Patent Application
20200044318
This application may be related to any of the following patent applications, each of which is herein incorporated by reference in its entirety:
All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
This invention pertains generally to a method and apparatus for therapeutic and prophylactic treatment of animal and human molecules, cells, tissues, organs, portions of entire organisms and entire organisms. In particular, an embodiment according to the present invention pertains to use of time-varying electromagnetic fields to accelerate the asymmetrical kinetics of the binding of intracellular ions to their respective buffers which, in turn, activates the enzymes involved in the biochemical signaling pathways living systems employ for growth, repair and maintenance. Another embodiment according to the present invention pertains to application of sinusoidal, rectangular, chaotic or arbitrary waveform electromagnetic signals, having frequency components below about 1000 GHz, configured to accelerate the binding of intracellular Ca2+ to a buffer, such as calmodulin (hereinafter known as CaM), to enhance biochemical signaling pathways in target structures such as plant, animal and human molecules, cells, tissues, organs, portions of entire organisms and entire organisms. Signals configured according to embodiments of the present invention produce a net increase in a bound ion, such as Ca2+ at the binding sites of an intracellular buffer, such as CaM, because the asymmetrical kinetics of such binding allows such signals to cause the excess voltage induced at the ion binding site to accumulate, thereby accelerating voltage-dependent ion binding. A particular embodiment according to the present invention pertains to the non-thermal application of the repetitive pulse bursts of the native electromagnetic field signal from mobile communications devices (including PDAs, cell phones, mobile phones, etc.) to instantaneously accelerate ion-buffer binding in biochemical signaling pathways in structures such as molecules, cells, tissues, organs of animals or humans. Another particular embodiment according to the present invention is application of specific therapeutic electromagnetic fields by a modification of the circuitry of mobile communications devices (including PDAs, cell phones, mobile phones, etc.) to instantaneously accelerate ion-buffer binding in biochemical signaling pathways in structures such as molecules, cells, tissues, organs of animals or humans.
The application of weak non-thermal electromagnetic fields (“EMF”) can result in physiologically meaningful in vivo and in vitro bioeffects. Time-varying electromagnetic fields, comprising rectangular waveforms such as pulsing electromagnetic fields (“PEMF”), and sinusoidal waveforms such as pulsed radio frequency fields (“PRF”) ranging from several Hertz to an about 15 to an about 40 MHz range, are clinically beneficial when used as an adjunctive therapy for a variety of musculoskeletal injuries and conditions.
Beginning in the 1960's, development of modern therapeutic and prophylactic devices was stimulated by clinical problems associated with non-union and delayed union bone fractures. Early work showed that an electrical pathway can be a means through which bone adaptively responds to mechanical input. Early therapeutic devices used implanted and semi-invasive electrodes delivering direct current (“DC”) to a fracture site. Non-invasive technologies were subsequently developed using electrical and electromagnetic fields. These modalities were originally created to provide a non-invasive “no-touch” means of inducing an electrical/mechanical waveform at a cell/tissue level. Clinical applications of these technologies in orthopaedics have led to approved applications by regulatory bodies worldwide for treatment of fractures such as non-unions and fresh fractures, as well as spine fusion. Presently several EMF devices constitute the standard armamentarium of orthopaedic clinical practice for treatment of certain fresh and difficult to heal fractures. The success rate for these devices has been very high. The database for this indication is large enough to enable its recommended use as a safe, non-surgical, non-invasive alternative to a first bone graft for a delayed union fracture. Additional clinical indications for these original PEMF technologies have been reported in double blind studies for treatment of avascular necrosis, tendinitis, osteoarthritis, wound repair, blood circulation and pain from arthritis as well as other musculoskeletal injuries.
Cellular studies have addressed effects of weak electromagnetic fields on both signal transduction pathways and growth factor synthesis. It has been shown that EMF enhances the production of cytokines and growth factors after a short, trigger-like duration, lon/ligand binding processes at intracellular buffers attached to the cell membrane are generally accepted as an initial EMF target pathway structure. The clinical relevance to treatments for example of bone repair, is enhanced growth factor production staged within the normal biochemical cascades which regulate bone repair. Cellular level studies have shown effects on calcium ion transport, cell proliferation, Insulin Growth Factor (“IGF-II”) release, IGF-II and Adenosine receptor expression in osteoblasts. Effects on Insulin Growth Factor-I (“IGF-I”), IGF-II and Adenosine receptors have also been demonstrated in rat fracture callus. Stimulation of transforming growth factor beta (“TGF-β”) messenger RNA (“mRNA”) with PEMF in a bone induction model in a rat has been shown. Studies have also demonstrated upregulation of TGF-β mRNA by PEMF in human osteoblast-like cell line designated MG-63, wherein there were increases in TGF-β1, collagen, and osteocalcin synthesis. PEMF stimulated an increase in TGF-β1 in both hypertrophic and atrophic cells from human non-union tissue. Further studies demonstrated an increase in both TGF-β1 mRNA and protein in osteoblast cultures resulting from a direct effect of EMF on a calcium/calmodulin-dependent signaling pathway. Cartilage cell studies have shown similar increases in TGF-β1 mRNA and protein synthesis from EMF, demonstrating a therapeutic application to joint repair. U.S. Pat. No. 4,315,503 (1982) to Ryaby, U.S. Pat. No. 7,468,264 (2008) to Brighton and U.S. Pat. No. 5,723,001 (1998) and above referenced U.S. Pat. No. 7,744,524 (2010), both to Pilla, typify the research conducted in this field.
