identifying a location
of increased presence of pain factors based upon the comparison;
and treating the location with local treatment modality based upon
the identification. Or a combination of one or more of the
foregoing may be used.
[0195] One mode of this aspect includes determining a degree of a
property of at least a portion of an intervertebral disc based upon
the information.
[0196] Another aspect of the invention is a method for
characterizing at least a portion of an intervertebral disc with
respect to a degree of a property thereof, and includes capturing a
signal related to the portion using a signal imaging system. The
signal imaging system provides information that indicates at least
in part the degree of the property.
[0197] According to one embodiment of the various method aspects
and modes just described, the information produced is based on
either or both of an annular portion or a nucleus portion of the
intervertebral disc.
[0198] In another embodiment, a curve is displayed that is related
to the presence of the labeled pain factor, and wherein a portion
of the curve provides the information.
[0199] Another embodiment includes distinguishing a degree of
degradation of the disc based upon the information. A still further
embodiment includes distinguishing the degree of degradation of the
disc in relation to a Thompson grade based upon the
information.
[0200] Another embodiment includes correlating the disc with degree
of pain, or at least one factor that correlates with pain, based
upon the information.
[0201] According to another embodiment, the information is related
to a ratio of magnitude of a signal imaged that corresponds with
the amount of labeled pain factor in a given area or volume of
tissue.
[0202] According to another embodiment, the information is related
to a cytokine, a precursor material thereof, an analog or
derivative thereof, or a metabolite or degradation product
thereof.
[0203] According to another embodiment, the information relates to
at least one chemical constituent of an intervertebral disc.
[0204] According to another embodiment, the property relates to at
least one of a degree of dehydration of the disc, a degree of
breakdown of a proteoglycan matrix of the disc, and a degree in a
breakdown of a collagen matrix.
[0205] Another embodiment includes producing the information at
least in part using a radiation imaging system.
[0206] Another aspect is a method for preparing a system for
performing a medical procedure on a patient, comprising: diagnosing
the patient with pain; and based upon the diagnosis, preparing a
volume of a targeted agent for delivery into the patient. The
prepared volume of targeted agent is configured to differentially
bind to a pain factor associated with the pain in a manner adapted
to enhance at least one of (i) diagnostic localization of the pain
and (ii) selective tissue therapy in an area associated with the
bound pain factor in response to a delivered energy to the
area.
[0207] According to one mode of this aspect, the pain factor
comprises MIF or a binding agent or antibody thereof.
[0208] According to another mode of this aspect, the targeted agent
comprises an MIF binding agent or antibody.
[0209] According to another mode of the present aspect, the
targeted agent comprises a nanoparticle.
[0210] According to another mode of the present aspect, the
targeted agent comprises at least one of gold or iron oxide.
[0211] According to another mode of the present aspect, the
targeted agent comprises an MRI contrast agent.
[0212] According to one embodiment of the preceding mode, the MRI
contrast agent comprises gadolinium.
[0213] According to another embodiment of the present mode, the
method further comprises MRI imaging an area of increased
concentration of the MRI contrast agent bound to the pain
factor.
[0214] According to another mode of the present aspect, the
targeted agent comprises an ultrasound contrast agent.
[0215] According to one embodiment of this mode, the method further
comprises ultrasonically imaging an area of increased concentration
of the ultrasound contrast agent bound to the pain factor.
[0216] According to another mode of the present aspect, the
targeted agent comprises a radiographic contrast agent.
[0217] According to one embodiment of this mode, the method further
comprises imaging an area of increased concentration of the
radiographic contrast agent bound to the pain factor using
X-ray.
[0218] According to another mode of the present aspect, the method
further comprises imaging a location of the targeted agent bound to
the pain factor in a manner allowing for enhanced localized therapy
to the location.
[0219] According to another mode of the present aspect, the method
further comprises delivering the targeted agent into the patient
via the patient's respiratory system.
[0220] Another aspect is a system for performing a medical
procedure on a patient, comprising: a therapeutic volume of a
targeted agent prepared for delivery into a patient diagnosed with
pain and that is configured to differentially bind to a pain factor
associated with the pain in a manner adapted to enhance at least
one of (i) diagnostic localization of the pain and (ii) selective
tissue therapy to a location containing the bound pain factor in
response to a delivered energy to an area containing the
location.
[0221] According to one mode of the present aspect, the pain factor
comprises MIF or a binding agent or antibody thereof. According to
another mode, the targeted agent comprises an MIF binding agent or
antibody. According to still another mode, the targeted agent
comprises a nanoparticle. According to yet still another mode, the
targeted agent comprises at least one of gold or iron oxide.
[0222] According to another mode of the present aspect, the
targeted agent comprises an MRI contrast agent. According to one
embodiment of this mode, the MRI contrast agent comprises
gadolinium. According to another embodiment, the system further
comprises an MRI system configured for MRI imaging an area of
increased concentration of the MRI contrast agent bound to the pain
factor.
[0223] According to another mode of the present aspect, the
targeted agent comprises an ultrasound contrast agent. According to
one embodiment of this mode, the system further comprises an
ultrasound imaging system configured for ultrasonically imaging an
area of increased concentration of the ultrasound contrast agent
bound to the pain factor.
[0224] According to still another mode of the present aspect, the
targeted agent comprises a radiographic contrast agent. In one
embodiment of this mode, the system further comprises an X-ray
imaging system configured for X-ray imaging an area of increased
concentration of the radiographic contrast agent bound to the pain
factor.
[0225] Another aspect is a method for selectively treating one or
more tissue regions associated with pain in a patient, comprising
delivering a targeted agent into the patient configured to
differentially bind to a pain factor associated with the pain; and
allowing the delivered targeted agent to differentially bind to the
pain factor so as to form a differentially bound pain factor; and
delivering energy into the patient in a manner that differentially
treats the one or more regions associated with the differentially
bound pain factor.
[0226] According to one mode of this aspect, the pain factor
comprises MIF or a binding agent or antibody thereof.
[0227] According to another mode of this aspect, the targeted agent
comprises an MIF binding agent or antibody.
[0228] According to another mode of the present aspect, the
targeted agent comprises a nanoparticles.
[0229] According to another mode of the present aspect, the
targeted agent comprises at least one of gold or iron oxide.
[0230] According to another mode of the present aspect, the
targeted agent comprises an MRI contrast agent.
[0231] According to one embodiment of the preceding mode, the MRI
contrast agent comprises gadolinium.
[0232] According to another embodiment of the present mode, the
method further comprises MRI imaging an area of increased
concentration of the MRI contrast agent bound to the pain
factor.
[0233] According to another mode of the present aspect, the
targeted agent comprises an ultrasound contrast agent.
[0234] According to one embodiment of this mode, the method further
comprises ultrasonically imaging an area of increased concentration
of the ultrasound contrast agent bound to the pain factor.
[0235] According to another mode of the present aspect, the
targeted agent comprises a radiographic contrast agent.
[0236] According to one embodiment of this mode, the method further
comprises imaging an area of increased concentration of the
radiographic contrast agent bound to the pain factor using
X-ray.
[0237] According to another mode of the present aspect, the method
further comprises imaging a location of the targeted agent bound to
the pain factor in a manner allowing for enhanced localized therapy
to the location.
[0238] According to another mode of the present aspect, the method
further comprises delivering the targeted agent into the patient
via the patient's respiratory system.
[0239] Another aspect is a system for selectively treating one or
more tissue regions associated with pain in a patient, comprising:
a volume of targeted agent; and an energy delivery system that is
configured to deliver energy into the patient. The volume of
targeted agent is configured for delivery into a patient and to
differentially bind to a pain factor associated with the pain in a
manner such that tissue regions containing a first concentration of
the differentially bound pain factor exhibit a differential and
selective therapeutic response to the delivered energy versus other
regions with lower concentrations of the differentially bound pain
factor.
