U.S. patent application number 15/920248 was filed with the patent office on 2018-07-19 for method and apparatus for electromagnetic treatment of living systems.
This patent application is currently assigned to Endonov Therapeutics, Inc.. The applicant listed for this patent is Endonovo Therapeutics, Inc.. Invention is credited to Arthur A. Pilla.
Application Number | 20180200531 15/920248 |
Document ID | / |
Family ID | 55851513 |
Filed Date | 2018-07-19 |
United States Patent
Application |
20180200531 |
Kind Code |
A1 |
Pilla; Arthur A. |
July 19, 2018 |
Method and Apparatus for Electromagnetic Treatment of Living
Systems
Abstract
Embodiments of the invention include methods of treating a
patient with physiological responses arising from an injury or
condition, such as post-operative pain, traumatic brain injury, and
cognitive defects. These treatment methods can include the steps of
generating a pulsed electromagnetic field from a pulsed
electromagnetic field source which is configured to simultaneously
increase the rate of ion-dependent signaling, such as CaM/NO/cGMP
signaling and to minimize the rate of inhibition of such signaling
by natural compounds and applying the pulsed electromagnetic field
in proximity to a target region affected by the injury or condition
for a first treatment interval followed by an inter-treatment
period with no electromagnetic field between treatment intervals to
reduce a physiological response to the injury or condition.
Inventors: |
Pilla; Arthur A.; (Oakland,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Endonovo Therapeutics, Inc. |
Woodland Hills |
CA |
US |
|
|
Assignee: |
Endonov Therapeutics, Inc.
Woodland Hills
CA
|
Family ID: |
55851513 |
Appl. No.: |
15/920248 |
Filed: |
March 13, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14932928 |
Nov 4, 2015 |
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15920248 |
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62075122 |
Nov 4, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 2/02 20130101; A61N
2/008 20130101 |
International
Class: |
A61N 2/00 20060101
A61N002/00 |
Claims
1-23. (canceled)
24. An apparatus for applying pulsed electromagnetic field (PEMF)
energy to a subject, the apparatus comprising: a generator unit
including a signal generator configured to generate a PEMF waveform
having configured to simultaneously increase the rate of
ion-dependent signaling and to minimize the rate of inhibition of
such signaling; a programmable control unit configured to
repeatedly provide a signal to the generator unit corresponding to
the PEMF waveform for a treatment interval that is 10 minutes or
greater followed immediately by an off time having an
inter-treatment period that is greater than six times the treatment
interval; and an applicator unit configured to be worn by the
subject, wherein the generator unit is configured to power the
applicator unit to drive transmission of a PEMF signal from the
applicator unit based on the PEMF waveform.
25. The apparatus of claim 24, wherein the programmable control
unit is programmed to provide an inter-treatment period that is
between six and 100 times the treatment interval.
26. The apparatus of claim 24, wherein the programmable control
unit is configured to prevent the generation of a pulsed
electromagnetic field during the inter-treatment period.
27. The apparatus of claim 24 further comprising a shut off to stop
the generator unit during the inter-treatment period.
28. The apparatus of claim 24, wherein the applicator comprises a
flexible loop.
29. The apparatus of claim 24, wherein the applicator comprises a
first loop configured to provide the PEMF waveform and a second
loop configured to provide a second PEMF waveform.
30. The apparatus of claim 24, wherein the programmable control
unit is configured to repeatedly provide the same signal to the
generator unit corresponding to the PEMF waveform.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional patent
application No. 62/075,122, filed on Nov. 4, 2014, and titled
"METHOD AND APPARATUS FOR ELECTROMAGNETIC TREATMENT OF LIVING
SYSTEMS," the entirety of which is herein incorporated by
reference.
INCORPORATION BY REFERENCE
[0002] All publications and patent applications mentioned in this
specification are herein incorporated by reference in their
entirety to the same extent as if each individual publication or
patent application was specifically and individually indicated to
be incorporated by reference.
FIELD
[0003] The disclosure relates generally to the field of therapeutic
devices and methods for treating patients.
BACKGROUND
[0004] Described herein are electromagnetic treatment devices,
systems and methods. Some embodiments pertain generally to a method
and apparatus for therapeutic and prophylactic treatment of animal
and human cells and tissues. In particular, some embodiments
pertain to use of non-thermal time-varying electromagnetic fields
configured to accelerate the asymmetrical kinetics of the binding
of intracellular ions to their respective binding proteins which
regulate the biochemical signaling pathways living systems employ
to reduce the inflammatory response to injury, and to enhance
healing and well-being. Other embodiments pertain to the
non-thermal application of repetitive pulse bursts of sinusoidal,
rectangular, chaotic or arbitrary waveform electromagnetic fields
to instantaneously accelerate ion-buffer binding in signaling
pathways in animal and human cells and tissues using ultra
lightweight portable coupling devices such as inductors and
electrodes, driven by miniature signal generator circuitry that can
be incorporated into an anatomical positioning device such as a
dressing, bandage, compression bandage, compression dressing;
lumbar or cervical back, shoulder, head, neck and other body
portion wraps and supports; garments, hats, caps, helmets, mattress
pads, seat cushions, beds, stretchers, and other body supports in
cars, motorcycles, buses, trains, airplanes, boats, ships and the
like.
[0005] In some embodiments, the proposed EMF transduction pathway
relevant to tissue maintenance, repair and regeneration, begins
with voltage-dependent Ca2+ binding to CaM, which is favored when
cytosolic Ca2+ homeostasis is disrupted by chemical and/or physical
insults at the cellular level. Ca/CaM binding produces activated
CaM that binds to, and activates, cNOS, which catalyzes the
synthesis of the signaling molecule NO from L-arginine. This
pathway is shown in its simplest schematic form in FIG. 1A. FIG. 1A
is a schematic summary of the body's primary anti-inflammatory
cascade and the proposed manner by which PEMF may accelerate
postoperative pain relief. Surgical injury increases cytosolic
Ca2+, which activates CaM. PEMF accelerates CaM activation thereby
enhancing NO/cGMP anti-inflammatory signaling. PEMF also enhances
CaM-dependent PDE activation, which accelerates cGMP inhibition.
PEMF dosing must take into account the competing dynamics of
NO/cGMP signaling and PDE inhibition of cGMP.
[0006] As shown in FIG. 1A, cNOS* represents activated constitutive
nitric oxide synthase (cNOS), which catalyzes the production of NO
from L-arginine, which, in turn, activates soluble gyanylyl
cyclase, sGC. The term "sGC*" refers to activated guanylyl cyclase
which catalyzes cyclic guanosine monophosphate (cGMP) formation
when NO signaling modulates the tissue repair pathway. "AC*" refers
to activated adenylyl cyclase, which catalyzes cyclic adenosine
monophosphate (cAMP) when NO signaling modulates differentiation
and survival.