However, prior art in this field typically involves large, expensive, and difficult to use and control applicators. Such devices may apply unnecessarily high amplitude and power to a target pathway structure, require unnecessarily long treatment time, and are not portable or disposable. Thus, there is a need for an apparatus and a method that more effectively modulates biochemical processes that regulate tissue growth and repair, shortens treatment times, and incorporates miniaturized circuitry and light-weight applicators, thus allowing the apparatus to be portable, easy to use, and if desired disposable.
The invention(s) described herein proposes modification of the circuitry of a PDA to apply its native RF communication signals for prophylactic and therapeutic purposes. Therefore, the use of a cellular or smart phone or tablet to apply therapeutic and/or protective EMF/PEMF may provide an opportunity to make a completely portable EMF/PEMF device available to address these shortcomings, and may also provide additional advantages as noted below.
The present invention relates to mobile (e.g., hand-held) communications devices (e.g. cell phones, PDAs, iPads, iphones, smart phones, laptops, etc.) that are configured or adapted for the application of therapeutic electromagnetic signals to treat a patient, including the application of therapeutic pulsed electromagnetic fields (PEMF). Also described are software, firmware, and hardware to adapt a pre-existing mobile communications device (which may be referred to generically as “smart phones”) for the application of therapeutic EMF and/or PEMF. For example, described herein are applications that may be configured to run on a smartphone to apply EMF to a subject. In some variations an applicator (e.g., EMF/PEMF antenna) may be connected to the phone for the application of EMF/PEMF. The antenna may be a loop, and may include a connector (e.g., USB or other smart-phone compatible connector) that may be driven or controlled by the application software/firmware on the smartphone. In some variations the pre-existing RF signal and antenna of the smartphone may be adapted for the application of therapeutic EMF/PEMF.
In one embodiment, a combination electromagnetic treatment apparatus and wireless communication device used for treatment of animals and humans is provided having at least one waveform parameter that includes at least one of a frequency component parameter that configures said at least one waveform to repeat between about 0.01 Hz and about 100 MHz according to a mathematical function, a burst amplitude envelope parameter that follows a mathematically defined amplitude function, a burst width parameter that varies at each repetition according to a mathematically defined width function, a peak induced electric field parameter varying between about 1 μV/cm and about 100 mV/cm in said target pathway structure according to a mathematically defined function, and a peak induced magnetic electric field parameter varying between about 1 μT and about 0.1 T in said target pathway structure according to a mathematically defined function.
In general, the applicator may include a user interface, including instructions to the user/patient, controls (e.g., start/stop, power/intensity level settings, timer settings, mode settings, etc.) for setting or controlling the application of the therapeutic EMF, logging (for recording the sessions of use and information about the session, etc.). The application may also include control logic for controlling the application of EMF/PEMF to the subject using an applicator and/or the existing antenna loop present in the smartphone. The applicator may also include display logic for displaying one or more indicators that the energy (EMF/PEMF) is being applied, and/or one or more timers indicating the timing of the application or the time to the next application. In some variations the application may be software but may also include additional hardware that may be integrated with the device (e.g., within the smartphone housing) or it may be external and may plug into the smartphone (via one or more ports on the smartphone).
Basal levels of certain intracellular ions are tightly maintained by a number of physiological calcium buffers. It is generally accepted that transient elevations in cytosolic, e.g., Ca2+ from external stimuli as simple as changes in temperature and mechanical forces, or as complex as mechanical disruption of tissue, rapidly activate CaM, which equally rapidly activates the cNOS enzymes, i.e., endothelial and neuronal NOS, or eNOS and nNOS, respectively. Studies have shown that both isoforms are inactive at basal intracellular levels of Ca2+, however, their activity increases with elevated Ca2+. Thus, nNOS and eNOS are regulated by changes in intracellular Ca2+ concentrations within the physiological range. In contrast, a third, inducible isoform of NOS (iNOS), which is upregulated during inflammation by macrophages and/or neutrophils, contains CaM that is tightly bound, even at low resting levels of cytosolic Ca2+, and is not sensitive to intracellular Ca2+.
