United States Patent: (45) Date of Patent: Mar - 12, 2019

US010226640B2
(12) United States Patent (10) Patent No.: US 10 ,226 ,640 B2

Pilla et al. (45) Date of Patent: Mar. 12 , 2019
(54) DEVICES AND METHOD FOR TREATMENT (52 ) CPC
U .S . CI. A61N 2 / 004 (2013 .01) ; A6IN 1 /40
OF DEGENERATIVE JOINT DISEASES
WITH ELECTROMAGNETIC FIELDS (2013.01); A6IN 2 /02 (2013.01); AGIN 2/008
( 2013 .01)
(71) Applicant: Endonovo Therapeutics, Inc., ( 58 ) Field of Classification Search
Woodland Hills , CA (US) CPC . A61N 1/40 ; A61N 2 /004 ; A61N 2 /02 ; A61N
2 /008
(72 ) Inventors : Arthur A . Pilla , Oakland , NJ (US); USPC .. .... .... ........ 600 / 9 – 15
Andre ' A . Dimino , Woodcliff Lake , NJ See application file for complete search history .
(US); Matthew E . Drummer , Fort Lee, (56 ) References Cited
NJ (US )
U . S . PATENT DOCUMENTS
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2 ,276 ,996 A 3 / 1942 Milinowski
( 21) Appl. No.: 14 /608 , 140 (Continued )
(22) Filed : Jan . 28 , 2015 FOREIGN PATENT DOCUMENTS
CA 0608693 11/ 1960
(65 ) Prior Publication Data CN 1052053 A 6 / 1991
US 2015 /0196771 A1 Jul. 16 , 2015 (Continued )
OTHER PUBLICATIONS
Related U .S . Application Data Pilla et al., EMF signals and ion /ligand binding kinetics: prediction
(63 ) Continuation of application No. 13/ 080 ,450 , filed on of bioeffective waveform parameters, 1999 , Electricity and Magne
Apr. 5 , 2011 , now Pat. No. 8 ,961, 385 , which is a tism in Biology and Medicine, pp . 391 - 394 .*
continuation - in -part of application No. 12 /819, 956 , (Continued )
filed on Jun . 21 , 2010 , now abandoned , which is a Primary Examiner — Navin Natnithithadha
continuation - in -part of application No . 12 /772,002, Assistant Examiner — Sunita Reddy
filed on Apr. 30 , 2010 , now abandoned , which is a
continuation of application No . 11 /003 ,108 , filed on (57) ABSTRACT
Dec . 3 , 2004, now Pat. No. 7 ,744,524 .
Described herein are devices and methods for treating
degenerative joint diseases with electromagnetic fields using
(60 ) Provisional application No. 61/ 321,044 , filed on Apr. one or more waveforms that are configured to modulate Ca2 +
5 , 2010 , provisional application No .61/326 , 582 , filed binding to calmodulin and thereby modulate calmodulin
(Continued ) dependent nitric oxide signaling within joint and other
affected tissue for the purpose of reducing pain and inflam
(51) Int. Ci. mation , as well as enhancing the healing and regeneration of
A61N 2 / 00 (2006 .01) such tissue.
A61N 1/ 40 ( 2006 .01 )
A61N 2 /02 (2006 .01) 21 Claims, 11 Drawing Sheets
501
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than effective US filing date and any foreign priority date ) 2002. lation for nerve regeneration . J Cell Biochem 52 , 404 - 409 (Apr.
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Bersani (ed .); Kluwer Academic / Plenum Publishers ; pp . 871-874 ; sentation abstract); Bioelectromagnetics Society; 21st Ann Meeting,
( year of pub . sufficiently earlier than effective US filing date and any Long Beach , Jun . 20 -24, 1999 .
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Clin Orthop, 199 - 208 (Dec . 1989). ballistic brain injury . J Neurotrauma 22 , 313 - 31 (Feb . 2005 ).
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Tehranian et al., Improved recovery and delayed cytokine induction Yu et al., Effects of 60 Hz electric and magnetic fields on maturation
after closed head injury in mice with central overexpression of the of the rat neopallium . Bioelectromagnetics 14 , 449 - 58 (year of
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Terpolilli et al., The novel nitric oxide synthase inhibitor 4 -amino Yumoto , et al.; Coordination Structures of Ca2 + and Mg2 + in
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Weintraub , M .;Magnetic bio -stimulation in painful diabetic periph Zizic et al., The treatment of osteoarthritis of the knee with pulsed
eral neuropathy: a novel intervention R a randomized double electrical stimulation . J Rheumatol 22 , 1757 -61 (Sep . 1995 ) .
placebo crossover study; Am J Pain Manag ; vol. 9 ; pp . 8 - 17 , Jan . 1,
1999 . * cited by examiner
U . S . Patent Mar. 12 , 2019 Sheet 1 of 11 US 10 ,226 ,640 B2
FIG . 1
Place PEMF device in

proximity to affected tissue ,
e . g., joint
101
Begin treatment regime

103
Apply burst of high frequency

(> 10 MHz ) waveform at low
amplitude (e.g., < 200 milliGauss)
105
Wait (no stimulation during

inter-treatment interval
107
Completed
No treatment
regime ?
109
Yes
FIG . 2
K 202
Shar
201 -
atent Mar . 12 , 2019 Sheet 3 of 11 US 10 ,226 ,640 B2
FIG . 3
High Frequency
User 110 Oscilliator
303 304
Carrier
Frequency
AMPLIFIED
PULSE MODULATED MODULATED OUTPUT
Microcontroller OUT Modulator PULSE RF PULSE STAGE
AMP OUTPUT
302 305 307
306
TO ALL BLOCKS
Power
Supply
301
300
U .S . Patent Mar. 12,2019 Sheet 4 of 11 US 10 ,226 ,640 B2
FIG . 4
400
- 402
401
- 403
wie
thith - wa -
TEAM
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her
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U . S . Patent Mar. 12 , 2019 Sheet 6 of 11 US 10,226,640 B2
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0.8 -
Burst Duration (msec )

FIG . 7
Rat CutaneousWound Repair

* P < 0 .01 vs Sham
pa = 0 . 97
3 msec
/Sham)(TSMeantreneastigeldh
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27 . 12 MHz, 2 Bursts /sec , 0 .05 G

0 .8
0 .00 0 . 03 0.06 0.09 0. 12 0.15 0.18
Average SA (uWs/cmº)
U . S . Patent Mar. 12, 2019 Sheet 9 of 11 US 10 ,226 ,640 B2
FIG . 8A
Articular Chondrocytes
* p < 0 .01
vs control
I *
oncEPfGEMecPFt )
SD
-
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FIG . 9
PEMF Effect on Early Knee OA Pain