[0007] According to some embodiments, an EMF signal can be
configured to accelerate cytosolic ion binding to a cytosolic
buffer, such as voltage dependent Ca2+ binding to CaM, because the
rate constant for binding, kon is much greater than the rate
constant for unbinding, koff, imparting rectifier-like properties
to ion-buffer binding, such as Ca2+ binding to CaM.
[0008] Yet another embodiment pertains to application of
sinusoidal, rectangular, chaotic or arbitrary waveform
electromagnetic signals, having frequency components below about
100 GHz, configured to accelerate the binding of intracellular Ca2+
to a buffer, such as CaM, to enhance biochemical signaling pathways
in animal and human cells and tissues. Signals configured according
to additional embodiments produce a net increase in a bound ion,
such as Ca2+, at CaM binding sites because the asymmetrical
kinetics of Ca/CaM binding allows such signals to accumulate
voltage induced at the ion binding site, thereby accelerating
voltage-dependent ion binding. Examples of therapeutic and
prophylactic applications are modulation of biochemical signaling
in anti-inflammatory pathways, modulation of biochemical signaling
in cytokine release pathways, modulation of biochemical signaling
in growth factor release pathways; edema and lymph reduction,
anti-inflammatory, post-surgical and post-operative pain and edema
relief, nerve, bone and organ pain relief, increased local blood
flow, microvascular blood perfusion, treatment of tissue and organ
ischemia, brain tissue ischemia from stroke or traumatic brain
injury, treatment of neurological injury and neurodegenerative
diseases such as Alzheimer's and Parkinson's; angiogenesis,
neovascularization; enhanced immune response; enhanced
effectiveness of pharmacological agents; nerve regeneration;
prevention of apoptosis; modulation of heat shock proteins for
prophylaxis and response to injury or pathology.
[0009] In some variations the systems, devices and/or methods
generally relate to application of electromagnetic fields (EMF),
and in particular, pulsed electromagnetic fields (PEMF), including
a subset of PEMF in a radio frequency domain (e.g., pulsed radio
frequency or PRF), for the treatment of any of the applications
disclosed herein in animals and humans, including pain, edema,
tissue repair and head, cerebral and neural injury, and
neurodegenerative conditions.
[0010] Transient elevations in cytosolic Ca2+, from external
stimuli as simple as changes in temperature and receptor
activation, or as complex as mechanical disruption of tissue, will
activate CaM. Once Ca2+ ions are bound, a conformational change
will allow CaM bind to and activate a number of key enzymes
involved in cell viability and function, such as the endothelial
and neuronal constitutive nitric oxide synthases (cNOS); eNOS and
nNOS, respectively. As a consequence, NO is rapidly produced,
albeit in lower concentrations than the explosive increases in NO
produced by inducible NOS (iNOS), during the inflammatory response.
In contrast, these smaller, transient increases in NO produced by
Ca/CaM-binding will activate soluble guanylyl cyclase (sGC), which
will catalyze the formation of cyclic guanosine monophosphate
(cGMP). The CaM/NO/cGMP signaling pathway can rapidly modulate
blood flow in response to normal physiologic demands, as well as to
inflammation. Importantly, this same pathway will also rapidly
attenuate expression of cytokines such as interleukin-1beta
(IL-1.beta.), and iNOS and stimulate anti-apoptotic pathways in
neurons. All of these effects are mediated by calcium and cyclic
nucleotides, which in turn regulate growth factors such as basic
fibroblast growth factor (FGF-2) and vascular endothelial growth
factor (VEGF), resulting in pleiotrophic effects on cells involved
in tissue repair and maintenance. PEMF can also accelerate the
inhibition of cGMP by phosphodiesterase (PDE). Improved PEMF signal
configurations and treatment regimens are disclosed herein that can
minimize the inhibition of cGMP by PDE.
[0011] Therefore, a need exists for an apparatus and a method that
modulates the biochemical pathways that regulate animal and human
tissue response to maximize the rate of cGMP production while
minimizing the rate of inhibition of cGMP. In some embodiments, an
apparatus incorporates miniaturized circuitry and light weight coil
applicators or electrodes to deliver any of the waveforms described
herein thus allowing the apparatus to be low cost, portable and, if
desired, disposable.
SUMMARY OF THE DISCLOSURE
[0012] The present invention relates to methods and apparatuses for
treating patients with pulsed electromagnetic therapies (PEMF). The
PEMF waveform and the period between PEMF waveform pulses can be
configured to simultaneously increase the rate of cGMP production
and to minimize the rate of inhibition of cGMP by compounds such as
PDE.
[0013] In particular, described herein are methods of optimizing
PEMF treatment based on the surprising finding that the
effectiveness of a non-invasive, relatively low-energy or very
low-energy PEMF treatment depends on the ratio of the duration of
the treatment interval and the duration of the inter-treatment
interval (also referred to herein as the inter-treatment period).
The methods described herein are invented from the new finding that
the for externally-applied low-energy or (in some variations) very
low-energy PEMF treatments, a ratio of treatment interval to
inter-treatment period of greater than about 1:6 (e.g., an
inter-treatment period that is greater than six times the treatment
interval) results in efficacious treatment, whereas ratios less
than 1:6 do not. In addition, in some variations it may be
beneficial to have ratios of treatment interval to inter-treatment
period of less than about 1:100. For example, the ratio of
treatment interval to inter-treatment period may be greater than
about 1:7, greater than about 1:8, greater than about 1:9, greater
than about 1:10, greater than about 1:11, greater than about 1:12,
greater than about 1:15, greater than about 1:18, etc., and/or
between about 1:6 and 1:1000, between about 1:6 and 1:500, between
about 1:6 and 1:100, between about 1:6 and 1:75, between about 1:6
and 1:50, between about 1:8 and 1:1000, between about 1:8 and
1:500, between about 1:8 and 1:100, etc.
[0014] The apparatuses described herein may be generally configured
to be worn against the body (e.g., incorporated into a garment,
jewelry, hat, bed, chair, etc.), and may be specifically
adapted/configured to deliver non-invasive, relatively low-energy
or very low-energy PEMF treatment in which the ratio of treatment
interval to inter-treatment period is as described herein.
[0015] For example described herein are methods for treating a
patient (e.g., human, animal, etc.) that may generally include:
generating a pulsed electromagnetic field (PEMF) from a pulsed
electromagnetic field source; applying the pulsed electromagnetic
field in proximity to a target region affected by an injury or
condition to reduce a physiological response to the injury or
condition for a treatment interval that is greater than 10 minutes;
discontinuing the application of the pulsed electromagnetic field
for an inter-treatment period that is greater than six times the
treatment interval; and repeating, for a plurality of times, the
steps of generating, applying and discontinuing.