Once cNOS is activated by CaM it converts its substrate, L-arginine, to citrulline, releasing one molecule of NO. As a gaseous free radical with a half-life of about 5 sec, NO diffuses locally through membranes and organelles and acts on molecular targets at a distance up to about 200 μm. The low transient concentrations of NO from cNOS can activate soluble guanylyl cyclase (sGC), which catalyzes the synthesis of cyclic guanosine monophosphate (cGMP). The CaM/NO/cGMP signaling pathway is a rapid response cascade which can modulate peripheral and cardiac blood flow in response to normal physiologic demands, as well as to inflammation. This same pathway also modulates the release of cytokines, such as interleukin-1beta (IL-1β) and growth factors such as basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) which have pleiotropic effects on cells involved in tissue repair and maintenance.
Following an injury, e.g., a bone fracture, torn rotator cuff, sprain, strain or surgical incision, repair commences with an inflammatory stage during which the pro-inflammatory cytokine IL-1β is rapidly released. This, in turn, up-regulates iNOS, resulting in the production of large amounts of NO in the wound bed. Continued exposure to NO leads to the induction of cyclooxygenase-2 and increased synthesis of prostaglandins which also play a role in the inflammatory phase. While this process is a natural component of healing, when protracted, it can lead to increased pain and delayed or abnormal healing. In contrast, CaM/eNOS/NO signaling has been shown to attenuate levels of IL-1β and down-regulate iNOS. As tissue further responds to injury, the CaM/NO/cGMP cascade is activated in endothelial cells to stimulate angiogenesis, without which new tissue growth cannot be sustained.
One EMF transduction pathway relevant to tissue maintenance, repair and regeneration, begins with voltage-dependent Ca2+ binding to CaM. Ca/CaM binding produces activated CaM which binds to, and activates, cNOS, which catalyzes the synthesis of the signaling molecule NO from L-arginine. This pathway is shown in its simplest schematic form in
The substantial asymmetry of Ca/CaM binding kinetics provides a unique opportunity for the communication signals from smartphones to selectively modulate kon. In general, if kon>>koff, and kon is voltage-dependent, according to the present invention, ion binding could be increased with an exogenous bipolar electric field signal having a carrier period or pulse duration that is significantly shorter than the mean lifetime of the bound ion. This applies to the CaM signaling pathway, causing it to exhibit rectifier-like properties, i.e., to yield a net increase in the population of bound Ca2+ because the forward (binding) reaction is favored. The change in surface concentration, ΔΓ, of Ca2+ at CaM is equal to the net increase in the number of ions that exit the outer Helmholtz plane, penetrate the water dipole layer at the aqueous interface of the binding site, and become bound in the inner Helmoltz plane. For the general case of ion binding, evaluation of Ca/CaM binding impedance, ZA(s), allows calculation of the efficacy of any given waveform in that pathway by evaluating the frequency range over which the forward binding reaction can be accelerated. Thus, binding current, IA(t), is proportional to the change in surface charge (bound ion concentration) via dq(t)/dt, or, in the frequency domain, via sqA(s). IA(s) is, thus, given by:
I
A(s)=sqA(s)=sΓof(ΔΓ(s)) (1)
where s is the real-valued frequency variable of the Laplace transform. Taking the first term of the Taylor expansion of equation 1 gives:
I
A(s)=qΓsΓoΔΓ(s) (2)
where qΓ=∂q/∂Γ, a coefficient representing the dependence of surface charge on bound ion concentration. ΔΓ(s) is a function of the applied voltage waveform, E(s), and, referring to the reaction scheme in
ΔΓ(s)=kon/Γos[−ΔΓ(s)+aE(s)+ΔΦ(s)] (3)
where Γo is the initial surface concentration of Ca2+(homeostasis), and a=∂Γ/∂E, representing the voltage dependence of Ca2+ binding. Referring to the reaction scheme in
ΔΦ(s)=υΦ/Φos[−ΔΦ(s)−ΔΓ(s)] (4)
where υΦ is the rate constant for Ca/CaM binding to eNOS and Φo is the initial concentration of eNOS* (homeostasis).
