Personalized Bioelectromagnetic Therapy

Abstract

The present invention provides a bioelectromagnetic therapy method for delivering a personalized and effective bioelectromagnetic therapy to the site of injury and disease in the microenvironment of a patient undergoing treatment, which is self-adaptive and bioresponsive to the microenvironment undergoing treatment and suitable for treating injury and disease.

Description

[Technical field]

[0001] (Field) The present application relates generally to methods, devices and systems for providing personalized, intelligent, self-adaptive bioelectromagnetic therapy. [Background technology]

[0002] (background) Bioelectromagnetic therapy has been used as a non-invasive physical therapy to address injuries and diseases including cancer, non-union fractures, and pain. For example, in the case of fractures, studies have shown that the rate of non-union of fractures may be reduced in people who have used electromagnetic stimulation for treatment. However, contrary studies have shown minimal or no benefit to using bioelectromagnetic therapy for bone healing.

[0003] One of the reasons for the inconsistency in the clinical efficacy of bioelectromagnetic therapy is due to the subjective nature of the practitioner's decision on the dosage and regimen of electrical stimulation. Clinicians may choose protocols based on animal studies or based on protocols used with other patients. Because there is no rigorous method for determining the ideal physical parameters of the applied bioelectromagnetic therapy, clinicians have generally adopted treatment approaches based on limited previous comparable experience. However, the lack of optimized conditions inevitably results in variability in clinical outcomes, including treatment failure. This variability has prevented bioelectromagnetic therapy from becoming the standard treatment for applicable diseases and injuries. In addition to variability, many protocols and systems used to apply bioelectromagnetic therapy are inconvenient and impractical to use, leading to poor patient compliance and other undesirable complications.

[0004] Knowledge processing has been incorporated into treatment methods to attempt to customize a treatment profile to closely resemble the patient's profile. Generally, these methods require the generation of a patient profile that includes demographic characteristics, physiological data, and characteristics of the condition for which treatment is sought. The patient profile is compared to a patient analysis database that includes data compiled for multiple individuals to determine a recommended treatment based on matching the patient profile to individuals with the most similar characteristics. Although treatment outcomes may be improved, this approach is not truly patient-specific, but rather most similar to the matched past individuals.

[0005] Identifying a less subjective, more individualized treatment approach for a patient's bioelectromagnetic therapy is expected to lead to more optimal treatment outcomes.

[0006] The above discussion is not intended to be an admission that any of the foregoing is pertinent prior art. Summary of the Invention

[0007] (overview) In view of the aforementioned limitations and shortcomings of currently used bioelectromagnetic therapy methods, as well as other shortcomings not specifically mentioned above, more precise and effective bioelectromagnetic therapy approaches are desirable.

[0008] There are several variables involved in the approaches and regimens currently used to apply therapeutic electric fields to the treatment target area. Electric fields can be applied using direct current through implanted electrodes to the treatment target area, either by transiently generating an alternating current at the treatment target area using capacitively coupled electrodes, or by inductive stimulation, using coils to generate an electromagnetic field (EMF) at the treatment target area. Various electrode or coil placements and designs are possible for capacitively or inductively coupled EMF treatment. The electrodes / coils are placed in close proximity to the treatment target area. Problems can arise due to self-inductance and background electrical interference. Depending on the size of the target treatment area, the active components may need to be spaced widely apart, reducing EMF strength. Additionally, electrodes / coils that are tailored to the curvature of the treatment area can distort the induced electric field, resulting in variable treatment results.

[0009] There is also considerable variability with respect to patient biological characteristics that may affect the outcome of EMF therapy. For example, there is variability due to patient biometrics, genetics, medical history, comorbidities, and high-risk lifestyle factors. There is also variability with respect to the type of injury, trauma, disorder, or disease. The injury may be superficial or reside in deeper structures. The tissue and cellular environment of the injury is unique, affecting cells electrical activation and activation selectivity.

[0010] There are also variations in the starting point for employing bioelectromagnetic therapy in the progression of disease or injury repair, along with the inherent changes in the biological cascades required throughout the healing process.

[0011] Living tissues contain complex cellular structures. The cells of the body have built-in electromagnetic properties such that they respond exquisitely to electromagnetic stimulation of precisely the right frequency and amplitude. In turn, the endogenous bioelectric fields and current propagation within tissues affect cell membrane capacitance, cell membrane permeability, cell membrane signaling mechanisms, intracellular mineral concentrations, nutrient flow to cells, and waste disposal. The composition of tissue and the degree of damage affect the bioelectric fields and current flow within them. Bioelectromagnetic therapy can induce or enhance ongoing intrinsic bioelectrical events within cells and tissues in response to injury or disease, thus aiding in healing and repair.

[0012] The cellular structure of an injury / disease varies depending on the onset of injury / disease in a subject and / or concurrent biological events such as inflammation, and the length of time since potential re-injury of the same tissue. This is more pronounced between different subjects for various reasons such as age, gender differences, and the presence of underlying health factors. Therefore, it is not clinically sound to provide the same treatment plan to different people and expect the same treatment outcome, even for the same type of injury / disease. Providing the precise and necessary stimulatory signals to promote proper proliferation and differentiation is an inherent feature of the cell type and location at the time of that particular treatment and the healing stage of the patient.

[0013] The interrelationships of the aforementioned variables have provided the basis for the development of the personalized bioelectrical therapy approach disclosed herein.

[0014] Individualized bioelectrical therapy for treating living tissues requires that the generated currents are not so strong as to cause undesirable physiological responses, but are sufficient in intensity, form, duration and time sequence to activate cell signaling processes and cascades of extracellular signals, and to initiate enzymatic reactions, membrane trafficking, cell proliferation and differentiation, and other biological processes involved in healing and repair. The electromagnetic fields (EMF) must meet the frequency, amplitude and temporal patterns that natural and repair cells innately possess, require and expect for proper growth and differentiation during the healing process.

[0015] It has not previously been recognized that the external parameters to the injury or disease microenvironment associated with the generation and propagation of therapeutic electromagnetic fields are linked and therefore intimately related to the ability to provide therapeutic bioelectromagnetic stimulation to meet the requirements of the microenvironment of the injury or disease targeted for treatment in a particular patient, nor has it previously been recognized that even subtle differences in one or more of the variables involved can render bioelectromagnetic therapy ineffective in different patients for the same type of anatomical injury / disease.

[0016] Thus, the present invention provides bioelectromagnetic therapy methods, devices and systems that include multiple individualization points throughout a bioelectromagnetic therapy protocol, thus compensating for variations associated with biological challenges, patient profile, EMF propagation paths, and device placement specifications to stimulate desired results.

[0017] The complex relationships between the variable biological parameters of the patient and the microenvironment of the treatment area and the variable parameters of the electromagnetic treatment modality prescribed to the patient are computationally defined to provide a patient-specific and effective individualized electromagnetic treatment protocol.

[0018] Described herein are bioelectromagnetic therapy methods, devices and systems that advantageously incorporate a specialized, intelligent, physics-based computational engine to provide a more robust, comprehensive and effective approach to delivering personalized bioelectromagnetic therapy. The unique computational engine employs artificial intelligence, machine learning, computation and mathematical analysis to organize data collections that represent (a) the biological characteristics of the patient, including clinical metadata related to the biological characteristics of similar patients and the target microenvironment, and the biological characteristics of the patient's microenvironment that is the target of the treatment; and (b) multi-dimensional parameters related to the electromagnetic treatment modality prescribed to the patient that emits an electromagnetic field to affect the target microenvironment, including parameters affecting the placement and electromagnetic field propagation efficiency of the electromagnetic field, to generate a personalized treatment for the patient.

[0019] The unique computational engine enables determination of ideal electromagnetic field requirements directed to a microenvironment targeted for treatment of a subject, and is further configured to determine a personalized electromagnetic field treatment protocol for the subject, including precise means for delivering the ideal electromagnetic field requirements determined during the personalized treatment protocol.

[0020] The individualization of treatment for a patient as described herein is not based on historical database comparisons, nor is it based on a generalized patient-matching treatment model. Instead, the individualized treatment protocols described herein precisely match the requirements of the microenvironment of the patient being treated with the prescribed electromagnetic treatment modality to more precisely affect healing at the cellular and molecular level and / or affect mediators of inflammation and / or affect biological factors to provide faster healing of injuries, improved quality of healing, reduced disease progression, and / or pain management.

[0021] The limits of the bio-electromagnetic field stimulation applied during a personalized treatment protocol are not predetermined, but instead are specifically established to match the target microenvironment in the patient, and then self-adaptively adjust in response to changes that occur at the target cellular level as a result of the applied electrical signals over the course of the treatment protocol.

[0022] The embodiments of the invention disclosed herein include, in aspects, a Microenvironment Computation Engine (MiCE) configured to use organized indexed data collections representing multidimensional parameters of a patient and biological characteristics of the patient's microenvironment targeted for therapy (patient-centric data), and clinical metadata regarding similar patients and biological characteristics of the target microenvironment to compute a patient-specific theoretically ideal personalized microenvironment stimulation target (PMST), which is the calculated ideal electromagnetic field stimulation required for the microenvironment targeted for therapy.

[0023] The embodiments of the invention disclosed herein include, in an aspect, a Macrotranslation Computational Engine (MaCE) configured to use an organized indexed collection of data (EMF modality centric data) representing the multi-dimensional parameters of the prescribed electromagnetic field modality to calculate the precise means to provide the ideal electromagnetic field requirements (i.e., PMST). The MaCE outputs an initial configuration characterizing the EMF source called the Personalized Treatment Protocol (PTP). The EMF modality centric data represents (a) propagation path data representing the signal path separating the EMF source and the microenvironment affected by material properties and physical dimensions and the movement of tissues and materials along the signal path; and (b) placement specification data representing the electromagnetic field generation modality and the physical structure of the EMF signal generation device configured for the patient and injury or disease.

[0024] The embodiments of the invention disclosed herein may further include optimization extensions.

[0025] In an aspect, the optimization extension comprises a feedback computation engine (FCE) configured for dynamic sensing, computation, and adaptive correction of the MaCE.

[0026] In an aspect, the optimization extension comprises a Learning Computation Engine (LCE) configured for dynamic clinical sensing, computation and adaptive correction of MiCE.

[0027] In an embodiment, the optimization extension comprises both an FCE and an LCE.

[0028] Described herein are computer-implemented methods, devices and systems comprising MiCE and MaCE, and optionally one or both of FCE and LCE, for the generation and application of individualized bioelectrical signals that overcome at least one of the shortcomings of the electromagnetic methods described above and provide precise stimulation required and specific to a patient's injury or disease microenvironment and are optimized to result in a desired biological response.

[0029] Desired biological responses to injury or disease may include, for example, but are not limited to, alterations in biological processes in the microenvironment involved in stabilizing, reversing and / or ameliorating the injury or disease state; improving / restoring function of tissues / organs affected by injury or disease; reducing the spread / growth of disease; stabilizing injury or disease; managing / reducing pain associated with injury or disease.

[0030] In aspects, the personalized electromagnetic field signals described herein more efficiently match frequency components to relevant cellular / molecular processes of the patient's injury or disease microenvironment in which they are computed.

[0031] In aspects, the personalized electromagnetic field signals described herein correspond more directly to signals of the patient's injury or disease microenvironment from which they are computed, resulting in accelerated healing.

[0032] In aspects, the personalized electromagnetic field signals described herein more precisely target biochemical and biophysical pathways of cells and associated structures in damaged or diseased microenvironments to promote cell proliferation, tissue growth, repair, and maintenance.

[0033] In aspects, application of the individualized electromagnetic field signals described herein can stimulate the action of growth factors and other cytokines in the target microenvironment.

[0034] In aspects, application of the individualized electromagnetic field signals described herein can alter gene regulation of cells within a target microenvironment.

[0035] In aspects, the individualized electromagnetic field signals described herein may have reduced effects on off-target cells / tissues.

[0036] In aspects, the individualized electromagnetic field is for application for a period of time effective to substantially heal the injury.

[0037] In aspects, the individualized electromagnetic field is applied for a period of time effective to reverse, stabilize, and / or cure the disease.

[0038] In an embodiment, the individualized electromagnetic field is a pulsed electromagnetic field (PEMF).

[0039] In an embodiment, the individualized electromagnetic field is a capacitively coupled electric field.

[0040] According to an aspect of the present invention, there is provided a device for providing an electromagnetic field (EMF) to an injury or disease in a patient, comprising: an EMF signal generator configured to generate an individualized electromagnetic field signal for a microenvironment target to meet the specific requirements of the patient's injury or disease; and At least one EMF source in operative communication with the signal generator to deliver / apply an individualized electromagnetic field signal to the injury or disease. The device includes:

[0041] In aspects, the device is configured to deliver a personalized electrical stimulation field to preferentially stimulate (upregulate, downregulate, or a combination of both) biochemical, cellular, and intracellular molecular responses to induce activation of known mammalian genes involved in regeneration, restoration, repair, maintenance, or any combination of cartilage, bone, or both.

[0042] In aspects, the device is configured to deliver a personalized electrical stimulation field to preferentially stimulate (upregulate, downregulate, or a combination of both) biochemical, cellular, and subcellular molecular responses specific to the patient's microenvironment, inducing activation of known mammalian genes involved in pain modulation, pain relief, and / or pain relief.

[0043] In aspects, the device is configured to deliver a personalized electrical stimulation field to preferentially stimulate (upregulate, downregulate, or a combination of both) biochemical, cellular, and intracellular molecular responses specific to the patient's microenvironment, inducing activation of known mammalian genes involved in slowing or reversing cancer growth.

[0044] In aspects, the device is configured to deliver a personalized electrical stimulation field to preferentially stimulate (upregulate, downregulate, or a combination of both) biochemical, cellular, and intracellular molecular responses to induce activation of known mammalian genes specific to the patient's microenvironment that are involved in an overall sense of well-being, or reduction in one or more symptoms of anxiety, or reduction in one or more symptoms of stress.

[0045] In aspects, the device is configured to deliver a personalized electrical stimulation field to preferentially stimulate (upregulate, downregulate, or a combination of both) biochemical, cellular, and subcellular molecular responses specific to the patient's microenvironment, inducing activation of known mammalian genes involved in slowing or reversing or managing neurological disorders.

[0046] In aspects, the EMF signal applicator is configured for inductive coupling with an EMF source(s), e.g., a coil(s), or capacitive coupling using an electrode(s) to make electrochemical contact with the surface of the treatment target.

[0047] In an aspect, the electromagnetic (EMF) signal generator comprises an engine means, processor(s) and memory for generating and delivering an individualized programmed treatment protocol to meet the requirements of an individualized microenvironment stimulation target at the site of injury or disease of the patient.

[0048] In embodiments, the EMF signal generator may further comprise a display and a touchpad or input keys to allow patient interaction or navigation within the display. In embodiments, the EMF may form a kit or part of a kit with instructions. In embodiments, the EMF signal generator may be in operative communication with one or more remote control networks.

[0049] In aspects, the devices are configured as wearable devices, including anatomical wraps, anatomical supports (e.g., bras), clothing (e.g., t-shirts, sweatshirts), chest supports (e.g., bras), hats / caps / helmets, footwear (e.g., sneakers, insoles for boots), fashion accessories (e.g., bracelets), dressings, bandages, compression bandages, and compression dressings.

[0050] In aspects, the device and / or its components are configured to be reusable.

[0051] In an embodiment, the device is configured to be reprogrammable.

[0052] In aspects, the device and / or its components are configured to be disposable, recyclable and / or replaceable.

[0053] In an embodiment, the device and / or components thereof are configured to be implanted in a patient.

[0054] In aspects, the device and / or components thereof are configured to be incorporated into a mattress, mattress pad, linen (sheets, pillowcases), furniture (e.g., bed, chair, sofa), exercise equipment, or support device (e.g., wheelchair) on which a subject may sit, recline, etc.

[0055] According to an aspect of the invention there is provided a personalized method for treating an injury or disease in a patient, comprising: The method includes applying an electromagnetic field to the injury or disease, where the electromagnetic field provides precise stimulating bioelectrical signals required and specific to the patient's injury or disease for healing.

[0056] In an embodiment, a personalized electromagnetic field is generated incorporating biological data parameters of the patient's injury or disease.

[0057] In an embodiment, a personalized electromagnetic field is generated incorporating patient biological data parameters related to the injury or disease.

[0058] In aspects, a personalized electromagnetic field is generated incorporating clinical metadata related to the injury or disease.

[0059] In aspects, a personalized electromagnetic field is generated incorporating clinical metadata related to the injury or disease.

[0060] According to an aspect of the present invention, there is provided a personalized electromagnetic field (EMF) treatment system for a patient, comprising: A microenvironment computation engine (MiCE) configured to compute a theoretically ideal personalized microenvironment stimulation target (PMST) for delivering electrical stimulation to a patient's microenvironment; and A Macro Translation Computational Engine (MaCE) configured to calculate precise measures to deliver the ideal personalized microenvironment stimulation target electromagnetic field to the patient's microenvironment as a personalized treatment protocol. The electromagnetic field (EMF) treatment system includes:

[0061] In an aspect, the Microenvironment Computation Engine (MiCE) comprises protocols for integrating and processing parametric data based on clinical metadata associated with the patient, the biological characteristics of the patient's microenvironment, and the biological characteristics of similar target microenvironments.

[0062] In an embodiment, the Macro Translation Computation Engine (MaCE) comprises protocols for integrating and processing parameter data based on EMF treatment modalities and patient factors external to the microenvironment to deliver an ideal personalized electromagnetic field to the patient's microenvironment.

[0063] According to an aspect of the present invention, there is provided a wearable electromagnetic field (EMF) therapy system for treating an injury or disease in a patient, comprising: EMF signal devices; Microcontroller; one or more flexible coil wire EMF sources connected to the EMF signal device; and Materials configured to immobilize EMF sources at the area of ​​injury or disease wherein the microcontroller is configured to generate a personalized treatment protocol that delivers ideal personalized EMF stimulation specific to the microenvironment of an injury or disease.

[0064] According to an aspect of the present invention, there is provided a computer-implemented electromagnetic field (EMF) therapy system, comprising: A microenvironment computation engine for computing individualized microenvironment stimulation targets; and A macro-translation computation engine for generating personalized treatment protocols based on ideal personalized electromagnetic fields; and One or more EMF sources connected to an EMF signal generator for applying an ideal individualized electromagnetic field to the patient The computer-implemented electromagnetic field (EMF) treatment system includes an electromagnetic field (EMF) signal generator having a memory or chip storing:

[0065] According to a further aspect, - a microenvironment computation engine configured to compute a theoretically ideal personalized microenvironment target specific to a patient's therapeutic target; - a macro-translational computational engine configured to generate personalized treatment protocols based on theoretically ideal personalized microenvironment targets; and - a signal generating device configured to emit a personalized treatment protocol The present invention relates to a bioelectromagnetic treatment system.

[0066] The systems, devices and methods described herein are suitable for individualizing treatment for a variety of clinical indications, including, but not limited to, treatment of injury, disease, pain management, the physical effects of stress and / or anxiety, as well as for systemic benefits throughout the body. The systems, devices and methods of the present invention may also be suitable, in embodiments, as preventative strategies for recurrent conditions.

[0067] The personalized, intelligent, self-adaptive bioelectromagnetic therapy of the present invention is well tolerated by the patient, does not need to be invasive or uncomfortable, and does not cause pain, which is beneficial in increasing patient compliance with the treatment. The method does not require manual adjustment of power, pulse rate duration, pulse width period, or treatment time by the treatment provider. The bioelectromagnetic therapy device programmed and configured to deliver the personalized, intelligent, self-adaptive bioelectromagnetic therapy described herein benefits from convenience of use, versatility, and the ability to treat single or multiple treatment targets on the same patient or to treat the entire patient's body.

[0068] This comprehensive individualized approach improves the effectiveness of bioelectromagnetic therapy and results in desirable, more durable therapeutic outcomes. The method is also advantageous because it calculates EMF treatment protocols specific to the patient's treatment target area, thus substantially avoiding potentially dangerous effects on adjacent tissues.

[0069] From the foregoing, those skilled in the art will appreciate that the present invention provides particularly effective methods, devices and systems for overcoming many of the limitations associated with conventional treatment of patients using electromagnetic energy, and will readily appreciate that the present invention is suitable for human treatment and has veterinary applications.