[0016] A pulsed electromagnetic field source may include any
apparatus, including those described herein or otherwise known in
the art, that can be used to apply relatively low-energy PEMF
signals. Examples of such devices and PEMF signals (including
low-energy PEMF signals) are described, for example, in U.S. patent
applications: U.S. Pat. Nos. 7,744,524, 7,740,574, 8,415,123,
7,758,490, 7,896,797 and 8,343,027, and pending applications no.:
US-2010-0210893, US-2010-0222631, US-2013-0274540, US-2014-0046115,
US-2014-0046117, US-2011-0207989, US-2012-0116149, US-2014-0213843,
US-2014-0213844, and US-2012-0089201-A1. Each of these patents and
pending applications is herein incorporated by reference in its
entirety, and in particular for its teaching of PEMF application
devices, waveforms, and therapies.
[0017] A relatively low-energy PEMF waveform may generally apply
milliTesla (mT), e.g., between about 1 and 100 mT, magnetic field
strength, or average magnetic field strength. Very low-energy PEMF
may apply microTesla (.mu.T), e.g., less than 1 mT, less than 100
.mu.T, less than 50 .mu.T, less than 20 .mu.T, less than 10 .mu.T,
less than 5 .mu.T, etc. The PEMF signal, though relatively or very
low energy may be applied in the specific pulsed waveforms as
described herein to any target region.
[0018] A target region may be any body region, including surface
(e.g., skin) or internal (e.g., brain, organ, etc.) region,
particularly those that are more superficially located. Wounds such
as surgical wounds are an example of a target region. Nerves,
including spinal, peripheral or central (e.g., brain) nervous
system regions may also be treated as described herein. The
treatments described herein may be used to treat a medical
disorder, and may modulate or improve a physiological response to
the injury or condition, including but not limited to,
swelling/inflammation, necrosis, healing (e.g., tissue growth, cell
migration), scarring, etc.
[0019] In general, a treatment interval may include the period
during which treatment (PEMF energy) is actively being applied, for
example, as a burst or plurality of bursts of pulses. The waveforms
may be applied at a regular, irregular or random duration, period
or wave-shape within the burst (envelope) and the amplitude of the
envelope may be regular (e.g., sinusoidal, square, etc.),
irregular, or random. In particular, sinusoidal pulses at a carrier
frequency (e.g., of 27.12 or a harmonic thereof) may be applied
within a rectangular envelope that had a burst duration (e.g.,
greater than 200 microseconds, greater than 300 microseconds,
greater than 400 microseconds, greater than 500 microseconds,
greater than 600 microseconds, between 500 microseconds and 1
second, etc.), and may be repeated at a burst repetition rate. The
treatment interval may therefore include quiescent periods, but
they are typically part of the inter-pulse or inter-burst periods
defining the periodicity of the waveforms or burst of waveforms. A
treatment interval may be between 5 and 600 minutes, but more
likely between 5 and 50 minutes. As described herein, it may be
particularly efficacious to apply treatment for a treatment
interval of greater than about 10 minutes, e.g., greater than about
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc. minutes.
[0020] During any of the treatments described herein the treatment
periods may be divided by off-times (inter-treatment periods)
during which no PEMF signals are applied by the apparatus, which
may be particularly configured to prevent the application of any
PEMF signal during this inter-treatment period.
[0021] The method of claim 1, wherein the pulsed electromagnetic
field is configured to simultaneously increase the rate of
ion-dependent signaling and to minimize the rate of inhibition of
such signaling by natural compounds. This period may be referred to
as a period during which the PEMF signal application is
discontinued, e.g., discontinuing the application of the pulsed
electromagnetic field for an inter-treatment period (or "off
time"). Following the discontinuation, another treatment period
(and another inter-treatment period, off-time) may be repeated. The
waveforms applied during the subsequent treatment periods may be
the same or different. For example, the waveform characteristics,
such as amplitude, frequency (e.g. burst frequency and/or pulse
frequency and/or carrier wave frequency), duration (burst duration,
pulse duration), and/or waveform and/or envelope (burst) shape, may
be different between, or in some variations within, subsequent
treatment periods. The duration of the subsequent treatment period
may be the same or different, though they may still be greater than
some minimum treatment period duration (e.g., greater than 10 min,
11 min, 12 min, 13 min, 14 min, 15 min, 20 min, 25 min, 30 min, 40
min, 50 min, 60 min, etc.) and/or less than a maximum treatment
period duration (e.g., less than 50 min, 60 min, 70 min, 80 min, 90
min, 2 hrs, 2.5 hrs, 3 hrs, etc.), where the minimum is always less
than the maximum. In some variations, the method or apparatus may
adjust one or more characteristics of the treatment period and/or
the treatment period duration based on feedback measured or
otherwise received from the patient, including feedback based on a
detected level of a biomarker.
[0022] The pulsed electromagnetic field may be configured to
simultaneously increase the rate of cGMP signaling and to minimize
the rate of inhibition of such signaling by compounds such as
phosphodiesterase (PDE). The pulsed electromagnetic field may be
configured to simultaneously increase the rate of cGMP signaling
and to minimize the rate of inhibition of such signaling by
compounds such as phosphodiesterase (PDE), is applied for a
duration consistent with the above.
[0023] The application treatment may include any appropriate number
of repetitions, and may be open-ended (e.g., stopped manually by
the patient and/or a medical professional). For example repeating
may comprise repeating for at least 10 times, 11 times, 12 times,
20 times, 30 times, 40 times, 50 times, etc. or for some minimum
time interval (e.g., 20 min, 25 min, 30 min, 35 min, 40 min, 50
min, 60 min, 90 min, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 18 hrs, 24 hrs,
36 hrs, 2 days, 3 days, 4 days, 5 days, 7 days, 14 days, etc.).
[0024] As mentioned, the pulsed electromagnetic field may consist
of a burst having any appropriate relatively or very low PEMF
waveform characteristics. For example, the PEMF signal within a
treatment period may have a duration of greater than 2 msec of a
27.12 MHz carrier repeating at between 1 and 20 bursts/sec at an
amplitude of between 2 and 10 .mu.T. The pulsed electromagnetic
field may include a burst having a duration of between 2 and 10
msec of a carrier wave repeating at between 1 and 10 bursts/sec at
an amplitude of between 3 and 8 .mu.T.
[0025] The length of the first treatment interval and the length of
the inter-treatment period are selected to minimize
phosphodiesterase (PDE) production in the patient.
[0026] Any of these methods may also include monitoring the
physiological response; and modifying the pulsed electromagnetic
field in response to the monitoring step. For example, they may
include monitoring the physiological response; and discontinuing
treatment once an acceptable level of the physiological response is
reached.
[0027] The methods may also include modulating inflammatory
cytokines and growth factors at the target region by applying the
pulsed electromagnetic field to simultaneously increase the rate of
such modulation and to minimize the rate of inhibition of such
modulation by natural compounds. These methods may also include
accelerating the healing of the target region by applying the
pulsed electromagnetic field to simultaneously increase the rate of
healing and to minimize the rate of inhibition of such healing.