Active
O Sham
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-
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0 5 10 15 20 25 30 35 40 45
PEMF Treatment Days
US 10 , 226 ,640 B2
DEVICES AND METHOD FOR TREATMENT
OF DEGENERATIVE JOINT DISEASES
BACKGROUND OF THE INVENTION
WITH ELECTROMAGNETIC FIELDS Chronic joint diseases are a major health problem . The
economic burden caused by progressive morbidity, loss of
CROSS REFERENCE TO RELATED 5 function and disability of these diseases is a challenge to
APPLICATIONS society . The outcome and severity of OA , RA and SpA
diseases is determined by the balance in the joint between
This patent application is a continuation of U .S . patent destructive and homeostatic or reparative pathways . The
application Ser. No. 13 /080 ,450 , filed Apr. 5 , 2011 , titled players in DJD include pro - inflammatory cytokines such as
“ DEVICES AND METHOD FOR TREATMENT OF 10 interleukin - 1 (IL - 1 ) and tumor necrosis factor-a ( TNF -a ).
prostaglandins , tissue destructive enzymes such as matrix
DEGENERATIVE JOINT DISEASES WITH ELECTRO metalloproteinases (MMP ) and cathepsins and cells such as
MAGNETIC FIELDS,” now U . S . Pat . No. 8 ,961,385, osteoclasts . The ultimate goal of treatment in DJD and all
issued on Feb . 24 , 2015 , which is herein incorporated by chronic diseases is not only the inhibition of excessive tissue
reference in its entirety . 15 destruction , but also restoration of homeostasis and eventu
U .S . patent application Ser. No. 13/ 080 ,450 claims prior ally tissue repair .
ity to U . S . Provisional Patent Application Nos. 61/ 321,044, It is well- established that application of weak , non -ther
filed Apr. 5 , 2010 , titled “ DEVICES AND METHOD FOR mal electromagnetic fields (“ EMF” ) can result in physiologi
TREATMENTOF OSTEOARTHRITIS BY ELECTRICAL cally meaningful in vivo and in vitro bioeffects. Time
STIMULATION ” and 61/ 326 , 582 , filed Apr. 21, 2010 , titled 20 varying electromagnetic fields, comprising rectangular
" DEVICES AND METHOD FOR TREATMENT OF waveforms, such as pulsing electromagnetic fields
DEGENERATIVE JOINT DISEASES WITH ELECTRO - (“ PEMF” ), and sinusoidal waveforms, such as pulsed radio
MAGNETIC FIELDS,” each of which are herein incorpo frequency fields (“PRF” ) ranging from several Hertz to an
rated by reference in their entirety . about 100 MHz range, are clinically beneficialwhen used as
U .S . patent application Ser. No. 13 /080 ,450 also claims 25 an adjunctive therapy for a variety ofmusculoskeletal inju
priority as a continuation -in - part of U . S . patent application ries and conditions .
Ser. No . 12/819,956 , filed Jun . 21, 2010 , titled “ APPARA Beginning in the 1960 's, development of modern thera
TUS AND METHOD FOR ELECTROMAGNETIC peutic and prophylactic devices was stimulated by clinical
TREATMENT," Publication No. US - 2011 - 0112352 -A1, problems associated with non - union and delayed union bone
now abandoned , which claims priority as a continuation - in - 30 fractures . Early work showed that an electrochemical path
part of U . S . patent application Ser. No. 12 / 772 , 002 , filed way can be a means through which bone adaptively
Apr. 30 , 2010 , titled “ APPARATUS AND METHOD FOR responds to mechanical input. Early therapeutic devices
ELECTROMAGNETIC TREATMENT OF PLANT. ANI- used implanted and semi-invasive electrodes delivering
MAL AND HUMAN TISSUE , ORGANS, CELLS AND direct current (“ DC ” ) to a fracture site. Non - invasive tech
MOLECULES .” Publication No. US - 2010 -0222631 -A1, 35 nologies were subsequently developed using capacitively
now abandoned , which is a continuation of U . S . patent and inductively coupled electromagnetic fields. These
application Ser. No. 11/003 , 108 , filed Dec . 3 , 2004, titled modalities were originally created to provide a non - invasive
“ APPARATUS AND METHOD FOR ELECTROMAG “ no - touch ” means of inducing an electrical/mechanical
NETIC TREATMENT OF PLANT, ANIMAL , AND waveform at a cell/tissue level. Clinical applications of these
HUMAN TISSUE , ORGANS. CELLS . AND MOL - 40 technologies in orthopaedics have led to approved applica
ECULES.” now U . S . Pat. No. 7 ,744,524 , which claims tions by regulatory bodies worldwide for treatment of frac
priority to U . S . Provisional Patent Application No . 60 /527 , tures such as non -unions and fresh fractures , as well as spine
327 . filed Dec . 5 . 2003 . titled “ APPARATUS AND fusion . Presently several EMF devices constitute the stan
METHOD FOR ELECTROMAGNETIC TREATMENTOF dard armamentarium of orthopaedic clinical practice for
PLANT, ANIMAL , AND HUMAN TISSUE, ORGANS, 45 treatment of difficult to heal fractures. The success rate for
CELLS AND MOLECULES,” . Each of these patents and these devices has been very high . The database for this
pending patent applications are herein incorporated by ref indication is large enough to enable its recommended use as
erence in their entirety . a safe , non - surgical, non - invasive alternative to a first bone
graft . Additional clinical indications for these technologies
INCORPORATION BY REFERENCE 50 have been reported in double blind studies for treatment of
avascular necrosis, tendinitis, osteoarthritis , wound repair ,
All publications and patent applications mentioned in this blood circulation and pain from arthritis as well as other
specification are herein incorporated by reference in their musculoskeletal injuries .
entirety to the same extent as if each individual publication Cellular studies have addressed effects of weak , low
or patent application was specifically and individually indi- 55 frequency electromagnetic fields on both signal transduction
cated to be incorporated by reference . pathways and growth factor synthesis . It can be shown that
EMF stimulates secretion of growth factors after a short,
FIELD OF THE INVENTION trigger - like duration . Ion / ligand binding processes at a cell
membrane are generally considered an initial EMF target
This invention pertains generally to electromagnetic 60 pathway structure . The clinical relevance to treatments of
devices and methods for delivering shaped and calibrated bone repair, for example , is upregulation such as modulation
electromagnetic signals to promote cell and tissue growth , of growth factor production as part of normal molecular
repair, and maintenance . In particular, the devices and regulation of bone repair. Cellular level studies have shown
methods described herein are intended and adapted to treat effects on calcium ion transport, cell proliferation , Insulin
degenerative joint diseases (“ DJD ” ) , including osteoarthritis 65 Growth Factor (“ IGF-II” ) release , and IGF- II receptor
("OA " ) , rheumatoid arthritis (“ RA " ) and spondyloarthritis expression in osteoblasts . Effects on Insulin Growth Factor- I
(SpA ” ), collectively known as arthritis. (“ IGF - I” ) and IGF- II have also been demonstrated in rat
US 10 , 226 ,640 B2
fracture callus. Stimulation of transforming growth factor asymmetrical kinetics of the binding of intracellular ions to
beta (“ TGF-8 " ) messenger RNA (“mRNA ” ) with PEMF in their respective buffers which regulate the biochemical
a bone induction model in a rat has been shown. Studies signaling pathways living systems employ for growth , repair
have also demonstrated upregulation of TGF-B mRNA by and maintenance. Another embodiment according to the
PEMF in human osteoblast - like cell line designated MG -63, 5 present invention pertains to the non - thermal application of
wherein there were increases in TGF-B1, collagen , and repetitive pulse bursts of bipolar sinusoidal, rectangular,
osteocalcin synthesis. PEMF stimulated an increase in TGF chaotic or arbitrary waveform electromagnetic fields to
B1 in both hypertrophic and atrophic cells from human instantaneously accelerate ion -buffer binding in signaling
non - union tissue . Further studies demonstrated an increase pathways in structures such as molecules, cells, tissues ,
in both TGF -B1 mRNA and protein in osteoblast cultures 10 organs, and entire organisms of plants , animals or humans
resulting from a direct effect of EMF on a calcium (Ca )/ using ultra lightweight portable coupling devices such as
calmodulin (CaM )- dependent pathway . Cartilage cell stud inductors and electrodes, driven by miniature signal genera
ies have shown similar increases in TGF-B1 mRNA and tor circuitry that can be incorporated into an anatomical
protein synthesis from PEMF, demonstrating a therapeutic positioning device such as a dressing , bandage , compression
application to joint repair. More recently it has been shown 15 bandage , compression dressing , knee , elbow , lumbar or
that PEMF can modulate CaM -dependent nitric oxide (NO ) cervical back , shoulder, foot, head , neck and other body
signaling. U . S . Pat.No. 4 ,315 , 503 ( 1982 ) to Ryaby and U .S . portion wraps.
Pat. No. 5 ,723,001 ( 1998 ) to Pilla typify the -research con Yet another embodiment according to the present inven
ducted in this field . tion pertains to application of bipolar sinusoidal, rectangu
However, prior art in this field has not produced electro - 20 lar, chaotic or arbitrary waveform electromagnetic signals ,
magnetic signals configured specifically to accelerate the having frequency components below about 100 GHz, con
asymmetrical kinetics of the binding of intracellular ions to figured to accelerate the binding of intracellular Ca² + to a
their associated buffers which regulate the biochemical buffer, such as calmodulin (hereinafter known as CaM ), to
signaling pathways living systems employ for growth , repair enhance biochemical signaling pathways in target structures
and maintenance . The result is that application of prior art 25 such as plant, animal and human molecules, cells , tissues ,
devices , such as BGS devices and PRF devices, requires organs, portions of entire organisms and entire organisms.
excessively long treatment times with associated prolonged Signals configured according to embodiments of the present
patient morbidity, equivocal outcomes, and unnecessarily invention produce a net increase in a bound ion , such as Ca2 +
higher health care expenses . Prior art in this field also at Cam binding sites because the asymmetrical kinetics of
typically required devices which use unnecessarily high 30 Ca/ CaM binding allows such signals to accumulate voltage
amplitude and power to induce a PEMF signal to a target induced at the ion binding site, thereby accelerating voltage
pathway structure , required unnecessarily long treatment dependent ion binding . Examples of therapeutic and pro
time, and were not portable . phylactic applications of the present invention are modula
Therefore , a need exists for an apparatus and a method tion of biochemical signaling in anti- inflammatory
that more effectively modulates biochemical processes that 35 pathways, modulation of biochemical signaling in cytokine
regulate tissue growth and repair, shortens treatment times , release pathways , modulation of biochemical signaling in
and incorporates miniaturized circuitry and light weight growth factor release pathways ; chronic and acute muscu
applicators thus allowing the apparatus to be portable and , if loskeletal pain relief; edema and lymph reduction , anti
desired , disposable . A further need exists for an apparatus inflammatory, post surgical and post operative pain and
and method that more effectively modulates biochemical 40 edema relief, nerve , bone and organ pain relief, increased
processes that regulate tissue growth and repair , shortens local blood flow , microvascular blood perfusion , treatment
treatment times , and incorporates miniaturized circuitry and of tissue and organ ischemia , cardiac tissue ischemia , brain
light weight applicators that can be constructed to be tissue ischemia from stroke or traumatic brain injury , treat
implantable . A further need exists for an apparatus and ment of neurological injury and neurodegenerative diseases
method that incorporates the asymmetrical kinetics of ion 45 such as Alzheimer ' s and Parkinson ' s ; wound repair , bone
binding to intracellular buffers to configure electromagnetic repair, tissue repair ; osteoporosis treatment and prevention ;
waveforms to increase the rate of ion binding and enhance degenerative bone disease treatment and prevention ; angio
the biochemical signaling pathways living systems employ genesis, neovascularization ; enhanced immune response ;
for growth , repair and maintenance . treatment of diabetes Types I and II; enhanced effectiveness
In particular, there is a need to treat DJD at the level of the 50 of pharmacological agents ; nerve regeneration , skeletal
joint and affected tissue , using a portable, wearable , light muscle regeneration , cardiac muscle regeneration ; cancer
