WO2007142901A1 - REGULATION OF TRANSFORMING GROWTH FACTOR-BETA (TGF-β) GENE EXPRESSION IN LIVING CELLS VIA THE APPLICATION OF SPECIFIC AND SELECTIVE ELECTRIC AND ELECTROMAGNETIC FIELDS - Google Patents
REGULATION OF TRANSFORMING GROWTH FACTOR-BETA (TGF-β) GENE EXPRESSION IN LIVING CELLS VIA THE APPLICATION OF SPECIFIC AND SELECTIVE ELECTRIC AND ELECTROMAGNETIC FIELDS Download PDFInfo
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- WO2007142901A1 WO2007142901A1 PCT/US2007/012560 US2007012560W WO2007142901A1 WO 2007142901 A1 WO2007142901 A1 WO 2007142901A1 US 2007012560 W US2007012560 W US 2007012560W WO 2007142901 A1 WO2007142901 A1 WO 2007142901A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/326—Applying electric currents by contact electrodes alternating or intermittent currents for promoting growth of cells, e.g. bone cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N13/00—Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/40—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals
Definitions
- the present invention is directed to a method of up-regulating transforming growth factor-beta (TGF- ⁇ ) gene expression in living cells via the application of electric and electromagnetic fields generated by specific and selective electric and electromagnetic signals for the treatment of injured or diseased tissues, as well as devices for generating such signals.
- TGF- ⁇ transforming growth factor-beta
- TGF- ⁇ Transforming growth factor - beta
- TGF- ⁇ is a pleiotropic growth factor that is present in most tissues and is implicated in cell proliferation, migration, differentiation, and survival. Consequently, TGF- ⁇ has clinical applications in diverse conditions such as angiogenesis, autoimmunity, bone repair (fractures, delayed unions, nonunions) and bone maintenance (osteoporosis), cartilage maintenance (degenerative arthritis), tumor suppression, and wound healing (Kim et al., J of Biochemistry and Molecular Biology, 38: 1-8, (2005); Janssens et al., Endocrine Reviews, 26: 743-774, (2005).
- BMPs bone morphogenetic proteins
- the optimal signal for the gene expression of BMPs is slightly different from that of TGF- ⁇ s, and this difference allows one to design a device that delivers one signal that maximally up-regulates the BMPs during the bone phase of fracture healing and another signal that primarily up-regulates the TGF- ⁇ s during the cartilage phase of fracture healing. This would be very useful in fracture healing, for instance, where the fracture callus is initially composed of cartilage that gradually is replaced by bone.
- Up-regulation of TGF- ⁇ may also be useful in the treatment of the disease commonly known as osteoporosis, where bone demineralizes and becomes abnormally rarefied.
- Bone comprises an organic component of cells and matrix as well as an inorganic or mineral component.
- the cells and matrix comprise a framework of collagenous fibers that is impregnated with the mineral component of calcium phosphate (85%) and calcium carbonate (10%) that imparts rigidity to the bone.
- the mineral component of calcium phosphate (85%) and calcium carbonate (10%) that imparts rigidity to the bone.
- bone formation and bone resorption are in balance.
- osteoporosis bone resorption exceeds bone formation, leading to bone weakening and possible vertebral body fracture and collapse.
- osteoporosis is generally thought as afflicting the elderly, certain types of osteoporosis may affect persons of all ages whose bones are not subject to functional stress. In such cases, patients may experience a significant loss of cortical and cancellous bone during prolonged periods of immobilization. Elderly patients are known to experience bone loss due to disuse when immobilized after fracture of a bone, and such bone loss may ultimately lead to a secondary fracture in an already osteoporotic skeleton. Diminished bone density may lead not only to vertebrae collapse, but also to fractures of hips, lower arms, wrists, ankles as well as incapacitating pains. Alternative non-surgical therapies for such diseases are needed.
- PEMF Pulsed electromagnetic fields
- CC capacitive coupling
- the present invention builds upon the technique described therein by describing the method of regulating expression of one targeted gene family, namely, TGF- ⁇ 's gene expression, through application of a field generated by a specific and selective electrical and electromagnetic signal, for the treatment of fresh fractures, fractures at risk, delayed unions, nonunion of fractures, bone defects, spine fusions, osteonecrosis or avascular necrosis, as an adjunct to other therapies in the treatment of one or all of the above, and in the treatment of osteoporosis.