[0028] Applying may include applying the pulsed electromagnetic
field in proximity to a target region affected by a neurological
injury or condition to reduce a physiological response comprises
reducing a concentration of IL-1.beta..
[0029] As mentioned above, these methods may be used to treat any
appropriate injury or condition, including a neurodegenerative
disease, e.g., Parkinson's disease. Alzheimer's disease, etc. The
injury or condition may be a traumatic brain injury (TBI). The
injury or condition may be a post-operative inflammation and
pain.
[0030] Also described herein are apparatuses configured to perform
any of these methods. For example, an apparatus for applying pulsed
electromagnetic field (PEMF) energy to a subject may include: a
generator unit including a signal generator configured to generate
a PEMF waveform having configured to simultaneously increase the
rate of ion-dependent signaling and to minimize the rate of
inhibition of such signaling; a programmable control unit
configured to repeatedly provide a signal to the generator unit
corresponding to the PEMF waveform for a treatment interval that is
10 minutes or greater followed immediately by an off time having an
inter-treatment period that is greater than six times the treatment
interval; and an applicator unit configured to be worn by the
subject, wherein the generator unit is configured to power the
applicator unit to drive transmission of a PEMF signal from the
applicator unit based on the PEMF waveform.
[0031] The programmable control unit may be programmed to provide
an inter-treatment period that is between six and 100 times the
treatment interval. The programmable control unit may be configured
to prevent the generation of a pulsed electromagnetic field during
the inter-treatment period.
[0032] Any of these apparatuses may include a shut off to stop the
generator unit during the inter-treatment period.
[0033] Any appropriate applicator may be used, particularly
flexible loop applicators, which may be bent or shaped, though
remain a coil. In some variations, the applicator comprises a first
loop configured to provide the PEMF waveform and a second loop
configured to provide a second PEMF waveform.
[0034] A programmable control unit may be configured to repeatedly
provide the same signal to the generator unit corresponding to the
PEMF waveform.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] The novel features of the invention are set forth with
particularity in the claims that follow. A better understanding of
the features and advantages of the present invention will be
obtained by reference to the following detailed description that
sets forth illustrative embodiments, in which the principles of the
invention are utilized, and the accompanying drawings of which:
[0036] FIG. 1A is a schematic representation of the biological EMF
transduction pathway which is a representative target pathway of
EMF signals configured according to embodiments described
herein.
[0037] FIG. 1B is a flow diagram of a method for treating a patient
according to an embodiment of the devices and methods described
herein.
[0038] FIG. 2A is a block diagram of miniaturized circuitry for use
with a coil applicator according to some embodiments described.
[0039] FIG. 2B illustrates a device for application of
electromagnetic signals according to an embodiment of the devices
and methods described herein.
[0040] FIG. 2C illustrates a waveform delivered to a target pathway
structure of a plant, animal or human, such as a molecule cell,
tissue, organ, or partial or entire organism, according to some
embodiments described.
[0041] FIG. 3 is a photograph illustrating a disposable dual coil
PEMF device used in some of the embodiments described herein. The
disposable dual coil PEMF includes a battery-powered signal
generator is at the bottom between the coils. A nonthermal
pulse-modulated radio frequency PEMF signal, configured to modulate
NO signaling, may be delivered to tissue with a preprogrammed
dosing regimen for each cohort.
[0042] FIG. 4 is a graph showing the effect of different PEMF
therapy regimens on the rate of pain reduction following breast
reduction surgery in accordance with various embodiments of pain
treatments.
[0043] FIG. 5 is a graph showing the effect of different PEMF
therapy regimens in accordance with the embodiments described
herein on pain medication usage of patients after surgery. The
results show approximately 2-fold more narcotic pills were taken by
24 h postoperatively in the Q4 (sham) and 5/20 (active) cohorts
versus the Q4 (active) and Q2 (active) cohorts. There was no
significant difference in postoperative narcotic use between the
5/20 (active) and Q4 (sham) cohorts.
[0044] FIGS. 6A and 6B are graphs showing the effect of signal
configuration on NO production from challenged fibroblasts and
chondrocytes (respectively) in culture.
[0045] FIG. 7 is a graph showing the effect of exposure time of a
given signal configuration on cGMP production in primary neuronal
cells.
DETAILED DESCRIPTION
[0046] Pulsed electromagnetic fields (PEMF) reduce postoperative
pain and narcotic requirements in breast augmentation, reduction,
and reconstruction patients. PEMF treatment can also be used to
reduce post-operative pain in other surgical procedures. PEMF
enhances calmodulin-dependent nitric oxide, which enhances cyclic
guanosine monophosphate signaling and phosphodiesterase activity,
which blocks cyclic guanosine monophosphate. This invention
describes means to configure PEMF dosing to minimize the effect of
the competing response of phosphodiesterace activity.
[0047] FIG. 1B is a flow diagram of a method for treating a subject
with a PEMF. In some variations, before beginning the treatment,
one or more (or a range of) waveforms may be determined that target
the appropriate pathway for the target tissue. In such embodiments,
once this determination is made, electromagnetic fields are applied
to the target location.
[0048] FIG. 2A illustrates a block diagram of an EMF delivery
apparatus as described according to some embodiments. As shown in
FIG. 2A, the apparatus may have miniaturized circuitry for use with
a coil applicator. In some embodiments, the apparatus may include a
CPU MODULATOR, a BATTERY MODULE, a POWER SUPPLY, On/Off switch, and
an output amplifier, AMP, as illustrated. In further variations,
the CPU MODULATOR may be an 8 bit 4 MHz micro-controller; however,
other suitable bit-MHz combination micro-controllers may be used as
well. For example, in some embodiments, the CPU MODULATOR may be
programmed for a given carrier frequency or pulse duration, such as
about 27.12 MHz sinusoidal wave. Moreover, the CPU MODULATOR may be
programmed for a given burst duration, for example about 3 msec. In
further variations, the CPU MODULATOR may be programmed to provide
a given in situ peak electric field, for example 20 V/m; or a given
treatment time, for example about 15 minutes; and/or a given
treatment regimen, for example about 10 minutes about every hour.
The CPU MODULATOR may also be programmed to deliver an EMF waveform
to the target ion binding pathway.
[0049] Some embodiments combine the signal generation and coil or
electrode applicator into one portable or disposable unit, such as
illustrated in FIG. 2B (which will be described in greater detail
below) for the case of an inductively coupled signal. In some
variations, when electrical coils are used as the applicator, the
electrical coils can be powered with a time varying magnetic field
that induces a time varying electric field in a target pathway
structure according to Faraday's law. An electromagnetic field
generated by a circuit such as shown in FIG. 2A can also be applied
using electrochemical coupling, wherein electrodes are in direct
contact with skin or another outer electrochemically conductive
boundary of a target pathway structure.