[0070] These and other features, embodiments, and advantages of the present disclosure are mentioned not to limit or define the disclosure, but to provide examples to aid in its understanding when read in conjunction with the following description and with reference to the accompanying drawings. [Brief description of the drawings]

[0071] BRIEF DESCRIPTION OF THE DRAWINGS For a more complete understanding of the present disclosure, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:

[0072] [Figure 1]FIG. 1: Operating components of a bioelectromagnetic therapy device according to an embodiment of the present disclosure. [Diagram 2] Figure 2: Abstraction of the interconnected factors that contribute to the effective generation and delivery of electromagnetic fields capable of producing desired biological responses in a microenvironment. [Diagram 3] FIG. 3: Operational flow chart illustrating the core elements of the personalized bioelectrical treatment protocol of the present invention. [Figure 4] FIG. 4: An operational flow chart of a personalized bioelectric treatment protocol for a bone exhibiting a tibial non-union fracture according to an embodiment of the present disclosure. [Diagram 5] Figure 5(A)-(C): (A) Simplified implementation of the electromagnetic source device showing the arrangement of components aligned with a tibial non-union fracture; (B) illustrates the configuration of parallel coils and shaped coils; (C) is an abstraction of the electromagnetic field generated around the microenvironment of a tibial non-union fracture. [Figure 6] FIG. 6: Operational flow chart of a personalized bioelectrical therapy protocol for the treatment of cancer indicative of glioma (cancer) according to an embodiment of the present disclosure. [Figure 7] Figures 7(A)-7(B): (A) Simplified implementation of the electromagnetic source device showing the placement of components aligned with the glioma; and (B) Abstraction of the generated electromagnetic field around the glioma microenvironment. [Figure 8] FIG. 8: Operational flow chart of a personalized bioelectrical treatment protocol for the treatment of chronic pain indicative of chronic knee pain associated with knee osteoarthritis according to an embodiment of the present disclosure. [Figure 9] Figures 9(A)-9(B): (A) Simplified implementation of the electromagnetic source device showing the placement of components tailored to the osteoarthritis of the knee; (B) Abstraction of the electromagnetic field generated around the osteoarthritis microenvironment. [Figure 10] Figure 10: Arrangement showing a cell culture plate exposed to a spatially uniform and time-varying magnetic field using Helmholtz coils. [Figure 11]Figure 11: Sample PCR array heatmap showing gains and losses in gene expression in "test" samples and standards ("control" cells / donors). In this example, unstimulated PC-1 gene expression levels are plotted against unstimulated LZ-1 levels. Each grid position is annotated with the fold change (FC) plotted in base 2 logarithm, with zero corresponding to no difference in expression levels between test and standard samples. Shaded boxes indicate genes with negligible expression in both test and control samples. [Figure 12] Figure 12: Array of gene expression heat maps showing the difference in baseline gene expression (cultured without EMF stimulation) for each donor compared to other donors. Heat maps should be identified as rows (test) vs. columns (control / standard), with PC-1 vs. LZ-1 being the polar opposite of LZ-1 vs. PC-1. A single color bar is applied to all heat maps. [Figure 13] Figure 13(A)-(B): Heatmaps showing donor-to-donor variation when cells were cultured in the presence of alternating magnetic fields: (A) a 75 Hz, 4 mT pulse waveform; and (B) a 50 Hz, 1 mT sine wave. Gene expression differs significantly between donors within the pulsed field. Each heatmap is normalized and represents exposed and unexposed controls of the same donor. Color bar applies to all 10 heatmaps. [Figure 14] Figure 14: Graph showing the fold change in expression of 10 osteogenic genes (compared to their own controls) for each donor selected from the PCR array in experiment 1. Values ​​less than 1 represent downregulation of that gene, while values ​​greater than 1 are upregulation of that gene. [Figure 15] Figure 15: Heatmap of cells from donor PC-1 exposed to six different forms of stimulation. Pulsed magnetic fields (top row) were varied within a day of exposure time (continuously 10 min / day) and sinusoidal waves (bottom row) were assessed at three different frequencies (15-250 Hz). Shaded lines indicate negligible gene expression from test and control samples. [Figure 16] FIG. 16: Graph showing osteogenic gene expression as affected by pulsed and sinusoidal magnetic field exposure. [Figure 17]FIG. 17: Graph showing changes in expression of chondrogenic genes as affected by exposure to pulsed and sinusoidal magnetic fields. [Figure 18] Figure 18 (A)-(B): Graph showing cell counts after incubation of MDA-MB-231 cells with EMF exposure (A) There is a statistically significant difference between the unexposed control and multiple experiments. The stimulation profile used in experiments 3 and 4 inhibited the proliferation of breast cancer cells. Repeating the exposure with chondrocytes (B) demonstrated no statistically significant effect on the proliferation of non-cancerous cells. [Figure 19] Figure 19(A)-(B): Heatmaps corresponding to the change in gene expression relative to the unstimulated control generated by the stimulation profiles of Experiments 3(A) and 4(B). Genes belonging to this Cancer Pathway Finder PCR array are involved in pathways including apoptosis, cellular senescence, and angiogenesis. Shaded areas indicate genes with negligible expression. [Figure 20] Figure 20(A)-(B): Graphs showing normalized cell counts for cultures with or without cisplatin and / or EMF exposure. Cisplatin vehicle has no significant effect on proliferation, while high concentrations of the drug are inhibitory (A). Addition of low concentrations of cisplatin and / or EMF exposure relative to unstimulated vehicle significantly reduced cell counts (B). The additional benefit provided by experiments 3 and 4 is statistically significant compared to chemotherapy alone at both concentrations. [Figure 21] Figure 21: Representative images (magnification x50) of donor NHA-2 astrocytes prior to viability arrest. Images A and B are of non-responsive and responsive control cell groups, respectively. [Figure 22] Figure 22: Graph showing quantitative PCR results of select genes used to confirm the responsive state of astrocytes. As seen here, the responsive (or pain) state shows lower levels of GFAP, TGFB, STAT3 and SOX9, and higher expression of IL6, TNFα, IL8, IL-1β and C3 compared to non-responsive control levels. The vertical axis shows the mRNA levels of the gene of interest (GOI) relative to the housekeeping gene GAPDH. [Figure 23]Figure 23: Heatmap of the pain PCR array revealing the difference in fold change between baseline expression levels of NHA2 cells in the responding state compared to the non-responding state (calibrator). Red and blue boxes represent up- and down-regulation of gene expression, respectively, relative to non-responding cells. Grey boxes indicate genes with negligible expression in both test and calibrator conditions. [Figure 24] Figure 24: An array of gene expression heat maps showing baseline gene expression variation between donors. Comparisons in the table are identified as rows (test) and columns (standard), with maps on one side of the diagonal being the polar opposite of the other side. A color bar applies to all heat maps. Diagonal lines indicate genes with negligible expression. [Diagram 25] Figure 25: Heatmaps demonstrating differences between donors when cells from three donors (top, NHA1; middle, NHA2; bottom, NHA3) were subjected to the same EMF stimulation (Experiment 1). Exposure strongly upregulated many genes in NHA1 compared to the NHA1 response control, while the majority of genes are downregulated in NHA3. [Figure 26] Figure 26: Graph showing gene expression in NHA1, NHA2 and NHA3 cells when exposed to extremely low frequency, low intensity magnetic fields for 10 minutes per day (Experiment 1). Selected inflammatory genes are shown. Upregulated genes have positive values ​​and vice versa for downregulated gene expression. [Figure 27] Figure 27: Heat maps showing gene expression changes of 84 unique genes in response to stimulation of NHA2 cell groups: Experiment 1 (left), Experiment 2 (middle) and Experiment 3 (right). Amounts represent log2(fold change) and fold change is relative to NHA2 response control. Shaded boxes are genes with negligible expression in both test and control samples. [Figure 28]Figure 28: Graph demonstrating intra-donor variability when cells from the same donor group (NHA2) were exposed to three different EMF stimulation profiles (named Experiments 1-3). Gene expression of exposed cells is plotted against the reactive control. The same genes are strongly upregulated by the transition from non-reactive to reactive astrocytes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0073] (explanation) Reference will now be made in detail to the embodiments, examples of which are illustrated in the accompanying drawings. In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the subject matter presented herein. However, it will be apparent to one of ordinary skill in the art that the subject matter may be practiced without these specific details. Furthermore, the specific embodiments described herein are provided as examples and should not be used to limit the scope of the invention to these specific embodiments. In other instances, well-known data structures, timing protocols, software operations, procedures, and components have not been described in detail so as not to unnecessarily obscure aspects of the embodiments of the invention.

[0074] As used herein, the term "invention" or "the present invention" is an open-ended term and is not intended to refer to any single embodiment of a particular invention, but encompasses all possible embodiments described in the specification and claims.

[0075] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such publication by virtue of prior invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0076] In case of conflict, the present specification, including definitions, shall prevail.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of this specification belongs.Furthermore, it will be understood that terms as defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology and this disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly defined in this specification.

[0077] Reference to "one embodiment," "an embodiment," "a preferred embodiment," or any other phrase stating the word "embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure, and also means that any particular feature, structure, or characteristic described in connection with an embodiment can be included in any embodiment, or can be omitted or excluded from any embodiment. The appearance of the phrase "in one embodiment" in various places in this specification does not necessarily all refer to the same embodiment, nor are separate or alternative embodiments mutually exclusive with other embodiments. Furthermore, various features are described that may be exhibited by some embodiments and not exhibited by other embodiments, or may be omitted from any embodiment. Furthermore, any particular feature, structure, or characteristic described herein may be optional. Similarly, various requirements are described that may be requirements for some embodiments but not other embodiments. Where appropriate, any of the features discussed herein in connection with one aspect or embodiment of the invention may apply to another aspect or embodiment of the invention. Similarly, where appropriate, any of the features discussed in this specification in relation to one aspect or embodiment of the invention may be optional and / or omitted with respect to that aspect or embodiment of the invention or any other aspect or embodiment of the invention discussed or disclosed herein.

[0078] It will be understood that any element defined herein as being included in any described embodiment may be explicitly excluded from the claimed invention by disclaimer or negative limitation.

[0079] As used herein, the articles "a" and "an" preceding an element or component are intended to be open-ended regarding the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be read to include one or at least one, and the singular form of an element or component also includes the plural, unless the number is clearly intended to be singular.

[0080] Additionally, the terms "comprises" and / or "comprising", or "includes", "including" and / or "having", as well as variations and conjugations thereof, as used herein, are understood to specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof. Words using the singular or plural form also include the plural or singular form, respectively. Additionally, the words "herein", "hereinafter", "above", "below" and words of similar import refer to this application as a whole and not to particular portions of this application.

[0081] As used herein, the term "about" refers to a variation in a quantity. In one embodiment, the term "about" means within 10% of the reported numerical value. In another embodiment, the term "about" means within 5% of the reported numerical value. However, in other embodiments, the term "about" means within 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of the reported numerical value.

[0082] "About" is equivalent to "approximately" or "substantially" as used herein and means within the range of acceptable deviation of a particular value, inclusive of the stated value, and taking into account the measurement in question and the error associated with the measurement of the particular quantity (i.e., the limitations of the measurement system). For example, "about," "approximately," or "substantially" can mean within one or more standard deviations, or within +30%, 20%, 10%, 5% of the stated value.

[0083] When a range of values ​​is listed, it is done merely for convenience or brevity and includes all possible subranges as well as individual numerical values ​​within and near the boundaries of that range. Unless otherwise specified, any numerical value includes values ​​that are substantially close, and integer values ​​do not exclude fractional values. The ranges given herein include the ends of the ranges.

[0084] As will be appreciated by those of skill in the art, all language such as "up to," "at least," "greater than," "less than," "more than," "or more than," and the like, is inclusive of the recited numbers and such terms refer to ranges which can then be divided into subranges, as described above. Thus, specific values ​​recited for radicals, substituents, and ranges are for illustrative purposes only and they do not exclude other defined values ​​or other values ​​within defined ranges for radicals and substituents.

[0085] As used herein, the term "may" refers to a choice or effect that may or may not be included and / or used and / or performed and / or occur, and further, the choice constitutes at least a part of some embodiments or results of the invention without limiting the scope of the invention.

[0086] The term "and / or" as used herein in the specification and claims should be understood to mean "either or both" of the elements so conjoined, e.g., elements that are conjunctive in some cases and disjunctive in other cases. Unless clearly indicated to the contrary, other elements may be optionally present other than the elements specifically identified by the "and / or" clause, whether or not related to those elements specifically identified. When the word "or" is used in reference to a list of two or more s, the word includes all of the following interpretations of the word: any of the s in the list, all of the s in the list, and any combination of the s in the list.

[0087] As used herein, a phrase such as "at least one" preceding a list of elements modifies the entire list of elements, and does not modify each individual element of the list.

[0088] For purposes of this invention, "combining or combining" means any method of placing two or more materials together, including, but not limited to, mixing, blending, intermingling, mixing, homogenizing, incorporating, mixing, fusing, joining, shuffling, stirring, combining, agglomerating, disrupting, joining, combining, and the like.

[0089] The terms "patient," "subject," "individual," and the like are used interchangeably herein.

[0090] In one non-limiting aspect, the patient, subject or individual is a mammal, including a human.

[0091] As used herein, "disease" refers to any abnormal condition that adversely affects the structure or function of all or part of a subject and is not due to injury. A disease is a medical condition that is associated with specific signs and symptoms, such as pain and impaired function, and includes, for example, disorders, syndromes, conditions, and abnormal psychological behaviors.

[0092] As used herein, an "injury" is an injury to the human body. Injury can include "trauma" as damage to human tissues and organs caused by external forces, ranging from minor (e.g., cuts and bruises) to severe (e.g., severe brain or spinal cord damage), and can be classified as blunt or penetrating.

[0093] As used herein, a "bioelectric signal" is an electrical signal that can be measured from a biological entity, e.g., a human, and includes endogenous bioelectrical signals that are generated within cells by the cumulative action of ion channels, pumps, and transporters, converted into second messenger responses, and that alter aspects of cellular behavior. In aspects, low amplitude and low frequency electrical signals.

[0094] As used herein, "bioelectricity" refers to the endogenous electrical potentials and currents that arise or are generated within living cells and tissues.

[0095] As used herein, an "electromagnetic field" (EMF) is a form of wave having both electric and magnetic components, the wave being characterized by energy, frequency and wavelength. EMF is a stimulation signal for providing therapy.

[0096] As used herein, "Pulsed Electromagnetic Field (PEMF)" refers to a time-varying (pulsed) electromagnetic field having a frequency and intensity.

[0097] "Bioelectromagnetic therapy" refers to the treatment of a subject using electromagnetic fields.

[0098] "Electromagnetic field (EMF) source" refers to a device / apparatus that includes components that generate an electromagnetic field.

[0099] "Stimulate" refers to the application of an individualized EMF treatment protocol to generate a desired response at the cellular level in the biological microenvironment of the treatment target. The desired response may change over the course of treatment, for example, an initial increase in proliferation and differentiation of cells in the biological microenvironment may occur first, followed by either a period of maintenance or a period of decrease in the rate of proliferation and differentiation of cells, and / or activation of additional cellular events. This is specific to the particular healing process of the biological microenvironment of the patient's particular injury, trauma, disease, or condition.

[0100] As used herein, "personalized" refers to therapy that is specifically created and customized for an individual patient, and more specifically, the biological microenvironment of the patient's therapeutic target.

[0101] "Treatment target" refers to the general anatomical region or tissue undergoing bioelectromagnetic treatment, and is not limited to it. Any part of the body may be injured or afflicted by disease. Treatment targets may also include the "whole body."

[0102] "Microenvironment" refers to the complex three-dimensional dynamic network of tissue architecture of the "therapeutic target" in terms of the composition of cells, extracellular matrix (ECM) components, soluble factors, and physical forces (e.g., fluid flow and mechanical stress). As a result of certain types of injury or disease, the biological microenvironment faces several physiological and / or biochemical challenges to initiate the complex process of healing and / or complex tissue growth, such as, for example, but not limited to, managing exudates, controlling bacteria, macerating cells / tissues, and dead cells / tissues.

[0103] As used herein, "individualized intelligent self-adaptive bioelectromagnetic therapy" generally refers to novel patient-specific optimized therapy designed specifically for a single patient using a computational engine configured to receive specific structured data related to (a) the microenvironment, which is data regarding the patient and the microenvironment of the treatment target, and (b) macro-translational factors, which is data regarding the placement and logistics of the EMF treatment to be used in relation to the microenvironment (a). Taken together, this allows for the calculation of patient-specific, theoretically ideal, calculated electromagnetic stimulation requirements for a desired cellular response within the microenvironment for a particular patient.

[0104] Structured data related to the patient and therapeutic target microenvironment is defined as follows: 1. "Biological Problem" refers to an organized collection of data that describes and characterizes an injury or disease, including, but not limited to, the type of injury or disease, the severity of the injury or disease, the current state of the disease, and the success or failure of previous treatments. This includes the physiological and / or biochemical problems described above. The data categories listed herein are not intended to be limiting. 2. "Patient Profile" refers to an organized collection of data representing comprehensive patient-specific factors that influence the microenvironment, such as demographic characteristics information; height, weight, body mass index (BMI); past and current medical conditions, such as, but not limited to, diabetes, allergies, vitamin deficiencies, blood conditions, heart conditions, vascular conditions; genetic data, which may be subject's full / partial genome sequencing, sequencing and identification of specific markers (e.g., differential gene expression); surgical procedures; and social history, such as, but not limited to, smoking, alcohol, cannabis, caffeine, and exercise. The data categories listed herein are not intended to be limiting. The combination of biological challenge data and patient profile data comprises patient-centric data. Table 1 lists non-exhaustive, non-limiting examples of data that may be collected in order for a patient to receive personalized bioelectromagnetic therapy. Table 1 [Table 1] 3. "Clinical Metadata" refers to organized collections of data representing publicly available data, including, but not limited to, physiological and biochemical data related to an injury or disease, patient outcomes previously treated with bioelectromagnetic therapy, and original interim and final experimental data from independent in vitro testing applicable to the type of injury or disease. The data categories listed herein are not intended to be limiting.

[0105] "Personalized Microenvironment Stimulation Target" (PMST) refers to patient-specific, theoretically ideal, calculated electromagnetic stimulation requirements for a desired cellular response within a microenvironment for a particular patient. It may specify, as a non-limiting example, a specific induced current or magnetic field density within a biological microenvironment.

[0106] "Microenvironment Computational Engine" (MiCE) refers to a physics-based engine for computing (e.g., generating, determining) personalized microenvironment stimulation targets (PMSTs) for a patient based on clinical metadata including biological challenge data, patient profile data, and unique experimental data.

[0107] Structured data on macro-translational factors, data on the placement of EMF treatment and the logistics of its use related to the microenvironment (a) are defined as follows: 1. "Propagation Pathway" refers to an organized collection of data describing patient characteristics that affect the propagation (and guidance) of electromagnetic fields through (and within) the medium separating the microenvironment and the EMF source. This includes the electrical and mechanical properties of cells and tissues relative to the treatment target's microenvironment, the three-dimensional shape of anatomical structures, the movement of anatomical structures, the physical distance within each medium, external components (e.g., clothing or air gaps), etc. The data categories listed herein are not intended to be limiting. 2. "Configuration Specification" refers to an organized collection of data that represents the parameters of a selected EMF delivery mode and the physical location and structure of the EMF source. For example, treatment may be delivered via electrodes or coils whose number, shape, size, orientation, and positioning are selectively adjusted depending on the application. The data categories listed herein are not intended to be limiting. This also includes the movement of the EMF delivery mode and possible deformation during treatment. The combination of propagation path data and configuration specification data comprises EMF modality-centric data.

[0108] "Macro Translation Computation Engine" (MaCE) refers to a physics-based engine configured to use the PMST and macro translation parameters to calculate / determine the initial output required from the EMF source, i.e., initial EMF settings that meet the specifications required to subject the translation effect along the propagation path to generate an "individualized microenvironmental stimulation target". The output of this engine is a "Individualized Treatment Protocol" (PTP).

[0109] A "Personalized Treatment Protocol" (PTP) refers to the combination of EMF signal parameters (frequency, intensity, waveform, driving voltage, current delivered to the coil / electrodes) required to meet the ideal PMST. Additionally, the protocol describes the duration of treatment, daily exposure time, and temporal variation of the individualized EMF target signal over the course of treatment.

[0110] "Feedback Calculation Engine" refers to a feedback engine configured to correct differences between the ideal PMST and the actual signal in the biological microenvironment based on inputs measured by one or more EMF sensors in or near the microenvironment being treated as a result of inaccuracies in the MaCE or distortions and / or attenuation of the PMST due to changes / perturbations that may occur during the treatment protocol. The corrections are sent as feedback data to modify the MaCE input parameters used in the calculation of the personalized treatment protocol.

[0111] "Learning Computation Engine" refers to an optimization engine configured as a self-contained feedback loop using clinical follow-up data and clinical sensor data (sensing of in vivo biological parameters) to optimize the "Personalized Treatment Protocol" and adaptively correct inaccuracies in the "Microenvironment Computation Engine." The Learning Computation Engine can incrementally adjust the parameters of the "Personalized Treatment Protocol" (including frequency, intensity, waveform, etc.), monitor and map the effects, and select optimal settings for continuing the treatment. To improve the solution, intermediate and final results of the treatment and related patient information are incorporated into the input parameters of the physics-based computation engine.