[0240] According to one mode of the present aspect described
immediately above, the pain factor comprises MIF or a binding agent
or antibody thereof. According to another mode, the targeted agent
comprises an MIF binding agent or antibody. According to still
another mode, the targeted agent comprises a nanoparticle.
According to yet still another mode, the targeted agent comprises
at least one of gold or iron oxide.
[0241] According to another mode of the present aspect, the
targeted agent comprises an MRI contrast agent. According to one
embodiment of this mode, the MRI contrast agent comprises
gadolinium. According to another embodiment, the system further
comprises an MRI system configured for MRI imaging an area of
increased concentration of the MRI contrast agent bound to the pain
factor.
[0242] According to another mode of the present aspect, the
targeted agent comprises an ultrasound contrast agent. According to
one embodiment of this mode, the system further comprises an
ultrasound imaging system configured for ultrasonically imaging an
area of increased concentration of the ultrasound contrast agent
bound to the pain factor.
[0243] According to still another mode of the present aspect, the
targeted agent comprises a radiographic contrast agent. In one
embodiment of this mode, the system further comprises an X-ray
imaging system configured for X-ray imaging an area of increased
concentration of the radiographic contrast agent bound to the pain
factor.
[0244] Another aspect of the invention is a method of performing a
medical procedure on a patient, comprising: delivering a material
to a region within a body of a patient; wherein the material has a
preferential binding affinity to a pain factor located within the
region sufficient to preferentially bind to the pain factor versus
other structures within the region, and such that the material
accumulates at a higher concentration within a first portion of the
region having a higher amount of the pain factor than other
portions within the region; and after delivering the material to
the region, delivering energy to the region in a manner that
selectively treats the first portion versus the other portions and
such that pain is reduced in the region.
[0245] According to one mode of the method just described, the
material comprises a metal. In one embodiment of this mode, the
material comprises gold. In another embodiment of this mode, the
material comprises a nanoparticle. In still another embodiment, the
material comprises a gold nanoparticle.
[0246] According to another mode of the present method aspect, the
material comprises an antibody.
[0247] In another mode of this aspect, the material comprises an
antibody and a metal associated with the antibody. According to one
embodiment of this mode, the material comprises an antibody and a
metal nanoparticle associated with the antibody. In a further
variation of this embodiment, the material comprises an antibody
and a gold nanoparticle associated with the antibody.
[0248] According to another mode of the present method aspect, the
region comprises a skeletal joint.
[0249] According to still another mode of the present method
aspect, the region comprises at least a portion of a spine. In one
embodiment of this mode, the first portion comprises at least one
spinal joint level along the spine, and the other portions comprise
at least one other spinal joint level along the spine. In another
embodiment of this mode, the first portion comprises a single
spinal joint. In still another embodiment of this mode, the region
comprises at least an area of a spinal joint. In one variation of
this embodiment, the first portion comprises at least part of an
intervertebral disc. In another variation, the first portion
comprises at least part of a vertebral body. In still another
variation, the first portion comprises at least part of a vertebral
body endplate. In yet another further variation, the first portion
comprises a facet joint. In another variation, the first portion
comprises a transverse process.
[0250] According to another mode of the present method aspect, the
pain factor comprises at least one of: a nerve factor, a blood
vessel factor, a microvessel factor, a cellular factor, an
inflammatory factor, a cell that produces at least one inflammatory
factor, a cellular factor associated with an intervertebral disc
cell that is actively producing inflammatory factors, a cellular
factor associated with an inflammatory cell of a type that is
attracted to a second pain factor at the location, a leukocyte, a
cytokine, substance P, CGRP, trkA, nerve growth factor (NGF), an
NGF receptor, an NGF antagonist, PGP 9.5, SYN, peripherin,
Neurofilament 200 kD (NF200), TNF-.alpha., a TNF-.alpha. blocker, a
TNF-.alpha. receptor, infliximab, PECAM, CD34, GFAP, interleukin,
IL-1, IL-6, IL-8, PGE-2, a factor associated with pH in tissue, a
factor associated with pO2 in tissue, a binding agent or antibody
thereof, a receptor thereof, an analog thereof, and a derivative
thereof.
[0251] According to still another mode of the present method
aspect, the method further comprises imaging the region in a manner
that sufficiently differentiates spatial relationships between
different concentrations of the material so as to substantially
identify the location of the first portion relative to the other
portions within the region.
[0252] According to one embodiment of this mode, the method further
comprises delivering the energy principally to the first portion in
a substantially localized manner sufficient to differentially treat
the first portion with the energy versus the other portions.
[0253] According to another mode of the present method aspect, the
method further comprises diagnosing the patient in a manner that
identifies the region as a painful region of the patient's
body.
[0254] According to yet another mode of the present method aspect,
the portion is not diagnosed to include cancer cells prior to
conducting the medical procedure.
[0255] According to another mode of this present aspect, the pain
factor comprises MIF or a binding agent or antibody thereof.
[0256] According to another mode of this aspect, the targeted agent
comprises an MIF binding agent or antibody.
[0257] According to another mode of the present aspect, the
targeted agent comprises a nanoparticles.
[0258] According to another mode of the present aspect, the
targeted agent comprises at least one of gold or iron oxide.
[0259] According to another mode of the present aspect, the
targeted agent comprises an MRI contrast agent.
[0260] According to one embodiment of the preceding mode, the MRI
contrast agent comprises gadolinium.
[0261] According to another embodiment of the present mode, the
method further comprises MRI imaging an area of increased
concentration of the MRI contrast agent bound to the pain
factor.
[0262] According to another mode of the present aspect, the
targeted agent comprises an ultrasound contrast agent.
[0263] According to one embodiment of this mode, the method further
comprises ultrasonically imaging an area of increased concentration
of the ultrasound contrast agent bound to the pain factor.
[0264] According to another mode of the present aspect, the
targeted agent comprises a radiographic contrast agent.
[0265] According to one embodiment of this mode, the method further
comprises imaging an area of increased concentration of the
radiographic contrast agent bound to the pain factor using
X-ray.
[0266] According to another mode of the present aspect, the method
further comprises imaging a location of the targeted agent bound to
the pain factor in a manner allowing for enhanced localized therapy
to the location.
[0267] According to another mode of the present aspect, the method
further comprises delivering the targeted agent into the patient
via the patient's respiratory system.
[0268] Another aspect of the present invention is a system for
treating a patient, comprising: a volume of material that comprises
a metal; wherein the material exhibits a binding affinity to a pain
factor such that when the material is delivered to a region within
a body of a patient that includes the pain factor the material
differentially binds to the pain factor with more affinity than to
other structures within the region, and such that the material
accumulates at a higher concentration within a first portion of the
region having a higher amount of the pain factor than other
portions within the region; and an energy source that is adapted to
deliver energy to the region in a manner that substantially locally
treats the first portion versus the other portions.
[0269] According to one mode of this present aspect just described
immediately above, the metal comprises gold.
[0270] According to another mode of this present aspect, the metal
comprises a metal nanoparticle.
[0271] According to another mode of this present aspect, the metal
comprises a gold nanoparticle.
[0272] According to another mode of this present aspect, the system
further comprises an imaging system that is adapted to image the
material in a manner that is adapted to sufficiently differentiate
spatial relationships between different concentrations of the
material so as to identify the location of the first portion
relative to the other portions within the region.
[0273] According to still another mode of this present aspect, the
material is adapted to preferentially bind to a pain factor that
further comprises: a nerve factor, a blood vessel factor, a
microvessel factor, a cellular factor, an inflammatory factor, a
cell that produces at least one inflammatory factor, a cellular
factor associated with an intervertebral disc cell that is actively
producing inflammatory factors, a cellular factor associated with
an inflammatory cell of a type that is attracted to a second pain
factor at the location, a leukocyte, a cytokine, substance P, CGRP,
trkA, nerve growth factor (NGF), an NGF receptor, an NGF
antagonist, PGP 9.5, SYN, peripherin, Neurofilament 200 kD (NF200),
TNF-.alpha., a TNF-.alpha. blocker, a TNF-.alpha. receptor,
infliximab, PECAM, CD34, GFAP for endothelial cells, interleukin,
IL-1, IL-6, IL-8, PGE-2, a factor associated with pH in tissue, a
factor associated with pO2 in tissue, a binding agent or an
antibody thereof, a receptor thereof, an analog thereof, and a
derivative thereof.