[0050] In yet another embodiment, the electromagnetic field
generated by the generating circuit of FIG. 2A (or FIG. 2B) can
also be applied using electrostatic coupling wherein an air gap
exists between a generating device such as an electrode and a
target pathway structure such as a molecule, cell, tissue, and
organ of a plant animal or human. Advantageously, the ultra
lightweight coils and miniaturized circuitry, according to some
embodiments, allow for use with common physical therapy treatment
modalities and at any location on a plant, animal or human for
which any therapeutic or prophylactic effect is desired. An
advantageous result of application of some embodiments described is
that a living organism's wellbeing can be maintained and
enhanced.
[0051] Referring to FIG. 2C, an embodiment according to the present
invention of an induced electric field waveform delivered to a
target pathway structure is illustrated. As shown in FIG. 2C, burst
duration and period are represented by T1 and T2, respectively. In
some embodiments, the signal within the rectangular box designated
at T1 can be, rectangular, sinusoidal, chaotic or random, provided
that the waveform duration or carrier period is less than one-half
of the target ion bound time. The peak induced electric field is
related to the peak induced magnetic field, shown as B in FIG. 2C,
via Faraday's Law of Induction.
[0052] FIG. 2B illustrates an embodiment of an apparatus 200 that
may be used. The apparatus is constructed to be self-contained,
lightweight, and portable. A circuit control/signal generator 201
may be held within a (optionally wearable) housing and connected to
a generating member such as an electrical coil 202. In some
embodiments, the circuit control/signal generator 201 is
constructed in a manner that given a target pathway within a target
tissue, it is possible to choose waveform parameters that satisfy a
frequency response of the target pathway within the target tissue.
For some embodiments, circuit control/signal generator 201 applies
mathematical models or results of such models that approximate the
kinetics of ion binding in biochemical pathways. Waveforms
configured by the circuit control/signal generator 201 are directed
to a generating member 202. In some variations, the generating
member 202 comprises electrical coils that are pliable and
comfortable. In further embodiments, the generating member 202 is
made from one or more turns of electrically conducting wire in a
generally circular or oval shape, any other suitable shape. In
further variations, the electrical coil is a circular wire
applicator with a diameter that allows encircling of a subject's
cranium. In some embodiments, the diameter is between approximately
6-8 inches. In general, the size of the coil may be fixed or
adjustable and the circuit control/signal generator may be matched
to the material and the size of the applicator to provide the
desired treatment.
[0053] The apparatus 200 may deliver a pulsing magnetic field that
can be used to provide treatment. In some embodiments, the device
200 may apply a pulsing magnetic field for a prescribed time and
can automatically repeat applying the pulsing magnetic field for as
many applications as are needed in a given time period, e.g. 6-12
times a day. The device 200 can be configured to apply pulsing
magnetic fields for any time repetition sequence. Without being
bound to any theory, it is believed that when electrical coils are
used as a generating member 202, the electrical coils can be
powered with a time varying magnetic field that induces a
biologically and therapeutically effective time varying electric
field in a target tissue location.
[0054] In other embodiments, an electromagnetic field generated by
the generating member 202 can be applied using electrochemical
coupling, wherein electrodes are in direct contact with skin or
another outer electrically conductive boundary of the target tissue
(e.g. skull or scalp). In other variations, the electromagnetic
field generated by the generating member 202 can also be applied
using electrostatic coupling wherein an air gap exists between a
generating member 202 such as an electrode and the target tissue.
In further examples, a signal generator and battery is housed in
the miniature circuit control/signal generator 201 and the
miniature circuit control/signal generator 201 may contain an
on/off switch and light indicator. In further embodiments, the
activation and control of the treatment device may be done via
remote control such as by way of a fob that may be programmed to
interact with a specific individual device. In other variations,
the treatment device further includes a history feature that
records the treatment parameters carried out by the device such
that the information is recorded in the device itself and/or can be
transmitted to another device such as computer, smart phone,
printer, or other medical equipment/device.
[0055] In other variations, the treatment device 200 has adjustable
dimensions to accommodate fit to a variety of patient sizes and
anatomy. For example, the generating member 202 may comprise
modular components which can be added or removed by mated attaching
members. Alternatively, the treatment device 200 may contain a
detachable generating member (e.g. detachable circular coil or
other configurations) that can be removed and replaced with
configurations that are better suited for the particular patient's
needs. A circular coil generating member 202 may be removed and
replaced with an elongate generating member such that PEMF
treatment can be applied where other medical equipment may obstruct
access by a circular generating member 202. In other variations,
the generating member may be made from Litz wire that allows the
generating member to flex and fold to accommodate different target
areas or sizes.
[0056] The PEMF devices disclosed herein can be used to treat
patients with post-operative pain. Acute postoperative pain is a
significant medical problem. Postoperative pain must be managed
effectively to optimize surgical outcomes, reduce morbidity,
shorten the duration of hospital stay, and control ever-increasing
health-care costs [1]. For the vast majority of surgical
procedures, pain mechanisms involve increased sensitivity of
nociceptors due to increased presence of proinflammatory cytokines
in the wound milieu [2]. Narcotics are most commonly used to treat
postoperative pain; however, narcotics do not reduce nociceptor
sensitivity and cause undesirable side effects and potential
addiction. Alternative approaches to decrease post-operative pain
involve slowing the appearance of proinflammatory agents at the
surgical site [2].
[0057] To this end, a new modality, nonthermal, nonpharmacologic
radio frequency pulsed electromagnetic field (PEMF) therapy has
been reported to instantaneously enhance calmodulin (CaM)-dependent
nitric oxide (NO) release in challenged cells and tissues. This, in
turn, enhances the body's primary anti-inflammatory pathway,
CaM-dependent nitric oxide/cyclic guanosine monophosphate (NO/cGMP)
signaling [3e7]. In the surgical context, NO/cGMP signaling
decreases the rate of release of proinflammatory cytokines, such as
interleukin-1 beta (IL [interleukin]-1b) [8], and increases the
release of growth factors, such as fibroblast growth factor-2
(FGF-2) [9], in the wound milieu. This mechanism is schematically
represented in FIG. 1A. PEMF modulation of angiogenesis via effects
on FGF-2 has been reported [10-15]. In some studies, the PEMF
effect could be blocked with an FGF-2 inhibitor, consistent with a
PEMF effect on NO/cGMP signaling [12, 13].
[0058] In the clinical setting, PEMF has been reported to
accelerate postoperative pain decrease, with a concomitant
reduction in narcotic requirements, in double-blinded, randomized
clinical studies on breast reduction (BR) [16], breast augmentation
[17, 18], and autologous flap breast reconstruction [19]. The BR
study also showed that PEMF reduced inflammation by reducing IL-1
beta more than two-fold in the wound exudate, which correlated with
the higher rate of pain reduction from PEMF [16]. PEMF can and has
been used throughout the body, including after abdominoplasties,
major intra-abdominal surgery, extremity procedures, and facial fat
grafting [20, 21].