weight device /apparatus capable of effecting tissue growth treatment; prevention of apoptosis ;modulation of heat shock
and repair. Described herein are devices that may meet the proteins for prophylaxis and response to injury or pathology .
needs described above. An embodiment according to the present invention can also
55 be used in conjunction with other therapeutic and prophy
SUMMARY OF THE INVENTION lactic procedures and modalities such as heat, cold , light,
ultrasound, mechanical manipulation , massage, physical
The present invention relates to the treatment of DJD by therapy , vacuum assisted wound closure , wound dressings,
the application of electromagnetic signals to joints and other orthopedic and other surgical fixation devices, and surgical
regions to prevent, cure, and / or alleviate DJD or symptoms 60 interventions. Yet another embodiment according to the
of DJD (generally referred to as “ treating arthritis” ) . present invention can also be used in conjunction with all
Described herein are weak electromagnetic field devices and pharmacological agents . Another embodiment of the present
methods designed to reduce pain from arthritis and achieve invention can be used with imaging or non - imaging diag
joint and affected tissue regeneration . nostic procedures .
In particular, an embodiment according to the present 65 The applied electromagnetic signal may be configured
invention pertains to use of non -thermal static and time- specifically to treat DJD by using signal to noise ratio
varying electromagnetic fields configured to accelerate the (“ SNR ” ) and/or power signal to noise ratio (“ PSNR ” )
US 10 , 226 ,640 B2
approaches to configure bio - effective waveforms. The fitted as stand-alone units or may be embedded within other
applied electromagnetic signal may also deliver bipolar products , to provide for manual or automatic treatment
electromagnetic signals configured specifically to accelerate regimens.
the asymmetrical kinetics of the binding of intracellular ions In operation , these devices may be used to apply bio
to their respective intracellular buffers, to enhance the bio - 5 effective waveforms ( electromagnetic fields having a pre
chemical signaling pathways plant animal and human mol determined waveform as described herein ) to one or more
ecules , cells , tissues, organs, portions of entire organisms joints to be treated for DJD . The bio - effective waveform
and entire organisms employ for growth , repair and main
tenance . A preferred embodiment according to the present may be calculated and configured specifically to modify a
biological pathway related to DJD ; For example, the device
invention utilizes a repetitive burst of bipolar arbitrary 10 may produce
non - thermal waveforms configured to maximize the bound waveform ) thata pulsed electromagnetic signal (bio -effective
comprises a series of pulse or sinusoidal
concentration of intracellular ions at their associated bursts . The pulses or sinusoids may have a specific duration ,
molecular buffers to enhance the biochemical signaling
pathways living systems employ for growth , repair and frequency and amplitude ; further the bursts may themselves
have a specific
maintenance. Non - thermal electromagnetic waveforms are 15 haveThusa specific duration
aura , frequency and amplitude .
selected first by choosing the ion and the intracellular buffer , , a device may apply a signal that accelerates a
for example Ca2 + and CaM , among the many ion -buffer specific electrochemical binding process with some speci
combinations within the living cell , which determines the ficity. In particular, the signal may modulate the binding of
frequency range within which the signal must have non Ca to CaM in target tissue within the joint. By accelerating
thermal frequency components of sufficient, but non -de - 20 the process of Ca /CaM binding, the cascade ofbiochemical
structive , amplitude to accelerate the kinetics of ion binding activity that follows may be likewise accelerated , and par
Signals comprise a pulse duration , random signal duration or ticularly modulating the local production of NO through
carrier period which is less than half of the ion bound time activation of the constitutive nitric oxide synthases (CNOS )
to increase the voltage in the target pathway so as to by modulation of CaM activation and then the increased
maximally accelerate ion binding to maximally modulate 25 production of growth factors to enhance healing in the joint
biochemical signaling pathways to enhance specific cellular and affected tissue , including cartilage , through the modu
and tissue responses to physical and chemical perturbations . lated production of cGMP and CAMP.
In preferred embodiments of the present invention , sig - For example, a device as described herein can be config
nals comprise bursts of at least one of sinusoidal, rectangu - ured so that it applies a bio - effective waveform for a
lar, chaotic or random wave shapes ; have burst duration less 30 predetermined amount of time using a predetermined ( or
than about 100 msec , with frequency content less than about modifiable ) treatment regime. In one variation , the signal
100 MHz, repeating at less than about 1000 bursts per frequency within a particular burst envelope is centered on
second . Peak signal amplitude in the ion -buffer binding a particular carrier frequency (e . g ., 27 . 12 MHz, 6 . 78 MHz,
pathway is less than about 1000 V /m . One preferred embodi etc .). For example , the waveform within a burst may use a
ment according to the present invention comprises about a 35 carrier frequency of 6 .78 MHz and the frequency between
10 to about a 50 millisecond burst of radio frequency bursts can be modulated by producing bursts at 1 Hz. In one
sinusoidal waves in the range of about 1 to about 100 MHz, variation , bursts are 7 ms in duration with a peak amplitude
incorporating radio frequencies in the industrial, scientific of 0 .05 Gauss . In another example , a device can be config
and medical (hereinafter known as ISM ) band , for example ured using a carrier frequency of 27 . 12 MHz that can be
27 . 12 MHz, but it may be 6 .78 MHz, 13 .56 MHz or 40 .68 40 modulated by producing a burst at 2 Hz, such bursts being
MHz in the short wave frequency band, repeating between 2 ms in duration with a peak amplitude of 0 .05 Gauss .
about 0 . 1 and about 10 bursts/ sec. Such waveforms can be In some variations, the device is configured to explicitly
delivered via inductive coupling with a coil applicator or via limit the peak signal strength of the applied signal. For
capacitive coupling with electrodes in electrochemical con example , the peak signal strength may be limited to approxi
tact with the conductive outer surface of the target . 45 mately 50 milliGauss ( e. g ., 0 .05 Gauss ). A proper signal
Also described herein are devices for delivery of these configuration to produce the necessary induced electric
bio -effective waveforms to the joints or other related tissues . fields in the range of 0 .1 - 100 millivolts per centimeter
Any of these devices may include and incorporate minia - (“mV/cm ” ) for a given carrier frequency may be determined
turized circuitry and lightweight flexible coils for delivery of as described herein . In general, the desired and specific
thebio -effective waveforms described herein . These devices 50 effect seen on the target pathway ( e. g., the Ca/CaM path
may be constructed as disposable, stand alone or may be way )may be very sensitive to the waveform parameters . The
integrated into one or more other braces, casts or prosthetic ranges of waveform parameters described herein are tuned
devices . to the desired effect.
A device (or apparatus) for treating DJD typically induces In addition , the treatment regime applied may be cali
pulsating electric currents in joints and affected tissue that 55 brated to the end effect. For example , in some variations, the
may reduce pro -inflammatory cytokines and other pro - treatment regime used to treat DJD may include: 15 minute
inflammatory pathways , and therefore , associated pain and applications twice a day. A 15 minute application may
inflammation directly in the joint or from affected bone, e . g ., include 7 ms bursts applied at a frequency of about once a
local bone marrow edema, and may slow or reverse the second ( 1 Hz ), so the total time that therapeutic currents are
destruction of joint tissue , including cartilage . The induced 60 delivered is about 8 . 1 seconds . Thus, the effective duty cycle
currents may improve growth factor production , leading to of the applied current is extremely low ( e . g ., the total energy
the re - growth of joint tissue , including cartilage . These applied over time), and may be less than 1 % ( e. g ., 0 . 9 % )
devices may be adapted to apply the electromagnetic wave “ on ” time during the treatment on -time; one treatment may
forms to any joint or synovial/ bone interface , but particu - be followed by a 4 - 12 hour (ormore ) recovery time, so the
larly joints of the knee , hip , and hand . 65 mean energy applied to the tissue over time is even less . For
In general, these devices may be lightweight, portable , example , to treat DJD , a patientmay receive therapy over a
rechargeable and /or disposable, and may be anatomically day for approximately 1 -60 minutes . That therapy may be
US 10 ,226 ,640 B2
delivered in a single 1 hour treatment, or as a series of 60 , Ca /CaM ) are detectable in the target tissue and target
1 minute treatments over a longer period . pathway structure above the evaluated baseline thermal
In some variations , an electromagnetic signal generator fluctuations in voltage . The bio - effective waveform may be
( for emitting signals comprising bursts of the bio - effective applied to the target tissue ( target pathway ) using a coupling
signal) may be used , and may be part of the device or a 5 device ( e . g ., applicator) which may be incorporated into the
system including the device . For example , the device may brace , dressing, garment, orthotic , or the like .
include a signal generator configured to generate the afore The bio - effective waveform is further determined by
mentioned bio - effective signal comprising at least one of configuring a repetitive burst of arbitrary non -thermal wave
sinusoidal, rectangular, chaotic , and random waveforms. forms to maximize the bound concentration of intracellular
The signal generator may have a frequency content in a 10 ions at their associated molecular buffers to enhance the
range of about 0 .01Hz to about 100 MHz at about 1 to about biochemical signaling pathways living systems employ for
100 ,000 waveforms per second, having a burst duration growth , repair and maintenance . Non -thermal electromag
from about 1 usec to about 100 msec , and a burst repetition netic waveforms are selected first by choosing the ion and
rate from about 0 .01 to about 1000 bursts /second , wherein the intracellular buffer, for example Ca2 + and CaM , among
the waveforms are configured to have sufficient SNR or 15 the many ion -buffer combinations within the living cell,
PSNR of at least about 0 .2 in respect of the target pathway which determines the frequency range within which the
within the target tissues of the joint or affected tissue to signal must have non -thermal frequency components of
modulate ion and /or ligand interactions in that target tissue . sufficient, but non -destructive , amplitude to accelerate the
When determining the bio -effective signal, the waveform kinetics of ion binding . Signals comprise a pulse duration ,
may be configured using the signal to noise ratio , SNR , or 20 random signal duration or carrier period which is less than
PSNR as evaluated by calculating a frequency response of half of the ion bound time to increase the voltage in the
the impedance of the target path structure divided by the root target pathway so as to maximally accelerate ion binding to
mean square (RMS) of baseline thermal fluctuations in maximally modulate biochemical signaling pathways to
voltage across the target path structure , assuming the elec - enhance specific cellular and tissue responses to physical
tromagnetic signal coupling device the device ) wherein the 25 and chemical perturbations.
coupling device comprises an inductive coupling member For example , described herein are methods of treating
and /or a capacitive coupling member, connected to the degenerative joint disease comprising: positioning a flexible
electromagnetic signal generator for delivering the electro - coil wire applicator of a lightweight wearable or stationary
magnetic signal to the target joint and affected tissue The pulsed EMF therapy device adjacent to a joint or tissue to be
electromagnetic signal generator and electromagnetic signal 30 treated ; applying a treatment regime from the therapy