- the present invention relates to regulating transforming growth factor-beta (TGF- ⁇ ) gene expression in bone cells (as an example) via the application of specific and selective electric and/or electromagnetic fields generated by specific and selective electric and/or electromagnetic signals applied to electrodes.
- TGF- ⁇ transforming growth factor-beta
- the optimal signal generated a capacitively coupled electric field with an amplitude of 20-40 mV/cm, a duration of 24 hours, a frequency of 60 kHz, and a duty cycle of 50%.
- the present invention relates to up-regulating TGF- ⁇ 1, 2, and 3 gene expression in bone cells via the application of fields generated by such signals.
- methods are provided to specifically and selectively up-regulate the gene expression (as measured by mRNA) of TGF- ⁇ 1, TGF- ⁇ 2, and TGF- ⁇ 3 with capacitively coupled electric fields, electromagnetic fields, or combined fields.
- Fresh fractures, fractures at risk, delayed unions, nonunion fractures, bone defects, osteonecrosis, osteoporosis, and the like are treated with a capacitively coupled electric field of about 20-40 mV/cm with an electric field duration of about 24 hours, a frequency of 60 kHz, a duty cycle of about 50%, and a sine wave configuration that causes the expression of TGF- ⁇ s 1, 2, and 3 to be up-regulated.
- a "specific and selective" signal is a signal that has predetermined characteristics of amplitude, duration, duty-cycle, frequency, and waveform that up-regulates the expression of the TGF- ⁇ genes (specificity). This allows one to choose different signals to up-regulate TGF- ⁇ gene expressions in order to achieve a given biological or therapeutic response (selectivity).
- the invention further relates to devices employing the methods described herein to generate specific and selective signals that create electric fields to up-regulate the expression of TGF- ⁇ genes.
- the invention relates to methods and devices for the treatment of fresh fractures, fractures at risk, delayed unions, nonunions, bone defects, spine fusion, osteonecrosis, as an adjunct to other therapies treating one or more of the above, and in the treatment of osteoporosis.
- the method of the invention also includes the methodology for determining the "specific and selective" signal for TGF- ⁇ gene expression by methodically varying the duration of a starting signal known to increase, or suspected to increase, cellular production of TGF- ⁇ s. After finding the optimal duration, the amplitude of the signal is varied for the optimal duration of time as determined by the gene expression of TGF- ⁇ 1, 2, and 3.
- the duty cycle, frequency, and waveform are varied methodically in the same dose response manner as above while keeping the other signal characteristics constant. This process is repeated until the optimal signal is determined that produces the greatest increase in the expression of TGF- ⁇ s.
- Figure 1 is a graphic representation of the mRNA expression of TGF- ⁇ s 1, 2, and 3 when bone cells are exposed to a 20 mV/cm capacitively coupled electric field for various time durations. As indicated, the maximum expression for the various TGF- ⁇ rnRNAs occurred with a signal of 24 hours duration.
- FIG. 2 is a graphic representation of the mRNA expression of TGF- ⁇ 1, 2, and 3 when bone cells are exposed to various capacitively coupled electric field amplitudes with a duration of 24 hours. As indicated, the maximum expression for the various TGF- ⁇ mRNAs occurred with a field amplitude of 20-40 mV/cm.
- FIG. 3 is a graphic representation of the mRNA expression of TGF- ⁇ 1, 2, and 3 when bone cells are exposed to various capacitively coupled electric field frequencies with a field amplitude of 20-40 mV/cm and a signal duration of 24 hours. As indicated, the maximum expression for the various TGF- ⁇ mRNAs occurred with a frequency of 60 kHz.
- FIG. 4 is a graphic representation of the mRNA expression of TGF- ⁇ 1, 2, and 3 when bone cells are exposed to various capacitively coupled electric field duty cycles with a frequency of 60 kHz, a field amplitude of 20 mV/cm, and a signal duration of 24 hours. As indicated, the maximum expression for the various TGF- ⁇ mRNAs occurred with a 50% to 100% duty cycle with a sine wave configuration.