[0059] Taken together, preclinical and clinical results support an
anti-inflammatory mechanism for PEMF based on modulation of
CaM-dependent NO/cGMP signaling. However, the NO/cGMP cascade is
dynamic [22] and regulated, in part, by phosphodiesterase (PDE)
inhibition of cyclic guanosine monophosphate (cGMP) [23]. This
inhibition is particularly important for PEMF therapy because PDE
isoenzymes are also CaM-dependent, meaning the timing of PDE
activity is modulated by the same PEMF signal that modulates the
timing of NO/cGMP signaling [24]. Thus, although the dynamics of
NO/cGMP signaling in challenged tissue can be modulated by PEMF,
the effect of PEMF dosing on the competing dynamics of
CaM-dependent NO/cGMP signaling and PDE inhibition of cGMP on pain
outcome must be taken into account.
[0060] For example, a number of patients with post-operative pain
were treated with PEMF and studied. Specifically, two prospective,
nonrandomized, active cohorts of breast reduction patients, with 15
min PEMF per 2 h; "Q2 (active)", and 5 min PEMF per 20 min; "5/20
(active)", dosing regimens were added to a double-blind clinical
study wherein 20 min PEMF per 4 h, "Q4 (active)", dosing was shown
to significantly accelerate postoperative pain reduction compared
with Q4 shams. Postoperative visual analog scale pain scores and
narcotic use were compared.
[0061] Data from 50 patients were available for analysis. The
change in VAS scores normalized to 1 h for each cohort is
summarized in FIG. 4. The rate of postoperative pain decrease in
the first 24 h postoperative for patients in the Q4 (active) and Q2
(active) cohorts was not significantly different (P=0.485), but was
nearly 3-fold faster than that for patients in the 5/20 (active)
and Q4 (sham) cohorts (P<0.01). In contrast, the rate of pain
decrease for patients treated with the 5/20 (active) regimen was
not significantly different from those receiving no PEMF treatment
in the Q4 (sham) cohort (P=0.271). Specifically, pain at 24 h
postoperative was, respectively, 43% and 35% of pain at 1 h
postoperative for patients in the Q4 (active) and Q2 (active)
cohorts (P<0.01). In contrast, pain at 24 h for patients in the
5/20 (active) cohort was 87% of pain at 1 h, compared with 74% for
patients in the Q4 (sham) cohort (P=0.451). These results can be
seen in FIG. 4. A similar pattern of results was found in narcotic
usage. Postoperative narcotic usage by 24 h postoperative for
patients in the 5/20 (active) cohort was not significantly
different from that in the Q4 (sham) cohort (P=0.478), and both
were approximately 2-fold higher compared with narcotic usage for
patients in the Q4 (active) and Q2 (active) cohorts (P<0.02).
Narcotic usage for patients in the Q2 (active) and Q4 (active)
cohorts was not significantly different (P=0.246). These results
can be seen in FIG. 5.
[0062] The identical PEMF signal configuration was used for all
active cohorts; however, the dosing regimen was different. Entry
criteria were identical for all patients. Surgery was performed by
the same surgeon on all patients. The results clearly suggest that
the effectiveness of PEMF therapy on the rate of postoperative pain
decrease and post-operative narcotic requirements in BR patients
depends on PEMF dosing regimen. A 5/20 (active) regimen was no
different than the Q4 (sham) regimen for pain reduction, whereas a
Q2 (active) regimen was as effective as the Q4 (active)
regimen.
[0063] The findings revealed that the regimen of PEMF can
significantly impact its effect on postoperative pain. It was
expected that the most frequent dosing at 5 min every 20 min would
have the greatest effect on pain reduction, but this was not the
case. Mean VAS pain scores for patients in the 5/20 (active) cohort
were not significantly different from those for patients in the Q4
(sham) cohort, which were more than two-fold higher at 24 h
postoperatively than VAS scores for patients in the Q4 (active) and
Q2 (active) cohorts. Similar comparative results were obtained for
postoperative narcotic usage for patients in each of the active
cohorts.
[0064] PEMF signal parameters, including repetition rate, were
identical for all patients in active cohorts. The dosing change was
treatment regimen. The rate of increase in CaM-dependent NO, and
therefore cGMP, from PEMF in tissue for the 5/20 regimen is nearly
2.5-fold higher than that for the Q2 (active) and 4-fold higher
than that for the Q4 (active) regimens. The NO/cGMP signaling
pathway is a principal anti-inflammatory pathway. CaM-dependent PDE
activity regulates this pathway by inhibiting cGMP. The PEMF signal
used in this study is known to enhance NO/cGMP signaling, and to
enhance CaM-dependent PDE activity [5-7]. It was proposed that the
5/20 regimen caused PDE activity to predominate, thereby inhibiting
all the enhanced cGMP produced by PEMF. The result is no effect of
PEMF on postoperative pain.
[0065] Two recent publications illustrate that PEMF effects depend
on signal configuration. The first showed that the PEMF effect on
breast cancer cell apoptosis was significant when the same
waveform, applied for the same exposure time, repeated at 20 Hz but
not at 50 Hz [35]. The second study showed that PEMF significantly
reduced the expression of inflammatory markers, tumor necrosis
factor, and nuclear factor-kappa beta in challenged macrophages
when the same waveform, applied for the same exposure time, was
repeated at 5 Hz, but not at 15 or 30 Hz [36]. In both studies,
CaM-dependent NO/cGMP signaling modulates the expressions of these
inflammatory markers [37, 38], suggesting the effect of increased
repetition rate is consistent with increased production of NO at a
rate high enough for PDE inhibition of cGMP isoforms to
predominate, thus blocking the PEMF effect. It is interesting to
note that similar dosing effects have been observed in studies
using low-level laser therapy, wherein the mechanism of action also
involves NO/cGMP signaling [39]. Comparable with our study,
low-level laser therapy improvement of neurologic performance in a
mouse traumatic brain injury model depended on treatment regimen
[40].
[0066] This study provides evidence that nonthermal radio frequency
PEMF therapy can accelerate pain reduction and decrease pain
medication requirements in the immediate postoperative period. The
effect of PEMF regimen has been elucidated and effective regimens
defined. Every 2 or 4 h dosing significantly decreases
postoperative pain, whereas every 20-min dosing has no effect
compared with placebo. The results of this study confirm dosing by
which a given PEMF signal, configured to enhance the body's primary
anti-inflammatory signaling pathway, CaM-dependent NO/cGMP, can
accelerate postoperative pain relief.
[0067] At the cellular level the effect of PEMF signal
configuration on PDE inhibition of cGMP was examined in cell
cultures. Cells were plated in DMEM containing low concentration
(challenge) of fetal calf-serum in 24-well plates. Two cell types
were tested; human fibroblasts (HFC) and human chondrocytes (HCC).