[0112] Traditional non-specific EMF treatment regimens and frequencies, large or small, that are pre-specified or suggested by manufacturers, completely lack any form of true clinical individualization that might take into account not only the application (e.g., disease or injury) but also the patient profile and hardware specifications for precise EMF placement and optimization of treatment protocols over time.

[0113] The diverse cellular responses to electromagnetic fields among different patients highlight the therapeutic limitations of a given electromagnetic field proposed as a universal patient treatment. The basis of the invention disclosed herein is that an ideal EMF exposure can and should be determined for a particular patient specific to (a) the biological challenge and microenvironmental factors contained in the patient profile; and (b) the macro-translational factors describing the specifics of the propagation path and placement of the device implementation. Furthermore, during treatment, the treatment can "learn" by intentionally making small changes to the initial ideal EMF exposure to find a true optimized solution. Real-time and intermittent sensing is necessary for the application of a treatment that is essentially "learning" and consistent, dynamically taking into account the sensed distortion or attenuation of the ideal EMF.

[0114] The present invention provides a bioelectromagnetic therapy system for delivering effective personalized bioelectromagnetic therapy to the microenvironmental damage / disease site of a patient receiving said therapy. The bioelectromagnetic therapy system is self-adaptive and bioresponsive to the microenvironment being treated and the device administering the therapy. No single electromagnetic field specification works effectively for everyone. A novel computer implemented computational engine processes parameters defining the patient and the damage and calculates the ideal personalized electromagnetic field. The microenvironment computational engine uses patient specific factors to calculate personalized stimulation targets, and the macro translation computational engine incorporates external macro parameters related to device placement to create an effective personalized EMF treatment protocol to achieve the calculated stimulation targets.

[0115] The methods, devices and systems described herein minimize undesirable effects of the electromagnetic field on adjacent / non-target cells / tissues as dispersion of the electromagnetic field to adjacent tissues is minimized. The prescribed treatment modalities, in combination with personalized treatment protocols, maintain the electromagnetic field concentration at the center of the microenvironment being treated.

[0116] In embodiments, disclosed herein are methods, devices, and systems for providing treatment of injury or disease in a patient by application of personalized bioelectromagnetic therapy, the methods comprising: A patient-centered and microenvironment-centric microenvironment computational engine (MiCE) configured to determine precise personalized microenvironment stimulation targets (PMST); An EMF-centric macro-translation computational engine configured to determine individualized treatment protocols based on PMST The method, device and system include

[0117] A computer-implemented platform in combination with an EMF device is developed for the treatment of a patient's injury and / or disease, providing personalized, intelligent, optimized and self-adaptive bio-electromagnetic therapy that results in better outcomes for the patient.

[0118] Patient-based biophysical / biological "microenvironment parameters" and EMF source placement and propagation "macro-translation parameters" must be individually tailored to effectively and successfully manipulate bioelectromagnetic therapy. These patient-specific factors ultimately influence how EMF produces the desired biological response in the patient's injury or disease microenvironment.

[0119] Mathematical calculations using the microenvironment calculation engine described herein provide a means to calculate a patient-specific, theoretically ideal electromagnetic stimulation, or PMST, for the microenvironment requiring treatment. The MaCE described herein calculates the PTP that constitutes the initial configuration of the EMF source to generate the PMST for the patient's microenvironment.

[0120] The MaCE is configured to create a PTP based on the device placement specifications and propagation path. Following the PTP, the EMF source provides an appropriate signal to generate a unique PMST. By taking into account and adapting the individual-specific microenvironmental and macro-translational parameters when calculating the personalized treatment protocol, biologically effective processes involved in repairing the damage are enhanced and / or the patient's disease progression is reduced and / or reversed.

[0121] The personalized bioelectromagnetic therapy may further comprise an optional optimization extension that adaptively modifies / adjusts the treatment protocol substantially in real time to further optimize the personalized treatment protocol. The optimization extension includes two stages that follow the calculation and delivery of the personalized treatment protocol and are designed to correct inaccuracies in the output MiCE and MaCE configurations using a series of sensors. The optimization extension may be continuous or intermittent.

[0122] The optimization extension comprises two stages: (a) a feedback calculation engine configured to obtain input data from EMF sensors at or near the microenvironment receiving treatment and determine and correct differences between the target EMF defined by the MaCE and the actual measured EMF as a result of inaccuracies in the MaCE and / or as a result of rotational movements and / or impact forces in the EMF modality; and (b) a learning calculation engine configured to use the following inputs to operate a self-contained optimization loop: clinical sensor data obtained via one or more clinical sensors at or near the microenvironment, clinical follow-up input data, and an adjusted treatment protocol.

[0123] The learning computation engine is configured to adjust small incremental changes to the initial settings of the EMF source (e.g., 10% increase or decrease in frequency) and monitor the impact using the sensor. After mapping the causal relationships, an optimized personalized treatment protocol is determined for the continuous treatment. The intermediate and final results of the treatment, as well as the associated patient data and microenvironment data based on the personalized treatment protocol, are relayed to MiCE. More specifically, the real-time intermediate result data is fed back and integrated into one of the databases accessed by the microenvironment computation engine to improve the personalized microenvironment stimulation target for the current patient. The real-time intermediate result data is accumulated during the treatment protocol so that it is continuously added to the database of patient data.

[0124] The final outcome data will be used to update organized clinical metadata collections and improve the determination of effective microenvironment stimulation targets for future patients.

[0125] The ability to logically and mathematically determine individualized microenvironmental stimulation targets specifically customized for the patient's target microenvironment is unique. Furthermore, the ability to logically and mathematically integrate the individualized microenvironmental stimulation targets into the calculations of the macro-translation computation engine to create individualized treatment protocols is unique. The generation of external EMF, whose parameters including waveform, frequency, amplitude, etc. are determined based on the causal relationship between the EMF-derived stimulation and the cellular response, the specific attributes of the patient's damage, the specific attributes of the local microenvironment that depend on unique patient characteristics such as metabolic activity and its limitations, the propagation path between the EMF source and the microenvironment, as well as the specific configuration and operation of the EMF source, induces a theoretically complete electromagnetic field that encompasses the cellular structures of the microenvironment. This represents a true customization of bioelectromagnetic therapy for a specific patient with a specific biological challenge, leading to clinically effective and lasting improved treatment outcomes.

[0126] (Personalized Bioelectromagnetic Devices) FIG. 1 shows the basic components of a personalized bio-electromagnetic device (10) for delivering personalized bio-electromagnetic stimulation therapy to a target microenvironment according to the invention described herein. The device (10) comprises a signal generator (20) operatively connected via wires / leads (22) for sending a configured signal to an EMF source(s) (24) to deliver a specific and selective electrical signal. Sensors relevant to the operation are incorporated into the system, such as EMF sensor(s) (26) for sensing deviations between personalized microenvironment stimulation targets and actual measured EMFs at or near the microenvironment, and clinical sensor(s) (28) for sensing in vivo parameters related to the biological microenvironment undergoing treatment. An amplifier (30) is operatively connected to the output of the signal generator (20) and provides the necessary input voltage signal to the EMF source (e.g., active coil / electrode). A power source (32) may be directly connected to the signal generator, or the signal generator may comprise a rechargeable removable battery, such as a lithium battery. In further embodiments, the device may feature a portable wireless power receiver for wirelessly transferring power over distance.

[0127] In general, an EMF signal generator (20) is powered to output a current having a defined waveform that flows into a coil or electrode to generate the EMF. The device may transmit the individualized EMF signal described herein via inductive coupling with a coil applicator, or via capacitive coupling, where the EMF applicator is an electrode in electrochemical contact with a conductive surface of a treatment target.

[0128] The coil applicator comprises a wire coil as a loop of flexible wire. As part of a wearable bio-electromagnetic treatment device, in embodiments, the coil is flexible / formable and lightweight. As will be appreciated by those skilled in the art, the EMF source(s) may comprise multiple or multiple coils / electrodes to provide individualized electromagnetic fields to the target microenvironment. Multi-coil applicators may be made from metal-containing materials such as metal wire (e.g., copper), and the coils of the applicator may be interconnected. Those skilled in the art will appreciate that any desired number of coils or electrodes of various sizes and shapes may be incorporated depending on the modality of EMF treatment prescribed.

[0129] The sensors may be incorporated externally and / or implanted at the tissue level. One of skill in the art will appreciate that the number and type of sensors (EMF and / or clinical) may be varied to allow for positioning of these sensors relative to the microenvironment targeted for treatment.

[0130] The EMF sensors provide dynamic sensing of parameters in the microenvironment that may cause deviations from the PMST. The EMF sensors may comprise one or more of a gaussmeter, a magnetometer, a spatial position sensor, a force sensor, a pressure sensor, a shape sensing sensor, reversible and irreversible strain sensors, and an impedance sensor.

[0131] The clinical sensor provides dynamic sensing of biochemical parameters in the microenvironment and may include one or more of a pH sensor, an ion concentration sensor, a glucose sensor, an oxygen sensor, a temperature sensor, and the like.

[0132] Safety sensors may be provided to alert patients and medical personnel to malfunctions, and these safety sensors act to immediately shut down the device.

[0133] In embodiments, the system may be configured to limit the degree of adjustment of the treatment protocol by the patient, such that the treatment protocol is not manually expanded unless approved by a clinical caregiver. In embodiments, the patient may only make self-directed changes to the therapy between sessions or within an ongoing session within predetermined limits, for example, programmed by a physician and / or device manufacturer. This prevents the patient from selecting harmful treatment protocol manipulations.

[0134] Such limiting or treatment governor functions can advantageously prevent a patient from radically altering their treatment in an uncontrolled manner that is very different from the most recent well-known operating point, which can advantageously prevent a patient from undergoing an inconsistent course of treatment that could reduce the therapeutic value of feedback regarding the patient's outcome.

[0135] In an embodiment, the system is configured to manage the maximum increment of any parameter change in the microenvironment.

[0136] In some embodiments, the system may send an electronic message or alert (e.g., email, text, phone call) to the physician when a patient attempts to extend a treatment protocol beyond the treatment protocol initialized in the system.

[0137] The device may include a housing with an LCD or LED display for displaying information to the patient, or may be a touch screen display. The housing may include a keypad for control, and jack(s) / socket(s) to receive wire(s) (leads / harness) for connecting to the EMF applicator or electrodes.

[0138] In some embodiments, the device and / or its components can be miniaturized for different configurations required for different treatment modalities.

[0139] The device may include one or more controllers / processors, each including a central processing unit for processing data and computer-readable instructions and memory. The device may be configured to apply a personalized programmed treatment protocol. The steps of the methods or treatment protocols described in connection with the embodiments disclosed herein may be directly implemented in hardware or executed by a processor in a software module. The memory may include volatile random access memory (RAM), non-volatile read-only memory (ROM), non-volatile magnetoresistive (MRAM) and / or other types of memory. The device may also include a data storage component for storing data and controller / processor executable instructions. The data storage component may include one or more non-volatile storage types such as magnetic storage, optical storage, solid state storage, etc. The device may be connected to removable or external non-volatile memory and / or storage (e.g., removable memory cards, memory key drives, network storage, etc.) via an input / output device interface.

[0140] The devices may be connected via any type of communication network implemented using wired infrastructure (e.g., cable, CATS, fiber optic cable, etc.), wireless infrastructure (e.g., WiFi, RF, cellular, microwave, satellite, Bluetooth, etc.), and / or other connection technologies. The devices may connect to the healthcare provider's network via either wired or wireless connections, which may further include local or private networks and / or the Internet. For example, the devices may be connected to the network via a WiFi connection or a cellular network connection through a wireless service provider. Network-connected support devices such as laptop computers, desktop computers, and servers may be connected to the network via wired or wireless connections.

[0141] Aspects of the systems disclosed herein may be implemented as a computer-implemented method or as a device or non-transitory computer-readable storage medium (e.g., floppy disk, CD-ROM, ROM, or fixed disk) or interface device (via a medium to a network). The computer-readable storage medium may be computer readable and may include computer-executable instructions for causing a computer or other device to perform the methods disclosed herein.

[0142] Some of the instructions executed during the execution of the method of the present invention are described with reference to operational flow charts. Those skilled in the art will understand that the functions, operations, decisions, etc. of all or part of each step or combination of steps in the flow charts or block diagrams can be implemented as computer program instructions, software, hardware, firmware, or combinations thereof. In addition, while the present invention may be embodied in software such as program code, the functions necessary to carry out the present invention are optionally or alternatively combined, in part or in whole, with combinatorial logic, firmware and / or hardware components such as application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), or other hardware, or some combination of hardware, software and / or firmware components.

[0143] Implementation of the disclosed embodiments based on the flowcharts and associated text descriptions sufficiently describes the invention, such that a particular set of program code instructions is not considered necessary for an adequate understanding of how to make and use the embodiments.

[0144] The methods and systems described herein provide several computational advantages: The methods efficiently and rapidly generate / transmit / maintain personalized patient-based microenvironment target signals; personalized treatment protocols and optional optimization enhancements can be achieved in near real-time.

[0145] (Interrelated factors - generation and delivery of EMF to produce desired biological responses in the microenvironment) FIG. 2 is a representation of the interconnected factors present in a microenvironment upon delivery of a theoretically idealized individualized microenvironment stimulation target signal.

[0146] The device's signal generator (20) is shown operatively connected to an EMF applicator (24) configured and positioned around the target microenvironment (M). Externally placed or tissue-level implanted EMF sensors (S) can monitor EMF induced in or near the microenvironment. The sensor data is fed into a feedback computation engine to continuously correct for inaccuracies in the macro-translation computation engine that dictates the EMF source output. Sensing of biological and functional progress can be continuous or periodic and includes one or more of the following steps: biosensor dynamic sensing of biochemical parameters in the microenvironment, patient self-assessment (e.g., pain levels) and compliance, and clinical follow-up. Biological sensing data is used to determine whether a biological response has been achieved as dictated by the personalized microenvironment stimulation target and is further incorporated into the unique clinical metadata.

[0147] Under the control of the signal generator (20), the EMF applicator (24) is positioned to induce a focused field (F) that encompasses the microenvironment (M) to stimulate a biological response at the cellular level (C). Such a positioning is to ensure that the entire microenvironment is exposed to the electromagnetic field and that the cells therein can experience the same magnetic forces and / or induced currents. With respect to bone injuries such as fractures, exposure can promote osteoblast differentiation and promote bone healing. Furthermore, EMF stimulation of cancerous tumors can selectively accelerate apoptosis of cancer cells. At the cellular level, the applied electromagnetic field can disrupt cell membranes, for example forming lipid nanopores for the passage of ions, activating many intracellular and physiological pathways. Mechanical actions at both the intracellular and cell membrane levels include ion channels, receptors, cytokines, enzymes, and peripheral inflammatory pain modulators (Ross CL et al., Altern Ther Health Med. 2016; 22:52-64). The behavior of cells in response to induced EMFs can be influenced by a number of patient-specific factors (x, y, z).

[0148] The signal used to generate the field (F) is a function of the microenvironment (M) with which it may need to interact, both its physical location and the behavior of the cells (C); the surrounding tissue (T); and the external media (Ex). The tissue (T) level includes the electrical properties of the various tissues surrounding the injury site, such as conductivity. External factors (Ex) encompass everything outside the body, such as the device configuration (e.g., a rigid support device such as a casting) and the configuration of the delivery system (e.g., coil size and number of turns, number of coils), or simply the air gap.

[0149] This expression will be specific to the injury and disease of the patient due to variations in the interconnected factors present in the microenvironment.

[0150] (Individualized Bioelectrical Treatment Protocols - Core Elements) 3 is a treatment flow chart illustrating the steps of the personalized stimulation therapy of the present invention. The sequence is for use as a treatment for injury or disease, and is further operatively applicable to the clinical embodiments described herein. The reference numbers in [square brackets] below refer to elements of the numbered sequence of FIG. 3.

[0151] Patients [1] presenting with an injury or disease are diagnosed and subsequently recommended bioelectromagnetic therapy by medical professionals (with associated counterindications) [2]. Commercial implementations of bioelectromagnetic therapy are divided into a microenvironmental translation, describing factors influencing the microenvironment of the injury / disease, a macro-translation, including details regarding the macroenvironment surrounding the microenvironment, and a component related to the electromagnetic field generating device itself.

[0152] Prior to application of the therapy, the location of the damaged or diseased tissue, the target volume, and the relative locations and types of normal tissue are determined by imaging and other medical techniques, as will be understood by those skilled in the art. Using this information, and optionally methods similar to those used in radiation therapy planning, external (fiducial) marks can be placed on the patient's surface as anatomical markers to provide a reference coordinate system for targeting the target volume of damaged or diseased tissue within the body. In addition, a physical assessment and analysis of the patient's past medical condition is performed [3], generating the following organized collection of data that is used to inform the physics-based computational engine: “Biological questions” – these are data related to the unique details of the patient’s injury or disease beyond just the type of injury / disease that may affect the microenvironment, for example, severity, current state of recovery, or the success or failure of previous treatments [3a]; “Patient profile” – data describing the patient’s overall characteristics and condition and how such condition affects the microenvironment. This may include demographic characteristics such as age, sex, height and weight, the patient’s comorbidities, smoking status, current medications or pre-existing medical conditions [3b]; "Transmission Path" - the path separating the microenvironment and the EMF source is influenced by the material properties and physical dimensions of the tissues and materials along the signal path. These path-dependent properties affect the delivery of the required stimulation signal [3c]; “Placement Specifications” – This describes the mode of electromagnetic field generation and the physical structure of the device that is configured for the individual patient and that patient’s injury / disease[3d].

[0153] All of the patient-specific information data is fed into a series of physics-based computational engines that are able to calculate effective treatment plans and optimize such plans in relation to the patient and the particular microenvironment of the patient being treated.

[0154] First, a "microenvironment computation engine" utilizes physics-based algorithms in combination with the patient-specific biological challenge and patient profile to calculate a theoretically ideal "personalized microenvironment stimulation target" [4]. The microenvironment computation engine also incorporates data from a continuously updated database of clinical metadata and proprietary experimental data so that treatment is optimized and completed [4a]. These additional parameters aid in the calculation of the initial personalized microenvironment stimulation target by considering data from similar patients, similar injuries, and / or similar diseases.

[0155] The personalized microenvironment stimulation targets are sent to a "macro-translation computation engine" [5], which uses macro-parameters such as the location and size of the injury / disease and device, as well as the "daisy-chain" of material properties separating the device and the microenvironment [5a] to calculate a "personalized treatment protocol." The personalized treatment protocol describes the initial settings (i.e., frequency, intensity and waveform of the signal sent to the active EMF generating elements) required to achieve the personalized microenvironment stimulation targets in the microenvironment. Additionally, the treatment protocol includes the daily exposures and expected treatment duration.

[0156] Patients receive a personalized treatment protocol [6a] based on their compliance with the recommended treatment, whereby the patient's microenvironment receives electromagnetic stimulation that is, ideally, the very personalized microenvironment stimulation target [6b].

[0157] Optionally, the treatment includes an optimization extension with two further computation engines that obtain information from a series of sensors at the micro and macro levels and provide feedback (dashed connector lines) to optimize the micro-environment computation engine and the macro-translation computation engine.

[0158] The first optional optimization engine is a "feedback calculation engine" [7] that takes input from EMF sensors [7a] in or near the microenvironment to determine and correct differences between the microenvironment stimulation targets and the actual measured EMF as a result of inaccuracies in the macro-translation calculation engine. Corrections are sent as feedback to parameters that affect the calculation of the personalized treatment protocol.

[0159] Throughout treatment, progress data are collected via clinical follow-up[8a] and clinical sensors[8b], including updated clinical assessments including, for example, radiographic or functional assessments, biomarker assays, real-time biosensors, compliance metrics, or direct input from the patient (e.g., pain scores and / or compliance scores on a visual analog scale).

[0160] The "learning computation engine" [9] uses input from follow-up observations and / or sensor data to provide a final round of optimization during active treatment via a self-contained feedback loop. The treatment protocol consists of the following sequence: i. gradually adjusting individual parameters of the treatment protocol (e.g., increasing or decreasing the frequency or intensity of stimulation by approximately 5%); ii. monitor the effects of small changes; iii. Collecting sensor data and mapping patient-specific response profiles for each parameter; and iv. Select the optimal combination of settings for patient recovery and output an optimized treatment protocol It has been optimized to compensate for inaccuracies in the microenvironment calculation engine via

[0161] The intermediate and final results of the bioelectromagnetic therapy, including all relevant patient information, are fed back into the system to improve the treatment of both current and future patients, respectively

[10] . The intermediate results [10a] are fed back into the microenvironment computation engine to improve the current stimulation targets. The final results [10b] are used to update the collection of clinical metadata that is used to compute personalized microenvironment stimulation targets for future patients.