- FIG. 5 is a graphic representation of the TGF- ⁇ l protein when bone cells are exposed 24 hours to a capacitively coupled electric field of a 50% duty cycle with a field amplitude of 20 mV/cm or 40mV/cm, a frequency of 60 kHz, and a sine wave configuration. As indicated, the amount of TGF- ⁇ l protein increase was the same with either 20 or 40 mV/cm.
- FIG. 6 is a graphic representation of BMP-2 protein when bone cells are exposed 24 hours to a capacitively coupled electric field of a 50% duty cycle with a field amplitude of 20 mV/cm or 40 mV/cm, a frequency of 60 kHz, and a sine wave configuration. As indicated, unlike the TGF- ⁇ l response shown in Figure 5, there was no significant increase in BMP-2 protein production at a field of 40 mV/cm as compared to that occurring at 20mV/cm.
- Figure 7 is a graphic representation of BMP mRNA expression when bone cells are exposed to a 50% duty cycle, capacitively coupled electric field (20 mV/cm, 60 kHz, sine wave) for 24 hours. Comparing this figure to Figure 2 shows the clear distinction between the lack of response of the bone cell production of BMP protein in a 40 mV/cm field versus the very significant increase of the bone cell production of TGF- ⁇ protein in a 40 mV/cm field.
- Figure 8 illustrates the BMP gene expression of Figure 7 on the same graph as the TGF- ⁇ gene expression of Figure 2.
- Figure 9 is a diagram illustrating a device for the treatment of osteoarthritis of the knee, in accordance with a preferred embodiment of the present invention.
- the present invention is based on the discovery that the expression of certain genes can be regulated by the application of fields generated by specific and selective electric and/or electromagnetic signals.
- a specific electric and/or electromagnetic signal that generates a field for regulating each gene in bone, cartilage and other tissue cells and that these specific signals are capable of specifically and selectively regulating the genes in such cells.
- gene expression governing the growth, maintenance, repair, and degeneration or deterioration of tissues or cells can be regulated in accordance with the invention via the application of fields generated by specific and selective electric and/or electromagnetic signals so as to produce a salutary clinical effect.
- the phrase "signal” is used to refer to a variety of signals including mechanical signals, ultrasound signals, electromagnetic signals and electric signals output by a device. It is to be understood that the term “field” as used herein refers to an electrical field within targeted tissue, whether it is a combined field or a pulsed electromagnetic field or generated by direct current, capacitive coupling or inductive coupling.
- remote is used to mean acting, acted on or controlled from a distance.
- Remote regulation refers to controlling the expression of a gene from a distance.
- To provide “remotely” refers to providing from a distance.
- providing a specific and selective signal from a remote source can refer to providing the signal from a source at a distance from a tissue or a cell, or from a source outside of or external to the body.
- the phrase "specific and selective" signal means a signal that produces an electric field that has predetermined characteristics of amplitude, duration, duty cycle, frequency, and waveform that up-regulate or down-regulate a targeted gene or targeted functionally complementary genes (specificity). This allows one to choose different "specific and selective" signals to up-regulate or down-regulate expression of various genes in order to achieve a given biological or therapeutic response (selectivity).
- the term "regulate” means to control gene expression. Regulate is understood to include both up-regulate and down-regulate. Up-regulate means to increase expression of a gene, while down-regulate means to inhibit or prevent expression of a gene.
- “Functionally complementary” refers to two or more genes whose expressions are complementary or synergistic in a given cell or tissue.
- tissue refers to an aggregate of cells together with their extracellular substances that form one of the structural materials of a patient.
- tissue is intended to include any tissue of the body including muscle and organ tissue, tumor tissue as well as bone or cartilage tissue. Also, the term “tissue” as used herein may also refer to an individual cell.
- Patient refers to an animal, preferably a mammal, more preferably a human.
- the present invention provides treatment methods and devices that target certain tissues, cells or diseases, hi particular, the gene expression associated with the repair process in injured or diseased tissues or cells can be regulated by the application of fields generated by electric signals that are specific and selective for the genes to be regulated in the target tissues or cells.