coupling device may be incorporated into a dressing, gar - device , wherein the treatment regime comprises bursts of
ment, orthotic , brace, or the like. electromagnetic waves having a peak amplitude of less than
A device comprising a waveform configuration element about 100 milliGauss , wherein the bursts have a duration of
( e. g ., shaping the desired waveform based on the bio - between about 0 .5 msec and about 50 msec , further wherein
effective signal determined ) may include dedicated circuitry 35 the bursts are repeated at an interburst interval of between
( e. g ., hardware , software , firmware ) or the like to time and about 2 sec and 0 . 1 sec for a treatment on -time, followed by
emit the desired bio -effective waveform . a treatment off -time that is greater than the treatment on
Asmentioned , the bio -effective waveform may be deter- time.
mined in advance by configuring at least one waveform to The treatment regime may be configured according to a
have sufficient SNR or PSNR of at least about 0 .2 , but 40 mathematicalmodel , as described herein . For example , the
preferably greater than about 1 , to modulate ion and /or mathematical model may include a signal to noise ratio
ligand interactions whereby the increases in ion and /or (SNR ) or power signal to noise ratio (PSNR ) in respect to
ligand interactions in the target joint tissue are detectable calmodulin - dependent NO signaling, and /or in respect to
above baseline thermal fluctuations in voltage , wherein SNR calmodulin -dependent signaling.
or PSNR may be evaluated by calculating a frequency 45 In general, the methods of treating degenerative joint
response of the impedance of the target path structure disease may be methods of treatment of osteoarthritis ,
divided by the RMS of baseline thermal fluctuations in rheumatoid arthritis , spondyloarthritis, and/or generally
voltage across the target path structure . A coupling device arthritis.
may be connected to the waveform configuration element by The duty cycle of the treatment regime may be extremely
at least one connector for generating an electromagnetic 50 low , particularly in comparison to other therapeutic device
signal from the configured at least one waveform and for for treating degenerative joint diseases. For example , the
coupling the electromagnetic signal to the target tissue , treatmenton -timemay be between about 1 minute and about
whereby the ion and / or ligand interactions may be modu - 60 minutes ( e . g ., between about 5 minutes and 15 minutes ),
lated . As mentioned , a dressing, garment, brace , or the like or less , and the treatment on timemay be about 1 hour to as
may incorporate the device , which may include a waveform 55 long as 48 hours ( e .g ., 12 hours ). During the on -time, the
configuration element, and at least one connecting element treatment regime is a repeated burst of pulses ( e .g ., sinu
( e . g., applicator). soidal, square waves, etc .) at a carrier frequency of6 .8 MHz,
The bio - effective waveform may be determined by estab 27 . 12 MHz (or a harmonic of these ), with a burst duration
lishing a baseline thermal fluctuation in voltage at a target that is relatively short compared to the interburst interval.
tissue ( e . g ., joint ) depending on a state of the target tissue , 60 In some variations, the devices and apparatus described
and evaluating SNR or PSNR by calculating a frequency herein are lightweight, wearable , battery -operated EMF
response of the impedance of the target pathway structure therapy apparatus for treating degenerative joint disease
divided by the RMS of baseline thermal fluctuations in which include: a flexible coil wire applicator coupled to
voltage across the target pathway structure , configuring at battery -operated EMF therapy microcontroller within a
least one waveform to have sufficient SNR or PSNR of at 65 lightweight, wearable housing ; wherein the microcontroller
least about 0 . 2 to modulate ion and /or ligand interactions is configured to drive the applicator to deliver bursts of
whereby the increases in ion and /or ligand interactions (e.g ., electromagnetic waves having a peak amplitude of less than
US 10 ,226 ,640 B2
10
about 200 milliGauss,wherein the bursts have a duration of and the dosing or treatment regime applied may be config
between about 0 . 5 msec and about 50 msec, further wherein ured so that this pathway is targeted specifically and effec
the bursts are repeated at an interburst interval of between tively . Further, the stimulation protocol and dosing regime
about 10 sec and 0 .1 sec for a treatment on -time of between may be configured so that the device (applicator device ) may
about 5 minutes and 30 minutes , followed by a treatment 5 be portable /wearable and lightweight, and operate at a
off -time that is greater than about 30 minutes . The micro - clinically significant level yet require low power.
controller may be configured to drive the applicator to For example, the electrical properties of a joint and
deliver bursts of 6 . 8 MHz sinusoidal electromagnetic waves affected tissue target structure may be included in the
having a peak amplitude of about 50 milliGauss, wherein the calculation , affecting the levels and distributions of induced
duration of the burst is about 7 msec , and bursts repeat 10 current. Molecules, cells, tissue , and organs are all in an
approximately every second . In some variations, the appa induced current pathway such as cells in a gap junction
ratus includes ( or is part of) a brace or garment incorporating contact may be modeled as equivalent electrical structures ,
the applicator. and the applied electromagnetic signalmay be tested against
In general, the flexible coil applicator may be a wire coil
applicator, and particularly wire coil applicators having a 15 this model to tune the applied signal to the desired response .
loop diameter ofbetween about 12 and about 5 inches ( e . g ., eculesor that
Ion ligand interactions at binding sites on macromol
6 inches, 7 inches, 8 inches, etc.). The applicatormay be part dependent may reside on a membrane surface are voltage
of a brace , orthotic , garment, or the like, as described herein . cess) that can respondprocesses
chemical ( e.g ., electrochemical pro
to an induced electromagnetic field
BRIEF DESCRIPTION OF THE DRAWINGS 20 (“ E ” ) in this model. Induced currentmay arrive at these sites
via a surrounding ionic medium . The presence of cells in a
FIG . 1 is a flow diagram of a method for treating DJD current pathway causes an induced current (“ J” ) to decay
( e .g ., osteoarthritis ) according to an embodiment of the more rapidly with time (" J (t)" ). This is due to an added
devices and methods described herein . electrical impedance of cells from membrane capacitance
FIG . 2 is a view of an apparatus for application of 25 and ion binding time constants of binding and other voltage
electromagnetic signals according to an embodiment of the sensitive membrane processes such as membrane transport .
devices and methods described herein . Ion binding time constants may be used to determine the
FIG . 3 is a block diagram of miniaturized circuitry optimal stimulation parameters and to determine the appro
according to an embodiment of the devices and methods priate SNR or PSNR to be evaluated for any proposed EMF
described herein . 30 signal configuration . Preferably ion binding time constants
FIG . 4 depicts features of a waveform that may be in the range of about 0 .1 to about 100 msec are used in the
delivered as described herein . model.
FIGS. 5A -5D illustrate variations of devices described Equivalent electrical circuit models representing various
herein that may be used directly or placed in a various membrane and charged interface configurations have been
dressings , garments and /or orthotics , so that the device may 35
be aligned with the target joint( s ) or other affected tissue . derived . For example , in Calcium (“ Ca2 + » ) binding , the
FIG . 6 is a curve illustrating the effect of burst duration on change in concentration of bound Ca2 + at a binding site due
myosin phosphorylation for an EMF signal configured to induced E may be described in a frequency domain by an
according to an embodiment of the devices and methods impedance expression such as:
described herein . 40
FIG . 7 is a curve illustrating the effect of burst duration of
PEMF, configured according to one variation of the devices Zb(w ) = Rion + iwCion
and methods described herein , on cutaneous wound repair in
a rat model.
FIGS. 8A -B illustrate the effect of PEMF, configured 45 which has the form of a series resistance -capacitance elec
according to one embodiment of the devices and methods trical equivalent circuit. Where w is angular frequency
described herein , on articular chondrocyte proliferation defined as 2tf. where f is frequency, j= - 11/2 Z . (w ) is the
through the use of inhibitors of early signaling pathways. binding impedance, and Rion and Cion are equivalent binding
FIG . 9 illustrates the clinical effect of PEMF, configured resistance and capacitance of an ion binding pathway . The
according to an embodiment of the devices and methods 50 value of the equivalent binding time constant, Tion = Rion Cion ,
described herein , on pain from osteoarthritis of the knee , in
a randomized , double -blind , placebo -controlled human Tion = RionCionto= 1/anky. Thus
is related ion binding rate constant, ky, via
, the characteristic time constant of
clinical trial.
this pathway is determined by ion binding kinetics .
DETAILED DESCRIPTION OF THE 55. Induced E from a PEMF or PRF signal can cause current
INVENTION to flow into an ion binding pathway and affect the number
of Ca2 + ions bound per unit time. An electrical equivalent of
Described herein are devices and methods for treating this is a change in voltage across the equivalent binding
DJD . capacitance Cion, which is a directmeasure of the change in
Induced time-varying currents from PEMF or PRF 60 electrical charge stored by Cion . Electrical charge is directly
devices may be configured to effect joint tissue including proportional to a surface concentration of Ca2 + ions in the
specific molecular pathways in the target tissue allowing binding site that is storage of charge is equivalent to storage
these tissues to react in a physiologically meaningful man - of ions or other charged species on cell surfaces and junc
ner. For example, a waveform may be configured within a tions. Electrical impedance measurements , as well as direct
prescribed set of parameters so that a particular pathway, 65 kinetic analyses of binding rate constants , provide values for
such as CaM -dependent NO synthesis within the tissue time constants necessary for configuration of a PEMF wave
target, is modulated specifically. Both the applied waveform form to match a bandpass of target (e.g ., joint) structures .
US 10 ,226 ,640 B2
This allows for a required range of frequencies for any given A typical approach to evaluation of SNR uses a single
induced E waveform for optimal coupling to target imped value of a root mean square (RMS) noise voltage . This is
ance , such as bandpass . calculated by taking a square root of an integration of
Ion binding which activates, e.g ., regulatory enzymes Sn (w ) = 4 KT Re[ZM (x , w )] over all frequencies relevant to
constitutes an EMF target pathway, for example Ca binding 5 either a complete membrane response , or to bandwidth of a
to CaM . Use of this pathway is based upon acceleration of target structure. SNR can be expressed by a ratio :
tissue repair, for example bone repair, wound repair, joint
and affected tissue repair, and repair of other molecules,
cells, tissues , and organs that involves modulation of cytok SNR == LVMRMS
SNR (W )
ages of tissue 10
ines and growth factors released in various stages
repair and maintenance . Growth factors such as platelet
derived growth factor (“ PDGF” ), basic fibroblast growth where IVMw ) is maximum amplitude of voltage at each
factor (“ FGF -2” ), vascular endothelial growth factor frequency as delivered by a chosen waveform to the joint
(“ VEGF' ) and epidermal growth factor (“ EGF" ) are all 15 tissue.
involved at an appropriate stage of healing. Angiogenesis In one embodiment, a burst ofsinusoidal waves, having a
and neovascularization are also integral to tissue growth and frequency between about 1 MHz and 50 MHz, is applied to
repair and can be modulated by PEMF. All of these factors the joint or affected tissue so that the effect of therapy upon
are CaM - dependent. the relevant dielectric pathways , such as, cellularmembrane
Utilizing a Ca/ CaM pathway a waveform can be config - 20 receptors , ion binding to macromolecules and general trans