[0274] According to still another mode of this present aspect, the
material comprises an antibody of at least one of the pain factors
provided in the immediately preceding mode.
[0275] According to another mode of the present aspect, the pain
factor comprises MIF or a binding agent or antibody thereof.
According to another mode, the targeted agent comprises an MIF
binding agent or antibody. According to still another mode, the
targeted agent comprises a nanoparticle. According to yet still
another mode, the targeted agent comprises at least one of gold or
iron oxide.
[0276] According to another mode of the present aspect, the
targeted agent comprises an MRI contrast agent. According to one
embodiment of this mode, the MRI contrast agent comprises
gadolinium. According to another embodiment, the system further
comprises an MRI system configured for MRI imaging an area of
increased concentration of the MRI contrast agent bound to the pain
factor.
[0277] According to another mode of the present aspect, the
targeted agent comprises an ultrasound contrast agent. According to
one embodiment of this mode, the system further comprises an
ultrasound imaging system configured for ultrasonically imaging an
area of increased concentration of the ultrasound contrast agent
bound to the pain factor.
[0278] According to still another mode of the present aspect, the
targeted agent comprises a radiographic contrast agent. In one
embodiment of this mode, the system further comprises an X-ray
imaging system configured for X-ray imaging an area of increased
concentration of the radiographic contrast agent bound to the pain
factor.
[0279] Each aspect, mode, embodiment, variation, or feature herein
described is considered independently beneficial without requiring
combination with the others. However, such further combinations and
sub-combinations thereof are also considered yet further beneficial
independent aspects invention. For example, where particular modes,
embodiments, variations, or features are herein described with
respect to one aspect hereunder, it is to be appreciated by one of
ordinary skill that such description is further applicable to other
aspects also described though such particular combination may not
be specifically mentioned. In further example, a more detailed
description provided with respect to a method aspect may provide
information that is to be clearly combined as further development
of a similar system-related aspect or description, or visa
versa.
[0280] Further aspects of the invention will be brought out in the
following portions of the specification, wherein the detailed
description is for the purpose of fully disclosing preferred
embodiments of the invention without placing limitations
thereon.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)
[0281] The invention will be more fully understood by reference to
the following drawings which are for illustrative purposes
only:
[0282] FIG. 1 shows a schematic of certain cascades associated with
inflammation and pain.
[0283] FIGS. 2A-D show stained cross-sectioned histology slides
indicating presence of certain factors associated with pain as
follows, wherein "N" is nucleus pulposus, "A" is annulus fibrosus,
and "G" designates growth plate.
[0284] FIG. 2A shows a mid-sagittal section of normal mouse-tail
disc demonstrating TNF-alpha localization in periphery of nucleus
pulposus (brown stain).
[0285] FIG. 2B shows a normal mouse disc wherein localization of
TNF-alpha is present in the hypertrophic zone of the growth plate
as generally expected.
[0286] FIG. 2C shows in the compressed disc wherein increased
amounts of TNF-alpha are apparent within the nucleus and inner
annulus.
[0287] FIG. 2D shows increased TNF-alpha in the nucleus, inner
annulus and irregularities in growth plate observed in compressed
disc.
[0288] FIG. 3 shows a schematic view of a mouse 30 according to an
experimental model wherein the mouse tail 36 is injured by a
fixture 40 for evaluating pain factors.
[0289] FIG. 4 shows an experimental set-up related to the mouse
injury model illustrated in FIG. 3, wherein a series of mice 30 are
positioned for viewing their respective tails via a phosphor
imaging plate 50.
[0290] FIG. 5 shows an image 60 taken from a phosphor imaging plate
according to the set-up shown in FIG. 4 for four treatment mice and
one control mouse tail (located centrally in the figure).
[0291] FIG. 6 shows a schematic view of MAPK signaling pathways
associated with certain pain factors.
[0292] FIG. 7 shows a schematic view of a NF-.kappa..beta. pathway
associated with certain pain factors.
[0293] FIG. 8 shows a schematic view of a prostaglandin pathway
associated with certain pain factors.
DETAILED DESCRIPTION OF THE INVENTION
[0294] Referring more specifically to the drawings, for
illustrative purposes the present invention is embodied in the
systems and methods generally shown in or illustrated by reference
to FIG. 1 through FIG. 8. It will be appreciated that the apparatus
may vary as to configuration and as to details of the parts, and
that the method may vary as to the specific steps and sequence,
without departing from the basic concepts as disclosed herein.
[0295] Label Disc Features Associated with Pain
[0296] Discogenic pain is generally believed to be a multifactoral
phenomenon in many cases. In particular, three illustrative factors
are summarized in varying levels of detail here as examples that
are considered contributors in various ways to (or otherwise
indicative of) the generation or transmission of discogenic pain.
It is believed that these illustrative factors frequently act as a
co-existent combination, often acting simultaneously. These types
of factors are summarized as follows.
[0297] One such factor type relates to the presence of nociceptors.
Normally, intervertebral discs are substantially avascular and only
sparsely innervated at the outer margins of the disc annulus. These
unmyelinated, substance P (SP) or calcitonin gene-related peptide
(CGRP) containing fibers are typically unresponsive and termed
silent nociceptors [Cavanaugh, 1996]. SP and CGRP are believed to
be the sensory transmitters of nociceptive information. As
degeneration proceeds, nerves can follow microvessels and grow
deeper into discs, which may occur for example either peripherally
or via the endplate. This nerve and vessel in-growth is facilitated
by degeneration-related decreases in disc pressure and proteoglycan
content.
[0298] A second such factor type is generally embodied by the need
for the intradiscal nociceptors to be sensitized, and thus
generally involves agents providing such sensitization. This can
occur for example via cytokines, which are typically small,
secreted proteins that mediate and regulate inflammation. Elevated
levels of certain cytokines have been measured in human discs, and
are associated with degeneration and pain. Such major cytokines
have been observed to include interleukin-1, -6, and -8, tissue
necrosis factor-alpha (TNF-.alpha.), macrophage migration
inhibitory factor (MIF), and prostaglandin E2 (PGE.sub.2). The
source of cytokines can be circulating inflammatory cells, such as
for example in the case of herniated discs, or disc cells, such as
for example in the case of contained disc degeneration. These
pro-inflammatory stimuli can trigger cells to initiate a number of
catabolic programs meant to stimulate tissue repair and remodeling
that includes production of matrix metalloproteinases 1, 9 and 13.
During this wound healing process, cytokines are also often
involved in stimulating angiogenesis and granulation tissue
formation.
[0299] In one particular beneficial embodiment of the present
invention, cytokines and/or their cell-surface receptors are imaged
at sites of inflammation in vivo using labeled markers, such as
radiolabels. In particular beneficial examples, cytokines are
tagged with one or more of the following, without limitation:
iodine-123, iodine-125, iodine-131, technetium-99m, fluorine-18, or
indium-111. In addition, positron-emitting radioisotopes (for
example and without limitation fluorine-18) can be imaged using
positron emission tomography (PET) or positron emission
tomography-computed tomography (PET-CT). Other radiolabeled
compounds can be imaged for example using single photon emission
computerized tomography (SPECT).
[0300] It is also to be appreciated that MRI may be employed
according to further embodiments for visualizing or observing
accumulation or binding of various labeled markers variously herein
described, such as for example in applying gadolinium as a marker
tagged to or conjugated with certain labels to be bound to pain
factors. Moreover, nanoparticles such as gold or iron oxide may be
used as labels or markers to bind and thereafter be viewed or
selectively targeted for therapy using appropriate visualization or
treatment modalities, respectively.