- Gene expression can be up-regulated or down-regulated by the application of signals that are specific and selective for each gene or each set of complementary genes so as to produce a beneficial clinical effect.
- a particular specific and selective signal may create an electric field that up-regulates a certain desirable gene expression, while the same or another particular specific and selective signal may create an electric field that down-regulates a certain undesirable gene expression.
- a certain gene may be up-regulated by a field generated by one particular specific and selective signal and down-regulated by a field generated by another specific and selective signal.
- certain diseased or injured tissues can be targeted for treatment by regulating those genes governing the growth, maintenance, repair, and degeneration or deterioration of the tissues.
- the methods and devices of the present invention are based on identifying those signals that generate fields that are specific and selective for the gene expression associated with certain targeted diseased or injured tissue.
- electricity in its various forms e.g., capacitive coupling, inductive coupling, combined fields
- the duration of time exposed to electricity can also influence the capability of electricity to specifically and selectively regulate gene expression in targeted tissues or cells in a patient's body.
- Specific and selective signals may generate electric fields for application to each gene systematically until the proper combination of frequency, amplitude, waveform, duty cycle, and duration is found that provides the desired effect on gene expression.
- a variety of diseased or injured tissues or disease states can be targeted for treatment because the specificity and selectivity of an electric field for a certain gene expression can be influenced by several factors.
- an electrical field of appropriate frequency, amplitude, waveform and/or duty cycle can be specific and selective for the expression of certain genes and thus provide for targeted treatments.
- Temporal factors e.g., duration of time exposed to the electrical field
- the regulation of gene expression may be more effective (or made possible) via the application of an electrical field for a particular duration of time.
- the present invention provides for varying the frequency, amplitude, waveform, duty cycle and/or duration of application of an electric field until the electric field is found to be specific and selective for certain gene expressions in order to provide for treatments targeting a variety of diseased or injured tissue or diseases.
- the present invention can provide for targeted treatments because it is possible to regulate expression of certain genes associated with a particular diseased or injured tissue via the application of electric fields generated by specific and selective signals of appropriate frequency, amplitude, waveform and/or duty cycle for an appropriate duration of time.
- the specificity and selectivity of a signal generating an electrical field may thus be influenced so as to regulate the expression of certain genes in order to target certain diseased or injured tissue or disease states for treatment.
- the present invention provides for the targeted treatment of fresh bone fractures, fractures at risk, nonunion, bone defects, spine fusion, osteonecrosis, as an adjunct in the treatment of one or any of the above, and in the treatment of osteoporosis.
- the devices of the present invention are capable of applying a field generated by • specific and selective signals directly to diseased or injured tissue and/or to the skin of a patient.
- the devices of the present invention may also provide for the remote application of specific and selective fields (e.g., application of a field at a distance from diseased or injured tissue yet which yields the desired effect within the targeted cells), although it will be appreciated that capacitively coupled devices must touch the subject's skin.
- the devices of the present invention may include means for attaching the electrodes to the body of a patient in the vicinity of injured or diseased tissue in the case of capacitive coupling.
- self-adherent conductive electrodes may be attached to the skin of the patient on both sides of a fractured bone.
- the device 10 of the present invention may include self-adherent electrodes 12 for attaching the device to the body of a patient.
- the device 10 of the present invention may include electrodes attached to a power unit 14 that has a VELCRO ® patch 16 on the reverse side such that the power unit 14 can be attached to a VELCRO ® strap (not shown) fitted around a cast on the patient.
- the device of the present invention may include coils attached to a power unit in place of electrodes.
- the device 10 of the present invention can be employed in a variety of ways.
- the device 10 may be portable or may be temporarily or permanently attached to a patient's body.
- the device 10 of the present invention is preferably non-invasive.
- the device 10 of the present invention may be applied to the skin of a patient by application of electrodes adapted for contact with the skin of a patient for the application of electric fields generated by the predetermined specific and selective electric signals.
- Such signals may also be applied via coils in which time varying currents flow, thus producing specific and selective electromagnetic fields that penetrate the tissue and create the specific and selective electric fields in the target tissue.
- the device 10 of the present invention may also be capable of implantation in a patient, including implantation under the skin of a patient.