ured for which induced power is sufficiently above back - membrane potential changes , is modulated . Accordingly , by
ground thermal noise power. Under correct physiological increasing a number of frequency components transmitted to
conditions, this waveform can have a physiologically sig relevant cellular pathways, a large range of biophysical
nificant bioeffect. phenomena , such as modulating growth factor and cytokine
Application of a SNR or PSNR model to Ca/CaM requires 25 release and ion binding at regulatory molecules, applicable
knowledge of electrical equivalents of Ca2+ binding kinetics to known tissue growth and repair mechanisms are acces
at CaM . Within first order binding kinetics, changes in sible. According to one embodiment, applying a random , or
concentration of bound Ca2 + at Cam binding sites over time other high spectral density envelope , to a pulse burst enve
may be characterized in a frequency domain by an equiva - lope of mono -polar or bipolar rectangular or sinusoidal
lent binding time constant, tion = R ; „ Ciom , where Ric, and 30 pulses inducing peak electric fields between about 10 - 8 and
Cion are equivalent binding resistance and capacitance of the about 100 mV / cm , produces an effect on biological healing
ion binding pathway . Tion is related to a ion binding rate processes applicable to both soft and hard tissues.
constant, ky , via Tion = Rion Vion
Cion = 1 /ky . Published values for k , One embodiment of the methods and devices described
can then be employed in a cell array or single cell model to herein comprises an electromagnetic signal having a pulse
evaluate SNR by comparing voltage induced by a PRF 35 burst envelope of spectral density to efficiently couple to
signal to thermal fluctuations in voltage at a Cam binding physiologically relevant dielectric pathways , such as cellular
site . Employing numericalvalues for PMF response , such as membrane receptors, ion binding to macromolecules, and
Vmax = 6 .5x10 - 7 sec - 1, [Ca2 + ]= 2 .5 uM , KD = 30 uM , [Ca2+ general transmembrane potential changes. The use of a burst
???
CaM ]= KD ([Ca2 + ]+ [CaM ]), yields kn = 665 sec - 1 (Tion = 1.5 duration which is generally below 100 microseconds for
msec ). Such a value for Tion can be employed in an electrical 40 each burst, limits the frequency components that could
equivalent circuit for ion binding while SNR or PSNR couple to the relevant dielectric pathways in cells and tissue,
analysis can be performed for any waveform structure . and will have marginal or no bioeffect unless excessive and
According to one embodiment, a mathematicalmodel can non -selective amplitudes are delivered to the target. In one
be configured to assimilate that thermal noise which is embodiment, the waveform comprises an increased number
present in all voltage dependent processes and represents a 45 of frequency components transmitted to relevant cellular
minimum threshold requirement to establish adequate SNR pathways whereby access to a larger range of biophysical
or PSNR . Power spectral density , S (W ), of thermal noise phenomena applicable to known healing mechanisms,
can be expressed as: including enhanced second messenger release , enzyme
activity and growth factor and cytokine release can be
Sn (w ) = 4kTRe[ZM (x,0 )] 50 achieved . By increasing burst duration and applying a ran
where Zy (x ,x ) is electrical impedance of a target pathway dom , or other envelope , to the pulse burst envelope of
structure (e .g., joint tissue), x is a dimension of a joint tissue mono -polar or bi-polar rectangular or sinusoidal pulses
structure and Re denotes a real part of impedance of a the which induce peak electric fields between 10 - 8 and 100
target pathway tissue structure. Zm (x ,w ) can be expressed mV /cm , a more efficient and greater effect can be achieved
55 on biological healing processes applicable to both soft and
as:
hard tissues in humans, animals and plants .
The present invention teaches that a time-varying elec
tromagnetic field for which pulse duration or carrier period
Zm(x,4)=[ +R;+Rs]tanhúyx) is less than about half of the bound ion lifetime of Ca2 +
60 binding to CaM will maximize the current flow into the
Ca/CaM binding pathway to accelerate the CaM -dependent
This equation shows that electrical impedance of the signaling which plants , animals and humans utilize for tissue
target pathway ( including the target tissue ), and contribu- growth , repair and maintenance . In particular, a time-vary
tions from extracellular fluid resistance (“ R ” ) , intracellular i ng electromagnetic field may be configured to modulate
fluid resistance (“ R ;" ) and intermembrane resistance (“ R " ) 65 CaM -dependent NO /CGMP signaling which accelerates;
which are electrically connected to target pathway structures pain and edema relief, angiogenesis , hard and soft tissue
and, all contribute to noise filtering . repair , repair of ischemic tissue , prevention and repair of
US 10 ,226 ,640 B2
13 14
neurodegenerative diseases , nerve repair and regeneration , associated with specific pathways within the cellular and
skeletal and cardiac muscle repair and regeneration , relief of tissue environment through the use of electromagnetic
muscle pain , relief of nerve pain , relief of angina, relief of means such as PRF generators and applicator heads. More
degenerative joint disease pain ,healing of degenerative joint particularly use of electromagnetic means may include the
disease, immunological response to disease , including can - 5 provision of a flux path to a selectable body region , of a
cer. succession of PEMF pulses having a minimum width char
A preferred embodiment according to the present inven - acteristic of at least 0 .01 microseconds in a pulse burst
tion is an electromagnetic signal which accelerates the envelope having between 1 and 100 ,000 pulses per burst, in
kinetics of Ca2 + binding by maximizing non -thermal E , (s ) at which a voltage amplitude envelope of said pulse burst is
its CaM binding sites , consisting of a 1 - 10 msec pulse burst 10 defined by a randomly varying parameter. Further , the
of 27 .12 MHz radio frequency sinusoidal waves, repeating repetition rate of such pulse bursts may vary from 0.01 to
between about 1 and about 5 bursts / sec and inducing a peak 10 , 000 Hz. Additionally a mathematically -definable param
electric field between about 1 and about 100 V /m , then eter can be employed in lieu of said random amplitude
coupling the configured waveform using a generating device envelope of the pulse bursts.
such as ultra lightweight wire coils that are powered by a 15 According to one embodiment, by applying a random , or
waveform configuration device such as miniaturized elec - other high spectral density envelope , to a pulse burst enve
tronic circuitry which is programmed to apply the waveform lope of mono -polar or bipolar rectangular or sinusoidal
at fixed or variable intervals , for example 1 minute every 10 pulses which induce peak electric fields between 10 - 8 and
minutes , 10 minutes every hour, or any other regimen found 100 mV / cm , a more efficient and greater effect can be
to be beneficial for a prescribed treatment. 20 achieved on biological healing processes applicable to both
According to the present invention , the application of soft and hard tissues in humans, animals and plants. A pulse
non -thermal EMF instantaneously accelerates the kinetics of burst containing high frequency waveforms can advanta
Ca2+ binding to CaM , the first step of a well characterized geously and efficiently couple to physiologically relevant
signaling cascade which a plant, animal or human organism dielectric pathways, such as, cellular membrane receptors ,
utilizes to respond to chemical or physical insults . Ca /CaM 25 ion binding to cellular enzymes, and general transmembrane
binding is kinetically asymmetrical, i.e ., the rate ofbinding potential changes thereby modulating angiogenesis and neo
exceeds the rate of dissociation by several orders of mag vascularization .
nitude (k > > k ), therefore the application of EMF will In some variations , themethods and /or device may utilize
instantaneously drive the reaction in the forward direction . a SNR or a PSNR approach to configure bioeffective wave
The Ca/CaM binding time constant is in the range of 1 to 10 30 forms in the Ca/CaM target pathway and incorporates min
milliseconds. In contrast, the release of Ca - + from Cam iaturized circuitry and lightweight flexible coils . This advan
cannot occur until CNOS * has converted L -arginine to tageously allows a device that utilizes a SNR or PSNR
citrulline and NO , which takes the better part of a second . approach in the Ca /CaM target pathway , miniaturized cir
Subsequent reactions involving NO depend upon the cell/ cuitry , and lightweight flexible coils, to be completely
tissue state . For example , tissue repair requires a temporal 35 portable and if desired to be constructed as disposable and
sequence of inflammatory , anti- inflammatory, angiogenic if further desired to be constructed as implantable . The
and proliferative components. Endothelial cells orchestrate lightweight flexible coils can be an integral portion of a
the production of FGF - 2 and VEGF for angiogenesis. For positioning device such as surgical dressings, wound dress
each of these phases , early NO production by endothelial ings, pads, seat cushions , mattress pads, wheelchairs, chairs,
cells, leading to increased cGMP by these , as well as other 40 and any other garment and structure juxtaposed to living
NO targets , such as vascular smooth muscle , are modulated tissue and cells for co -treatment or co -maintenance thereof.
by an EMF effect on GC via Ca /CaM binding. In contrast, By advantageously integrating a coil into a positioning
nerve or bone regeneration require other pathways leading to device therapeutic treatment can be provided to living tissue
differentiation during development and growth , and preven - and cells in an inconspicuous and convenient manner.
tion of apoptosis , as in response to injury or neurodegen - 45 Specifically , broad spectral density bursts of electromag
erative diseases. For these cases , early cAMP formation is netic waveforms, configured to achieve optimum signal
modulated by an EMF effect on AC via Ca/CaM binding. amplitude within a bandpass of a biological target, are
Another embodiment comprises known cellular responses selectively applied to affected tissue to treat DJD . Wave
to weak external stimuli such as heat, light, sound , ultra - formsmay be selected using the amplitude / power compari
sound and electromagnetic fields. For cells in homeostasis , 50 son with that of thermal noise in a target structure . Signals
i.e ., no injury, responses to such stimuli , if configured to may comprise bursts of at least one of sinusoidal, rectan
modulate CaM -dependent signaling can be the production of gular, chaotic and random wave shapes, have frequency
protective proteins, for example, heat shock proteins, which content in a range of 0 .01 Hz to 100 MHz at 1 to 100 , 000
enhance the ability of the cell , tissue, organ to withstand and bursts per second , have a burst duration from 0 .01 to 100
respond to external stimuli which further disrupt homeosta - 55 milliseconds, and a burst repetition rate from 0 .01 to 1000
sis . Electromagnetic fields configured according to one bursts / second . Peak signal amplitude at the target structure
embodiment modulate the release of such compounds by may fall in a range of 1 microvolt per centimeter ( uV /cm " )
modulating CaM -dependent NO signaling thus advanta to 100 mV /cm . Each signal burst envelope may be a random
geously providing an improved means to enhance prophy - function providing a means to accommodate different elec
lactic protection and wellness of living organisms from 60 tromagnetic characteristics of healing tissue . The signalmay
diseases such as DJD . comprise a 20 millisecond pulse burst, repeating at 1 to 10
The methods and devices described herein may relate to bursts/second and comprising 0 . 1 to 200 microsecond sym
therapeutically beneficial methods and apparatus for non metrical or asymmetrical pulses repeating at 10 -5 to 100
invasive pulsed electromagnetic treatment for enhanced kilohertz within the burst. The burst envelope can be modi
condition , repair and growth of living tissue in animals, 65 fied 1/ f function or any arbitrary function and can be applied
humans and plants . This beneficial method operates to at random repetition rates . Fixed repetition rates can also be
selectively change the bioelectromagnetic environment used between about 0.1 Hz and about 1000 Hz . An induced
US 10 , 226 ,640 B2
15 16
electric field from about 10 -8 mV /cm to about 100 mV/cm In some variations, the stimulation device is pre -pro