Cells were grown for 24-hours to allow for attachment and repair
after initial plating. Cells were exposed to PEMF signals for 15
minutes. Immediately after treatment conditioned media (CM) was
collected and assayed for NO levels using the Griess reaction
combined with vanadium. The Griess assay tests for nitrite (NO2-).
Vanadium was used to reduce nitrate (NO3-) to NO2- since NO
immediately reacts with water to form NO3- and NO2- and the Griess
assay only measures NO2-.
[0068] Two PEMF signals with 27.12 MHz sinusoidal carrier were
tested. One PEMF signal had a burst width of 2 msec repeating at 2
Hz (Signal I) while the second signal (Signal II) had a burst width
of 3 msec repeating at 5 Hz. Both signals were tested at amplitudes
ranging from 0.5 to 8 .mu.T. Exposure time was 15 min for each
amplitude condition. Since each waveform was configured to target
Ca/CaM binding, Signal II would be expected to produce
approximately 4-fold more NO than that produced by Signal I, at all
amplitudes studied.
[0069] The results are shown in FIGS. 6A and 6B, wherein it may be
seen that Signal I produced significant increases in NO over a
range of amplitudes. In contrast, Signal II did not produce
increased NO at any amplitude tested. As for the clinical example
CaM-dependent PDE activity regulates NO/cGMP signaling by
inhibiting cGMP. It was proposed that Signal II with increased
burst duration and repetition rate compared to Signal I increased
NO too rapidly causing the PEMF effect on PDE activity to
predominate, thereby inhibiting all the enhanced NO produced by
PEMF. The result is no effect of PEMF on NO release in challenged
fibroblasts and chondrocytes for Signal II at any amplitude
tested.
[0070] In another cellular study the effect of exposure time of a
PEMF signal consisting of a 2 msec burst of a 27.12 MHz carrier
repeating at 2 Hz and delivering 4 .mu.T amplitude was tested.
Primary neuronal cells were subjected to oxygen glucose deprivation
(OGD) which subjects the cells to ischemic conditions such as those
which exist in cardiac and brain ischemia. OGD is expected to
reduce NO and therefore cGMP. The parameters of the PEMF signal
were chosen to modulate CaM/NO/cGMP signaling so that exposure to
PEMF during OGD would be expected to produce increased cGMP.
However, as exposure time increases, the PEMF effect on PDE
activity also increases. Referring to the results given in the
previous clinical and cellular examples, an exposure time of 60
minutes would be expected to produce about 4-fold more NO than the
standard effective 15 minute exposure. The results are shown in
FIG. 7 wherein it may be seen that 15 minute PEMF exposure
maximally restored cGMP production. In contrast, an exposure time
of 60 minutes was not effective.
[0071] Therefore, in some embodiments any of the PEMF parameters
can be selected to minimize the PDE inhibition of cGMP and/or
maximize the production of cGMP. In some embodiments the length of
the inter-treatment period and the length of the treatment interval
are selected to minimize the PDE inhibition of cGMP. Any of the
PEMF waveform parameters can be optimized in conjunction with the
length of the treatment interval and inter-treatment period to
achieve a desired change to the production of PDE and/or to
decrease the inhibition of cGMP by PDE.
[0072] In the example shown in FIG. 1B, once treatment begins 103,
the device, in some variations, applies an envelope of
high-frequency waveforms at low amplitude (e.g. less than 50
milliGauss, less than 100 milliGauss, less than 200 milliGauss,
etc.) 105. This envelope of high-frequency pulses is then repeated
at a particular frequency (repetition rate) after an appropriate
delay. The repetition rate may be varied to minimize PDE inhibition
of PDE. The amplitude may be varied to minimize PDE inhibition of
PDE. The burst duration may be varied to minimize PDE inhibition of
PDE.
[0073] The initial signal configuration (burst duration, burst
repetition and amplitude) can be repeated for a first treatment
time and then followed by a delay during which the treatment is
"off" 107. This waiting interval (inter-treatment interval) may
last for minutes or hours and then the treatment interval may be
repeated again until the treatment regime is complete 109.
[0074] In some embodiments the length of the inter-treatment period
can be selected to minimize the PDE inhibition of cGMP. In some
embodiments the inter-treatment period is greater than about 15
minutes. In some embodiments the inter-treatment period is greater
than about 30 minutes. In some embodiments the inter-treatment
period is greater than about 60 minutes. In some embodiments the
inter-treatment period is greater than about 90 minutes. In some
embodiments the inter-treatment period is greater than about 120
minutes. In some embodiments the inter-treatment period is greater
than about 180 minutes. In some embodiments the inter-treatment
period is greater than about 240 minutes
[0075] In some embodiments the inter-treatment period can be
expressed as a multiple of the PEMF treatment interval. In some
embodiments the inter-treatment period is at least three times
longer than the treatment interval. In some embodiments the
inter-treatment period is at least four times longer than the
treatment interval. In some embodiments the inter-treatment period
is at least five times longer than the treatment interval. In some
embodiments the inter-treatment period is at least six times longer
than the treatment interval. In some embodiments the
inter-treatment period is at least seven times longer than the
treatment interval. In some embodiments the inter-treatment period
is at least eight times longer than the treatment interval. In some
embodiments the inter-treatment period is at least ten times longer
than the treatment interval. In some embodiments the
inter-treatment period is at least fifteen times longer than the
treatment interval. In some embodiments the inter-treatment period
is at least twenty times longer than the treatment interval.
[0076] Any of the PEMF treatment intervals disclosed herein can be
used with any of the inter-treatment intervals disclosed herein. In
some embodiments the treatment interval is about 5 minutes or
longer. In some embodiments the treatment interval is about 10
minutes or longer. In some embodiments the treatment interval is
about 15 minutes or longer. In some embodiments the treatment
interval is about 20 minutes or longer.
[0077] In some embodiments the PEMF treatment period is five
minutes with a 15 minute inter-treatment period. In some
embodiments the PEMF treatment period is 15 minutes with a 105
minute inter-treatment period (e.g. 15 minutes of PEMF treatment
per two hours). In some embodiments the PEMF treatment period is 20
minutes with a 160 minute inter-treatment period (e.g. 20 minutes
of PEMF treatment per three hours).
[0078] In some variations, the treatment device is pre-programmed
(or configured to receive pre-programming) to execute the entire
treatment regime (including multiple on-periods and/or
intra-treatment intervals) punctuated by predetermined off-periods
(inter-treatment intervals) when no treatment is applied. In
further variations, the device is pre-programmed to emit a PEMF
signal at 27.12 MHz at 2 msec bursts repeating at 2 bursts/sec. In
other embodiments, the device is pre-programed to emit a PEMF
signal at 27.12 MHz (at about amplitude 250-400 mV/cm) pulsed in 4
msec bursts at 2 Hz.