[0301] A third such factor related to discogenic back pain involves
disc depressurization that leads to mechanical instability while a
pre-stress in the annulus and interspinal ligaments is diminished.
Depressurization and instability, in turn, lead to abnormal
internal disc stress that may stimulate nerves, leading to
discogenic pain. Abnormal disc stress may also cause disc cells to
be pro-inflammatory, compounding the adverse effects of an abnormal
mechanical environment.
[0302] Labeling and Imaging Nerve Factors
[0303] According to certain particular embodiments, one or more
materials associated with nerves in or around intervertebral discs
are labeled with markers that are imaged for localization of pain.
This is premised in part on the presence of certain such factors as
indicators that pain may originate or transmit in the area. These
embodiments include, without limitation, labeling structures or
substances associated with nerves themselves. Further detailed
modes of this include labeling substances within nerves, such as in
particular but without limitation substance P or "CGRP". Other
nerve fiber factors, substances or components that may be labeled
according to such further embodiment(s) include, without
limitation: TRK-.alpha.; anti-TRK-.alpha. antibody; nerve growth
factor (NGF); anti-NGF antibody; NGF antagonist; anti-NGF
antagonist antibody; PGP 9.5; SYN; peripherin; or other form of
nerve antibodies or related materials in general. Other materials
such as neurofilament 200 kD (NF200) [Johnson, 2001; Ashton, 1994]
may also be the target of such labeling and subsequent imaging.
[0304] As apparent from these highly beneficial illustrative
embodiments just noted immediately above (and elsewhere herein),
endogenous substances such as TrkA or NGF may be targeted as the
pain factor for labeling, or related antibodies or other substances
having particular binding affinity or specificity to such resident
materials may be bound to them in the area of pain and then
thereafter provide the binding site for targeted labels to be
subsequently delivered. In this regard, it is to be appreciated
that various forms binding agents are broadly contemplated
hereunder this description, though they may not be particularly
antibodies affecting function of the target for binding. For
example but without limitation, an antibody mimetic may be employed
according to the present embodiments. Furthermore, various such
substances described hereunder as targeted pain factors may be
themselves labeled as markers and delivered to other targets. For
example, NGF may be labeled and artificially delivered as the agent
to mark TrkA as the targeted pain factor for imaging. In each of
these different types of exemplary cases, the ultimate target for
labeling via a separately delivered agent (e.g. whether the target
is an endogenous resident substance or an artificially delivered
substance) is considered a "nerve factor" as a pain factor
according to the present embodiments.
[0305] The following description provides further understanding of
the role of these types of chemicals and other materials with
respect to these present embodiments. Further description of the
benefits of various particular illustrative examples are also
provided elsewhere herein for a further understanding.
[0306] The intervertebral disc is normally avascular and only
sparsely innervated at the outer layers of the annulus fibrosus and
the vertebral endplate [Fagan, 2003]. The outer 1/3 of the
posterior annulus is believed to be most typically innervated by
the afferent fibers from the sinovertebral nerve, which is
considered a `recurrent branch` of the ventral ramus of the spinal
nerve at the same level [Nakamura, 1996]. The ventral and lateral
aspects of the annulus are believed to be most typically innervated
by the dorsal root ganglion (DRG) [Aoki, 2004]. Also, it has been
reported that sensory fibers from upper level DRGs are believed to
most typically innervate the dorsal portion of discs via the
paravertebral sympathetic trunk [Ohtori, 2001].
[0307] The endplate is also suggested to be innervated by the
basivertebral nerve, which as further suggested may be a branch of
the sinovertebral nerve entering the vertebral body through the
posterior neurovascular foramen [Antonacci, 1998].
[0308] Nerves usually accompany blood vessels, but can be found as
isolated nerves in disc matrix. These non-vessel-associated fibers
found in back pain patients have been observed to express
growth-associated protein 43 (GAP43) as well as SP [Freemont,
1997]. Small disc neurons contain CGRP and also express the
high-affinity nerve growth factor (NGF) receptor, tyrosine kinase A
(trkA)[Aoki, 2004]. Disc inflammation has been observed to cause an
increase in CGRP positive neurons [Aoki, 2004]. A recent study
showed that NGF is expressed in microvascular blood vessels in a
painful lumbar disc, and that there are trkA (TRK-.alpha.)
expressing nerve fibers adjacent to the vessels that enter painful
discs primarily through the endplate [Freemont, 2002; Brown, 1997].
Along with nerves growing into degenerated discs are specialized
nerve support cells termed `glia` or Schwann cells localized using
glial fibrillary acidic protein (GFAP) [Johnson, 2001].
[0309] Accordingly, various such materials may provide the
requisite binding affinity or specificity to painful regions (or
highly innervated regions) to play the role as the labeled marker
agent for delivery to pain factor targets. Or, these materials may
provide the particular target as the pain factor to be labeled with
selectively bound markers according to various embodiments of the
present invention. In one particular beneficial example, TrkA
antibody (or other binding agent) is labeled and delivered as a
marker for binding and visualization at a location associated with
pain. In another beneficial example, NGF itself is labeled and
delivered as a marker to itself bind to TrkA. In further
embodiments, the resident quantities of these materials are treated
as the pain factors themselves for targeted labeling, e.g. using
antibodies or other agents with beneficial binding affinity and/or
specificity to these types of resident compounds in painful
regions.
[0310] The following Published PCT Patent Applications are herein
incorporated in their entirety by reference thereto: WO
2004/032870; WO 2004/058184; WO 2004/073653; WO 2004/096122; and WO
2005/000194.
[0311] The various compositions and methods described in these
incorporated references may be adopted where appropriate to one of
ordinary skill as label/marker vehicles and/or pain factor targets
according to further embodiments of the various aspects and modes
of the present invention herein described. For example without
limitation, NGF antagonists, anti-NGF antibodies, anti-NGF
antagonist antibodies, and various combinations or blends of these,
or analog or derivatives thereof, may be so incorporated as further
embodiments of the aspects herein described. Moreover, additional
compounds may also be included in the agent delivery scheme, or as
additional targets for labeled markers, such as for example
opioids, NSAID, or other molecules or drug agents related to pain
therapy.
[0312] Labeling and Imaging Blood Vessel Factors
[0313] Since blood vessels typically run along side and co-existent
with nerves, factors related to blood vessels may also be labeled
and imaged as indicia regarding vascularity itself, or as a measure
of concomitant innervation in an area. Such constitutes a further
embodiment contemplated hereunder, and described in some further
detail as follows. In one regard, PECAM and/or CD34 [Freemont,
2002; Brown, 1997] may be appropriate targets as factors related to
blood vessels and thus indicating their presence in a particular
location or region. Another example of an appropriate target
includes GFAP for endothelial cells [Johnson, 2001]. Other
microvessel-related factors are considered as included, though not
specifically listed here, as would be apparent to one of ordinary
skill based upon review of this disclosure and other available
information.
[0314] Labeling and Imaging Inflammatory Factors
[0315] According to still further embodiments contemplated
hereunder, inflammatory factors themselves may be labeled with
targeted markers and imaged as indicators of pain in a location or
area. One exemplary type of such factor includes cytokines, such as
for example but without limitation (though considered of particular
benefit): tnf-a, or certain interleukins such as IL-1, 6, or 8 (or
other interleukins). Another exemplary pro-inflammatory factor
includes MIF and PGE.sub.2.
[0316] Other factors considered indicative of certain activities or
environmental considerations believed linked to pain, and thus
appropriate targets for labeling and imaging using targeted
markers, include: pH (e.g. in particular marking low pH as
indicator of pain; or O2 levels, e.g. in particular marking low O2
as indicator of pain).
[0317] Cytokines, in the present context, are generally described
as small, secreted proteins that mediate and regulate inflammation.