is generated . Another embodiment comprises a 4 millisec grammed (or configured to receive pre -programming ) to
ond burst of high frequency sinusoidal waves , such as 27 .12 execute the entire treatment regime ( including multiple
MHz, repeating at 1 to 100 bursts per second . An induced on -periods ( intra - treatment intervals ) punctuated by prede
electric field from about 10 - 8 mV/ cm to about 100 mV/ cm 5 termined off -periods (inter -treatment intervals ) when no
is generated . Resulting waveforms can be delivered via stimulation is applied .
inductive or capacitive coupling for 1 to 30 minutes treat- signal
As mentioned , in general, a generated electromagnetic
may be comprised of a burst of arbitrary waveforms
ment sessions delivered according to predefined regimes by having
which PEMF treatment may be applied for 1 to 50 daily 10 plurality atofleast one waveform parameter that includes a
sessions, repeated daily . The treatment regimens for any Hz to about 100 MHzcomponents
frequency
wherein
ranging from about 0 .01
the plurality of frequency
waveform configured according to an embodiment of the components satisfies a SNR or PSNR model in respect to an
devices and methods described herein may be fully auto ion binding pathway. A repetitive electromagnetic signal can
mated . The number of daily treatments may be programmed be generated , for example inductively or capacitively , from
to vary on a daily basis according to any predefined protocol. 15 the configured at least one waveform . The electromagnetic
Applying a burst of high frequency waveforms signifi signal may be coupled to the affected tissue structure so that
cantly reduces the power requirements to inductively couple a target pathway ( e.g ., molecular pathway of ions and ligand
a PEMF signal configured according to an embodiment of binding) is effected by the output of the coupling element
the devices and methods described herein . This is because ( such as an electrode or an inductor ) placed in close prox
the rate of change of the magnetic field (“ dB /dt” ) of a high 20 imity to the target structure . The coupling may modulate
frequency waveform is substantially greater than that of a binding of target ions and ligands to regulatory molecules,
low frequency waveform , allowing the required amplitude/ tissues, cells , and organs (e .g ., the activity of the Ca/CaM
power to be applied to target pathways in affected tissue with pathway and the production of NO ). In one variation , PEMF
significantly less power. In addition , a high frequency wave - signals configured using SNR or PSNR analysis match the
form can be more easily configured to modulate the target 25 bandpass of a second messenger, e . g ., Ca - + whereby the
pathway. Accordingly , the dual advantages , of selective PEMF signals can act as a first messenger to modulate
transmitted dosimetry to the relevant dielectric pathways biochemical cascades such as production or inhibition or up
and of decreased power requirement may be achieved . or down -regulation of cytokines, Nitric Oxide , Nitric Oxide
FIG . 1 is a flow diagram of a method for treating a subject Synthase and growth factors that are related to tissue growth
for DJD . Before beginning themethod of treatment, one or 30 and repair. A detectible E field amplitude is produced within
more (or a range of) waveforms may be determined that a frequency response of Ca2 + binding to CaM .
target the appropriate pathway (e.g ., the Ca /CaM pathway ) FIG . 2 illustrates an embodiment of an apparatus that may
in the target tissue . Method of determining appropriate be used . The apparatus is constructed to be self - contained ,
waveforms are described herein , and exemplary waveforms, lightweight, and portable . A miniature control circuit 201
as well as a range of values ( e . g ., on - time/off -time, fre - 35 may be heldwithin a (wearable ) housing and connected to a
quency, power, etc.) are provided herein for treatment of generating device such as an electrical coil 202 . The min
DID . iature control circuit 201 is constructed in a manner that
As described in FIG . 1 , a method of treating DJD may applies a mathematical model, the results of a mathematical
include the step of placing the tissue to be treated (one or model, or that otherwise incorporates the asymmetrical
more joints ) in contact with , or in proximity to , the PEMF 40 kinetics of ion binding to intracellular buffers to configure
device 101 . Thus, the PEMF device may be coupled to a electromagnetic waveforms to increase the rate of ion bind
target tissue ( e. g ., joint). Any appropriate PEMF device may ing and enhance the biochemical signaling pathways living
be used . In general, the PEMF device may be configured to systems employ for growth , repair and maintenance . The
apply electromagnetic energy of the appropriate power and configured waveforms may satisfy a SNR or a PSNR model,
waveform to selectively and specifically modulate the 45 or the asymmetrical kinetics of intracellular ion binding to a
Ca/CaM pathway, as described herein . The PEMF device buffer, so that for a given and known target pathway within
may include an applicator ( e .g ., an inductor applicator ) a joint (e . g ., the Ca/CaM pathway ), it is possible to choose
which may be placed adjacent to or in contact with the waveform parameters that satisfy a frequency response of
affected tissue, e. g ., joint. The PEMF device may also the target pathway within the target tissue and SNR or PSNR
include a signal conditioner /processor for forming the 50 of at least about 0 . 2 to modulate ion and /or ligand interac
appropriate waveform . The stimulator may include a timing tions whereby the ion and /or ligand interactions are detect
element (e.g., circuit, etc .) for controlling the timing auto - able in the target tissue pathway above baseline thermal
matically after the start of stimulation 103 . fluctuations in voltage , wherein SNR or PSNR is evaluated
In the example shown in FIG . 1, once stimulation is begun by calculating a frequency response of the impedance of the
103, the PEMF device typically applies an envelope of 55 target path structure divided by the RMS of baseline thermal
high - frequency waveforms at low ( e . g ., less than 50 milli - fluctuations in voltage across the target path structure . A
Gauss , less than 100 milliGauss , less than 200 milliGauss, mathematical model to induce a time-varying magnetic field
etc . ) amplitude . The envelope of high - frequency pulses is and a time -varying electric field in a target tissue ( e . g ., joint
then repeated at a particular frequency after an appropriate and surrounding affected tissue ) may be used to determine
delay ( e . g ., at 2 Hz, 1 Hz, etc .). This series ofbursts can be 60 the waveform (s ) that effect a specific molecular pathway
repeated for a first treatment time (e . g ., 5 minutes , 15 such as the Ca /CaM pathway ; for example a waveform may
minutes, 20 minutes, 30 minutes ) and then followed by a include about 0 .001 to about 100 msec bursts of about 1 to
delay during which the stimulation is “ off ” 107 . This waiting about 100 microsecond rectangular pulses, having a burst
interval (inter -treatment interval) may last for minutes or duration of about 0 .01 to 100 ,000 microseconds and repeat
hours (e .g ., 15 minutes, 2 hours, 4 hours, 8 hours , 12 hours, 65 ing at about 0 .1 to about 100 pulses per second. Peak
etc .), and then the stimulation interval can be repeated again amplitude of the induced electric field is between about 1
until the treatment regime is complete 109. uV /cm and about 100 mV/ cm , that can be constant or varied
US 10 ,226 ,640 B2
17 18
according to a mathematical function , for example a modi- described above in FIG . 2 . The miniature control circuit can
fied 1/ f function where f = frequency . A waveform configured be activated by any activation means such as an on /off
as described herein may be applied to a joint ( e.g ., knee, hip , switch 303. The miniature control circuit 300 has a power
elbow , shoulder, wrist, ankle, etc .), preferably for a total source 301 . Preferably the power source has an output
exposure time of under 1 minute to 240 minutes daily . 5 voltage of 3 . 3 V but other voltages can be used . In another
However other exposure times can be used . Waveforms embodiment, the power source can be an external power
configured by the miniature control circuit 201 are directed source such as an electric current outlet such as an AC /DC
to a generating device 202 such as electrical coils. Prefer - outlet, coupled to the device, for example by a plug and wire .
ably, the generating device 202 is a conformable coil for The micro - controller 302 uses an 8 bit 4 MHz micropro
example pliable, comprising one or more turns of electri - 10 cessor but other bit/MHz combination microprocessors may
cally conducting wire in a generally circular or oval shape be used . The micro -controller 302 also controls a pulse
however other shapes can be used . The generating device modulator 305 . The pulse modulator 305 determines pulse
202 delivers a pulsing magnetic field configured according shape, burst width , burst envelope shape , and burst repeti
to a mathematical model that can be used to provide treat- tion rate . In one embodiment, the pulse modulator 305
ment of DJD . The miniature control circuit may apply a 15 produces waveforms that are configured to be detectable
pulsing magnetic field for a prescribed time and can auto - above background electrical activity at a target structure
matically repeat applying the pulsing magnetic field for as (e.g ., at the target Ca/ CaM pathway in the target tissue ) by
many applications as are needed in a given time period , for satisfying a SNR and /or PSNR mathematical model. An
example 12 times a day. The miniature control circuit can be integral high frequency oscillator 304 , such as a sine wave
configured to be programmable applying pulsing magnetic 20 or arbitrary number generator, can also be incorporated to
fields for any time repetition sequence . In one variation , the provide specific waveforms. A radio frequency amplifier 306
devices described herein can be positioned to treat one or increases the amplitude of the modulated pulse prior to the
more joints by being incorporated with a positioning device output stage 307. The output stage 307 delivers the amplified
such as a bandage , a dressing, a vest, a brassiere , or an waveform to at least one coupling device such as an induc
anatomical support thereby making the unit self - contained . 25 tor. The micro - controller 302 can also control total exposure
Coupling a pulsing magnetic field to the target tissue may time of a single treatment. The miniature control circuit 300
reduce existing inflammation thereby reducing pain and can be constructed to be programmable and apply a pulsing
promoting healing in treatment areas. Coupling a pulsing electromagnetic field for a prescribed time and to automati
magnetic field to healthy target tissue may prevent inflam - cally repeat applying the pulsing electromagnetic field for as
mation and subsequent joint destruction by modulation of 30 many applications as are needed in a given time period , for
CaM -dependent HSP resease . When electrical coils are used example 10 times a day . Preferably treatments times of about
as the generating device 202, the electrical coils can be 1 minute to about 30 minutes are used .
powered with a time varying magnetic field that induces a Referring to FIG . 4 , one variation of a waveform 400 is
time varying electric field in a target joint according to illustrated . A high frequency sinusoid of amplitude 401 is
Faraday ' s law . An electromagnetic signal generated by the 35 repeated within a burst 402 that has a finite duration ,
generating device 202 can also be applied using electro - alternatively referred to as width . The duration 402 is such
chemical coupling , wherein electrodes are in direct contact that a duty cycle which can be defined as a ratio of burst
with skin or another outer electrically conductive boundary duration to signal period 403 is between about 1 to about
of joint. Yet in another embodiment, the electromagnetic 10 - 9 . A sinusoidal waveform having a frequency in the
signal generated by the generating device 202 can also be 40 1 - 100 MHz range may be utilized , but any waveform with
applied using electrostatic coupling wherein an air gap exists any fixed or variable duration and any fixed or variable
between a generating device 202 such as an electrode and modulation , or any arbitrary waveform may be employed .
the target tissue . An advantage of the devices described FIGS. 5A to 5D illustrate variations of the devices as
herein is that the ultra lightweight coils and miniaturized described herein for the treatment of DJD in which the