[0079] In further variations, the method may include a pulsed
electromagnetic field comprising a 2 msec burst of 27.12 MHz
sinusoidal waves repeating at 2 Hz. In other variations, the method
may include a pulsed electromagnetic field comprising a 3 msec
burst of 27.12 MHz sinusoidal waves repeating at 2 Hz. In further
embodiments, the pulsed electromagnetic field may comprise a 4 msec
burst of 27.12 MHz sinusoidal waves repeating at 2 Hz.
[0080] The patient can be monitored during the PEMF treatment
regime to determine the physiological response to the PEMF
treatment regime. The treatment cycle (e.g. treatment period and
inter-treatment period) can be repeated until a desired
physiological response is achieved. Depending on the patient's
response to the treatment, the subsequent treatment cycle
parameters can be adjusted by a health professional to achieve a
desired physiological response in the patient.
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[0123] When a feature or element is herein referred to as being
"on" another feature or element, it can be directly on the other
feature or element or intervening features and/or elements may also
be present. In contrast, when a feature or element is referred to
as being "directly on" another feature or element, there are no
intervening features or elements present. It will also be
understood that, when a feature or element is referred to as being
"connected", "attached" or "coupled" to another feature or element,
it can be directly connected, attached or coupled to the other
feature or element or intervening features or elements may be
present. In contrast, when a feature or element is referred to as
being "directly connected", "directly attached" or "directly
coupled" to another feature or element, there are no intervening
features or elements present. Although described or shown with
respect to one embodiment, the features and elements so described
or shown can apply to other embodiments. It will also be
appreciated by those of skill in the art that references to a
structure or feature that is disposed "adjacent" another feature
may have portions that overlap or underlie the adjacent
feature.
[0124] Terminology used herein is for the purpose of describing
particular embodiments only and is not intended to be limiting of
the invention. For example, as used herein, the singular forms "a",
"an" and "the" are intended to include the plural forms as well,
unless the context clearly indicates otherwise. It will be further
understood that the terms "comprises" and/or "comprising," when
used in this specification, specify the presence of stated
features, steps, operations, elements, and/or components, but do
not preclude the presence or addition of one or more other
features, steps, operations, elements, components, and/or groups
thereof. As used herein, the term "and/or" includes any and all
combinations of one or more of the associated listed items and may
be abbreviated as "/".
[0125] Spatially relative terms, such as "under", "below", "lower",
"over", "upper" and the like, may be used herein for ease of
description to describe one element or feature's relationship to
another element(s) or feature(s) as illustrated in the figures. It
will be understood that the spatially relative terms are intended
to encompass different orientations of the device in use or
operation in addition to the orientation depicted in the figures.
For example, if a device in the figures is inverted, elements
described as "under" or "beneath" other elements or features would
then be oriented "over" the other elements or features. Thus, the
exemplary term "under" can encompass both an orientation of over
and under. The device may be otherwise oriented (rotated 90 degrees
or at other orientations) and the spatially relative descriptors
used herein interpreted accordingly. Similarly, the terms
"upwardly", "downwardly", "vertical", "horizontal" and the like are
used herein for the purpose of explanation only unless specifically
indicated otherwise.
[0126] Although the terms "first" and "second" may be used herein
to describe various features/elements (including steps), these
features/elements should not be limited by these terms, unless the
context indicates otherwise. These terms may be used to distinguish
one feature/element from another feature/element. Thus, a first
feature/element discussed below could be termed a second
feature/element, and similarly, a second feature/element discussed
below could be termed a first feature/element without departing
from the teachings of the present invention.
[0127] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" and "comprising" means various
components can be co jointly employed in the methods and articles
(e.g., compositions and apparatuses including device and methods).
For example, the term "comprising" will be understood to imply the
inclusion of any stated elements or steps but not the exclusion of
any other elements or steps.
[0128] As used herein in the specification and claims, including as
used in the examples and unless otherwise expressly specified, all
numbers may be read as if prefaced by the word "about" or
"approximately," even if the term does not expressly appear. The
phrase "about" or "approximately" may be used when describing
magnitude and/or position to indicate that the value and/or
position described is within a reasonable expected range of values
and/or positions. For example, a numeric value may have a value
that is +/-0.1% of the stated value (or range of values), +/-1% of
the stated value (or range of values), +/-2% of the stated value
(or range of values), +/-5% of the stated value (or range of
values), +/-10% of the stated value (or range of values), etc. Any
numerical values given herein should also be understood to include
about or approximately that value, unless the context indicates
otherwise. For example, if the value "10" is disclosed, then "about
10" is also disclosed. Any numerical range recited herein is
intended to include all sub-ranges subsumed therein. It is also
understood that when a value is disclosed that "less than or equal
to" the value, "greater than or equal to the value" and possible
ranges between values are also disclosed, as appropriately
understood by the skilled artisan. For example, if the value "X" is
disclosed the "less than or equal to X" as well as "greater than or
equal to X" (e.g., where X is a numerical value) is also disclosed.
It is also understood that the throughout the application, data is
provided in a number of different formats, and that this data,
represents endpoints and starting points, and ranges for any
combination of the data points. For example, if a particular data
point "10" and a particular data point "15" are disclosed, it is
understood that greater than, greater than or equal to, less than,
less than or equal to, and equal to 10 and 15 are considered
disclosed as well as between 10 and 15. It is also understood that
each unit between two particular units are also disclosed. For
example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are
also disclosed.
[0129] Although various illustrative embodiments are described
above, any of a number of changes may be made to various
embodiments without departing from the scope of the invention as
described by the claims. For example, the order in which various
described method steps are performed may often be changed in
alternative embodiments, and in other alternative embodiments one
or more method steps may be skipped altogether. Optional features
of various device and system embodiments may be included in some
embodiments and not in others. Therefore, the foregoing description
is provided primarily for exemplary purposes and should not be
interpreted to limit the scope of the invention as it is set forth
in the claims.
[0130] The examples and illustrations included herein show, by way
of illustration and not of limitation, specific embodiments in
which the subject matter may be practiced. As mentioned, other
embodiments may be utilized and derived there from, such that
structural and logical substitutions and changes may be made
without departing from the scope of this disclosure. Such
embodiments of the inventive subject matter may be referred to
herein individually or collectively by the term "invention" merely
for convenience and without intending to voluntarily limit the
scope of this application to any single invention or inventive
concept, if more than one is, in fact, disclosed. Thus, although
specific embodiments have been illustrated and described herein,
any arrangement calculated to achieve the same purpose may be
substituted for the specific embodiments shown. This disclosure is
intended to cover any and all adaptations or variations of various
embodiments. Combinations of the above embodiments, and other
embodiments not specifically described herein, will be apparent to
those of skill in the art upon reviewing the above description.
* * * * *