- the devices of the present invention can be provided in a variety of forms including a capacitively coupled power unit with programmed, multiple, switchable, specific and selective signals for application to one pair or to multiple pairs of electrodes, electromagnetic coils or a solenoid attached to a power unit with switchable, multiple, specific and selective signals, and an ultrasound stimulator with a power supply for generating specific and selective signals.
- a capacitively coupled power unit with programmed, multiple, switchable, specific and selective signals for application to one pair or to multiple pairs of electrodes electromagnetic coils or a solenoid attached to a power unit with switchable, multiple, specific and selective signals
- an ultrasound stimulator with a power supply for generating specific and selective signals.
- device preference is based on patient acceptance and patient compliance.
- the smallest and most portable unit available in the art at the present time is a capacitive coupling unit; however, patients with extremely sensitive skin may prefer to use inductive coupling units.
- ultrasound units require the most patient cooperation, but may be desirable for use by certain patients.
- MC3T3-E1 bone cells (5 x 10 5 cells/cm 2 ) were plated onto specially-modified Cooper dishes. The cells were grown for seven days with the medium changed just prior to beginning of the experimental condition. The experimental cell cultures throughout these studies were subjected to a capacitively coupled 60 kHz sine wave signal electric field with an output of 44.81 V peak-to-peak. This produced a calculated-field strength in the culture medium in the dishes of 20 mV/cm with a current density of 300 ⁇ A/cm 2 . Control cell culture dishes were identical to those of the stimulated dishes except that the electrodes were not connected to a function generator.
- Oligonucleotide primers to be used in the real time RT-PCR technique were selected from published cDNA sequences or designed using the Primer Express software program. Quantitative real-time analysis of RT-PCR products was performed using an ABI Prism ® 7000 Sequence Detection System.
- TGF tumor necrosis factor
- mRNA gene expression
- a dose-response curve is first performed by varying the duration of the signal while holding all the other signal characteristics constant (amplitude, duty cycle, frequency, and waveform) ( Figure 1). This determines the optimal duration of the starting signal for the gene expression of that protein.
- a second dose-response curve is then performed, this time varying the amplitude of the electric field (in mV/cm) while holding the optimal duration and other signal characteristics constant ( Figure 2).
- a third dose response is performed, this time varying the signal frequency while holding constant the optimal duration and optimal amplitude as found previously ( Figure 3).
- a fourth dose-response is performed varying the duty cycle from 100% (constant) to 10% or less while holding constant the optimal duration, amplitude, and frequency as found previously ( Figure 4).
- a fifth experiment is performed using a continuous 50% duty cycle (capacitive coupling, 60 kHz, sine wave) to compare a 20mV/cm field to a 40mV/cm field in the production of the TGF- ⁇ l protein. As indicated, the TGF- ⁇ l protein increased significantly and equally in the two fields. (Figure 5).
- a sixth experiment is performed to demonstrate an increase in production of the BMP-2 protein in the same two fields as described in Figure 5 (20mV/cm and 40mV/cm).
- FIG. 8 illustrates the BMP gene expression of Figure 7 on the same graph as the TGF- ⁇ gene expression of Figure 2.
- the optimal electric field described in the example can very significantly up-regulate TGF- ⁇ 1,2, and 3 mRNA and, hence, increase bone formation in fracture healing, delayed healing, nonunion, bone defects, spine fusions, and in osteoporosis.
- an appropriate electric field, as described herein with capacitive coupling is also equally effective with inductive coupling and all electromagnetic systems that produce equivalent, or nearly equivalent, electric field characteristics.
- the optimal field described herein can be applied to any bone via two or more appropriate surface electrodes, in pairs or strips, incorporated in braces, wraps, or casts, and delivered by means of capacitive coupling.
- the optimal field described here can be applied to any bone via coil(s) or solenoid incorporated into braces, wraps, or casts, and delivered by means of inductive coupling. Accordingly, the scope of the invention is not intended to be limited to the preferred embodiment described above, but only by the appended claims.