circuitry allow for use with common physical therapy treat- 45 devices can be stand -alone or incorporated into one or more
ment modalities , and at any location for which tissue garments, braces , orthotics , or the like. Asmentioned above ,
growth , pain relief, and tissue and organ healing is desired the devices ( or systems) may include an applicator, a signal
An advantageous result of application of the devices and generation component and a power component . These com
methods described herein is that tissue growth , repair, and ponents may be in a single , integrated unit, or they may be
maintenance can be accomplished and enhanced anywhere 50 may be modular or separate (in any sub - combinations ). The
and at anytime. Yet another advantageous result of applica - device of the various components may be embedded or
tion as described herein is that growth , repair , and mainte - integral with other products or elements .
nance of molecules, cells, tissues, and organs can be accom - For example , in the stand -alone PEMF device which
plished and enhanced anywhere and at anytime. Another delivers a signal configured according to an embodiment of
embodiment delivers PEMF to treat DJD , regardless of the 55 the devices and methods described herein , shown in FIG .
actual mechanism of action . 5A , an applicator 501 and signal generation unit and power
The electrical coil may be referred to as a coil applicator, components are shown. A patient may place this unit in
a flexible coil, a coil wire applicator, or the like. In some proximity to the affected tissue, e . g ., knee joint, and manu
variation , the coil is a wire applicator that has a diameter ally start the treatment regime. This is the device utilized in
(When circular ) of approximately 6 inches , 7 inches , 8 60 the clinical study of Example 4 . In FIG . 5B , the applicator
inches , etc . In general, the size of the coil may be fixed , and portion 503 is attached to the brace to apply the PEMF signal
the control circuit may be matched to the material and size to the affected tissue, while the other elements (e .g., the
of the applicator to provide the desired stimulation . signal generation and power components ) are shown housed
FIG . 3 depicts a block diagram of an embodiment of the within a removable and replaceable activation unit 513 ,
devices described herein , comprising a miniature control 65 connected by a wire (not visible ). In another example shown
circuit 300 . The miniature control circuit 300 produces in FIG . 5C , an integrated applicator can be adapter to fit
waveforms that drive a generating device such as wire coils directly on the affected area of the body and be used as a
US 10 ,226 ,640 B2
20
stand -alone unit, as needed . This example includes an appli FIG . 9 is a plot describing the results of a randomized
cator 507 and a separate activation unit 505 , and is config - double -blind clinical study on the effect of a PEMF signal,
ured to be part of a hip brace . Similarly , FIG . 5D illustrates configured to modulate CaM -dependent NO signaling as
a variation configure to be part of a belt or girdle structure described herein , significantly reduced pain from osteoar
which also includes an applicator 509 and may include a 5 thritis of the knee . Patients in this study received the stand
separate activation unit 511 . In the hip , the brace could have alone portable PEMF device shown in FIG . 5A , which
the same independent, modular components , and in the back delivered a 7 msec burst of 6 . 8 MHz sinusoidal waves
as well . repeating at 1/ sec with 0 .05 G peak amplitude, to the
Other potential forms include full modular systems in affected knee for 15 minutes twice daily , or as needed for
ely 10 pain relief. The results show PEMF caused a significant
which a " family ” of braces embeds (visibly or completely
integrated ) applicator and specific system components and decrease in mean maximum pain , measured using a visual
analogue scale, VAS , to approximately 45 % of mean start
the signal generator is completely interchangeable with all VAS for the treated group by the end of day 1 , which
the anatomical applicators.
FIG . 6 is a plot describing the experimental results of the 15 gradually fell to 55 % of mean start VAS (P < 0 .001). In
contrast, there was no significant decrease in mean maxi
study given in EXAMPLE 1. A pulse modulated radio mum VAS vs mean start VAS at any time point in the sham
frequency signal, configured to modulate CaM - dependent group (P = 0 .555 ). There was no significant difference in
enzyme kinetics as described herein , accelerated myosin mean start VAS between the active and sham groups (Ac
phosphorylation as a function of burst duration . The SNR tive = 7 + 0 .31, Sham = 7 . 1 + 0 .34 , P = 0 . 903 ). It is believed these
and PSNR mathematical models predicted that significant 20 clinical results were obtained because the PEMF signal was
increases in phosphorylation would be observed for burst able to be configured to modulate CaM -dependent signaling
durations of between 1 and 5 milliseconds at an amplitude according to an embodiment of the devices and methods
of 50 mg . The plot shows that maximum acceleration of described herein .
phosphorylation occurred at about 4 msec , with statistically It is further intended that any other embodiments of the
significant increases starting at about 1 msec . 25 devices and methods described herein that result from any
FIG . 7 is a plot describing the experimental results of the changes in application or method of use or operation ,
study given in EXAMPLE 2 . A pulse modulated radio method of manufacture , shape, size or material which are
frequency signal, configured to modulate CaM - dependent not specified within the detailed written description or
NO signaling as described herein , was applied to a cutane -
illustrations and drawings contained herein , yet are consid
ous wound healing model in the rat. The effect of burst 30 ered apparent or obvious to one skilled in the art, are within
duration was examined . The SNR and PSNR mathematical the scope of the present invention .
models predicted that significant acceleration of wound
repair as measured by maximum tensile strength for burst Example 1
durations of between 1 and 5 milliseconds at an amplitude
of 50 mg , with no significant increases at smaller burst 35 The teachings for EMF signal configuration in the present
durations . The results, which are given in termsof PSNR (in invention have been tested experimentally on CaM - depen
units of specific absorption , SA ), show that healing is a dent myosin phosphorylation in a standard enzyme assay .
linear function of burst duration , with statistical significance The cell - free reaction mixture was chosen for phosphory
starting at about 1 msec , in accord with the devices and lation rate to be linear in time for several minutes , and for
methods described herein . 40 sub - saturation free Ca2 + concentration . This opens the bio
FIGS . 8A - 8B are bar graphs describing the experimental logical window for Ca /CaM to be EMF- sensitive . This
results of the study given in EXAMPLE 3 . A PEMF signal, system is not responsive to PEMF if Ca is at saturation levels
configured to modulate CaM -dependent NO signaling as with respect to CaM , and reaction is not slowed to a minute
described above, was applied to human cartilage cells in time range. Experiments were performed usingmyosin light
culture dishes to accelerate proliferation . After one 30 min - 45 chain (“MLC ” ) and myosin light chain kinase (“ MLCK " )
utes PEMF treatment FIG . 8A shows that cGMP production isolated from turkey gizzard . A reaction mixture consisted of
was significantly increased at 30 minutes vs control cultures. a basic solution containing 40 mM Hepes buffer, pH 7 . 0 ; 0 . 5
This experiment incorporated the use of W -7 , a CaM antago - mM magnesium acetate ; 1 mg/ml bovine serum albumin ,
nist which blocks activated CaM from binding to and 0 . 1 % ( w / v ) Tween80 ; and 1 mM EGTA12 . Free Ca2+ was
activating CNOS , and thereby annihilated the effect of PEMF 50 varied in the 1 -7 uM range . Once Ca2 + buffering was
on cGMP by preventing its effect on NO release . This established , freshly prepared 70 nM CaM , 160 nM MLC and
experiment also incorporated the use of L -NAME a general 2 nM MLCK were added to the basic solution to form a final
CNOS inhibitor which also annihilated the effect of PEMF reaction mixture. The low MLC /MLCK ratio allowed linear
on cGMP release . These results indicate that this waveform , time behavior in the minute time range . This provided
configured according to an embodiment of the devices and 55 reproducible enzyme activities and minimized pipetting
methods described herein , modulates CaM -dependent NO time errors.
signaling, as measured by cGMP release . The reaction mixture was freshly prepared daily for each
FIG . 8B shows that cartilage cells receiving one 30 series of experiments and was aliquoted in 1004 portions
minute treatment with a signal configured to modulate into 1. 5 mlEppendorf tubes . All Eppendorf tubes containing
CaM -dependent NO signaling produced a significant 60 reaction mixture were kept at 0° C . then transferred to a
increase in DNA synthesis vs control cultures . Use of the specially designed water bath maintained at 37 + 0 . 1° C . by
NOS inhibitor, L -NAME and the soluble guyanylyl cyclase constant perfusion of water prewarmed by passage through
inhibitor , LY83583 , annihilated the PEMF effect on DNA a Fisher Scientific model 900 heat exchanger. Temperature
synthesis. These results indicate that this waveform , config - was monitored with a thermistor probe such as a Cole
ured according to an embodiment of the devices and meth - 65 Parmer model 8110 - 20 , immersed in one Eppendorf tube
ods described herein , modulates CaM -dependent NO sig - during all experiments. Reaction was initiated with 2 .5 uM
naling for DNA synthesis. 32P ATP , and was stopped with Laemmli Sample Buffer
US 10 ,226 ,640 B2
21 22
solution containing 30 uM EDTA . A minimum of five blank determined by taking the average of the maximum load in
samples were counted in each experiment. Blanks com - kilograms per mm ' of the two strips from the same wound .
prised a total assay mixture minus one of the active com The results showed average ratio of treated /sham tensile
ponents Ca2 +, CaM ,MLC or MLCK . Experiments for which strength was linearly dependent upon burst duration . PSNR
blank counts were higher than 300 cpm were rejected . 5 analysis , a priori, predicted that the tensile strength of
Phosphorylation was allowed to proceed for 5 minitures and treated wounds would be significantly higher in the PEMF
was evaluated by counting 32P incorporated in MLC using treated wounds only for burst durations of 1 msec and above.
a TM Analytic model 5303 Mark V liquid scintillation The results are given in FIG . 7 , wherein the data is plotted
counter. using a PSNR analysis. Thus SA is specific absorption of
The signal comprised repetitive bursts of a high frequency 10 PEMF signal energy in the Ca/CaM pathway. These results
waveform . Amplitude was maintained constant at 0 .05 G further confirm that a bioeffective signalmay be configured
and repetition rate was 1 burst/ sec for all exposures. Burst on the basis of SNR or PSNR in the CaM - dependent NO
duration varied from 65 usec to 5000 usec based upon devices signaling pathway according to an embodiment of the
projections of SNR and PSNR analyses which predicted that 15 and methods described herein .
optimal SNR and PSNR would be achieved as burst duration Example 3
approached 1 -2 msec. The results are shown in FIG . 6
wherein burst width 601 in msec is plotted on the x -axis and This example illustrates the effects of a PEMF signal
Myosin Phosphorylation 602 as treated /sham is plotted on configured to modulate CaM -dependent NO signaling in a
the y - axis. It can be seen that the PEMF effect on Ca - + 20 culture of articular cartilage cells. A PEMF signal having a
binding to CaM approaches its maximum at approximately 5 msec burst of asymmetrical rectangular waves, applied for
3 msec , in excellent agreement with the predictions of the 30 minutes increased DNA synthesis in articular chondro
SNR and PSNR model. cytes by 150 % over 72 hours. That PEMF acted as a first
These results confirm that a PEMF signal, configured a messenger to modulate CaM - dependent NO / cGMP signal
priori as described above , would maximally increase myosin 25 ing was confirmed by systematically using a CaM antagonist
phosphorylation for burst durations sufficient to achieve ( W -7 ) to inhibit CaM activation of NOS. Further support
optimal SNR and PSNR for a given magnetic field ampli was obtained when L - nitrosoarginine methyester
tude . ( L -NAME ), a cNOS inhibitor, and LY83583 a SGC inhibitor,