[0162] (Implementation - Bioelectromagnetic Treatment Planning) These embodiments are provided for illustrative purposes only and are not intended to be limiting unless specifically stated, and as such, the invention should in no way be construed as being limited by the following study, but rather should be construed to encompass any and all variations that become evident as a result of the teachings provided herein.

[0163] Personalized Bioelectrical Treatment Protocols for Bone Figures 4(A) and 4(B) show a treatment flow chart illustrating the steps of the personalized stimulation therapy of the present invention from diagnosis to the end of treatment for the treatment of a fracture. As a representative non-limiting clinical example, the protocol is presented for a non-union fracture. The following reference numbers refer to the numbered sequence elements of Figures 4(A) and (B).

[0164] 1. Symptoms: A patient presents to the healthcare provider with pain from a tibial fracture several months ago that has persisted despite previous treatment(s). 2. Diagnosis: A medical professional evaluates the fracture (radiographically and functionally) and diagnoses the patient with a nonunion fracture. 3. PEMF Therapy Recommended: Healthcare professionals recommend Bioelectromagnetic Therapy using a non-invasive, individualized (patient-specific) Pulsed Electromagnetic Field (PEMF) therapy device to enhance the body's natural healing process. Indications for use include fracture gaps less than 5mm, no synovial fluid, mechanical alignment, no significant atrophy, etc. 4. Collect Patient Data: The practitioner collects patient historical data and interprets the clinical assessment to determine: a. Collect details of the injury, called the “biological challenge”, based on radiographic and functional assessment of the fracture, providing a definition of the microenvironment and its treatment history [4a]; b. patient profile, including age, sex, body mass index, smoking, and comorbidities that may affect the microenvironment and its susceptibility to electromagnetic stimuli [4b]; c. the propagation pathway, which is a description of the tissues and materials (and their mechanical and electrical properties) that separate the microenvironment and the EMF source [4c]; d. The placement specification includes the selection of the electromagnetic therapy mode by the healthcare professional, a physical description of the device, and how it is connected to the patient.[4d] 5. Prescription of personalized microenvironment stimulation targets: The microenvironment computation engine uses data from the biological challenge [4a] and the patient profile [4b], as well as the following parameters: a. Clinical metadata on tibial nonunion (collected from previous clinical trials or literature, and previous patients) and original experimental data, including animal study data or in vitro results (e.g., the effect of PEMF on osteoblasts) [5a] By incorporating these parameters, we calculate the electromagnetic target to effectively stimulate bone repair at the fracture site. These parameters [5a] are continuously updated and are primarily used to estimate the range of the personalized microenvironment stimulation target, while 4a and 4b are used to generate targets that are truly personalized to the patient and their injury. 6. Calculation of the personalized treatment protocol: The macro-translation computation engine calculates the EMF source signal parameters (amplitude, frequency, waveform, etc.) that need to be delivered to the treatment coil to generate the desired stimulation target in the microenvironment. Additionally, the calculation is performed taking into account: Parameters that physically describe factors between the microenvironment and the device, such as the depth to the fracture, the size and shape of the treatment coil, and the conductivity and / or attenuation of muscle, bone or fabric (to name a few) with which the EMF may interact. These factors derive directly from 5c and 5d. 7. Initiation of treatment according to the individualized treatment protocol: a. Patients wear a prescribed active therapeutic device for at least 6 hours per day for a period of at least 6 months [7a]; b. The microenvironment receives stimuli that are ideally matched to the microenvironmental stimulus target [7b]. 8. In or near the microenvironment, an EMF sensor [8b] detects the difference between the target stimulus and the actual electromagnetic stimulus: The feedback computation engine receives input from the EMF sensor [8b] and sends feedback to update the parameters of the macro-translation computation engine to compensate for the difference between the personalized microenvironment stimulus target and the actual electromagnetic quantity detected by the sensor. This feedback occurs for the current patient. 9. Data reflecting progress towards union will be collected: Information will be collected during treatment using the following methods: Clinical Follow-up - Radiographic and functional evaluations are performed and compared with previous results. In addition, blood and serum tests are performed to measure the expression of biochemical factors in the microenvironment. b. Clinical sensors - all forms of in vivo biosensors c. Patient Compliance - The device tracks compliance by daily exposure time. 10. Learning and Optimizing Individualized Treatment Protocols: To compensate for inaccuracies in the microenvironment computation engine, the learning computation engine accepts the sensor data and the current treatment protocol and executes a self-contained feedback loop that includes the following steps: i. Stepwise adjustment (±5~10%) of EMF source parameters such as frequency, driving voltage or waveform shape; ii. Monitor (via sensors) the impact of each change; iii. Collect data and map the reaction profile by repeating these three steps; iv. Select the optimal combination of settings to continue treatment. 11. The results will be used as feedback for current and future patients: a. The intermediate results serve as feedback for the current patient. Further follow-up and progress after optimization will be used as feedback to the microenvironment computation engine to further refine the personalized microenvironment stimulation targets [11a]; b. Update the metadata using the final results: Upon successful completion of the treatment (union achieved), the individualized stimulation targets, treatment protocol and all patient-specific data are used to update the clinical metadata of the tibial non-union fracture, which is then incorporated into the computational physics engine for future patients [11b].

[0165] Prescribed PEMF device configurations are shown in Figures 5(A) and 5(B). Figure 5(A) shows a signal generator (100) controlling an EMF source (130) (i.e., coil) positioned to induce a focused field (F) that encompasses the microenvironment (M) to stimulate a biological response (C) at the cellular level. The EMF device components, power source (120), amplifier (110), and signal generator (100) are operatively connected via wires / leads to the EMF source (130), each positioned substantially adjacent to the fracture and a sensor (140). The hardware is positioned such that the individualized EMF stimulation signal encompasses the fracture region (150). Figure 5(B) shows two configurations of the EMF applicator (130) shaped to the placement area for treatment, either as a parallel coil (160) or a shaped coil (170). Figure 5(C) is an expanded schematic of the tibial nonunion fracture microenvironment (M), illustrating the theoretically ideal PMST signal delivery and how it influences interconnected factors present in the fracture microenvironment, similar to those described with respect to Figure 2.

[0166] Example 1 presents experimental data demonstrating the variability in the response of cells from a particular donor and between different donors to different EMF stimuli, supporting the need for the described individualized bioelectrical treatment protocol for the treatment of bone, as demonstrated in non-union fracture healing.

[0167] ( Personalized Bioelectrical Treatment Protocols - Cancer) 6 shows a flow chart of a treatment method showing the steps of the personalized stimulation therapy of the present invention from diagnosis to the end of treatment for the treatment of cancer. The personalized electrical stimulation is applied to the cancerous tumor as a form of adjunctive treatment in combination with an appropriate chemotherapy regimen. As a non-limiting representative example of a clinical embodiment of cancer, the protocol is presented for glioma.

[0168] The following reference characters refer to the numbered sequence elements in FIG. 1. Diagnosis: A patient is diagnosed with a glioma brain tumor that requires treatment to stop the rapid growth of the cancer cells. 2. Evaluation and indications for electrical stimulation: When considering eligibility for bioelectromagnetic stimulation therapy, physicians will scan the affected tissue and review any previous tumor treatment history. 3. Prescribe adjunctive bioelectromagnetic therapy: A healthcare professional recommends electromagnetic field stimulation (using a personalized capacitively coupled bioelectromagnetic therapy device) as an adjunct to chemotherapy. a. The combination allows for lower chemotherapy doses and fewer harmful side effects compared to chemotherapy alone [3a]; b. Bioelectromagnetic therapy specifically targets cancer cells within tumors with the goal of inducing apoptosis (cell death) [3b]. 4. Chemotherapy drug plan: Oncologists will develop a drug plan that focuses on attacking the cancerous tumor. 5. Patient Data Collection for Bioelectromagnetic Therapy: The practitioner will use clinical and historical evaluations to define: a. Biological question data include the stage of the cancer, the likelihood / extent of metastasis, and the relative success of previous chemotherapy / radiotherapy treatments [5a]; b. patient profile, including age, sex, body mass index, smoking, comorbidities, etc. that may affect the microenvironment and its susceptibility to electromagnetic stimuli [5b]; c. The propagation pathway accounts for the physical size and location of the tumor, as well as the electrical properties of both cancerous and healthy tissue that separate the microenvironment from the stimulating electrode [5c]; d. Placement specifications – The active electrodes are integrated into a headpiece that maintains field focus and is comfortable to wear all day [5d]. 6. Calculation of personalized microenvironment stimulation targets: A microenvironment computation engine is used to calculate the initial stimulation targets required to disrupt tumor-specific cell division. Stimulation is delivered via a low-intensity electric field induced into the tumor alternating at less than 150 kHz. The engine incorporates data from the biological challenge [5a] and patient profile [5b], as well as the following parameters: a. Clinical metadata and original experimental data regarding the treatment of glioma with chemotherapy and / or bioelectromagnetic therapy [6a]. 7. Calculate the Individualized Treatment Protocol: The macro translation calculation engine calculates the signal required to meet the stimulation target, which is a square wave of less than 150 kHz, with a peak-to-peak drive voltage of 18V. The treatment protocol is considered to continue indefinitely until adequate progress is confirmed by the medical professional. The calculation is made taking into account: a. The electrical properties of the tumour and brain tissue, as well as the size, shape and position of both the tumour and the electrode[7a]. 8. Initiate treatment according to individualized treatment protocol and physiotherapy regimen: a. Patients wear the headpiece during daily activities and while sleeping [8a]; b. The microenvironment receives stimuli that are ideally matched to the stimulation target [8b]; c. The patient begins chemotherapy.[8c] 9. The EMF sensor [9a] detects the difference between the target stimulus and the stimulus provided by the treatment protocol in or near the microenvironment: The feedback computation engine receives the input from the EMF sensor [9a] and sends feedback to update the parameters of the macro-translation computation engine to compensate for the difference between the individualized microenvironment stimulus target and the actual value detected by the sensor. This feedback occurs for the current patient. 10. Regular follow-up by oncologist: Every month, the patient will be re-evaluated by the oncologist and the drug plan will be updated, if necessary. 11. Sensor Data Collection and Follow-Up Assessment: Information will be collected during treatment using the following methods: a. Clinical follow-up – brain scans of the tumor are compared with previous results[11a]; b. Clinical sensors - all forms of in vivo biosensors[11b]; c. Patient Compliance - The device tracks compliance via daily active exposure time [11c]. 12. Learning and Optimizing Individualized Treatment Protocols: The learning computation engine uses the sensor data and the current treatment protocol to correct inaccuracies in the microenvironment computation engine, implementing a self-contained feedback loop that includes the following steps: i. Adjust the parameters of the EMF source in steps (±5~10%); ii. monitoring (via sensors) the effects of each change; iii. Collect data and map the reaction profile by repeating these first three steps; iv. Select the optimal combination of settings for continuing treatment. 13. The results will be used as feedback for current and future patients: a. The intermediate results serve as feedback for the current patient. Further follow-up and progress after optimization will be used as feedback to the microenvironment computation engine to further refine the personalized microenvironment stimulation targets [13a]; b. Update the metadata using the final results: Upon successful completion of the treatment, the personalized stimulation targets, treatment protocols, chemotherapy plans, and all patient-specific data are used to update the clinical metadata of the glioma treatment, which is then incorporated into the physics-based computational engine for future patients [13b].

[0169] The configuration of the prescribed capacitively coupled EMF device is shown in Figures 7A-7B. Figure 7A shows the components of the EMF device and the location of the EMF applicator substantially adjacent to the tumor for individualized EMF stimulation to encompass the tumor. Figure 7B is a close-up schematic of the tumor microenvironment showing the theoretically ideal delivery of a PMST signal and how it may affect the interconnected biological factors present in the tumor microenvironment, similar to that described with respect to Figure 2.

[0170] The experimental data presented in Example 2 demonstrate that EMF therapy inhibits cell proliferation in breast cancer cells and also enhances chemotherapy efficacy, supporting the need for individualized bioelectrical treatment protocols to be described in the context of cancer treatment.

[0171] ( Personalized Bioelectrical Therapy Protocols for Pain Management Figure 8 shows a treatment flow chart illustrating the steps of the personalized stimulation therapy of the present invention from diagnosis to the end of treatment for promoting pain relief. As a non-limiting representative example of a clinical embodiment of pain relief, a protocol for chronic pain due to knee osteoarthritis is presented. The following reference numbers refer to the numbered sequence elements of Figure 8. 1. Chronic Knee Pain: Patients present with pain and stiffness in the knee joint with movement or prolonged immobility. 2. Diagnosis: A healthcare professional takes an x-ray of the affected knee, performs a functional assessment, and diagnoses osteoarthritis of the knee. 3. Prescribe a combination of physical therapy and bioelectromagnetic therapy: Healthcare professionals recommend pulsed electromagnetic field stimulation (using a personalized bioelectromagnetic therapy device) as an adjunct to traditional physical therapy. a. Physical therapy aims to strengthen the tissues around the joint, reduce stiffness and improve range of motion [3a]; b. Bioelectromagnetic therapy targets the osteoarthritis microenvironment to promote cellular activity that relieves pain.[3b] 4. Physical Therapy Regimen: Your physical therapist will use the x-ray results and their own assessment to develop a plan of exercises and stretches focused on strengthening the muscle groups around the knee joint and increasing range of motion. 5. Bioelectromagnetic Therapy Patient Data Collection: The practitioner will use the patient's historical data and physical and radiographic evaluations to define: a. Biological task data included the degree of articular cartilage degeneration, pain measured on a visual analogue scale (VAS), and treatment history [5a]; b. patient profile, including age, sex, body mass index, smoking, comorbidities, etc. that may affect the microenvironment and its susceptibility to electromagnetic stimuli [5b]; c. The propagation pathway defines the electrical properties and relative position / geometry of the surrounding microenvironment of cartilage, bone, muscle and tendon [5c]; d. Placement Specifications – Circular / elliptical stimulation coils are incorporated into a supportive knee brace with one coil placed on each side of the knee joint [5d]. 6. Calculation of personalized microenvironment stimulation targets: A microenvironment calculation engine is used to calculate initial stimulation targets aimed at alleviating chronic symptoms of knee osteoarthritis. Stimulation is delivered via frequencies below 100Hz and magnetic flux densities B<1.5mT induced within the microenvironment. The engine incorporates data from the biological challenge [5a] and patient profile [5b], as well as the following parameters: a. Clinical metadata related to knee osteoarthritis and original experimental data, including animal study data or in vitro results (e.g., downregulation of interleukin-1β in vitro)[6a]. 7. Calculation of personalized treatment protocols: The macro-translation calculation engine calculates the signal required to match the microenvironmental stimulation targets to a sine wave with B<5mT and less than 100Hz. Treatment protocols require activation of the device twice a day for 1 hour for at least 4 weeks each. The calculation is performed taking into account: a. The electrical properties of the interacting medium, the size of the joint cavity, and the size, shape and position of the coil [7a]. 8. Initiate treatment according to individualized treatment protocol and physiotherapy regimen: a. Patients wear a supportive brace whenever possible and undergo two activity sessions daily [8a]; b. The microenvironment receives stimuli that are ideally matched to the stimulation target [8b]; c. The patient performs daily exercises and stretches as recommended by the physical therapist.[8c] 9. The EMF sensor [9a] detects the difference between the target stimulus and the stimulus delivered by the treatment protocol in or near the microenvironment: The feedback computation engine receives the input from the EMF sensor [9a] and sends feedback to update the parameters of the macro-translation computation engine to compensate for the difference between the individualized microenvironmental stimulus target and the actual value detected by the sensor. This feedback occurs for the current patient. 10. Regular Physical Therapy Appointments: Every two weeks, the patient will visit the physical therapist and the physical therapy plan for the following two weeks may be updated. 11. Sensor Data Collection and Follow-Up Assessment: Information will be collected during treatment using the following methods: a. Clinical follow-up – radiological and functional evaluations are performed and compared with previous results [11a]; b. Clinical sensors - all forms of in vivo biosensors[11b]; c. Patient compliance – the device tracks compliance via daily active exposure time [11c]; d. Daily VAS score - Before and after each set of two daily sessions of EMF exposure, patients are required to record their level of pain using a VAS score. Data is recorded using a user interface via an internet-connected mobile device [11d]. 12. Learning and Optimizing Individualized Treatment Protocols: The learning computation engine uses the sensor data and the current treatment protocol to correct inaccuracies in the microenvironment computation engine, implementing a self-contained feedback loop that includes the following steps: i. Adjust EMF source parameters stepwise (±5~10%); ii. monitoring (via sensors) the effects of each change; iii. Collect data and map the reaction profile by repeating these first three steps; iv. Select the optimal combination of settings for continuing treatment. 13. The results will be used as feedback for current and future patients: a. The intermediate results serve as feedback for the current patient. Further follow-up and progress after optimization will be used as feedback to the microenvironment computation engine to further refine the personalized microenvironment stimulation targets [13a]; b. Update the metadata using the final results: Upon successful completion of the treatment, the personalized stimulation targets, treatment protocol, physical therapy plan, and all patient-specific data are used to update the clinical metadata of knee osteoarthritis-associated pain, which is then incorporated into the physics-based computational engine for future patients [13b].

[0172] The prescribed PEMF device configuration is shown in Figures 9A-9B. Figure 9A shows the components of the EMF device and the location of the EMF applicator substantially adjacent to the knee joint for personalized EMF stimulation to encompass the source of pain. Figure 9B is an expanded schematic of the knee joint microenvironment showing the theoretically ideal delivery of a PEMF signal and how it may affect the interconnected biological factors present in the knee joint microenvironment, similar to that described with respect to Figure 2.

[0173] The experimental data presented in Example 3 demonstrate inter- and intra-donor variability in pain-related gene expression in human astrocytes associated with different EMF stimulation profiles, confirming the need for the described individualized bioelectrical treatment protocol for pain management.

[0174] (Scope of treatment) The personalized bioelectromagnetic therapy methods, devices and systems described herein are suitable for non-invasive or invasive treatment of injuries or diseases, and advantageously do not have the negative side effects of pharmacological treatments. However, they can be used in combination with pharmacological treatments. Furthermore, they can be used before other treatments, after completing a different treatment approach, or in combination with other therapeutic and preventative procedures and modalities, such as high temperature, low temperature, ultrasound, wound dressings, orthopedic fixation devices, and surgical interventions.

[0175] Treatment of injuries or diseases includes, but is not limited to, cancer, cardiovascular disease, inflammatory diseases, autoimmune diseases, neurological diseases, musculoskeletal pain management, wound repair, bone repair, osteoporosis, tissue repair, trauma rehabilitation, sports injuries and surgical rehabilitation. Injuries and diseases are not limited.

[0176] The methods of the present invention modulate physiologically relevant pathways of the targeted injury / disease microenvironment, such as general transmembrane potential changes that are involved in injury or disease stabilization, reversal, and healing. Some of the physiologically induced changes may include variations in cell membranes, enzyme activity, cell apoptosis, nerve conduction, collagen synthesis, vasodilation, vasoconstriction, fluid / blood viscosity, pain signaling, endorphin production, tissue metabolism, inflammation, oxygen & nutrient supply, tissue / muscle repair or healing, fibroblast activity, collagen fiber density, protein synthesis, and tissue regeneration.

[0177] The methods of the present invention also provide improved means for increasing blood flow and biochemical activity through the action of exogenous factors (e.g., growth factors and cytokines) to accelerate cell, organ and tissue repair and to regulate angiogenesis and neovascularization.

[0178] The methods of the present invention may modulate the activity of a variety of biochemical molecules / markers involved in promoting the healing of injury or disease. Non-limiting representative examples include cytokines, growth factors, tumor markers, inflammatory markers, endocrine markers and metabolic markers.

[0179] Exemplary growth factors can include EGF ligand, EGF, TGFα, the EGFR / ErbB receptor family, the FGF family, the IGF family, the IGF binding protein (IGFBP) family, receptor tyrosine kinases, proteoglycans, the TGFβ superfamily, and the VEGF / PDGF family.

[0180] Exemplary inflammatory markers may include ICAM-1, RANTES, MIP-2, MIP-1β, MIP-1α, MMP-3, adhesion molecules, vitronectin, fibronectin, collagen, laminin, ICAM-1, ICAM-3, BL-CAM, LFA-2, VCAM-1, NCAM, PECAM, cytokines such as the IFN family, chemokines, tumor necrosis factor (TNF), TNF superfamily receptors and modulators, TGFβ, superfamily ligands BMP (bone morphogenetic proteins), EGF ligand, fibrinogen, glial markers, (MHC) glycoproteins, microglial markers, α2 macroglobulin receptor, fibroblast growth factor, angiogenic factor-1, MIF, angiogenic factor-2, CD14, β defensin 2, MMP-2, nitric oxide, endothelin-1, and VEGF.