They generally act over short distances, short times, and at very
low concentrations. They typically function by binding to specific
membrane receptors, which often then signal the cell via second
messengers (discussed below) to alter gene expression. Responses to
cytokines include increasing or decreasing expression of membrane
proteins (including cytokine receptors), cell proliferation, and
secretion of effector molecules. Cytokines may act on the cells
that secrete them (autocrine action), on nearby cells (paracrine
action), or in some instances on distance cells (endocrine action).
It is common for different cells types to secrete the same cytokine
or for a single cytokine to act on several different cell types
(pleiotropy). Cytokines are redundant in their activity, and are
often produced in a cascade, as one cytokine stimulates its target
cells to make additional cytokines. Cytokines can also act
synergistically or antagonistically.
[0318] Elevated levels of certain cytokines have been measured in
human discs, and have been associated with degeneration and pain.
Among the major cytokines found are, for example and without
limitation: interleukin-1, -6, and -8, tissue necrosis factor-alpha
(TNF-.alpha.), and prostaglandin E2 (PGE.sub.2)[Miyamoto, 2000;
Ahn, 2002; Olmarker, 1998; Weiler, 2005]. The source of cytokines
can be circulating inflammatory cells in the case of herniated
discs [Kawaguchi, 2002; Woertgen, 2000], or disc cells in the case
of contained disc degeneration [Burke, 2002].
[0319] For disc cells, inflammatory factor production may be
stimulated for example as part of several signaling cascades
(described below), by fragments of degraded extracellular matrix,
or matrix deformation (FIG. 1). These exemplary pro-inflammatory
stimuli can trigger cells to initiate a number of catabolic
programs meant to stimulate tissue repair and remodeling that
includes production of matrix metalloproteinases 1, 9 and 13
[Anderson, 2002]. During this wound healing process, cytokines are
also involved in stimulating angiogenesis and granulation tissue
formation [Gillitzer, 2001].
[0320] IL-1 and TNF-.alpha.
[0321] IL-1b and TNF-.alpha. have been observed to demonstrate
overlapping pro-inflammatory effects, activate common signaling
cascades, and induce similar target genes (see ref in Faur).
Effector cascades mediating inflammatory responses to IL-1 and
TNF-.alpha. include the mitogen-activated protein kinases (MAPK),
NF-.kappa..beta. and prostaglandin signal transduction pathways
(shalom-barak). The signaling molecule nitric oxide may also form
important component of the inflammatory cascade.
[0322] Imaging via labeling tissue necrosis factor-alpha
(TNF-.alpha.) provides one particular beneficial example of marking
for imaging a pro-inflammatory cytokine that can chemically
hypersensitize the intervertebral disc and spinal nerve roots,
thereby contributing to low back pain. Studies have been conducted
that utilize immunohistochemistry to localize TNF-.alpha. in
histologic sections of normal and degenerated mouse-tail discs.
These studies suggest that the levels of TNF-.alpha. are increased
after compression-induced degeneration of the intervertebral disc
(FIGS. 2A-D).
[0323] To demonstrate a TNF-.alpha. based localization modality of
the present invention, compositions and methods have been developed
that label TNF-.alpha. antibodies with I-125 so that variations in
TNF-.alpha. content can be imaged in vivo. An experiment was
conducted to observe and confirm the beneficial use of this
approach as follows. Mice such as mouse 30 shown in FIG. 3 were
subjected to conditions that initiate tail-disc degeneration (FIG.
3), and were then injected intravenously with I-125 labeled
TNF-.alpha. antibody. These animals were then imaged with a
phosphor imaging plate, such as plate 50 shown in FIG. 4. Use of
this composition and imaging methods demonstrated readily observed
increased uptake in the regions of the injured discs, such as seen
in image 60 in FIG. 5 wherein four injured tails are shown in
2-group sets on either side of a centrally located control tail in
the image that was not injured though received similar labeled
marker injection.
[0324] This particular experiment was performed using a particular
radio-labeled TNF-.alpha. blocker, more specifically infliximab
(Trade name "Remicade.TM." commercially available from Johnson
& Johnson), and demonstrates one exemplary embodiment adapted
for beneficial use according to the present invention. While this
particular modality is considered highly beneficial in the specific
mode described, it is also exemplary of a number of broad aspects
of the present invention that may be illustrated by many
alternative or combinatorial approaches that are herein
contemplated.
[0325] In one regard, the present illustrative embodiment provides
an example of using a therapeutic compound that actually provides
some pain-related therapy (e.g. TNF-.alpha. antibody or other form
of blocker) that is also used to image the location of the pain
being treated (as the labeled marker, as conducted in the
illustrative experiment, or targeted factor itself). This step may
be followed by additionally treating the imaged region thereafter
with additional spacially localized or directed therapies. Examples
include, without limitation, directed energy therapies such as
those elsewhere herein described, or further localized injection of
similar or other therapeutic compound(s)).
[0326] In another more specific regard, TNF-.alpha. blockers or
antibodies are contemplated as a class of therapeutic compounds
beneficially adapted for use according to the invention, within
which infliximab or Remicade.TM. (or analogs or derivatives
thereof) is used in a particular beneficial embodiment as just
described. These provide the benefit of selective uptake at nerve
endings where pain may be occurring, and thus a particular
beneficial target agent for labeling to image pain. They also
provide the benefit of some therapeutic value to the pain
itself.
[0327] Furthermore, it is to be appreciated that targeted agents,
such as antibodies as herein described by way of example, may
provide the label for imaging, or may take the form of the targeted
factor (either by itself or by virtue of its conjugation or binding
with a first resident factor). In the later case, delivery of the
first factor is then subjected to subsequent labeling by delivery
of a second agent as the labeled marker (again either by its
imagability itself or as bound, associated, or conjugated with the
first delivered agent to the region imaged).
[0328] MAPK Pathway
[0329] MAPKs form an intracellular signaling pathway built upon a
self-propagating phosphorylation system (FIG. 6). Activation of
MAPKs are one of the pivotal intracellular pathways triggered by
cytokine receptors (Shalom-berak). Three MAPK subgroups have been
identified: extracellular signal regulated kinase (ERK); the Jun
NH.sub.2-terminal kinases (JNK); and p38 (geng, others). In
chondrocytes, ERK activation occurs in response to diverse stimuli,
while JNK and p38 is only seen in response to IL-1 and TNF-.alpha.
(Firestein, Iiancini): this signaling pathway is thought
responsible for cartilage degradation (geng). JNK and p38 are
collectively termed stress activated protein kinases (SAPKs). The
signal is initiated by membrane-proximal small GTPases of the Rho
family, activation of MLK, and phosphorylation and activation of
MKK3/6 that in turn phosphorylates and activates p38. Faur).
[0330] One important endpoint of MAPK activation is the production
of the phosphorylated active activator protein 1 (AP-1)
transcription factor (heterodimer of c-Jun and c-Fos), which in
turn, can influence chondrocyte collagenase activity (mengshol,
Ferreria refs). AP-1 plays a central role in the transcriptional
regulation of many MMP genes including collagenase and stromelysin
(mengshol refs, Firestein). Similarly, MIF activates the MAPK
pathway and AP-1 leading to cell proliferation, and PGE.sub.2
production, which eventually promotes monocyte/macrophage
activation. Certain published data suggests that MIF is in
particular upregulated under conditions of chronic emotional stress
and can potentiate elevated levels of other inflammatory factors
such as for example those examples herein described. Accordingly,
labeling MIF provides yet a further embodiment of the various
present aspects.
[0331] JNK and p38 are essential for IL-1 induction of mmp-13,
while ERK pathway is not. p38 is essential for multiple
inflammatory genes, including II-1, TNF-.alpha., 11-6,
stromelysin-1 (mmp-3) and mmp-1 (mengeshol).