to prevent the formation of GMP, inhibited the increase in
Example 2 30 DNA . When either the CaM antagonist, or the NO , or the
SGC inhibitor, was present during PEMF exposure, each one
According to one variation , the teachings of the present individually eliminated the PEMF effect on DNA synthesis
invention in respect to CaM - dependent signaling allowed a at 72 hours . These results provide direct support that PEMF
priori configuration of PEMF signals to modulate cutaneous acted as a first messenger to modulate CaM -dependent
wound repair . A rat wound model has been well character- 35 NO / CGMP signaling when the signalwas configured accord
ized both biomechanically and biochemically , and was used ing to an embodiment of the devices and methods described
in this study to examine the effect of modeled waveforms. herein . A summary of these results showing abolition of the
Healthy, young adult male Sprague Dawley rats weighing PEMF effect on cGMP at 15 minutes by W -7 and L -NAME
approximately 300 grams were utilized . is shown in FIG . 8A , and on DNA content at 72 hours by
The animals were anesthetized with an intraperitoneal 40 L -NAME and LY83583 in FIG . 8B .
dose of Ketamine 75 mg/kg and Medetomidine 0 .5 mg/kg .
After adequate anesthesia had been achieved , the dorsum Example 4
was shaved , prepped with a dilute betadine/alcohol solution ,
and draped using sterile technique. Using a # 10 scalpel, an This example illustrates the clinical effect of a PEMF
8 -cm linear incision was performed through the skin down 45 signal, configured according to an embodiment of the
to the fascia on the dorsum of each rat. The wound edges devices and methods described herein to modulate CaM
were bluntly dissected to break any remaining dermal fibers , dependent NO signaling, in a clinical study on pain from
leaving an open wound approximately 4 cm in diameter. knee OA . This was a double - blind , randomized , placebo
Hemostasis was obtained with applied pressure to avoid any controlled study of a total of 37 patients ( 19 active , 18
damage to the skin edges. The skin edges were then closed 50 sham ). Patient selection required an initialmax visual ana
with a 4 - 0 Ethilon running suture. Post -operatively , the logue scale (“ VAS ” ) score > 4 , at least 2 hours of standing
animals received Buprenorphine 0 .1 - 0 .5 mg/kg, intraperito activity in a physical occupation , and no recent interventions
neal. They were placed in individual cages and received such as cortisone injections or surgery . A PEMF signal,
food and water ad libitum . configured , a priori, to modulate Ca2+ binding to CaM , and
PEMF exposure comprised pulsed radio frequency wave - 55 consisting of a 7 msec burst of 6 . 8 MHz sinusoidal waves
forms comprising a 100 usec to 3 msec burst of 27 . 12 MHz repeating at 1/ sec with 0 .05 G peak amplitude , in a portable
sinusoidal waves at 50 m amplitude and repeating at 2 battery operated device ( see FIG . 5A ) was used for 15
bursts /sec. PEMF was applied for 30 minutes twice daily . minutes twice daily, or as needed for pain relief. The device
Tensile strength was performed immediately after wound was lightweight and patients could easily position the coil
excision . Two 1 cm width strips of skin were transected 60 directly over the knee , even over clothing. Minimum and
perpendicular to the scar from each sample and used to maximum VAS scores were obtained at baseline (day 0 ) and
measure the tensile strength in kg/mm². The strips were daily for the first 14 days and from day 29 to day 42 . All
excised from the same area in each rat to assure consistency patients received PEMF treatment to day 14 . Thereafter, 31
of measurement. The strips were then mounted on a tensi- ( 16 active , 15 sham ) at day 35 , and 28 ( 16 active, 12 sham )
ometer. The strips were loaded at 10 mm /min and the 65 at day 42, were available for analysis . The devices were well
maximum force generated before the wound pulled apart tolerated and no adverse events were reported . The results
was recorded . The final tensile strength for comparison was show PEMF caused a significant decrease in mean maxi
US 10 , 226 ,640 B2
23 24
mum VAS to approximately 45 % of mean start VAS for the 4 . The system of claim 1, wherein the orthotic is a knee
treated group by the end of day 1, which gradually fell to brace .
55 % of mean start VAS (P < 0 .001). In contrast, there was no 5 . The system of claim 1, wherein the orthotic is a back
significant decrease in mean maximum VAS vs mean start brace .
VAS at any time point in the sham group (P = 0 . 555 ). There 5 6 . The system of claim 1 , wherein the orthotic is a hip
was no significant difference in mean start VAS between the brace .
active and sham groups (Active = 7 + 0 .31, Sham = 7 . 1 + 0 .34 , 7 . The system of claim 1, wherein the applicator is
P = 0 . 903) . These results are summarized in FIG . 9 . Com removably coupled to the orthotic .
pared to known treatments for OA , this treatment interven 8 . The system of claim 1, wherein the microcontroller is
tion was effective even on a patient population that did not 10 configured
have end stage disease and had to be on their feet at least two a treatmenttoonapply an automatic treatment regimen having
- time of between 5 minutes and 30 minutes ,
hours a day ; in addition , the PEMF treatment time was short followed by a treatment off - time that is greater than 30
( e. g ., 15 minutes ), and use did not interfere with work or
off-work activities . It has been proposed that CaM -depen minutes.
dent NO release can orchestrate OA pain relief by increasing 15 9 . The system of claim 1 , wherein the microcontroller is
circulation, decreasing nerve irritation , and decreasing configured to apply an automatic treatment regimen having
inflammation . The rapid onset response in the active group a treatment on -time of between 15 minutes and 30 minutes,
is remarkably similar to that reported for a similar PEMF followed by a treatment off-time that is greater than 30
signalwhich produced a 3 -fold reduction in pain from breast minutes .
reduction surgery within 5 hours post -op (Rohde et al., 20 10 . The system of claim 1 , wherein the microcontroller is
Plastic Reconst Surg . 2009). That study also showed IL - 12 , configured to drive the applicator to deliver bursts of 6 .8
a master inflammatory cytokine, was also reduced by 3 -fold MHz sinusoidal electromagnetic waves having a peak
in the wound bed by PEMF within the same post-op time. amplitude of 50 milliGauss , wherein the duration of the
This supports a mechanism of action of PEMF in this study burst is about 7 msec , and bursts repeat every second .
that is anti- inflammatory, caused by a PEMF signal chosen 25 11. The system of claim 1, wherein the microcontroller is
a priori, according to the devices and methods described configured to drive the applicator to deliver bursts of 27 . 12
herein , to modulate the CaM / constitutive nitric oxide syn - MHz sinusoidal electromagnetic waves having a peak
thase ( CNOS) pathway which produces an initial rapid and amplitude of 50 milliGauss .
transientrelease of NO leading to vaso and lymph dilatation . 12 . A lightweight, wearable, battery -operated electromag
This could cause a rapid reduction of effusion ( edema) with 30 peti
netic field therapy system for treating degenerative joint
the concomitant rapid reduction of pain observed here . It
may also be an effect that the mechanism of PEMF effect disease a
, the system comprising:
flexible coil wire applicator ;
involved the down -regulation of IL - 1ß , with its consequent a battery - operated electromagnetic field therapy micro
effect on inflammation , in this patient population . controller contained within a lightweight, wearable
While the devices, apparatus and method have been 35
described herein in terms of what are presently considered to housing and configured to drive the applicator to
be the most practical and preferred embodiments , it is to be deliver bursts of electromagnetic waves having a peak
understood that the disclosure need not be limited to the amplitude within a range of between 50 and 200
disclosed embodiments . This disclosure is intended to cover milliGauss , wherein the bursts have a duration of
various modifications and similar arrangements included 40 between 0 .5 msec and 50 msec , further wherein the
within the spirit and scope of the disclosure , encompassing bursts are repeated at an interburst interval of between
modifications and similar structures . about 2 seconds and 0 . 1 second for a treatment on - time,
followed by a treatment off-time that is in a range of
What is claimed is : between 30 minutes and 12 hours ;
1 . A lightweight, wearable, battery -operated electromag - 45 timing circuitry in the microcontroller wherein the timing
netic field therapy system for treating degenerative joint circuitry is configured to automatically repeat delivery
disease, the system comprising: of the electromagnetic waves and periods of off-time;
a battery - operated electromagnetic field therapy micro and
controller within a lightweight, wearable housing; an orthotic configured to secure the applicator over a body
a flexible coil wire applicator coupled to the microcon - 50 joint.
troller; and
an orthotic configured to secure the applicator over a body n The into
13 .
iintegrated system of claim 12 , wherein the applicator is
the orthotic .
joint; 14 . The system of claim 12 , wherein the applicator is
wherein the microcontroller is configured to drive the - embedded within a skin - contacting portion of the orthotic .
applicator to deliver bursts of electromagnetic waves 55
having a peak amplitude within a range of between 50 15 . The system of claim 12 ,wherein the orthotic is a knee
and 200 milliGauss , wherein the bursts have a duration brace .
of between 0 .5 msec and 50 msec . further wherein the 16 . The system of claim 12 , wherein the orthotic is a back
bursts are repeated at an interburst interval of between brace .
10 seconds and 0 . 1 second for a treatment on - time of 60 17 . The system of claim 12 , wherein the orthotic is a hip
between 5 minutes and 30 minutes, followed by a brace.
treatment off-timeWarethat is in a range of between 30 18 . The system of claim 12 , wherein the applicator is
minutes and 12 hours . removably coupled to the orthotic .
2 . The system of claim 1 , wherein the applicator is 19 . The system of claim 12 , wherein the microcontroller
integrated into the orthotic . 65 is configured to drive the applicator to deliver bursts of 6 .8
3 . The system of claim 1 , wherein the applicator is MHz sinusoidal electromagnetic waves having a peak
embedded within a skin -contacting portion of the orthotic . amplitude of 50 milliGauss.
US 10 ,226 ,640 B2
25 26
20 . The system of claim 12 , wherein the microcontroller
is configured to drive the applicator to deliver bursts of 27. 2
MHz sinusoidal electromagnetic waves having a peak
amplitude of 50 milliGauss .
21 . A lightweight, wearable , battery -operated electromag
netic field therapy system for treating degenerative joint
disease , the system comprising:
a flexible coil wire applicator;
a battery - operated electromagnetic field therapy micro
controller contained within a lightweight, wearable 10
housing and configured to drive the applicator to
deliver bursts of electromagnetic waves having a peak
amplitude within a range of between 50 and 200
milliGauss, wherein the bursts have a duration of
between 0 . 5 msec and 50 msec, further wherein the 15
bursts are repeated at an interburst interval of between
2 seconds and 0 . 1 second for a treatment on -time,
followed by a treatment off-time that is in a range of
between 30 minutes and 12 hours ;
timing circuitry in the microcontroller wherein the timing 20
circuitry is configured to automatically repeat delivery
of the electromagnetic waves and periods of off - time;
and
a housing surrounding the microcontroller that is config
ured to be coupled to an orthotic . 25

United States Patent: (45) Date of Patent: Mar - 12, 2019

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United States Patent: (45) Date of Patent: Mar - 12, 2019

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US010226640B2

(12) United States Patent (10) Patent No.: US 10 ,226 ,640 B2

Related U . S . Application Data 5 ,792 , 209 A

( 56 ) References Cited Bassett , C . A ., Biological significance of piezoelectricity . Calc . Tiss .

Place PEMF device in

Begin treatment regime

Apply burst of high frequency

Wait (no stimulation during

27 .12 MHZ, 1 Burst/sec , 0 .05 G

Burst Duration (msec )

Rat CutaneousWound Repair

27 . 12 MHz, 2 Bursts /sec , 0 .05 G

PEMF PEMF PEMF PEMF

PEMF PEMF PEMF PEMF

PEMF Effect on Early Knee OA Pain

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