[0181] Exemplary cytokines can include FGF basic, G-CSF, GCP-2, granulocyte macrophage colony stimulating factor GM-CSF (GM-CSF), proliferation-related oncogene-keratinocyte (GRO-KC), HGF, ICAM-1, IFN-α, IFN-γ, interleukin, interferon-inducible protein, MCP-1, macrophage inflammatory protein, tumor necrosis factor family, VCAM-1, and VEGF.

[0182] Exemplary tumor markers can include EGF, TNF-α, PSA, VEGF, TGF-β1, FGFb, TRAIL, and TNF-RI (p55).

[0183] Exemplary markers of endocrine function can include 17β-estradiol (E2), DHEA, ACTH, gastrin, and human growth hormone (hGH).

[0184] Exemplary markers of autoimmune function can include GM-CSF, C-reactive protein, and G-CSF.

[0185] Exemplary cardiovascular markers may include cardiac troponin I, cardiac troponin T, brain natriuretic peptide, NT-proBNP, C-reactive protein HS, and beta thromboglobulin.

[0186] Exemplary metabolic markers can include biointact PTH(1-84) and PTH.

[0187] In some embodiments, the individualized bio-electromagnetic targeting signals can affect stem cell homing signals (SDF-1 and PDGF), stem cell differentiation signals, blood vessel growth signals, and organ-specific tissue architecture signals in vivo.

[0188] In some embodiments, the bioelectromagnetic targeting signal can affect vascular growth factors in vivo, such as VEGF, SDF-1, PDGF, HIF 1α, eNOS, tropoelastin, HGF, and EGF.

[0189] In some embodiments, the personalized bioelectromagnetic targeting signal can affect in vivo, for example, SDF-1, IGF-1, HGF, EGF, PDGF, eNOS, VEGF, follistatin, activin A and B, relaxin, tropoelastin, GDF-10, GDF-11, and neurogenin-3.

[0190] In one embodiment, the personalized bio-electromagnetic target signal can affect in vivo a protein selected from the group consisting of SDF-1, IGF-1, HGF, EGF, PDGF, VEGF, HIF 1α, eNOS, activin A, activin B, IL-6, follistatin, tropoelastin, GDF-10, GDF-11, neurogenin 3, FGF, TGF, TNFα, RANKL, OPG, and combinations thereof.

[0191] In some embodiments, the personalized bio-electromagnetic targeted signals can affect the activity of osteoblasts, osteocytes, osteoclasts, fibroblasts, chondrocytes, keratinocytes, endothelial cells, epithelial cells, mature macrophages, and granulocytes in vivo.

[0192] In one embodiment, the personalized bio-electromagnetic targeted signal can be influenced in vivo to stimulate pluripotent adult stem cells (mesenchymal stem cells or bone marrow stem cells) to promote proliferation and differentiation of pluripotent adult stem cells into specific pathways such as bone, connective tissue, or fat.

[0193] In certain embodiments, bioelectromagnetic methods according to the present disclosure may be applied to the treatment of osteoarthritis and associated pain and / or inflammation in peripheral structures such as the inflamed knee joint, where neurochemical and metabolic changes in the area of ​​the inflamed knee joint result in chronic pain.

[0194] In some embodiments, the bioelectromagnetic methods disclosed herein may be applied to the treatment of damaged or diseased bones to promote the growth and repair of bone tissue in vivo. The bone microenvironment is composed of intercellular mineralized material, osteoblasts, osteocytes and osteoclasts, while the extracellular matrix contains organic components of collagen, proteoglycans, hyaluronic acid and other proteins, phospholipids and growth factors. The mineralized inorganic components are mainly crystallized calcium and phosphorus in the form of hydroxyapatite. The methods described herein have the effect of releasing BMP-2, BMP-7 for osteoblast proliferation and differentiation, increasing the number of osteoblasts for mineralization, enhancing the mineralization process and ossification of new bone tissue, regulating calcium / calmodulin mediated action and the activity of G protein-coupled receptors and mechanoreceptors, and increasing bone density in vivo. This enhances the generation of sufficient tissue for proper tissue healing in vivo.

[0195] The bioelectromagnetic therapy methods described herein are suitable for accelerating the healing of bone fractures, including but not limited to those occurring accidentally or following intentional surgical intervention, to promote vertebral fusion following spinal fusion surgery and to treat osteopenia and osteonecrosis.

[0196] More specifically, fractures are classified into simple and compound fractures, which occur when a bone breaks but does not break through the epidermis (closed fracture); compound fractures, also known as open fractures, which are the opposite of simple fractures and involve dislocation of the bone that breaks through the epidermis and is therefore more susceptible to infection; oblique fractures, where the crack runs diagonally to the axis of the bone; transverse fractures, which are perpendicular to the axis of the bone; spiral fractures, which involve a fracture line that twists around the bone; comminuted fractures, where the bone is broken into several pieces; liner fractures, where the break is parallel to the long axis of the bone; greenstick fractures, where one side of the bone is intact; and partial fractures, where the bone splits into two pieces. They are subdivided into impact fractures; complete and incomplete fractures; compression fractures, where at least two bones are forced against one another; avulsion fractures, which occur when a bone breaks due to the forceful contraction of muscles; fatigue fractures (hairline fractures) due to overuse; displaced fractures, where the bone splits into two pieces such that it loses its alignment; non-displaced fractures, where the bone breaks into two pieces but remains aligned; stress fractures, where the bone undergoes trauma due to everyday stressors that cause weakness over a period of time; and pathological fractures as a result of intrinsic health conditions, such as osteoporosis or when cancer cells have spread to the bone.

[0197] In aspects, the methods are used to accelerate the healing of damaged or torn cartilage associated with injured bone.

[0198] In aspects, the methods are used to treat bone diseases, including, but not limited to, osteoporosis, metabolic bone disease, bone cancer, and scoliosis.

[0199] In aspects, the methods are used to treat joint diseases, including, but not limited to, osteoarthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, lupus, gout, and bursitis.

[0200] In some embodiments, bioelectromagnetic methods according to the present disclosure may be applied in combination with surgery, radiation therapy, and chemotherapy to treat cancer, including, but not limited to, breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain tumors (gliomas), head and neck cancer, colon cancer, osteosarcoma, small cell lung tumors, smooth muscle tumors, osteosarcomas, and other sarcomas.

[0201] In brain tumor (e.g., glioma) embodiments, the personalized bioelectromagnetic methods described herein can reduce uncontrolled cell division and help regenerate healthy, functional tissues / organs after cancer tumor eradication, including, for example, proteins involved in stem cell homing, proliferation control, differentiation and vascular sprouting, growth and maturation expression.

[0202] In some embodiments, personalized bioelectromagnetic methods according to the present disclosure can be applied to the treatment of pain-related disorders, where the therapeutic response includes a reduction or elimination of the pain experienced by the patient. Examples of pain-related disorders include, for example, pain responses induced during tissue injury (e.g., inflammation, infection, and ischemia), and pain associated with musculoskeletal disorders (e.g., joint pain such as that associated with arthritis, toothache, and headaches).

[0203] In some implementations, personalized bioelectromagnetic methods according to the present disclosure may be applied to reduce or eliminate pain associated with injury or disease, which may include, but are not limited to, adhesive capsulitis, tennis elbow, osteoarthritis, lower back pain, multiple sclerosis, tendon inflammation, and carpal tunnel syndrome.

[0204] In some implementations, personalized bioelectromagnetic methods according to the present disclosure can be applied to treat patients with bone, joint, soft tissue, or connective tissue disorders, where the methods reduce or eliminate inflammation in the patient's bone, joint, soft tissue, or connective tissue, thereby reducing or eliminating pain associated with the disorder.

[0205] In some implementations, personalized bioelectromagnetic methods according to the present disclosure can be applied to treat dental conditions, where the treatment response includes reduction or elimination of pain associated with the dental condition.

[0206] In some implementations, personalized bioelectromagnetic therapy according to the present disclosure may be applied to treat patients with post-traumatic and post-operative pain and swelling in soft tissues, wound healing, burn treatment, and nerve regeneration. In aspects, this is by reducing the inflammatory response associated with painful conditions. The personalized bioelectromagnetic therapy described herein targets calcium ("Ca"), which binds to calmodulin ("CaM"). 2+ "), which in turn can inhibit inflammatory leukotrienes, reducing the inflammatory process.

[0207] ( EMF Device Configuration) The electromagnetic field device is used to provide the personalized self-adaptive bioresponsive bioelectromagnetic therapy described herein and includes components for generating personalized microenvironment stimulation targets and implementing personalized treatment protocols for patients. The device can be configured in a variety of ways as prescribed by a medical professional for a patient depending on the injury or disease.

[0208] In either configuration, the device is programmable to perform personalized microenvironment stimulation targets and transmit personalized treatment protocols for the patient. One or more processor(s) / control module(s) are integral to the device and / or external to the device and are configured to receive the device's operational signals via the healthcare provider's electronic computing device (e.g., smartphone, laptop, tablet, etc.). In one non-limiting example, a Bluetooth chip can be provided in the device and in the transceiver unit of the wearable device to transmit treatment and sensor data from the device to the electronic computing device and / or transmit operational commands from the electronic computing device to the EMF device. Data can be wirelessly transmitted from the computer-implemented platform described herein to cloud storage and vice versa. Some or all of the components of the therapeutic electromagnetic field supplying device may be incorporated into a control circuit chip to miniaturize the device for various configurations. A timing circuit can be provided in the device or a remote microcontroller, configured to automatically cycle between supplying electromagnetic waves and off-time periods.

[0209] In embodiments, conductive contact of the device with an anatomical region is not required to induce a current in tissue. As a non-invasive device, the more prepared the patient is to experience and comply with the method involving its use, the better the outcome may be. Furthermore, non-invasive methods avoid possible adverse effects on living tissue, are generally painless, and can be performed without the risk of surgery or the need for local anesthesia. The use of non-invasive procedures by medical professionals utilizing the devices described herein does not require much training, making them suitable for use at home by patients or family members, or by first responders at home or at work.

[0210] In a further embodiment, the device is configured to ensure that the conductive coil is positioned immediately adjacent to the treatment target area.

[0211] In still further embodiments, for some applications, the device or components thereof may be configured for implantation into a patient.

[0212] The device may be stationary (i.e., fixed), portable, disposable, and / or implantable. The device may be configured as a standalone device of any size, for use at home, in a clinic, hospital, treatment center, and / or outdoors. The device may be suitable for long-term or intermittent use. In some implementations, the device may be placed directly over / juxtaposed / substantially adjacent to an anatomical region of a patient to provide bioelectromagnetic therapy to the microenvironment of an injury or disease in that region.

[0213] Static configurations may include, but are not limited to, incorporation into furniture (e.g., beds) for example, with respect to a mattress that provides whole-body bio-electromagnetic treatment to a patient during periods of rest and / or sleep. The mattress may include a plurality of current carrying interconnected coils arranged in a desired pattern and operably connected to an EMF source. Other configurations may include integration with mattress pads, cushions, sheets, pillows, blankets, wheelchairs, chairs, automotive body supports, exercise devices, and other therapeutic and wellness devices as understood by those of skill in the art.

[0214] Alternatively, the device may be configured as a wearable device that provides an ergonomic fit to a specific anatomical region (e.g., head, neck, chest, shoulder, knee, foot, ankle, back, wrist, and elbow) of a patient's body that has an injury or disease and applies a personalized treatment protocol to a target microenvironment. The wearable device may be unisex, configured in any shape and size to fit any patient, lightweight, hands-free (once placed on the patient's body), and portable, in embodiments incorporating, attached to, or implanted with a rechargeable and replaceable battery (or wireless operating configuration); a central processing unit; a wireless transceiver; an optional display for input or status monitoring; a power switch; and a bio-electromagnetic EMF circuit comprising one or more sensors and one or more coils. As a wearable device, components may be miniaturized as needed.

[0215] Wearable devices may include, but are not limited to, anatomical wraps, anatomical supports, clothing, chest supports (e.g., bras), hats / caps / helmets, footwear (e.g., sneakers, boots), fashion accessories (e.g., bracelets), dressings, bandages, compression bandages, and compression dressings. In embodiments of anatomical wrap devices, such devices are shaped to surround a particular area of ​​the patient's body in need of treatment, such as, for example, an arm, leg, head, neck, or hand.

[0216] The wearable wrap device includes a means for securely fastening the device to an anatomical site, e.g., a therapeutic target, on a patient's body, e.g., with a reversible fastener, such as a Velcro™-like strap, hooks, snaps, or combinations thereof.

[0217] The wearable device may be manufactured to include a variety of materials that may be soft, pliable, stretchable, body-compatible, natural or synthetic, such as cotton, wool, polyester, rayon, Gore-Tex®, rubber, neoprene, resin, or other fibers or materials known to those skilled in the art as non-irritating and in some aspects breathable (i.e., for clothing). The material may be a smart material that can sense the environment and respond to changes in strain, temperature, humidity, and pH. The material may be selected depending on the treatment target area, for example, a snug fit may be desired for a wrap placed around the patient's treatment target. The configuration of the wearable device may provide some structural support and may also function as an orthopedic support device. The wearable device may also be layered. Flexible plastics that can be molded to a body part are also suitable for use. Alternatively, the device may be constructed in a non-flexible material such as a plaster cast. The wrap device may also include other semi-rigid components such as bendable plastics found in orthopedic applications.

[0218] The wearable devices described herein, once placed on the patient in juxtaposition to the treatment target, are prescribed for the patient in an individualized configuration such that the coils or electrodes are strategically placed to effectively deliver an individualized treatment protocol.

[0219] Those skilled in the art will appreciate that the wearable devices described herein may, in embodiments, be provided as a kit including a rechargeable and replaceable battery (or a wireless operating configuration), a central processing unit, a wireless transceiver, an optional display for input or status monitoring, a power switch, one or more sensors and one or more coils; an anatomical wrap or support, clothing, a chest support (e.g., a bra), a hat / cap / helmet, footwear (e.g., sneakers, boot insoles), fashion accessories (e.g., bracelets), dressings, bandages, compression bandages and compression dressings; and instructions for use.

[0220] ( Treatment System) It will be understood that the inventions described herein may be implemented as a system, and that such a system may comprise and / or include various general-purpose computer components such as, but not limited to, software modules, a general-purpose central processing unit (CPU) and main memory (RAM).

[0221] The inventions described herein may be implemented using other heterogeneous or different software, hardware and / or firmware components, for example, software or other components implemented in or on general purpose or special purpose computing devices or configurations, server computing devices such as, but not limited to, personal computers, servers, or routing / connection components, handheld or laptop devices, multiprocessor systems, microprocessor-based systems, set-top boxes, consumer electronics devices, network PCs, other existing computer platforms, distributed computing environments including one or more of the above systems or devices.

[0222] The invention described herein may be accomplished or performed through logic and / or logic instructions, including, for example, program modules, executed in conjunction with such components or circuits, in some cases. Generally, program modules may include routines, programs, objects, components, data structures, etc., that perform particular tasks or implement particular instructions herein. The invention may also be practiced in the context of a distributed software, computer, or circuit configuration, where circuits are connected via communication buses, circuits, or links. In a distributed configuration, control / instructions may originate from both local and remote computer storage media, including memory storage devices.

[0223] The innovative software, circuits and components herein may also include and / or utilize one or more computer readable media present on, associated with, or accessible to such circuits and / or computing components; for example, computer readable media may include computer storage media and communication media. Computer storage media include volatile and non-volatile, removable and non-removable media implemented in any method or technology for storage of information, such as computer readable instructions, data structures, program modules, or other data. Computer storage media include, but are not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVDs) or other optical storage, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium that can be used to store the desired information and that can be accessed by a computing component. Communication media may include computer readable instructions, data structures, program modules, and / or other components. Communication media may include wired media, but does not include transitory media.

[0224] Aspects of the methods, devices and systems described herein with respect to logic may be functionality programmed into any of a variety of circuits, including programmable logic devices ("PLDs"), such as field programmable gate arrays ("FPGAs"), programmable array logic ("PAL") devices, electrically programmable logic and memory devices and standard cell-based devices, as well as application-specific integrated circuits. Other aspects of the methods, devices and systems described herein may be implemented in memory devices, microcontrollers with memory (such as EEPROMs), embedded microprocessors, firmware, software, and the like. Aspects may be incorporated into microprocessors with software-based circuit emulation, discrete logic (sequential and concatenated), custom devices, fuzzy (neural) logic, quantum devices, and hybrids of any of the above device types.

[0225] The logic and / or functionality disclosed herein may be enabled using any number of combinations of hardware, firmware, and / or as data embodied in various machine-readable or computer-readable media in terms of operations, register transfers, logic components, and / or other features.

[0226] The needs of the present invention are further illustrated in the following examples, however, it should be understood that these examples are for illustrative purposes only and should not be used to limit the scope of the present invention in any way. EXAMPLES

[0227] (Example experiment demonstrating proof of concept) These examples are provided for illustrative purposes only and are not intended to be limiting unless specifically specified, and as such, the present invention should in no way be construed as being limited to the following examples, but rather to encompass any and all variations that become evident as a result of the teachings provided herein.

[0228] To support the assertion that electromagnetic therapy should be individualized to the biological characteristics of the specific patient and the injury / disease being treated, the impact of EMF stimulation on biological effects at the cellular level among different donors was investigated (Examples 1-3).

[0229] Results demonstrated that baseline levels of biological activity at the cellular level for different donors were fundamentally different, as expected. Furthermore, when cells from different donors were provided with the same EMF exposure (inter-donor variability), the biological effects at the cellular level were different. Also, when cells from the same donor were exposed to different electromagnetic fields (intra-donor variability), the resulting biological effects were different. Inter- and intra-patient differences support the need for individualization and optimization of patient treatment.

[0230] EMF stimulation profiles demonstrated differential gene expression in donor mesenchymal stem cells (Example 1). From the same EMF exposure, differences in gene upregulation or downregulation were demonstrated for each of the five donors. As quantified by gene expression, each donor cell group responded differently. In addition, one donor was subjected to a different stimulation profile, but only one (1 mT, 75 Hz pulse administered for 10 minutes per day) resulted in a significant increase in the expression of osteogenic and chondrogenic genes. This same exposure resulted in a different response in each donor.

[0231] EMF exposure profiles also demonstrated intra-donor variability in breast cancer cell line MDA-MB-231 with respect to gene expression, including genes belonging to cell proliferation and apoptosis, cell senescence and angiogenesis pathways (Example 2). EMF was demonstrated to enhance the effect of cisplatin (a chemotherapy drug), supporting the use of personalized bioelectromagnetic therapy as described herein as an adjunct to conventional chemotherapy. EMF exposure profiles also demonstrated inter- and intra-donor variability with respect to astrocyte cell donors (Example 3), with altered gene expression levels along inflammatory signaling pathways.

[0232] The results of this experiment also support the use of gene expression as a useful tool to monitor and characterize the effects of EMF treatment on cells of the injury / disease microenvironment, and may further provide guidance for identifying optimal initial treatment protocols, modifying treatment protocols during treatment, or using adjunctive therapies. Baseline gene expression profiles can be obtained from patient cells prior to the start of treatment to determine EMF gene targeting efficacy.

[0233] This clinical data becomes supplemental data to be included in the "patient profile" as one of the variable biological parameters fed into MiCE to calculate personalized microenvironment stimulation targets for the patient. Any suitable cell type may be extracted / harvested from the patient, for example, from a blood draw, oral swab, or invasively from the microenvironment. Gene expression and control levels can be assessed at different time points throughout the treatment protocol to allow for progressive treatment optimization. Gene selection may also depend on the cell / tissue type, as well as the type of injury and disease. Non-limiting examples of genes for expression array evaluation are listed in Appendices I-III.

[0234] The following examples further illustrate the necessity and practice of the present invention, however, it should be understood that these examples are for illustrative purposes only and should not be used to limit the scope of the invention in any way.

[0235] Example 1: EMF-induced gene expression variations - inter- and intra-donor bone marrow-derived mesenchymal stem cells This in vitro experimental study demonstrates that there is variation in the response of cells from a particular donor to different EMF stimuli (intra-donor differences), as well as donor-to-donor (i.e., inter-donor) differences to equivalent EMF stimuli. The response of different donor cells to a variety of harmless and undetectable extremely low frequency magnetic fields is compared using PCR arrays. Outcomes related to bone formation and bone repair are quantified and compared using relative gene expression levels.

