Genetic regulation of bone and cells by electromagnetic stimulation fields and uses thereof
Inventors
Goodwin, Thomas J. • Shackelford, Linda C.
Assignees
National Aeronautics and Space Administration NASA
Publication Number
US-9896681-B2
Publication Date
2018-02-20
Expiration Date
2030-10-07
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Abstract
The present invention provides methods to modify the genetic regulation of mammalian tissue, bone, cells or any combination thereof by preferential activation, up-regulation and/or down-regulation. The method comprises steps of tuning the predetermined profiles of one or more time-varying stimulation fields by manipulating the B-Field magnitude, rising slew rate, rise time, falling slew rate, fall time, frequency, wavelength, and duty cycle, and exposing mammalian cells or tissues to one or more tuned time-varying stimulation fields with predetermined profiles. Examples of mammalian cells or tissues are chondrocytes, osteoblasts, osteocytes, osteoclasts, nucleus pulposus, associated tissue, or any combination. The resulted modification on gene regulation of these cells, tissues or bones may promote the retention, repair of and reduction of compromised mammalian cartilage, bone, and associated tissue.
Core Innovation
The present invention provides methods to modify the genetic regulation of mammalian tissue, bone, cells or any combination thereof by preferential activation, up-regulation and/or down-regulation through the use of one or more time-varying stimulation fields with predetermined profiles. This method involves tuning the stimulation field profiles by manipulating parameters such as B-Field magnitude, rising slew rate, rise time, falling slew rate, fall time, frequency, wavelength, and duty cycle, then exposing mammalian cells or tissues to these tuned fields. The targeted cells or tissues include chondrocytes, osteoblasts, osteocytes, osteoclasts, nucleus pulposus, associated tissue, or any combination.
The problem being solved is related to the limited repair capabilities of cartilage and bone due to the avascular nature of cartilage and the slow growth and repair rate, as well as the invasiveness and limitations of current therapies for diseases like osteoarthritis and osteoporosis. Existing electromagnetic and electrical field therapies mainly focus on frequency and B-Field magnitude but do not address the tuning of comprehensive stimulation field profiles capable of preferentially up-regulating or down-regulating specific genes to promote tissue repair and regeneration effectively. This invention addresses this deficiency by providing specific stimulation field profiles — including waveform shape and slew rates — to modify genetic regulation non-invasively in targeted mammalian tissues, promoting repair, retention, and reduction of compromised cartilage and bone.
The innovation further encompasses an apparatus comprising a power source, control component, and transmission component to generate and deliver these tuned stimulation fields of predetermined profiles. The apparatus can be embodied, for example, as a sleeve that wraps around a region of interest, delivering electromagnetic stimulation to affected tissues non-invasively. The methods and apparatus are applicable to treating diseases such as osteoarthritis, osteoporosis, and fractures, and to reducing muscle atrophy from body unloading. The invention is supported by empirical techniques utilizing rotating wall vessels and gene expression analyses to tune stimulation fields for optimized anabolic or catabolic genetic effects.
Claims Coverage
The patent presents two independent claims concerning methods for using time-varying stimulation fields to modulate gene expression and activate mammalian bone-related genes, along with apparatus components to generate said fields.
Method for up-regulating or down-regulating human gene expression using specific time-varying stimulation fields
A method involving positioning an apparatus proximate to human chondrocyte or osteoblast samples and generating a time-varying stimulation field characterized by specific B-Field magnitudes (about 0.059 G or 0.65 G for chondrocytes; about 0.65 G and frequency of 10 Hz or 15 Hz for osteoblasts), frequency of about 10 Hz, rising slew rate from about 2.0 kG/s to 4.5 kG/s, fall slew rate from about 4.5 kG/s to 15.5 kG/s, rise and fall times, a wavelength of about 500 ms, duty cycle of about 80% or 30%, and exposure time of 720 hours predetermined to achieve desired genetic regulation.
Time-varying stimulation field generating apparatus with components for producing tuned electromagnetic fields
An apparatus comprising a power source, a control component connected to the power source, and a transmission component connected to the control component and power source, operative to generate stimulation fields with predetermined profiles for genetic regulation of cells.
Use of stimulation fields for preferential gene modulation in specific gene families
Method targeting the regulation of defined mammalian gene families in human chondrocyte cells (e.g., Wnt signaling, forkhead box, sex determining region Y, parathyroid hormone, transforming growth factor beta super gene, integrin, interleukin, thrombospodin, laminin, proteoglycan, collagen, insulin, disintegrin and metalloproteinase, actin, catenin, and cadherin super genes) and human osteoblast cells (including forkhead box genes, parathyroid hormone genes, integrin genes, interleukin genes, thrombospondin, laminin, proteoglycan, osteoglycin, collagen, insulin, metalloproteinase, actin, apoptosis, calmodulin, cathepsin, clusterin, cytochrome P450, endoglin, fibrillin, fibroblast growth factor, leptin, mitogen-activated protein kinase, homeobox, notch, peroxisome proliferator-activated receptor genes, platelet derived growth factor, transcription factors, stanniocalcin, superoxide dismutase, syndecan, tumor necrosis factor super genes, AKT/protein kinase B, and importin genes).
Method to activate mammalian bone formation genes using time-varying stimulation fields with specified parameters
A method to stimulate gene activation associated with bone formation by generating substantially square, biphasic waveform time-varying stimulation fields with controlled B-Field magnitude between about 0.6 G to 50 G, frequency from about 10 Hz to 16 Hz, rise time from about 0.75 ms to 1 ms with rising slew rate 2.0-4.5 kG/s, fall time between 125 μs to 300 μs with falling slew rate from 4.5 to 15.5 kG/s, duty cycle about 65% to 80%, and exposure schedules predetermined for gene activation. This includes contacting the cells with Vitamin D, Vitamin K, or both.
The claims define inventive methods and apparatuses that specify comprehensive tuning of stimulation field parameters—including waveform, slew rates, frequency, duty cycle, B-Field magnitudes, exposure times, and targeted gene families—to modulate genetic expression in human chondrocytes and osteoblasts and to promote bone and cartilage regeneration, with apparatus embodiments incorporating power sources, control components, and transmission components.
Stated Advantages
Non-invasive stimulation of targeted mammalian cells to promote retention, repair, and regeneration of cartilage, bone, and associated tissues without surgery or drug administration.
Ability to preferentially up-regulate or down-regulate specific genes and gene families responsible for anabolic or catabolic effects, enabling customized therapeutic protocols.
Tuning of multiple stimulation field parameters (beyond frequency and B-Field magnitude) such as slew rates, waveform shape, duty cycle, and exposure time enhances control over cellular responses and genetic regulation.
Modular and versatile apparatus design allowing tailored delivery of electromagnetic fields to different tissues, improving efficacy for treatment of diseases such as osteoarthritis, osteoporosis, fractures, and muscle atrophy from unloading.
Documented Applications
Treatment and repair of osteoarthritis by promoting cartilage regeneration.
Treatment and repair of osteoporosis and bone fractures through activation of bone growth and repair genes.
Neuromuscular stimulation to reduce muscle atrophy in conditions such as hospitalization or spaceflight.
Non-invasive biomedical therapeutic applications for regeneration and repair of cartilage, bone, and associated soft tissue using time-varying magnetic fields.
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