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2007255038A AU2007255038B2 (en) | 2006-05-31 | 2007-05-29 | Regulation of transforming growth factor-beta (TGF-beta) gene expression in living cells via the application of specific and selective electric and electromagnetic fields |
MX2008015123A MX2008015123A (en) | 2006-05-31 | 2007-05-29 | Regulation of transforming growth factor-beta (tgf- ) gene expression in living cells via the application of specific and selective electric and electromagnetic fields. |
JP2009513220A JP2009538694A (en) | 2006-05-31 | 2007-05-29 | Regulation of transforming growth factor-beta (TGF-β) gene expression in living cells through the application of specific and selective electric and electromagnetic fields |
CA002653431A CA2653431A1 (en) | 2006-05-31 | 2007-05-29 | Regulation of transforming growth factor-beta (tgf-beta) gene expression in living cells via the application of specific and selective electric and electromagnetic fields |
BRPI0711846-5A BRPI0711846A2 (en) | 2006-05-31 | 2007-05-29 | device for treating a bone fracture, fracture risk, delayed joint, non-welding fractures, bone insufficiency, spinal fusion, osteonecrosis, Oesteoporosis and / or other conditions |
EP07777294A EP2024003A4 (en) | 2006-05-31 | 2007-05-29 | REGULATION OF TRANSFORMING GROWTH FACTOR-BETA (TGF- ß) GENE EXPRESSION IN LIVING CELLS VIA THE APPLICATION OF SPECIFIC AND SELECTIVE ELECTRIC AND ELECTROMAGNETIC FIELDS |
NZ573556A NZ573556A (en) | 2006-05-31 | 2007-05-29 | Regulation of transforming growth factor-beta (tgf-beta) gene expression in living cells via the application of specific and selective electric and electromagnetic fields |
IL195549A IL195549A (en) | 2006-05-31 | 2008-11-27 | Device for the treatment of conditions related to transforming growth factor -beta (tgf-β) utilizing selective electric and electromagnetic fields and method of determining a specific and selective electric signal |
NO20085399A NO20085399L (en) | 2006-05-31 | 2008-12-29 | Regulation of Gene Expression of Transforming Growth Factor Beta (TGF-β) in Living Cells via the Use of Specific and Selective Electric and Magnetic Fields |
Applications Claiming Priority (2)
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US11/444,179 | 2006-05-31 | ||
US11/444,179 US7465546B2 (en) | 2000-02-23 | 2006-05-31 | Regulation of transforming growth factor-beta (TGF-β) gene expression in living cells via the application of specific and selective electric and electromagnetic fields |
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US (1) | US7465546B2 (en) |
EP (1) | EP2024003A4 (en) |
JP (1) | JP2009538694A (en) |
KR (1) | KR20090029749A (en) |
CN (1) | CN101516435A (en) |
AU (1) | AU2007255038B2 (en) |
BR (1) | BRPI0711846A2 (en) |
CA (1) | CA2653431A1 (en) |
IL (1) | IL195549A (en) |
MX (1) | MX2008015123A (en) |
NO (1) | NO20085399L (en) |
NZ (1) | NZ573556A (en) |
RU (1) | RU2008152084A (en) |
WO (1) | WO2007142901A1 (en) |
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US8065015B2 (en) | 2000-02-23 | 2011-11-22 | The Trustees Of The University Of Pennsylvania | Regulation of genes via application of specific and selective electrical and electromagnetic signals |
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KR20090029749A (en) | 2009-03-23 |
AU2007255038B2 (en) | 2011-03-17 |
JP2009538694A (en) | 2009-11-12 |
EP2024003A4 (en) | 2010-08-04 |
NO20085399L (en) | 2009-02-27 |
RU2008152084A (en) | 2010-07-10 |
EP2024003A1 (en) | 2009-02-18 |
ZA200810486B (en) | 2009-10-28 |
NZ573556A (en) | 2012-03-30 |
US20060235473A1 (en) | 2006-10-19 |
BRPI0711846A2 (en) | 2011-12-13 |
IL195549A0 (en) | 2009-09-01 |
CA2653431A1 (en) | 2007-12-13 |
MX2008015123A (en) | 2009-03-05 |
IL195549A (en) | 2014-05-28 |
US7465546B2 (en) | 2008-12-16 |
AU2007255038A1 (en) | 2007-12-13 |
CN101516435A (en) | 2009-08-26 |
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