[0332] It is to be appreciated that various such materials
associated with pathways or molecular cascades associated with pain
may provide the target for labeled markers and subsequent imaging
as herein described, and various such materials are provided here
as beneficial examples which, though of particular value, are also
not intended to limit broad aspects contemplated hereunder. In
addition, such otherwise indigenous materials may also demonstrate
selective uptake in tissues associated with pain. In such case,
these otherwise indigenous materials (or synthetic or other
biologic constructs similar to them, such as analogs or derivatives
thereof) may also be harnessed and labeled for delivery as the
labeled marker. Moreover, due to their selective uptake, particular
accumulated concentrations of certain molecules in areas of pain
also render them viable targets as the pain factors themselves for
labeling with labeled markers that bind to them.
[0333] NF-.kappa..beta. Pathway
[0334] In addition to the MAPK induction, IL-1 and TNF-.alpha.
activate NF-.kappa..beta.. NF-.kappa..beta. is a transcription
factor that exists in a latent form in the cytoplasm of
unstimulated cells and is composed of a transcriptionally active
dimer (p65 and p50) bound to an inhibitor protein (|.kappa..beta.)
(Bowie, Magnani). NF-.kappa..beta. is activated by a large number
of different signals that include similar cell stress signals that
activate SAPKs. IL-1 and TNF-.alpha. trigger the phosphorylation
and degradation of |.kappa..beta., resulting in the release of
NF-.kappa..beta. to enter the nucleus (refs in Shalom; Baeuerle).
NF-.kappa..beta. activation occurs through a cascade starting with
NF-.kappa..beta.-inducing kinase (NIK), which then phosphorylates
and activates the inhibitor of NF-.kappa..beta. (|.kappa..beta.)
kinases. Phosphorylation of |.kappa..beta. results in
ubiquitination and degradation of |.kappa..beta. inhibitory
subunit, allowing NF-.kappa..beta. to translocate to the nucleus
where it acts as a transcription factor and regulates its target
genes, which include collagenase (MMP-1; Barchowsky) (Mengshol,
magnani) and COX-2 (Mifflin). FIG. 7 shows certain further details
of this cascade and relationship between components.
[0335] Prostaglandin Pathway
[0336] Eicosanoids are signaling molecules that act in an autocrine
fashion. Pro-inflammatory stimuli can lead to increased
phospholipid-derived eicosanoid synthesis that involves a cascade
of three enzyme reactions (FIG. 8). First, arachidonic acid (AA) is
liberated from its phospholipid storage sites by phospholipase A2
(PLA2). The next rate-limiting step is conversion of AA to
prostaglandin H2 by cyclooxgenase (COX).
[0337] The prostaglandin pathway is stimulated by IL-1b. This
cytokine increases the activity of PLA2 and induces COX-2 gene
expression by binding to a specific cell-surface receptor (IL-1RI)
that ultimately leads to increases in COX-2 promoter activity via
the NF-.kappa..beta. pathway (Faur refs, geng). In chondrocytes,
COX activity is not increased by TNF-.alpha.. Rather, TNF-.alpha.
can amplify COX activity in IL-1 stimulated cells. (Berenbaum).
[0338] Prostaglandin E2 (PGE.sub.2) stimulates the catabolism of
chondrocytes, having both anti-proliferative and pro-apoptotic
effects (berenbaum ref, also goldring ref in Iiancici). An increase
in PGE.sub.2 may therefore tip the balance toward catabolism.
[0339] Nitric Oxide
[0340] Nitric oxide (NO) is a small signaling molecule that is part
of the catabolic program in chondrocytes induced by IL-1 and
TNF-.alpha. (Lotz; Goldring). It is produced within the cell by the
inducible isoform of NO synthase (iNOS), and then passes readily
through the cell membrane to affect neighboring cells. Because it
has a short half-life (5 to 10 seconds) it acts only locally, yet
it plays an important role in the pathophysiology of arthritic
disease (Ferreira Mendes). It has been shown to: induce apoptosis
(by stimulating release of cytochrome c from mitochondria) and
inflammation (by activating COX and PLA2 (Vassalle, clancey));
suppress collagen and proteoglycan synthesis; and upregulate MMP
synthesis (Scheurwegh).
[0341] IL-1 and TNF-.alpha. increase the gene expression and
synthesis of iNOS, through the transcription factors
NF-.kappa..beta. and AP-1. Activation of NF-.kappa..beta. is an
essential step for iNOS induction (see Mendes refs). Also, there is
some evidence that the MAPK p38 may be involved in the activation
of NF-.kappa..beta. and subsequent iNOS expression, since p38 is
reported to be required for IL-1-induced iNOS expression in
chondrocytes (Mendes).
[0342] Labeling/Imaging Cellular Factors Associated with
Inflammation
[0343] Cells that produce or are associated with inflammatory
factors can also be labeled with targeted markers and thereafter
imaged as an indicator that pain exists in the area. For example,
disc cells that are actively synthesizing inflammatory factors may
be labeled as such (or components thereof may be labeled).
Inflammatory cells that are attracted to painful discs, such as for
example leukocytes, may be labeled and imaged for this purpose.
[0344] The following articles are herein incorporated in their
entirety by reference thereto. [0345] 1. Haro H, Crawford, H. J.
Clin. Invest. 2000; 105:143-150. [0346] 2. Mow V, Hayes, W. Basic
Orthopaedic Biomechanics. In. New York: Raven Press, 1991; 339-342.
[0347] 3. Thompson J P, Pearce, R. H., Schechter, M. T., Adams, M.
E., Tsang, I. K., Bishop, P. B. Preliminary evaluation of a scheme
for grading the gross morphology of the human intervertebral disc.
Spine 1990; 15:411-415. [0348] 4. Iatridis J C, Setton, L. A.,
Weidenbaum, M., Mow, V. C. Alterations in the mechanical behavior
of the human lumbar nucleus pulposus with degeneration and aging.
In:Journal of orthopaedic research, 1997; 318-322. [0349] 5. Urban
J P, McMullin, J. F. Swelling pressure of the intervertebral disc:
influence of proteoglycan and collagen contents. Biorheology 1985;
1985. [0350] 6. Beall P T, Amety, S. R. et al. States of Water in
Biology: NMR Data Handbook for Biomedical Applications. New York:
Pergamon Press, 1984. [0351] 7. Boos N, Boesch, C. Quantitative
magnetic resonance imaging of the lumbar spine: potential for
investigations of water content and biochemical composition. Spine
1995:2358-2366. [0352] 8. Bottomley Pa., Foster, T. H. et al. A
review of normal tissue hydrogen NMR relaxation times and
relaxation mechanisms from 1-100 MHz: dependence on tissue type,
NMR frequency, temperature, species, excision, and age. Medical
Physics 1984:425-448. [0353] 9. Lyons G, Eisenstein, S. M. et al.
Biochemical changes in intervertebral disc degeneration. Biochim
Biophys Acta 1981:443-453. [0354] 10. Majors A W, McDevitt, C. A.
et al. A correlative analysis of T2, ADC and MT ratios with water,
hydroxyproline and GAG content in excised human intervertebral
disk. In:40th Annual Meeting Orthopaedic Research Society. New
Orleans, Louisiana: Orthopaedic Research Society, 1994. [0355] 11.
Maroudas A. The Biology of the Intervertebral Disc. In: Ghosh P,
ed. The Biology of the Intervertebral Disc. Boca Raton: CRC Press,
1988; Ch. 9. [0356] 12. Pearce R H, Grimmer, B. J. et al.
Degeneration and the chemical composition of the human lumbar
intervertebral disc. Journal of orthopaedic research 1987:198-205.