[0236] Data collected from mesenchymal stem cell specific PCR arrays provide evidence that gene expression changes depending on the donor and EMF stimulation. Different donors showed up- or down-regulation of different genes with the same exposure, and the response of donor cell groups was specific to the parameters of the EMF field. A significant increase in osteogenic and chondrogenic gene expression was observed when donor PC-1 was exposed to six different stimulation profiles and subjected to only 10 minutes of 1mT, 75Hz pulses per day. This same exposure did not produce a similar response from the other four donors. While beneficial for PC-1, this exposure was not optimized, but at the cellular level it demonstrates the need for donor-to-donor individualization and optimization for the development of the personalized treatment protocols described herein.

[0237] The technology described herein can utilize and "learn" from identified baseline gene expression differences that are unique to the patient profile and further influenced by the biological challenge in order to calculate individualized microenvironmental stimulation targets and then proactively optimize treatment during exposure to fracture EMFs.

[0238] Materials and Methods (Cell donor - Mesenchymal stem cells) Bone marrow-derived mesenchymal stem cells (BM-MSCs) were procured from a wide range of donors, each carrying a unique patient profile (Table 2). MSCs from a donor with no pre-existing conditions (donor LZ-1) were obtained from Lonza (Lonza Walkersville, Walkersville, MD, USA). Cells sourced from PromoCell (PromoCell GmbH, Heidelberg, Germany) provide an expanded donor profile including age, sex, ethnicity, smoking status, body mass index, and whether or not the patient suffers from osteoarthritis (Table 2). MSCs from four different donors obtained from PromoCell provide a diverse set of characteristics (donors PC-1 to PC-4). Comparison of baseline gene expression levels between donors (inter-donor) prior to exposure inevitably reveals significant differences that likely influence the response to EMF stimulation.

[0239] Table 2 - List of mesenchymal stem cell donors procured for EMF treatment [Table 2]

[0240] (cell culture) Bone marrow-derived mesenchymal stem cells (BM-MSCs) were sourced from different donors (PromoCell: C-12974 / Lonza: PT-2501). Cells were thawed from freezing (-150°C) and seeded in T75 flasks containing DMEM supplemented with 1% GlutaMAX™ and 5% human platelet lysate. Cells were placed in an incubator set at 37°C and 5.0% CO2. One day after thawing, the medium was changed and DMSO was removed. Thereafter, the medium was changed every 2-3 days. Cells were grown to 70-90% confluence. When this threshold was reached, cells were washed with DPBS and detached using TrypLE Select. Detached cells were neutralized, centrifuged, and plated at 5000 cells / cm in culture vessels for passaging. 2 The seeds were seeded at a concentration of 1000×1000.

[0241] For PCR analysis, dissociated cells (approximately 500,000 cells) were neutralized using an equal volume of complete medium and centrifuged at 4000 RPM for 2 minutes. After centrifugation, the supernatant was aspirated and the cell pellet was immediately frozen at -80°C for future RNA extraction.

[0242] (electromagnetic field stimulation) Figure 10 shows a schematic of the setup for applying an electromagnetic field to cultured cells. Cells were exposed to a spatially uniform and time-varying magnetic field using a Helmholtz coil, a configuration of two copper magnet wire coils with equal number of turns and diameter, axially aligned and separated by a distance equal to the radius. The space inside the Helmholtz coil creates a large volume in which the induced magnetic field is uniform (within 5%). Experiments were performed with pairs of coils prepared internally with 10 cm or 30 cm diameter Helmholtz coils purchased from Serviciencia (Serviciencia, SLU, Spain). The usable area of ​​the uniform magnetic field can be approximated as a cylinder accommodating a chamber slide and a 6-well plate, approximately 4.2 cm in diameter and 4.96 cm in length for the small coil and 25.4 cm in diameter and 29.3 cm in length for the large coil, respectively. Culture dishes stacked within the uniform area all receive the same alternating magnetic field. Several fields were investigated by varying one or more parameters from the waveform, frequency, magnetic flux density, and timing of exposure. The Helmholtz coils were oriented vertically so that the magnetic field lines were horizontal-perpendicular to the axis of the wells on a 6-well plate. The coils and exposed cells (those receiving EMF stimulation) were placed directly inside a 37°C incubator and the local temperature was closely monitored. Control cells from each donor were cultured for the same amount of time at the same temperature and CO2 settings, but in separate incubators isolated from the stimulation field.

[0243] Stimulation in vitro profiles were designed consisting of a biphasic alternating current (AC) magnetic field with either a sinusoidal or pulsed waveform. The driving waveform (signal) was varied in shape as well as frequency and amplitude. Table 3 lists the details of each exposure evaluated, as well as the daily stimulation time and time spent in culture. The pulse waveform was driven using a biphasic square wave with a 10% duty cycle, and each of experiments 1-3 differed in the daily exposure time. The sinusoidal input (experiments 4-6) oscillated near zero (i.e., zero DC offset) and only the frequency was varied. To demonstrate intra-donor variability, the stimulation profile was varied for the same donor (PC-1). Inter-donor comparisons are made by exposing cells from each of the five donors to the same electromagnetic field therapy (experiments 1 and 5 for pulsed and sinusoidal stimulation, respectively).

[0244] Table 3 - Waveform parameters and exposure times for each experiment [Table 3]

[0245] The current through the coil was generated by a DG2052 waveform generator (Rigol Technologies, China) and amplified by a BOP 100-4DL power supply (KEPCO, INC., USA). The waveform generator can generate sine waves up to 50 MHz (square waves at 15 MHz), but the stimulation frequency was kept in the very low frequency range (below 300 Hz). Low intensity AC magnetic fields in this frequency range have been shown to be harmless, without generating heat or sound. The magnetic flux density of the induced field was in all cases directly proportional to the current in the coil (monitored using a RP1001C current probe (Rigol Technologies, China)) and measured using a 5180 Gaussmeter and a SAD18-1904 axial probe (FW Bell, USA). The maximum peak magnetic flux density was 4 mT. At high currents, power was dissipated in the coil, increasing its temperature, but the heating effect was negligible in the center of the coil, where the cells were located. The timing of exposure was controlled via remote commands sent to the waveform generator via LabVIEW (National Instruments, USA).

[0246] (Imaging) Before each feed and on the day of cessation of viability, cells were imaged at 50x magnification using a Zeiss Axio Vert A1 inverted microscope.

[0247] (PCR array) RNA was extracted from frozen cell pellets using the RNeasy kit (Qiagen: 74004) and then reverse transcribed into cDNA (Qiagen: 330404). 2 Reverse transcribed templates were analyzed by Profiler Array (Qiagen: 330231; PAHS-082ZD). Each experimental point was performed in triplicate. Gene expression of the 84 genes of interest on each PCR array was normalized to a reference gene (ΔC t ), then averaged within the experimental groups. Then, the ΔΔC tAfter calculating between groups, 2 (-ΔΔCt) Fold changes were calculated according to In the results below, some data are presented in the form of heat maps, with fold changes displayed as base 2 logarithms.

[0248] (EMF exposure does not affect cell morphology) To monitor morphology, cell culture groups from control and exposed donors were imaged before each feeding and before ceasing viability. No morphological changes were observed with or without EMF stimulation of any intensity or duration.

[0249] (PCR array analysis reveals donor-to-donor variation in the absence of electromagnetic fields) A PCR array designed specifically for mesenchymal stem cells (Qiagen) measures the levels of expression of 84 different genes A1-G12 listed in Appendix I. Target genes in the array include stemness markers, differentiation markers, and other known mesenchymal stem cell specific genes. RNA isolated from control cells belonging to each donor was analyzed using the PCR array to elucidate unstimulated baseline expression differences between donors (note that controls are also used to quantify the effects of EMF exposure). Figure 11 shows a PCR array heat map of the relative differences in expression levels of PC-1 and LZ-1 (LZ-1 is the "standard" of choice). The color bar corresponds to the base 2 logarithm of the fold change (FC) between the two donors, such that red (positive values) correspond to upregulation of genes and blue (negative values) correspond to downregulation. The example in Figure 11 shows five genes (A7: BGLAP, C4: GDF6, C9: HGF, E6: NGFR, and G5: THY1) that are strongly upregulated in PC-1 compared to LZ-1.

[0250] Figure 12 is an array of gene expression heat maps comparing the baseline expression levels of each donor to the baseline expression levels of other donors. Qualitatively, there are clear differences in gene expression for each donor when cultured without any form of external stimuli. The differences observed in the cell groups in Figure 12, and the control responses to EMF treatment, can be used as a basis for developing personalized therapeutic specificities.

[0251] (Donor-to-donor variability in response to EMF exposure) (Pulse Wave Stimulation - Experiment 1) All five donor cell groups were exposed to a pulsed magnetic field after cell seeding. Field parameters were set according to experiment 1 in Table 2, with an input pulse width of 1.3 ms (duty cycle = 10%). Cells were exposed for 10 min per day until confluent. Cells were not exposed on the finishing day. Figure 13 shows gene expression of each set of donor cells when exposed to a pulsed field compared to its own unexposed control. Figure 13(a) AC field 75 Hz, 4 mT pulse waveform; and Figure 13(b) AC field 50 Hz, 1 mT sine wave. On average, gene expression of donor LZ-1 is slightly upregulated compared to the other genes, but the effect is much stronger in PC-1, where most genes are upregulated. In comparison, expression of PC-2, PC-3, and PC-4 are all downregulated, with PC-2 being strongly downregulated. These MSCs show inter-donor specificity to the stimulation profile.

[0252] By selecting specific osteogenic genes from the PCR array shown in FIG. 13, it is possible to focus and highlight the differences in the heatmap in terms of the specific responses due to the targeted biological process. FIG. 14 plots the expression levels of 10 osteogenic genes as part of experiment 1. The pathways associated with each of these 10 genes promote bone formation, and therefore the processes associated with bone formation benefit from the upregulation of gene expression. Compared to the other donors, there is a significant upregulation in PC-1, with at least a two-fold change in expression levels for all 10 genes in the PC-1 study, whereas PC-2, PC-3, and PC-4 have little or no upregulation with the same exposure protocol. Some of the highly expressed genes in PC-1 that are essential for fracture repair include: bone morphogenetic protein-2 (BMP2), a growth factor of the transforming growth factor-beta (TGF-β) superfamily that plays an essential role in osteogenesis and is involved in the induction of cartilage and bone formation; RUNX2, which is highly expressed in bone marrow and activates the differentiation of MSCs into immature osteoblasts; TBX5, which promotes bone growth and maturation; and FGF10 and SMURF1, both involved at different points in the BMP pathway.

[0253] (Sine wave stimulation - Experiment 5) Exposing cells from five donors to an oscillating sinusoidal magnetic field (experiment 5 in Table 2) produces strikingly different results. The sinusoidal wave, apart from being lower in intensity and frequency (experiment 1), has a gentler slope and induces weaker currents than the pulsed wave. Figure C(b) shows the gene expression heatmap after a 6-hour daily exposure to the sinusoidal wave. The sinusoidal wave produces fewer extremes than the pulsed signal, resulting in less discriminatory factors between donors. The results (especially the lack of a significant response from PC-1) suggest that some EMF treatments affect biological responses at the cellular level in different ways for different patients.

[0254] (Intra-donor variability demonstrated by varying EMF treatment parameters ) Growing PC-1 cells were stimulated using each of the field parameters defined in experiments 1-6 (Table 3). After normalization to the unexposed control, the heatmap in Figure 15 reveals intradonor variability when cells are exposed to different waveforms at different intensities, frequencies, and exposure times. Gene expression is most upregulated by brief daily exposure to the pulse. Longer exposure times result in stronger gene downregulation, suggesting that optimization through timing of exposure is possible. Furthermore, changing to a sinusoidal wave resulted in substantially less change from control than each pulsed waveform. The magnitude of fold change values ​​(either positive or negative) for sinusoidal magnetic field exposure is greatest at low frequencies. These results suggest that by fine-tuning EMF treatments at the cellular level to a given donor, personalized treatment regimens can be generated that are specifically optimized for the microenvironment.

[0255] The focus on a selection of 10 osteogenic genes (Figure 16) and 10 chondrogenic genes (Figure 17) highlights the different responses to EMF treatment. Daily exposure to 75Hz, 4mT pulses for 10 minutes strongly upregulates genes related to osteogenesis and chondrogenesis. Continuous exposure strongly downregulates some genes as well as others. Each of the genes upregulated by the 10 minute exposure, including BMP2, RUNX2, etc. (discussed in detail above), are involved in signaling pathways that promote osteogenesis and chondrogenesis.

[0256] (Example 2: EMF therapy inhibits cell proliferation in MDA-MB-231 breast cancer cells and enhances the efficacy of the chemotherapy drug cisplatin) A breast cancer cell line (MDA-MB-231) was cultured in the presence of various time-varying electromagnetic fields capable of inducing electrical currents in the medium and across the cells themselves. Growth cultures with four different exposure profiles yielded different responses from each experiment. Two exposures resulted in a statistically significant decrease in cell proliferation (a positive outcome for cancer cell inhibition). The two exposure profiles were (i) a 432 Hz sine wave given continuously from seeding until the cells ceased viability and (ii) a series of low-frequency triangular waves of increasing separation for 3 hours per day. These two waveforms were further investigated using PCR arrays configured for cancer-related pathways. Despite the two exposures having very similar effects on cell numbers, intradonor variability was observed with the PCR array. To name a few, genes belonging to the apoptosis, cellular senescence and angiogenesis pathways were all upregulated in favor of inhibition of cell proliferation. However, some indicators of increased proliferation and apoptosis inhibitors were also upregulated. Furthermore, the benefit of bioelectromagnetic therapy as an adjunct to chemotherapy was demonstrated using cisplatin. When the two modalities are combined, EMF acts to enhance the effect of cisplatin, resulting in a significant reduction in cell numbers.

[0257] These results support personalized treatment optimization using EMFs based on cancer type to slow tumor growth and demonstrate bioelectromagnetic therapy as an attractive alternative (or adjunct) to conventional chemotherapy and / or radiation therapy.

[0258] Materials and Methods (cell culture) MDA-MB-231 cells, a human triple-negative breast cancer cell line, were obtained at passage 40 (Sigma: 92020424). The culture medium used was high glucose DMEM (Gibco: 31053-028) supplemented with 1% GlutaMAX™ (Gibco: 35050-061) and 10% fetal bovine serum (Gibco).

[0259] Cells were thawed from freezing (-150°C), placed in a tube containing warm medium, and spun down at 240 x g for 5 min. After the cells were pelleted, the medium was removed, the cells were resuspended, and seeded into a T225 flask containing 45 mL of medium. The cells were placed in an incubator set at 37°C and 5.0% CO2. Medium was changed every 2-3 days. Cells were grown until 80-90% confluent. When this threshold was reached, the cells were passaged. Cells were washed with DPBS and detached using TrypLE Express (Gibco). Detached cells were neutralized, centrifuged, and plated at 10,000 cells / cm in culture vessels. 2 The seeds were sown at a density of 1000 x 1000 mm.

[0260] For harvesting experiments, cells were detached and neutralized with medium as for passaging. A 100 μL aliquot was taken and used for cell counting. Cells were counted on an NC-200 Nucleocounter (ChemoMetec). The remaining dissociated cells were centrifuged at 4000 RPM for 2 minutes. After centrifugation, the supernatant was aspirated and the cell pellet was immediately frozen at -80°C for future RNA extraction.

[0261] Before each feed and on the day of cessation of viability, cells were imaged at 50x magnification using a Zeiss Axio Vert A1 inverted microscope.

[0262] (Cisplatin Preparation) Cisplatin is a platinum-based chemotherapy drug that inhibits DNA synthesis. Cisplatin is used to treat many cancers, including breast cancer. Cisplatin (Millipore-Sigma: 232120) was dissolved in DPBS with 140 mM NaCl at a concentration of 1 mg / mL and stored at room temperature protected from light. This solution was further diluted with culture medium to obtain the desired concentration for the experiments. DPBS with 140 mM NaCl was used as a vehicle control. 20 μM cisplatin was used as a positive control, at which cell numbers decreased by more than 90%. Lower concentrations of 2 μM and 0.667 μM (1 / 10 and 1 / 30 of the concentration of the positive control, respectively) were used in combination with PEMF stimulation.

[0263] (PCR array) RNA was extracted from frozen cell pellets using the RNeasy kit (Qiagen: 74004) and then reverse transcribed into cDNA (Qiagen: 330404). Human Cancer PathwayFinder™ PCR Arrays (Human Cancer PathwayFinder™ RT 2 Reverse transcribed templates were analyzed by Profiler Array (Qiagen: 330231; PAHS-033Z). Each experimental point was performed in triplicate. Gene expression of the 84 genes of interest (Appendix II) on each PCR array was normalized to a reference gene (ΔC t ), then averaged within the experimental groups. Then, the ΔΔC t is calculated between groups, and 2 (-ΔΔCt) Fold changes were calculated according to In the results below, some data are presented in the form of heat maps, with fold changes displayed as base 2 logarithms.

[0264] (electromagnetic field stimulation) Cells were exposed to a spatially uniform, time-varying magnetic field using Helmholtz coils as previously described for mesenchymal stem cells. A description of the exposure system (coils, signal generator, incubator, etc.) is provided in Example 1.

[0265] We demonstrate the effect of four low-frequency magnetic fields (non-invasive and painless) on the proliferation and gene expression of breast cancer cell lines. Extremely low-frequency magnetic fields on cancer cells demonstrated inhibition of proliferation (Bergandi L, Lucia U, et al., BBA - Mol Cell Res. 2019; 1866:1389-1397) and / or increased apoptosis (Giladi M, Schneiderman RS, et al., Sci Rep. 2015; 5:18046). Table 3 contains parameters describing four different fields encompassing a wide range of shapes, intensities and frequencies. The two sine waves are simple sine waves with no offset. The pulse waveform with a 10% duty cycle produces a sudden large change in the magnetic flux density (B) of the field. Finally, experiment 4 consists of a pair of triangular waves with increasing separation, equivalent to a decrease in frequency from 36 Hz to 10 Hz. The waveform consists of 15 pairs with a period of approximately 900 ms. Following the positive results in experiments 3 and 4 (see below), the exposure was repeated with the addition of the chemotherapy drug cisplatin. Additionally, experiments 3 and 4 were also performed with "healthy" chondrocytes.

[0266] Table 4 – Experiments using different EMF stimulus profiles [Table 4]

[0267] (EMF stimulation inhibits proliferation of MDA-MB-231 cell line) Breast cancer cells were exposed to one of four experimental stimulation profiles listed in Table 4 for the entire duration of culture (4-5 days). The desired outcome is a reduction in proliferation to inhibit uncontrolled division of cancer cells. Figure 18(A) shows normalized cell counts using each stimulation profile compared to unexposed controls. When breast cancer cells were treated with exposure in experiments 1 and 2, respectively, there was no effect and proliferation increased. However, when the same cell lines were exposed to experiments 3 or 4, the effect was reversed and cell proliferation was inhibited (statistically significant, Student's t-test, p<0.01). To ensure that EMF exposure was not harmful to healthy non-cancerous cells that would necessarily be subjected to the same magnetic field, experiments 3 and 4 were repeated with human chondrocytes. The normalized cell counts in Figure 18(B) show that there is no statistically significant difference in chondrocyte proliferation with or without the same exposure that inhibits breast cancer cell proliferation.

[0268] (Exposure to time-varying EMFs alters gene expression in breast cancer cells) The effective stimulation profiles (3 and 4) were further analyzed using a cancer pathway finder PCR array designed specifically for cancer cells. The array contains primers for 84 genes related to one or more of, for example, apoptosis, cellular senescence, and angiogenesis. The list of genes is included in Appendix II. The heat map in Figure 19 shows the relative differences in gene expression between the two exposed samples and the control cells. The 432Hz sine wave in experiment 3 appears to have a stronger effect than the triangular pulse, with more genes being upregulated compared to the unexposed control. However, the most strongly expressed genes (both upregulated and downregulated) are common to both exposures.

[0269] The biological mechanisms of cancer cell growth inhibition by EMF exposure are not fully understood, and studies are currently underway to investigate the effects of a very wide range of EMF parameters and delivery methods in and beyond the extremely low frequency range. Gene expression levels for two seemingly effective stimuli in Figure I highlight genes involved in affected pathways. The reduction in cell numbers after exposure may be associated with increased expression of the pro-apoptotic genes APAF1 (heatmap location: A6) and CASP2 (B2), while the apoptosis inhibitors NOL3 (E8) and XIAP (G12) are also upregulated. Furthermore, cellular senescence, which generally leads to cell growth arrest, is promoted: IGFBP3 (D7) and IGFBP7 (D9), MAP2K3 (E4) and MAPK14 (E5) were all increased in expression. Markers of DNA damage and repair (DDB2 (C1), PPP1R15A (F2) and GADD45G (D3)) were altered in favor of apoptosis and tumor suppression. Conversely, many of the genes related to the cell cycle pathway (e.g., MCM2 (E6) and MKI67 (E7)), which are typically high in cancer cells, are further expressed after exposure, which favors increased proliferation. Finally, both genes, ANGPT1 (A4) and CCL2 (B5), involved in angiogenesis and supplying blood to grow tumors, are downregulated by EMF. The described genes are some of the genes more strongly regulated by either stimulus.