Using equations 2, 3 and 4, and for kon>>υΦ, ZA(s) may be written:
Equation (5) describes the overall frequency response of the first binding step in a multistep ion binding process at an electrified interface, wherein the second step requires that the bound ion remain bound for a period of time significantly longer than the initial binding step. For this case, the first ion binding step is represented by an equivalent electrical impedance which is functionally equivalent to that of a series RA-CA electric circuit, embedded in the overall dielectric properties of the target. RA is inversely proportional to the binding rate constant (kon), and CA is directly proportional to bound ion concentration.
The present invention teaches that a bipolar electromagnetic field, for which pulse duration or carrier period is less than about half of the bound ion lifetime can be configured to maximize current flow into the capacitance CA, which will increase the voltage, Eb(s), where s is the Laplace frequency, across CA. Eb(s) is a measure of the increase in the surface concentration of the binding ion in the binding sites of the buffer, above that which occurs naturally in response to a given physiological state. The result is an increase in the rate of biochemical signaling in plant, animal and human repair, growth and maintenance pathways which results in the acceleration of the normal physiological response to chemical or physical stimuli. The following equation demonstrates the relation between the configured electromagnetic waveform, E(s) and Eb(s).
The present invention further teaches that a time-varying bipolar electromagnetic field for which pulse duration or carrier period is less than about half of the bound ion lifetime of Ca2+ binding to CaM will maximize the current flow into the Ca/CaM binding pathway to accelerate the CaM-dependent signaling which plants, animals and humans utilize for tissue growth, repair and maintenance. In particular, a time-varying bipolar electromagnetic field may be configured to modulate CaM-dependent NO/cGMP signaling which accelerates; pain and edema relief, angiogenesis, hard and soft tissue repair, repair of ischemic tissue, prevention and repair of neurodegenerative diseases, nerve repair and regeneration, skeletal and cardiac muscle repair and regeneration, relief of muscle pain, relief of nerve pain, relief of angina, relief of degenerative joint disease pain, healing of degenerative joint disease, immunological response to disease, including cancer. In addition, prophylactic application of such signals can provide a protective effect to any tissue or organ in the living system in anticipation of stress or physical or chemical insult.
It has been shown that quiescent cells and tissues can respond to EMF by producing heat shock proteins (HSP). These studies showed that tissue protection is related to an increase, by EMF, in the release of HSP70. This is consistent with the use of EMF for signaling. Thus, because ion binding is voltage-dependent and kinetically asymmetrical, EMF signals, can be configured to drive the forward (binding) reaction and activate the buffer even when cytosolic ion concentrations are at baseline (tissue at rest). The physiological import of this stems from evidence that NO induces the expression of HSP. It follows that HSP expression can be enhanced via an EMF effect on CaM-dependent NO signaling, even for quiescent cells and tissues. Release of HSP prior to injury can reduce the inflammatory response because it is poised to rapidly downregulate IL-1β and iNOS, which would protect tissue from injury.
Utilization of the above analysis on the RF communication signals emitted by smartphones shows that these signals satisfy the requirements to affect, e.g., Ca2+ binding to CaM. Therefore, a preferred embodiment according to the present invention is modification of the software of a smartphone, activated by a switch, to apply predefined periods of the RF communication signal to target structures such as plant, animal and human molecules, cells, tissues, organs, portions of entire organisms and entire organisms for therapeutic and prophylactic purposes.
In general, the PCD may be any appropriate communications device, including smart phones (e.g., iPhones™, Droids™, etc.), laptop/palmtop computers (e.g., iPad™, etc.), or any other mobile communications device having sufficient processing power to run the application “driver” 103. In
Returning now to
The applicator, either internal or external, may be flexible (e.g., made of cable, wire, etc.) or it may be substantially stiff or rigid.
When a feature or element is herein referred to as being “on” another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when a feature or element is referred to as being “directly on” another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being “connected”, “attached” or “coupled” to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being “directly connected”, “directly attached” or “directly coupled” to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.
Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as “/”.
Spatially relative terms, such as “under”, “below”, “lower”, “over”, “upper” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “under” can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.
Although the terms “first” and “second” may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention.
As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word “about” or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and/or position to indicate that the value and/or position described is within a reasonable expected range of values and/or positions. For example, a numeric value may have a value that is +/−0.1% of the stated value (or range of values), +/−1% of the stated value (or range of values), +/−2% of the stated value (or range of values), +/−5% of the stated value (or range of values), +/−10% of the stated value (or range of values), etc. Any numerical range recited herein is intended to include all sub-ranges subsumed therein.
Although various illustrative embodiments are described above, any of a number of changes, modifications, alterations and variations may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.
The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2018/019457 | 2/23/2018 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62463475 | Feb 2017 | US |