[0357] 13. Tertti M, Paajanen, H. et al. Disc degeneration in
magnetic resonance imaging: a comparative biochemical, histologic,
and radiologic study in cadaver spines. Spine 1991:629-634. [0358]
14. Chui E, David C. Newitt, Mark R. Segal, Serena S. Hu, Jeffrey
C. Lotz, Sharmila Majumdar. Magnetic Resonance Imaging Measurement
of Relaxation and Water Diffusion in the Human Lumbar
Intervertebral Disc Under Compression In Vitro. Spine 2001;
26:E437-444. [0359] 15. Gundry C R, Fritts, H. M. Magnetic
resonance imaging of the musculoskeletal system: Part 8. The spine.
Clin Orthop Rel Res 1997:275-287. [0360] 16. Gunzburg R PRea. A
cadaveric study comparing discography, magnetic resonance imaging,
histology and mechanical behavior of the human lumbar disc. Spine
1991:417-423. [0361] 17. Modic Mont., Pavlicek, W. et al. Magnetic
resonance imaging of intervertebral disc disease: clinical and
pulse sequence considerations. Radiology 1984:103-111. [0362] 18.
Modic Mont., Masaryk, T. J. et al. Lumbar herniated disk disease
and canal stenosis: prospective evaluation by surface coil MR, CT
and myelography. ANJR 1986:709-717. [0363] 19. Modic Mont.,
Masaryk, T. J. et al. Imaging of degenerative disc disease.
Radiology 1988:177-186. [0364] 20. Sether La., Yu, S. et al.
Intervertebral disk: Normal age-related changes in MR signal
intensity. Radiology 1990:385-388. [0365] 21. Pfirrmann C,
Metzdorf, A., Zanetti, M. Magnetic Resonance Classification of
Lumbar Intervertebral Disc Degeneration. Spine 2001; 26:1873-1878.
[0366] 22. Nieminen Mont., Rieppo, J., Silvennoinen, J. et al.
Spatial assessment of articular cartilage proteoglycans with
Gd-DTPA-enhanced T1 imaging. Magnetic Resonance in Medicine 2002;
48:640-648. [0367] 23. Mosher T J, Dardzinski, B. J., Smith, M. B.
Human articular cartilage: influence of aging and early symptomatic
degeneration on the spatial variation of T2-preliminary findings at
3 T. Radiology 2000; 214:259-266. [0368] 24. Boos N, Wallin, A.,
Boesch, C. H., Aebi, M. Quantitative MR Imaging of diurnal water
content variations in lumbar intervertebral disc. In:38th Annual
Meeting, Orthopeadic Research Society. Washington, D.C.: The
Orthopaedic Research Society, 1992; 165. [0369] 25. Boos N, Wallin,
A., Harms, S., Vock, P., Boesch, C. H., Aebi, M. Tissue
characterization of normal and herniated lumbar intervertebral
discs by quantitative MRI. In:39th Annual Meeting, Orthopaedic
Research Society. San Francisco, Calif.: Orthopaedic Research
Society, 1993; 417. [0370] 26. Burstein D, Gray, M. L. et al.
Diffusion of small solutes in cartilage as measured by nuclear
magnetic resonance (NMR) spectroscopy and imaging. Journal of
orthopaedic research 1993:465-478. [0371] 27. Koh K, Kusaka, Y. et
al. Self diffusion coefficient of water and its anisotropic
property in bovine intervertebral discs analyzed by pulsed gradient
NMR method. Orthop Trans 1992:483. [0372] 28. Koh K, Kusaka, Y. et
al. Self diffusion coefficient of water in human intervertebral
discs analyzed by pulsed gradient NMR method. In:39th Annual
Meeting Orthopaedic Research Society. San Francisco, Calif., 1993.
[0373] 29. Abdulkarim J A, Dhingsa, R., Finlay, D. B. Magnetic
Resonance Imaging of the Cervical Spine: Frequency of Degenerative
Changes in the Intervertebral Disc with Relation to Age. Clinical
Radiology 2003:980-984. [0374] 30. Swanson M G, Vigneron D B,
Tabatabai Z L, et al. Proton HR-MAS spectroscopy and quantitative
pathologic analysis of MRI/3D-MRSI-targeted postsurgical prostate
tissues. Magnetic Resonance in Medicine 2003; 50:944-954. [0375]
31. Schiller J, Naji, L., Huster, D., Kaufmann, J., Arnold, K. 1H
and 13C HR-MAS NMR investigations on native and enzymatically
digested bovine nasal cartilage. Magnetic Resonance Materials in
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Purcell, E. M. Effects of Diffusion on Free Precession in Nuclear
Magnetic Resonance Experiments. Physical Review 1954; 94:630-638.
[0377] 33. Kupce E. Applications of adiabatic pulses in
biomolecular nuclear magnetic resonance. In:Methods in Enzymology,
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13C nuclear magnetic resonance identification and characterization
of components of chondroitin sulfates of various origin.
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I., Valat, J. P., Freemont, A. J. Matrix metalloproteinases: the
clue to intervertebral disc degeneration? Spine 1998; 23:1612-1626.
[0380] 36. Kang J D, Stefanovic-Racic, M., Mclntyre, L. A.,
Georgescu, H. I., Evans, C. H. Toward a biochemical understanding
of human intervertebral disc degeneration and herniation.
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Weiler C, Nerlich, A. G., Zipperer, J., Bachmeier, B. E., Boos, N.
2002 SSE Award Competition in Basic Science: Expression of major
matrix metalloproteinases is associated with intervertebral disc
degradation and resorption. European Spine Journal 2002:308-320.
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Intervertebral Disc from Development to Degeneration. In: American
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Best, B. A., Saed-Nejad, F., Nickoloff, E., Newhouse, J.,
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[0386] It is to be appreciated based upon the foregoing disclosure
that pain factors are labeled and imaged in order to identify, with
a useful degree of geographic specificity, active pain sites in and
around skeletal joints. Such is considered highly beneficial in
particular for use in diagnosing the cause of pain, and
understanding where and how to treat for pain relief, such as for
example with local ablation or energy delivery systems, and/or
local drug delivery.
[0387] Various terms have been used herein of a certain technical
nature, and should be given their standard technical meaning in the
context of the particular art to which this disclosure pertains,
and in the context of their use in this description together with
other accompanying disclosure, unless otherwise given a specific
meaning hereunder. Notwithstanding the foregoing, it is understood
that certain specific materials or types of materials are
identified, whereas other similar materials or types of materials
are also intended to be implicated within the broad scope intended
for the current invention. For example, "pain factors" are herein
identified as playing a role in various of the present embodiments.
Such terms are intended to mean any and all materials, whether
structural, chemical, or otherwise, that have an association,
either directly or indirectly, with pain such that binding them
provides a vehicle to enhance diagnosis or therapy in relation to
the associated pain. In one particular example, factors related to
transmitting pain signals along or between nerves are to be
included. Or, factors that stimulate pain, such as "inflammatory"
materials, are indicated. Materials related to other points in a
chemical or biological cascade related to pain are also implicated,
such as factors that relate to secondary or tertiary products or
components of such pain generation or transmission process. If a
factor is distinctly present (or absent) in a somewhat recognizable
manner when and where pain is present, and in a different level or
manner than when and where pain is not present, then it is
considered a "pain factor" as herein described. This use of the
term "factor" similarly applies in other contexts herein provided,
such as for example "inflammatory factors", "cellular factor(s)",
"nerve factors", etc.
[0388] In another regard, it is also contemplated that, where
certain specific examples of chemicals or materials are herein
provided, other related compounds may be interposed in addition or
in the alternative to such specified compound. For example, agents
related to a certain material may be suitable substitutes and may
include for example precursor materials, such as a material that
may be metabolized or otherwise altered to produce the specified
"factor" or "label" or other compound or material referenced.
Analogs or derivatives of the specified material may also be
suitable in similar uses or preparations or systems. This includes
for example modified molecular forms of a specified material that
retain the related binding or other activity of the specified
material so as to perform as herein described as a labeled pain
factor or targeted label.