[0270] (EMF exposure enhances the effectiveness of cisplatin) Chemotherapeutic drugs, including cisplatin, are a common and proven way to treat cancer tumors, despite their many side effects. Large doses of these drugs can be a significant financial and health concern for many patients, so a way to reduce the dosage with adjuvant therapy would be welcome. To test the combined effect of cisplatin and EMF exposure, two low concentrations of cisplatin (2 μM and 0.667 μM) were added to the medium of MDA-MB-231 cells subjected to exposure in experiments 3 and 4. Additionally, as a "positive" control, cells were cultured with 20 μM cisplatin and not exposed. Figure 20 shows the combined effect of cisplatin and EMF exposure on cell number after 5 days of exposure. In the absence of stimulation, vehicle medium appears to have no effect on proliferation compared to the control, but a high dose of cisplatin (20 μM) has a dramatic effect on cell number. When the exposed cell groups are plotted against the unstimulated vehicle samples, the same reduction in cell number is seen when cultured with vehicle as in Figure H (no vehicle). The cellular response to cisplatin is clear, with a non-linear negative relationship between concentration and cell number. Adding EMF exposure at the two lower cisplatin concentrations inhibits cells further. The difference between the lower concentrations of cisplatin alone and cisplatin in combination with either EMF exposure is statistically significant. The effects of cisplatin and EMF exposure do not appear to be additive, but instead EMF stimulation enhances the inhibition of cell proliferation induced by cisplatin. At a positive control concentration of 10% cisplatin, the combination treatment reduces cell number by more than 80% (compared to the negative control), compared to the 90% reduction seen with a cisplatin dose of 20 μM.

[0271] Example 3: Bioelectromagnetic therapy alters the response state of astrocytes in vitro The effect of EMF stimulation on pain-related gene expression in normal human astrocytes from three different donors was tested. These findings demonstrate inter- and intra-donor variability in response to different EMF stimulation profiles. This supports that patient-to-patient differences influence response to EMF treatment at the cellular level and that an individualized set of parameters is required for each patient to achieve the desired outcome.

[0272] Astrocytes are an abundant cell type in the central nervous system and are involved in many important processes required to maintain a healthy system. Astrocytes were chosen for this in vitro study because they are involved along pain perception and regulation pathways that are involved in the production and regulation of pro- and anti-inflammatory substances. In the case of chronic pain, reactive astrocytes may intensify pain perception and inflammatory responses long after the pain-inducing injury has occurred. It has now been demonstrated that the expression of inflammatory genes in reactive astrocytes can be downregulated using EMF stimulation. Stimulation was not universally beneficial, and altering the field waveform, frequency, or intensity affected gene expression levels. Furthermore, different cell donors responded variably to the same stimulation profile. This finding supports patient-specific optimization, whereby personalized microenvironmental stimulation targets are generated based on the patient's profile and then actively modified and optimized in response to pain level feedback from the patient.

[0273] Materials and Methods Astrocytes as a model of pain The sensation of pain is a complex biophysical process involving many neuroanatomical and neurochemical systems. Primarily, nociceptive pathways are used to convey and process information to and from the brain upon noxious stimulation of tissue. At a macroscopic level, this involves the propagation of signals from the area of ​​noxious stimulation using afferent pathways to the dorsal root ganglion, which then conveys the information to the brain.

[0274] Within nociceptive pathways, interactions between neurons and neuroglial cells are known to contribute to pain perception. As the most abundant cell type in the CNS, astrocytes have been identified as actively contributing to pain sensation through the process of reactive astrogliosis. In the presence of noxious stimuli, astrocytes undergo phenotypic and functional changes to become reactive, which are accompanied by inflammatory and neurotoxic responses that contribute to pain sensation. In particular, cortical reactive astrocytes have been demonstrated to have the ability to create a chemical imbalance of glutamate and gamma aminobutyric acid (GABA), leading to synaptic remodeling and chronic pain. Therefore, induction of astrocytes into a reactive state may be considered as a reasonable model of pain by examining the ability of EMFs to revert reactive astrocytes to a naive or non-inflammatory state.

[0275] (Cell donor – normal human astrocytes) Normal human astrocytes (NHA) isolated from brain tissue (cerebral cortex) of three different donors were purchased. NHA1 from the first donor was sourced from Lonza (Lonza Walkersville, Walkersville, MD, USA), while NHA2 and NHA3 were purchased from ScienCell (ScienCell Research Laboratories, Inc., Carlsbad, CA, USA). No information was provided about the donors themselves, but baseline gene expression levels (see below) reveal differences between donors before EMF treatment.

[0276] (cell culture) Astrocytes were obtained from different donors (Lonza: CC-2565 / ScienCell: 1800). Cells were thawed from freezing (-150°C) and seeded in poly-D-lysine coated T75 flasks containing astrocyte medium (Lonza: CC-3186 / ScienCell: 1801-prf). Cells were placed in an incubator set at 37°C and 5.0% CO2. One day after thawing, medium was changed and DMSO was removed. Thereafter, medium was changed every 2–3 days. Cells were grown until 70–90% confluence. When this threshold was reached, cells were washed with DPBS and detached using 0.05% trypsin supplemented with neutral protease. Detached cells were neutralized, centrifuged, and plated at 5000 cells / cm on poly-D-lysine coated culture vessels for passaging. 2 The seeds were seeded at a concentration of 1000 μg / ml.

[0277] For PCR analysis, dissociated cells (approximately 500,000 cells) were neutralized with an equal volume of complete medium and centrifuged at 4000 RPM for 2 minutes. After centrifugation, the supernatant was aspirated and the cell pellet was immediately frozen at -80°C for future RNA extraction.

[0278] (Reactive growth factor) To induce an inflammatory response in astrocytes, the cytokines TNFα (R&D Systems: 210-TA-005 / CF) and IL-1β (201-LB-005 / CF) were added to the cultures at a concentration of 10 ng / mL according to the method described by Hyvarinen et al., 2019 (Hyvarinen T, Hagman S, et al., Sci Rep. 2019; 9:16944). The medium was changed every 2–3 days.

[0279] (electromagnetic field stimulation) Cells were exposed to a spatially uniform, time-varying magnetic field using Helmholtz coils as previously described for mesenchymal stem cells. The exposure system (coils, signal generator, incubator, etc.) was as described in Example 1 (bone healing).

[0280] Previous pain management systems have implemented a diverse set of stimulation profiles using various placement methods. There is no consensus on the most effective EMF parameters, but there is a trend towards using low intensity, very low frequency stimulation resulting in imperceptible electromagnetic fields. Table 5 contains the exposure parameters used in each of three experiments designed to demonstrate inter- and intra-donor variability in astrocytes exposed to electromagnetic stimulation. Experiment 1 tested the response of all three donors to a 10 min / day 15 Hz sine wave, whereas experiments 2 and 3 included only one donor (NHA2). Relative to the sine wave, the ramp function (experiment 2) and pulse function (experiment 3) induce stronger currents in the medium due to the abrupt changes in the input signal, at significantly higher and lower frequencies, respectively.

[0281] Table 5 - Exposure parameters for normal human astrocyte experiments [Table 5]

[0282] (Imaging) Before each feed and on the day of cessation of viability, cells were imaged at 50x magnification using a Zeiss Axio Vert A1 inverted microscope.

[0283] (qPCR) RNA was extracted from frozen cell pellets using the RNeasy kit (Qiagen: 74004), and then cDNA was reverse transcribed (Qiagen: 330404). Expression levels of glial fibrillary acidic protein (GFAP), interleukin 6 (IL6), interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα), complement component 3 (C3), transforming growth factor beta 1 (TGFβ1), signal transducer and activator of transcription (STAT3), interleukin 8 (IL8), and SRY box transcription factor 9 (SOX9) were measured by real-time RT-PCR relative to the reference gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH) using the SYBR Green detection system. Each sample was diluted 1:10 and analyzed in duplicate on a CFX96 Touch™ real-time RT-PCR machine (Bio Rad) using iTaq Universal SYBR Green Supermix (Bio Rad: 1725122) and optimal concentrations of forward and reverse primers (0.6 μM). The program used to analyze all samples included an enzyme activation step at 95°C for 30 s, followed by 40 cycles of 95°C for 3 s and 60°C, 61°C, 62°C, or 63°C (depending on the target gene) for 30 s. After the amplification phase, a dissociation curve was generated to ensure the presence of a single amplicon. Reaction efficiency was 100 ± 10% with an R2 > 0.990 and was calculated by CFX Manager software (Bio Rad, Mississauga, ON, Canada). For each assay, a standard curve was generated with gBlocks (designed specifically for each gene amplicon), and a no template control and a no reverse transcription control (to ensure that no genomic DNA was present in the sample) were run with the samples. The standard curve was generated by serial dilution of gBlocks. The standard curve was then used to interpolate and calculate the mRNA levels of the target and reference genes for each sample. The mRNA levels of each target gene were calculated relative to the reference gene GAPDH.

[0284] (PCR array) RNA was extracted from frozen cell pellets using the RNeasy kit (Qiagen: 74004) and then reverse transcribed into cDNA (Qiagen: 330404). Human Pain: Neuropathic and Inflammatory PCR Arrays were run on a BioRad CFX96 real-time PCR detection system. 2 Reverse transcribed templates were analyzed by Profiler Array (Qiagen: 330231; PAHS-162Z). Each experimental point was performed in triplicate. Gene expression of the 84 genes of interest on each PCR array was normalized to a reference gene (ΔC t ), then averaged within the experimental groups. Then, the ΔΔC t After calculating between groups, 2 (-ΔΔCt) Fold changes were calculated according to In the results below, some data are presented in the form of heat maps, with fold changes displayed as base 2 logarithms.

[0285] (result) (Astrocyte phenotypic morphology) To monitor morphology, cell culture groups from control and exposed donors were imaged before each feed and before viability was terminated. For groups treated with reactive cytokines (IL-1β and TNFα), morphological changes are expected as astrocytes change phenotype. Figure 21 demonstrates this difference in morphology, with non-reactive cells (A) being more filamentous, whereas reactive cells (B) adopt a more polygonal morphology.

[0286] (Putting astrocytes into a reactive state) Normal human astrocytes were put into a reactive state by culturing them with a set of additional growth factors including IL-1β and TNFα. The state of the astrocytes was confirmed by arresting cell viability at 72 hours after seeding, isolating RNA, and detecting specific marker genes using qPCR. Nine genes were quantified as markers of the reactive state, four of which should be downregulated (GFAP, TGFβ, STAT3, and SOX9) and five of which are expected to have increased expression levels (IL6, TNFα, IL8, IL-1β, and C3). Figure 22 plots the expression levels of each gene in the donor NHA2 cell group. The expected trends were observed, confirming the reactive state of the astrocytes. The reactive (or pain) state shows lower levels of GFAP, TGFB, STAT3, and SOX9, and increased expression of IL6, TNFα, IL8, IL-1β, and C3, compared to non-responsive control levels.

[0287] The PCR array heat map in Figure 23 shows the expression levels of genes selected for pain and neuroinflammation in reactive astrocytes (compared to non-responsive astrocytes). The gene array contains 84 genes (Appendix III). The inflammatory cytokines IL-1β (position C12) and IL6 (D2) are both highly expressed when cells are reactive, indicating a neuroinflammatory state. The aim of EMF exposure is to counteract the increased expression of genes belonging to the inflammatory pain signaling pathway, thus returning expression levels to those of the non-responsive state.

[0288] (Baseline expression in reactive astrocytes) Pain PCR arrays were utilized to compare the baseline gene expression levels of each donor cell group to other donor cell groups, while in a responsive state. Figure 24 shows a heat map using one donor as the test subject and the other as the calibrator. Upregulation or downregulation between donors indicates higher or lower baseline expression, respectively. These differences are derived and incorporated into the patient profile and the transition from a non-responsive state to a responsive state, and may affect the cellular response to EMF stimulation. When comparing two donors, there are significant differences (up and down) between each other, but no bias.

[0289] (Differences in donor responses to EMF exposure) To demonstrate donor-to-donor variability with EMF exposure, the stimulation profile tested in experiment 1 (Table 4) was applied to each astrocyte donor cell group. Brief daily exposures result in quantifiable changes in gene expression levels and notable variations from donor to donor (compared to their own controls). Figure 25 contains heat maps corresponding to each donor demonstrating markedly different responses to the same exposure. NHA1 responded with increased gene expression across the majority of the array, including many inflammatory markers that were already highly upregulated by the change to a reactive state. In contrast, many of the same genes that are upregulated in NHA1 are downregulated in NHA3. It is clear that a single stimulation profile is unlikely to suit all donors and individualization will be required.

[0290] In FIG. 26, the fold change values ​​of selected genes for each donor are plotted against unexposed reactive cells from the same donor group. All of these genes are involved in pain response regulation, specifically along the inflammatory response pathway. The 13 genes highlighted in FIG. 28 are listed in Appendix III. Astrocytes are actively involved in these pathways when in a reactive state, and gene expression is increased in this pain condition. The aim of EMF treatment is to counter the changes caused by (reactive) growth factors and trend expression levels back towards non-reactive measurements. Exposure upregulated the expression of almost all genes in NHA1, suggesting that the stimulation was pro-inflammatory in that donor. Exposure resulted in a more favorable response from NHA3, but the inflammatory markers IL-1β and IL6 were upregulated, indicative of reactive astrocytes. The stimulation was most suitable for NHA2, which responded by mostly downregulating gene expression (compared to unstimulated reactive cells), particularly for the key inflammatory markers IL-1β and IL6.

[0291] (Intra-donor variability demonstrated by varying EMF treatment parameters) Donor NHA2 was exposed to three different EMF stimulation profiles encompassing a wide range of frequencies, exposure times, and signal shapes (Table 4). Each of the three experiments alters gene expression (relative to the response state quantity), demonstrating the various effects that treatment with EMF can cause. The heatmap in Figure 27 shows the change in gene expression of 84 unique genes as a result of the three different stimulation profiles. It is immediately evident that the higher frequency signal used in experiment 2 increases gene expression of almost all genes, which further exacerbates the (pain) problem. Experiments 1 and 3 resulted in a more desirable response, as many pain-related genes were downregulated and many others returned to the levels of non-responsive astrocytes.

[0292] Figure 28 shows 13 inflammatory genes affected by induced current in experiments 1-3. Gene expression levels are modulated relative to the responsive control. For reference, a comparison of the responsive and non-responsive controls is also included. In experiments 1 and 3, most of the genes strongly upregulated by the responsive change show a decrease in expression after only 2-4 short exposures. IL-1β and IL6, in particular, are markers of the change back to the non-responsive state, and are both downregulated (strongest effect) in experiments 1 and 3. These two experiments affect the same genes in the same direction despite utilizing significantly different EMF parameters, but experiment 2 increases the expression of all genes. With only slight changes in the electromagnetic field (different, but each EMF is in the extremely low frequency range and imperceptible to the patient), it is clear that positive and negative results can be identified for the same donor and that the treatment must be tailored to the patient to achieve optimal results.

[0293] (Summary of Examples) The results of Examples 1-3, taken together, demonstrate inter-donor differences at the cellular level and support the need for individualization and optimization of therapy for each donor.

[0294] The results also support the use of gene expression as a useful tool to monitor and characterize the effects of EMF treatment on cells in the microenvironment and may further modify the treatment protocol or provide guidance for the use of adjunctive therapies. A baseline gene expression profile can be obtained from patient cells prior to the start of treatment to determine EMF gene targeting effects. This clinical data becomes supplemental data to be included in the "patient profile" as one of the variable biological parameters fed into MiCE to calculate personalized microenvironment stimulation targets for the patient. Any suitable cell type can be extracted / harvested from the patient, for example, from a blood draw, oral swab, or invasively from the microenvironment. Gene expression and control levels can be assessed at different time points throughout the treatment protocol, allowing for progressive optimization of therapies. The choice of genes may depend on the cell / tissue type, as well as the type of injury and disease. Non-limiting examples of genes for expression array assessment are listed in Appendices I-III.

[0295] (Appendix) Appendix I Human mesenchymal stem cell PRC array genes [Table 6] TIFF2025502803000008.tif233170TIFF2025502803000009.tif122170

[0296] Osteogenesis genes selected from MSC PCR arrays [Table 7]

[0297] Chondrogenic genes selected from MSC PCR array [Table 8]

[0298] Appendix II - Genes for Cancer Pathway Finder PCR Arrays [Table 9] TIFF2025502803000013.tif236170TIFF2025502803000014.tif159170

[0299] List of functions of key genes in cancer-related pathways [Table 10]

[0300] Appendix III - Neuropathic and Inflammatory Pain Genes for PCR Arrays [Table 11] TIFF2025502803000017.tif236170TIFF2025502803000018.tif62170

[0301] Description of 13 inflammatory genes discussed in experimental studies of pain management [Table 12]