[0389] Moreover, use of a "marker" or "label" to tag or label a
"factor" is generally herein described in fairly simple terms for
the purpose of providing a general overall understanding of the
broad aspects contemplated hereunder. However, the actual steps
and/or materials used in order to achieve such "labeled pain
factor" result may be more extensive than herein described, though
may be carried out by one of ordinary skilled in the art based upon
review of this disclosure in its entirety in combination with other
available related information and thus further contemplated
hereunder. For example, intermediary tagging, labeling, or binding
may be beneficially used in order to achieve the labeled marking
necessary to provide differential imaging of the labeled result in
a useful manner.
[0390] In one further exemplary embodiment, bi-specific antibodies
may be used in such a manner as follows. One binding site of the
bi-specific antibody provides a particular binding affinity for the
pain factor being targeted, and thus differentially binds to that
factor. However, this is done in a manner leaving a second binding
site exposed, and which second binding site has binding specificity
to a second material as a label agent. This second material
thereafter binds to the second binding site of the bi-specific
antibody bound at the first site to the pain marker. The result
provides a labeled marker on the pain factor via the second
material, which is tagged to the pain factor via use of this
intermediary bi-specific antibody.
[0391] It is also to be understood that the labeled marking of pain
factors herein described is of particular benefit with respect to
thereafter image the result. While imaging the "labeled pain
factor" may be generally described, it is to be understood that
what is imaged by the particular imaging modality may include
without limitation: the overall conjugate or combination of
label-plus-factor; the label itself; the factor itself (e.g. to the
extent modified in a recognizable way by the labeled marking); or
combinations of the above, including in further modes use of
intermediary binding materials such as for example bi-specific
antibodies as herein described.
[0392] One particular example of a labeled marker and pain factor
combination believed to be useful according to certain of the
embodiments herein described is provided in finer detail to provide
a further understanding. This relates to radiolabeled TNF-.alpha.
antibodies and related imaging tools herein described. However, it
is to be appreciated that this approach, though in particular
highly beneficial, is exemplary of broader aspects of the present
invention and other labeling and/or marker modalities, or targeted
vehicles such as without limitation antibodies, and/or imaging
tools are contemplated and may be used without departing from the
intended broad scope according to various aspects of the
invention.
[0393] The invention according to further aspects provides a unique
ability to direct therapy to pain, including without limitation
pain associated with musculoskeletal joints and in particular the
spine. Accordingly, the systems and methods of the invention
according to further embodiments also include therapeutic device
assemblies for delivering such therapy. Such may include local drug
or other chemical delivery modalities. Or, therapeutic dosing of
energy may be delivered, such as for example radiofrequency (RF)
energy delivery probes, ultrasound probes, high intensity focused
ultrasound (HIFU), light energy (e.g. lasers for example),
microwave energy, or cryovascular therapeutic tools may be used. By
identifying where treatment is required due to the selectively
visualized pain factors there, these tools may be used in a more
efficient manner. Accordingly, the compositions of labeled markers,
the visualization or imaging tools, and the therapeutic tools are
thus used in an overall symphony that together provides beneficial
healthcare results in treating pain.
[0394] This is in particular the case with respect to back pain.
For example, a disc may be identified as a source of pain, whereas
lack of further clarity may render it difficult to treat the pain
in a selective way. Often, ablation of the entire disc is not
desired. According to certain further embodiments, the labeled
marking of pain factors and related imaging is used to identify
more specifically where pain occurs. In one mode, at least one-half
of the disc is identified as the target for therapy. In another
mode, the labeled marker visualization localizes the target for
therapy to one or more quarter quadrants of the disc. In still
further embodiments, directionally localized energy delivery, e.g.
laser, ultrasound, or microwave, may be particularly beneficial for
isolating the therapy to the isolated region of visualized, labeled
pain factors. Furthermore, local injections of pain medication may
be directed via such targeted labeling and related imaging of pain
localization.
[0395] In another highly beneficial aspect, pain factors that are
visualized with targeted markers as described hereunder may relate
to nerves that are located at least in part within bones. This may
be the case for example with respect to bony end-plates that are
innervated with nociceptive nerve fibers. In one particular
beneficial embodiment, pain factor imaging as herein described is
used to locally identify one or more particular end-plates of
vertebral bodies as the pain source. Accordingly in many such
instances, a basivertebral ablation tool set and method may be used
to ablate the basivertebral nerve that innervates that end-plate.
This may be done for example using a mono- or bi-polar electrode
assembly that is delivered via one or more needle or drill probes
into the vertebral body that is used to RF ablate the nerve closer
to a root trunk section within the bone. Despite this particular
beneficial combination of tools and methods for treating pain in a
uniquely localized manner, however, it is to be appreciated that
other localized pain sources may be selectively visualized using a
variety of useful targeted markers, and a variety of tools or
methods may be used to direct therapy accordingly, without
departing from the present intended scope of the present
invention.
[0396] The following US Patents are herein incorporated in their
entirety by reference thereto: 5,391,197 to Burdette et al.; U.S.
Pat. No. 6,074,352 to Hynynen et al.; U.S. Pat. No. 6,126,682 to
Sharkey et al.; U.S. Pat. No. 6,231,528 to Kaufman et al.; U.S.
Pat. No. 6,368,292 to Ogden et al.; U.S. Pat. No. 6,470,220 to
Kraus, Jr. et al.; 6,562,033 to Shah et al.; U.S. Pat. No.
6,575,969 to Rittman III et al.; U.S. Pat. No. 6,699,242 to
Heggeness; U.S. Pat. No. 6,736,835 to Pellegrino et al.; U.S. Pat.
No. 6,827,716 to Ryan et al.; U.S. Pat. No. 6,907,884 to Pellegrino
et al. The following published PCT Patent Applications are herein
incorporated in their entirety by reference thereto: WO 2003/059437
to Diederich et al.; and WO 03/061756 to Diederich et al. The
following Published US Patent Applications are also herein
incorporate in their entirety by reference thereto: US 2004/0064137
to Pellegrino et al.; and US 2004/0064136 to Papineau et al.
[0397] Various different modes of "imaging" and related tools are
herein contemplated, as apparent to one of ordinary skill to match
the targeted marker modalities employed to accomplish the general
objectives hereunder. In one regard, a variety of diagnostic tools
may be used to acquire information related to the targeted pain
factor(s) and related spacial location relative to surrounding
tissues. This information may be processed and converted into a
representation that may be displayed or otherwise conveyed to a
healthcare provider in a manner sufficient and useful to understand
the spacial location of the associated pain. Accordingly, various
different types of sensors, data acquisition systems, processors,
and displays may be used in various combinations to convert the
labeled marking to useful information to such healthcare providers.
Many of these are commercially available in sufficient form to
readily integrate with the targeted marker agents and delivery
systems herein described (which may further include therapeutic
aspects) in an overall system sufficient to provide useful
information in medical patient management.
[0398] Although the description above contains many details, these
should not be construed as limiting the scope of the invention but
as merely providing illustrations of some of the presently
preferred embodiments of this invention. Therefore, it will be
appreciated that the scope of the present invention fully
encompasses other embodiments which may become obvious to those
skilled in the art, and that the scope of the present invention is
accordingly to be limited by nothing other than the appended
claims, in which reference to an element in the singular is not
intended to mean "one and only one" unless explicitly so stated,
but rather "one or more." All structural, chemical, and functional
equivalents to the elements of the above-described preferred
embodiment that are known to those of ordinary skill in the art are
expressly incorporated herein by reference and are intended to be
encompassed by the present claims. Moreover, it is not necessary
for a device or method to address each and every problem sought to
be solved by the present invention, for it to be encompassed by the
present claims. Furthermore, no element, component, or method step
in the present disclosure is intended to be dedicated to the public
regardless of whether the element, component, or method step is
explicitly recited in the claims. No claim element herein is to be
construed as a "means plus function" element unless the element is
expressly recited using the phrase "means for". No claim element
herein is to be construed as a "step plus function" element unless
the element is expressly recited using the phrase "step for".
* * * * *