[0302] (Non-limiting examples of embodiments of the disclosure) Aspects, including embodiments of the subject matter described herein, may be beneficial alone or in combination with one or more other aspects or embodiments. Without limiting the foregoing, certain non-limiting aspects of the disclosure, numbered 1 through 66, are provided below. As will be apparent to one of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or succeeding individually numbered aspects. This is intended to support all combinations of such aspects, and is not limited to the combinations of aspects expressly provided below: 1. A method for treating injury or disease in a patient using electromagnetic fields, comprising: Determining ideal personalized microenvironmental stimulation targets (PMSTs) to induce a desired biological response in the microenvironment of the injury or disease; and generating a personalized treatment protocol (PTP) for the patient based on the prescribed electromagnetic field modality, the PTP being configured to achieve the PMST required for ideal personalized electromagnetic field (EMF) stimulation of the injury or disease microenvironment; Including, wherein the PMST is calculated from patient-centric data and clinical metadata, and the PTP is calculated to achieve the PMST taking into account characteristics of EMF modality-centric data. 2. The method of claim 1, wherein said PMST is computed by a Microenvironment Computational Engine (MiCE) comprised of one or more physics-based computational algorithms for integrating and processing said patient-centric data and clinical metadata. 3. The method of claim 2, wherein the MiCE utilizes the patient-centric, organized, indexed data collection representing multidimensional parameters including the patient's biological characteristics; the biological challenges of the patient's injury or disease microenvironment that are targets for treatment; and clinical metadata. 4. The biological characteristics of the patient are: - Overall patient characteristics and conditions that influence the microenvironment; - how the patient's characteristics and condition influence the microenvironment; - Demographic characteristics, including age, sex, height and weight; and - Comorbidities, smoking status, current medications, and existing medical conditions 4. The method of claim 3, further comprising data relating to one or more of: 5. The method of claim 3 or 4, wherein the biological challenge comprises data relating to one or more of the specific details of the patient's injury or disease, the microenvironment of the injury or disease, the severity of the injury or disease, the current recovery state of the injury or disease, and the success or failure of previous treatments for the injury or disease. 6. The method of any one of claims 3 to 5, wherein said clinical data includes any available data regarding the biological characteristics of similar patients and similar microenvironments. 7. The method of any one of claims 1 to 6, wherein the PTP is generated by a macro translation computation engine (MaCE) comprised of one or more physics-based computational algorithms for integrating and processing EMF-centric data. 8. The method of claim 7, wherein said EMF-centric data comprises an organized, indexed collection of data representing multi-dimensional parameters of a prescribed electromagnetic field modality to calculate said PTP necessary to achieve said PMST. 9. The method of claim 7 or 8, wherein said PTP defines an EMF that achieves said PMST required by the patient's injury or disease microenvironment to affect mediators of inflammation and / or biological factors present in said microenvironment. 10. Data representing multidimensional parameters of the prescribed electromagnetic field modality are - propagation path data describing the signal path separating the microenvironment and the EMF source, as influenced by the material properties and physical dimensions of the tissues and materials along the signal path; and - specification data describing the modality of electromagnetic field generation and the physical structure of the EMF signal-generating device configured for the patient and the injury or disease; 10. The method of claim 8 or 9, comprising: 11. The method of any one of claims 2 to 10, further comprising an optimization extension comprising one or more computational engines that collect information from sensors in the microenvironment and outside the microenvironment and provide feedback for optimizing the MiCE and the MaCE. 12. The method of claim 11, wherein the one or more optimization engines are feedback calculation engines configured to obtain input data from EMF sensors in or near the microenvironment, determine and correct differences between a target EMF defined by the MaCE and an actually measured EMF as a result of inaccuracies in the MaCE, and send modifications as feedback to parameters affecting the generation of the PTP. 13. The method of claim 11 or 12, wherein the one or more optimization engines are learning computational engines configured to optimize during active treatment via a self-contained feedback loop that obtains input data from follow-up observations and / or microenvironmental sensor data that compensates for inaccuracies in the MiCE. 14. Compensation for inaccuracies in the MiCE is (a) gradually adjusting individual parameters of the PTP, including increasing or decreasing the frequency or intensity of stimulation; (b) monitoring the effect(s) of the adjustment(s) in (a); (c) collecting sensor data and mapping patient-specific response profiles for each parameter; and (d) selecting an optimal combination of settings for the patient's recovery and outputting an optimized PTP; 14. The method of claim 13, comprising: 15. The method of any one of claims 1 to 14, further comprising acquiring newly emerged data including intermediate data and final treatment data, feeding the intermediate data back to the MiCE for improving the effectiveness of the PMST calculation, and integrating the final treatment data into the clinical metadata for calculating PMST for future patients. 16. The method of any one of claims 1-15, further comprising collecting progress data throughout the method, the progress data comprising clinical follow-up data and clinical sensor(s) data from clinical sensors located in the microenvironment. 17. The method of claim 16, wherein the progress data comprises one or more of: x-ray data, functional assessment data, biomarker assay data, real-time biosensor(s) data, compliance metric(s) data, or direct patient-entered data. 18. The method of any one of claims 1-17, wherein the PTP affects biological processes in the microenvironment involved, for example, in stabilizing, reversing and / or ameliorating the injury or disease state; improving / restoring function of injury or tissue / organ affected by the disease; reducing the spread / growth of the disease; stabilizing the injury or disease; and managing / relieving pain associated with the injury or disease. 19. The method of any one of claims 1 to 18, wherein application of the PTP induces a bioelectric effect at the cellular level within the microenvironment. 20. The method of any one of claims 1 to 19, wherein the achievement of PMST more precisely targets biochemical and biophysical pathways of cells and associated structures in the injured or diseased microenvironment that promote cell proliferation, tissue growth, repair, and maintenance. 21. The method of any one of claims 1 to 20, wherein the achievement of PMST stimulates / modulates biochemical markers in the microenvironment including cytokines, growth factors, tumor markers, inflammatory markers, endocrine markers and metabolic markers. 22. The method of claim 21, wherein said stimulation / modulation of said biochemical markers accelerates cell, organ and tissue repair and increases blood flow to modulate angiogenesis and neovascularization. 23. The achievement of the PMST is (a) stimulate / modulate physiologically relevant pathways in the microenvironment, including common transmembrane potential changes involved in stabilizing, reversing, or healing injury or disease; and / or (b) stimulating physiologically induced changes including cell membrane changes, enzyme activity, cell apoptosis, nerve conduction, collagen synthesis, vasodilation, vasoconstriction, fluid / blood viscosity, pain signaling, endorphin production, tissue metabolism, blood flow, inflammation, oxygen & nutrient delivery, tissue / muscle repair or healing, fibroblast activity, collagen fiber density, protein synthesis, and tissue regeneration; 23. The method according to any one of claims 1 to 22. 24. The method of any one of claims 1-22, wherein said PTP defines a treatment period effective to effect healing of said injury or disease. 25. The method of any one of claims 1-24, wherein the injury or disease involves one or more of cancer, cardiovascular disease, inflammatory disease, autoimmune disease, neurological disease, musculoskeletal pain management, wound repair, bone repair, osteoporosis, tissue repair, trauma rehabilitation, sports injury, and surgical rehabilitation. 26. The method of claim 25, wherein the injury is a fracture, including but not limited to, occurring accidentally or due to intentional surgical intervention, simple fractures (closed fractures); compound fractures; oblique fractures; transverse fractures; spiral fractures; comminuted fractures; liner fractures; greenstick fractures, partial fractures; impact fractures; complete and incomplete fractures; compression fractures; avulsion fractures; fatigue fractures; hairline fractures; displaced fractures; non-displaced fractures; fatigue fractures; pathological fractures; and non-unions. 27. The method of claim 25, wherein the injury is torn cartilage and the method is for accelerating the healing of damaged or torn cartilage. 28. The method of claim 25, wherein the disease is a bone disease selected from osteoporosis, metabolic bone disease, bone cancer, and scoliosis. 29. The method of claim 25, wherein the disease is osteoarthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, lupus, gout, and bursitis. 30. The method of claim 25, wherein the disease is cancer and the method is optionally combined with surgery, radiation therapy and chemotherapy. 31. The method of claim 30, wherein the cancer is breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer (glioma), head and neck cancer, colon cancer, osteosarcoma, small cell lung tumor, smooth muscle tumor, osteosarcoma and other sarcomas. 32. The method of claim 31, wherein said method reduces uncontrolled cell division and helps regenerate healthy and functional tissues / organs after eradication of cancer tumors, including stem cell homing, control of proliferation, differentiation and blood vessel sprouting, growth and maturation of protein expression. 33. The method of any one of claims 1 to 25, wherein the method is for the treatment of pain. 34. The method of any one of claims 1 to 33, further comprising transmitting the PTP and optionally the optimization engine program to the EMF generating device. 35. An EMF signal generating device for delivering said PTP to achieve said PMST in the microenvironment of a patient's injury or disease according to any one of claims 1 to 34. 36. - Software-based controllers; - an EMF signal generator capable of executing a time-based sequence defined by said software-based controller; - at least one EMF source in operative communication with said EMF signal generator; 36. The EMF signal generating device of claim 35, wherein the EMF source achieves the PMST in a microenvironment of the injury or disease. 37. A system comprising an EMF signal generating device according to claim 35 or 36. 38. A device for providing an electromagnetic field (EMF) that is personalized to the microenvironment of a patient's injury or disease, comprising: - one or more software based controller(s) comprising MiCE, MaCE and optionally an optimization engine; - an EMF signal generator capable of executing the sequences defined by said software-based controller(s); and - at least one EMF source in operative communication with said EMF signal generator; wherein the at least one EMF source is configured to achieve the PMST in the microenvironment of the injury or disease. 39. The device of claim 38, wherein said PMST is calculated by a Microenvironment Computation Engine (MiCE). 40. MiCE, - 1 or more physics-based computational algorithms; - patient - Biological characteristics of the patient's microenvironment that will be targeted for treatment; and - Clinical metadata about the biological characteristics of similar target microenvironments An organized, indexed collection of data representing multidimensional parameters of; 40. The device of claim 39, wherein said MiCE calculates patient-specific, theoretically ideal, personalized microenvironmental stimulation targets required to induce a required biological response in said injury or disease microenvironment. 41. The device of any one of claims 38 to 40, wherein the personalized treatment protocol is calculated by a macro translation computation engine (MaCE). 42. The macro translation computation engine (MaCE), - 1 or more physics-based computational algorithms; - an organized, indexed collection of data representing multi-dimensional parameters of the electromagnetic field modality prescribed for said patient; and - a characteristic of a propagation path separating the location of said electromagnetic field source and said individualized microenvironment stimulation target; 42. The device of claim 41, wherein the MaCE calculates a precise individualized electromagnetic field output from an EMF source to provide the precise stimulation needed in a target microenvironment of the patient to stimulate healing of the patient's injury or disease. 43. The device of any one of claims 41 or 42, wherein the MiCE calculates an ideal stimulus in a microenvironment of a patient's injury or disease, and the MaCE calculates an ideal operation of an EMF source to generate the ideal stimulus in the microenvironment. 44. The device of any one of claims 38 to 43, wherein the personalized treatment protocol includes a PEMF signal. 45. The device of any one of claims 38-44, wherein the EMF source is configured for inductive coupling. 46. ​​The device of any one of claims 38-44, wherein the EMF source is configured for capacitive coupling with electrodes for electrochemical contact with the surface of the injury or disease. 47. The device of any one of claims 38-45, wherein the EMF source comprises one or more coils of wire having multiple coplanar loops. 48. The device of claim 47, wherein the signal applicator comprises one or more shaped coils. 49. The device of any one of claims 38 to 48, wherein the device is configured as a wearable device. 50. The device of claim 49, wherein the wearable device is selected from an anatomical wrap, an anatomical support, a garment, a chest support, a hat, a cap, a helmet, footwear, a dressing, a bandage, a compression bandage, and a compression dressing. 51. The device of any one of claims 38 to 50, wherein the device and / or its components are configured to be reusable. 52. The device of any one of claims 38-51, wherein the device further comprises a replaceable or rechargeable power source. 53. The device of any one of claims 38-52, wherein the device and / or its components are configured to be disposable, recyclable and / or replaceable. 54. The device of any one of claims 38-53, wherein the device and / or components thereof are configured to be incorporated into a device that is in close proximity to the patient on a daily basis, including a mattress, mattress pad, linen, furniture, exercise equipment, automobile, or support device. 55. A wearable electromagnetic field therapy system, comprising: EMF signal generator; Microcontroller; one or more wire coil EMF sources operably connected to the EMF signal generator; and A material configured to immobilize an EMF source adjacent to an area of ​​injury or disease. wherein the microcontroller is configured to generate a personalized treatment protocol (PTP) that achieves an ideal personalized microenvironment stimulation target (PMST) to induce a required biological response in the microenvironment of the injury or disease. 56. A microenvironment computation engine for computing personalized microenvironment stimulation targets (PMSTs) for bioelectromagnetic therapy prescribed to a patient for the treatment of an injury or disease; and A macro-translation computational engine for generating personalized treatment protocols (PTPs) a signal generator comprising a memory or chip storing To achieve the PMST, one or more EMF sources connected to a signal generator for providing the PTP. 1. A computer-implemented EMF treatment system comprising: 57. - A microenvironment computation engine configured to compute a theoretically ideal personalized microenvironment stimulation target (PMST) specific to the patient's treatment; - a macro-translation computation engine configured to generate personalized treatment protocols (PTPs) for achieving theoretically ideal personalized microenvironment stimulation targets; and - a signal generating device configured to implement said personalized treatment protocol. A bioelectromagnetic therapy system comprising: 58. A software product comprising machine-executable code for executing a Microenvironment Computation Engine (MiCE), - A set of physics-based computational algorithms; - An organized, indexed collection of data representing the following multidimensional parameters: - patient - Biological characteristics of the patient's microenvironment that will be targeted for treatment; and - Clinical metadata about the biological characteristics of similar target microenvironments wherein MiCE calculates patient-specific, theoretically ideal personalized microenvironment stimulation targets (PMSTs) to induce a required biological response in the microenvironment of the injury or disease. 59. A software product comprising machine executable code for executing a macro translation computation engine (MaCE), - a set of physics-based computational algorithms; propagation path data representing a signal path separating the microenvironment and the EMF source, as influenced by the material properties and physical dimensions of the tissues and materials along the signal path; and - Specification data describing the modality of electromagnetic field generation and the physical structure of the EMF signal-generating device configured for the patient and injury or disease; wherein the MaCE calculates precise individualized electromagnetic field output from an EMF source to provide the precise stimulation needed in a patient's target microenvironment to stimulate healing of the patient's injury or disease. 60. A therapeutic garment configured to apply individualized electromagnetic field (EMF) stimulation for the treatment of an injury or disease in a patient, comprising: a plurality of wire coil EMF sources integrated into the garment; and An EMF signal generator that is integrated into the garment and connected to a multiple wire coil EMF source wherein the EMF signal generator is configured to deliver a personalized treatment protocol (PTP) to achieve the personalized microenvironment stimulation target (PMST). 61. A wearable device, a mount for mounting the wearable device on a surface of the patient's body proximate to the microenvironment of the patient's injury or disease; an EMF signal generator operably connected to one or more EMF sources; Communication interface; Processor; non-transitory computer-readable medium; and calculating a personalized microenvironment stimulation target (PMST) signal and setting a personalized treatment protocol (PTP) for the patient based on the device modality, the PTP configured to achieve the PMST in the microenvironment of the injury or disease; and Optionally, transmitting data representative of the injury or disease microenvironment via said communication interface. a computation engine stored in a non-transitory computer-readable medium each executable by a processor to cause the wearable device to perform functions including The wearable device. 62. The wearable device of claim 61, wherein the wearable device is selected from the group consisting of anatomical wraps, anatomical supports, garments, chest supports, hats, caps, helmets, footwear fashion accessories, dressings, bandages, compression bandages and compression dressings. 63. A method for treating a physical injury or disease in a patient, comprising: Positioning an electromagnetic treatment device substantially adjacent to an area of ​​the patient's body to be treated; activating the electromagnetic therapy device to generate personalized microenvironmental stimulation targets (PMSTs) applied by a capacitively coupled EMF source and calculated to provide the ideal electromagnetic stimulation required to heal the patient's injury or disease; The method comprising: 64. A system comprising: an EMF signal generator configured to deliver a personalized treatment protocol (PTP) to achieve a personalized microenvironment stimulation target (PMST) ideal for stimulating the patient's injury or disease microenvironment; At least one sensor; a processor operatively connected to the EMF signal generator and the at least one sensor; and a memory communicatively coupled to the processor and including instructions configured to be executed by the processor, where the processor is configured to receive instructions from the memory and execute the instructions to perform operations including calculating the PMST and determining a PTP for the patient. A bioelectromagnetic therapy device comprising: providing the PTP using at least one EMF source operatively connected to the EMF signal generator to achieve the PMST in the microenvironment. The system comprising: 65. A system for providing an individualized electromagnetic signal to target a patient's microenvironment, comprising: a microenvironment computation engine incorporating at least one of artificial intelligence, machine learning, computation, and mathematical analysis; and Physiological and / or biochemical data characterizing the biological challenges of the microenvironment A patient profile including at least one of measured patient disease data and user data related to disease management; and Clinical Metadata A database of stored patient-centered information related to wherein the microenvironment computation engine comprises a protocol that uses at least one of artificial intelligence, machine learning, computation, and mathematical analysis to integrate and process a database of stored patient-centric information and compute an individualized electromagnetic signal that uniquely targets the microenvironment. 66. The system, A macro-translation computation engine incorporating at least one of artificial intelligence, machine learning, computation, and mathematical analysis; and A database of stored EMF modality-centric information related to macro-translation factors regarding the configuration of the individualized electromagnetic signals. 66. The system of claim 65, further comprising: wherein the macro translation computation engine comprises a protocol that uses at least one of artificial intelligence, machine learning, computation, and mathematical analysis to integrate the computed personalized electromagnetic signal with a database of stored EMF modality-centric information to output a personalized treatment protocol (PTP) for the patient.

[0303] The description of various embodiments and / or examples of the present invention has been presented for illustrative purposes, but is not exhaustive and is not intended to be limited to the disclosed embodiments and / or examples. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terms used herein have been selected to best explain the principles, practical applications of the embodiments, or to enable a better understanding of the embodiments disclosed herein.

Claims

1. 1. An electromagnetic field (EMF) signal generating device for providing an electromagnetic field (EMF) that is personalized to the microenvironment of a patient's injury or disease, comprising: - one or more software-based controller(s) comprising a computational engine configured to generate a personalized treatment protocol (PTP) for the patient based on a prescribed electromagnetic field modality, the PTP configured to achieve an ideal personalized microenvironment stimulation target (PMST) to induce a desired biological response in the injury or disease microenvironment; an EMF signal generator capable of executing time-based EMF sequences defined by said one or more software-based controller(s); at least one EMF source in operative communication with the EMF signal generator; and at least one sensor operatively connected to the EMF signal generator and / or the EMF source; wherein the EMF source is configured to achieve the PMST in the microenvironment of the injury or disease in the patient.

2. the one or more software-based controller(s); a microenvironment computation engine (MiCE) configured to compute a theoretically ideal personalized microenvironment stimulation target (PMST) for delivering electrical stimulation to the patient's injury or disease microenvironment; and 10. The device of claim 1, comprising: a macro-translation computation engine (MaCE) configured to calculate, integrate, and process EMF-centric data for ideal operation of the EMF source to generate ideal stimulation in the microenvironment of the injury or disease of the patient.

3. The MiCE comprises a multidimensional parameter: a patient, a biological characteristic of the patient's microenvironment that is the target of treatment, and clinical metadata about the biological characteristics of similar target microenvironments; one or more physics-based computational algorithms that use organized indexed data collections that represent The device of claim 2, wherein the MiCE calculates patient-specific and theoretically ideal personalized microenvironment stimulation targets required to induce the necessary biological response in the damaged or diseased microenvironment.

4. The MaCE comprises a multidimensional parameter: an electromagnetic field modality prescribed to said patient; and a characteristic of a propagation path separating an electromagnetic field source from a location of the individualized microenvironment stimulation target; one or more physics-based computational algorithms that use an organized indexed data collection representing The device of claim 3, wherein the MaCE calculates precise, individualized electromagnetic field output from an EMF source to provide the precise stimulation needed in the patient's target microenvironment to stimulate healing of the patient's injury or disease.

5. The device of any one of claims 1 to 4, wherein the one or more software-based controller(s) includes an optimization-enhanced computational engine that collects information from sensors in the microenvironment and external to the microenvironment and provides feedback to optimize the MiCE and the MaCE.

6. 6. The device of claim 5, wherein the optimization enhancement calculation engine includes a feedback calculation engine configured to obtain input data from EMF sensors in or near the microenvironment, determine and correct differences between a target EMF defined by the MaCE and an actually measured EMF as a result of any inaccuracies in the MaCE, and send any corrections as feedback to parameters affecting the generation of the PTP.

7. 6. The device of claim 5, wherein the one or more optimization engines include a learning computation engine configured to optimize during treatment delivery via a self-contained feedback loop that obtains input data from follow-up data and / or microenvironment sensor data to compensate for inaccuracies in the MiCE.

8. Compensation for inaccuracies in the MiCE is (a) incrementally adjusting individual parameters of the PTP, including increasing or decreasing the frequency or intensity of stimulation; (b) monitoring the effect(s) of any change(s) resulting from adjustment(s) under (a); (c) collecting sensor data and mapping patient-specific response profiles for each parameter; and (d) selecting an optimal combination of settings for recovery of the patient and outputting an optimized PTP; 8. The device of claim 7, comprising:

9. 5. The device of any one of claims 1 to 4, wherein the personalized treatment protocol comprises a pulsed electromagnetic field (PEMF) signal.

10. The EMF source is: configured for inductive coupling; and / or configured for capacitive coupling with an electrode for electrochemical contact with the surface of the injury or disease; and / or 5. The device of any one of claims 1 to 4, comprising one or more wire coils having a plurality of coplanar loops, Optionally, the signal applicator comprises one or more shaped coils.

11. the device and / or its components are configured to be reusable; and / or the device further comprises a replaceable or rechargeable power source; and / or The device of any one of claims 1 to 4, wherein the device and / or its components are configured to be disposable, recyclable, and / or replaceable.

12. 5. The device of any one of claims 1 to 4, wherein the device is configured as a wearable device, optionally the wearable device is selected from an anatomical wrap, an anatomical support, a garment, a chest support, a hat, a cap, a helmet, footwear, a dressing, a bandage, a compression bandage, and a compression dressing.

13. 5. The device of any one of claims 1 to 4, wherein the device and / or its components are configured to be incorporated into a device that is routinely in the patient's vicinity, including a mattress, mattress pad, linen, furniture, exercise equipment, automobile, or support device.

14. 1. A wearable electromagnetic field therapy system, comprising: An electromagnetic field (EMF) signal generating device according to any one of claims 1 to 4; and a material configured to immobilize the EMF source adjacent to an area of ​​injury or disease; The system comprising:

15. 1. A system for providing a personalized electromagnetic signal targeted to a microenvironment of a patient, comprising: (A) A microenvironment computation engine (MiCE), At least one of artificial intelligence, machine learning, computation, and mathematical analysis; and physiological and / or biochemical data characterizing the biological challenges of the microenvironment; a patient profile including at least one of measured patient disease data and user data related to disease management; and clinical metadata, a database of stored patient-centered information relating to the microenvironment computation engine incorporating a protocol that uses at least one of the artificial intelligence, machine learning, computation, and mathematical analysis to integrate and process the stored database of patient-centric information and compute the personalized electromagnetic signal that uniquely targets the microenvironment; and / or (B) a macro translation computation engine (MaCE), At least one of artificial intelligence, machine learning, computation, and mathematical analysis; and a database of stored EMF modality-centric information relating to macro-translation factors related to the configuration of said individualized electromagnetic signals; wherein the macro translation computation engine includes a protocol that uses at least one of the artificial intelligence, machine learning, computation, and mathematical analysis to integrate the computed personalized electromagnetic signal with a stored database of EMF modality-centric information to output a personalized treatment protocol (PTP) for the patient. The system comprising:

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