Nanopulses tweak the innards of cells

A method that would allow doctors to tweak the innards of cells without even touching a patient's body is being developed in the US and Greece..

The technique is still in its infancy, and it is still not clear exactly what it does to cells. But initial experiments suggest it might one day be possible to use the technique to treat cancer, speed up healing or even tackle obesity.

The method involves exposing cells to an extremely powerful electric field for very brief periods. "The effects of these pulses are fairly dramatic," says Tom Vernier of the University of Southern California in Los Angeles, who will present some of his team's results at a nanotechnology conference in Boston in March. "We see it as reaching into the cell and manipulating intracellular structures."

Applying electric pulses to cells is not new. In a technique called electroporation, electric fields that last hundreds of microseconds are applied to cells. The voltage charges the lipid molecules in the cell membrane, creating transient holes in the membrane. The method can be used to help get drugs or genes into cells.

Major physiological event

But the latest technique involves more powerful electric fields, with gradients of tens of megavolts per metre, applied for much shorter periods. These nanosecond-pulsed electric fields are too brief to generate an electric charge across the outer membrane of cells, but they do affect structures within cells.

One of the main effects seems to be calcium release from a cellular structure called the endoplasmic reticulum. "In a nanosecond, we cause this major physiological event in the cell," says Vernier. "It's completely indirect and remote, and it's an extremely rapid transition."

The nanopulses can also trigger cell suicide. Teams led by Vernier, Karl Schoenbach of Old Dominion University and Stephen Beebe of Eastern Virginia Medical School, both in Norfolk, Virginia, have shown that nanopulsing can kill tumour cells in culture.

The pulses do not just fry cells, but lead to changes such as the activation of enzymes called caspases, an early step in cell suicide. How the pulses do this is not clear, but Vernier says the effect is not related to calcium release.

Cell suicide

So could nanopulsing help treat cancer? In a preliminary test, Schoenbach and Beebe used needle-like electrodes to generate pulses near tumours in mice. Nanopulsing slowed the growth of tumours in four mice by 60 per cent compared with tumour growth in five untreated mice. The researchers hope that with better delivery systems they could make the tumours shrink.

Beebe's team has also found that the pulses can trigger suicide in the cells that give rise to fat cells, possibly opening up a new way of treating obesity, Beebe speculates.

And Vernier is working with doctors at the Cedars-Sinai Medical Center in Los Angeles to see if nanopulses can speed up the healing of wounds. "We do see an effect, but that's about all I can say now," he says.

The next step is to develop a way to deliver the pulses to cells and organs deep within the body. Theoretical models suggest that nanosecond pulses of broadband radio signals could do it. "An array of such antennas would create, through superposition of electric fields, a very high electric field right where we need it," says Schoenbach.
 

Source:
Anil Ananthaswamy, 06 February 04, New Scientist http://www.newscientist.com/news/news.jsp?id=ns99994635


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Electrical Nanopulses Might Kill Tumors

Killing cells affected by cancer while leaving healthy ones alone is not a new idea.  But, in "Ultra-fast shocks scramble cells," Nature describes a new approach based on electrical nanopulses. These electric shocks last only a few billionths of a second while reaching during this very short amount of time power levels of terawatts. They also are very intriguing, apparently forcing cancer cells to commit suicide. 

The technique involves blasting cells with nanopulses. These are high-power electrical bolts that last a few billionths of a second. They deliver millions of volts - enough power to light up a city, but each burst lasts much less than the blink of an eye. 

Longer shocks blow a cell apart, but researchers have found that the fleeting nanopulses leave the cell membrane unaffected while mixing up its insides. Now they are working out how to vary the timing and intensity of the shocks to make cells behave in specific ways.

Here are two images showing how ultrashort pulses affect the intracellular structure, leaving the cell membrane intact (Credit: Center for Bioelectrics).
Is this technique ready for human deployment? Not quite yet.

There is plenty to be worked out before the human body is zapped with nanopulses. James Weaver, who studies electrical effects in cells at the Massachusetts Institute of Technology, Boston, says they are at an early stage: "There are maybe ten papers published showing that something dramatic is happening."

One puzzling aspect of this technique is the electric shocks are pushing cells to commit suicide. Scientists are not sure why.

One of the most significant discoveries was that nanopulses make mammalian cells commit suicide, rather than blowing them up. This is a relatively gentle way of killing, because scavenger cells come and swallow the debris. By contrast, long electric shocks explode cells and liberate toxic molecules that cause inflammation and pain.

For this reason, researchers hope to use nanopulses to kill cancer cells while leaving healthy tissue intact. Karl Schoenbach's team at the Center for Bioelectrics in Norfolk, Virginia, has already shown that the pulses can shrink mouse tumours by over 50%, and is working on catheters or non-invasive ways to deliver the shocks to the body.

For more information about their research projects, you can look at this page or check this presentation (PDF format, 19 pages, 1.31 MB).
Source: Helen Pearson, Nature, March 16, 2004

The PAP IMI operating principle and mechanism of action

The PAPIMI device produces pulsed electromagnetic type ELF (Extremely Low Frequency), also known as waves PEMF (Pulsed Electro Magnetic Field). These waves, given their very short duration (40-50 microseconds) do not heat the tissue and are able to cross biological tissue up to 15 to 20 inches deep, thus favoring the stimulation and regeneration because they act directly on the physiology the cell.

The pulse is produced in a Plasma ROOM, located inside a solenoidal probe in concentric coils. The probe consists of a silicone tube containing air is circulated in which an electric current that turns the air into plasma. The way that gets the electromagnetic pulse makes it 100% biocompatible, because it is rich of typical frequencies of the constituent elements of air and the necessities of life, such as oxygen and nitrogen.

Figure 1 Membrane potential

The PAPIMI device is used to reactivate the cell physiology in all pathologies osteo-articular muscle and nerve, and also eliminates the pain.

The pain is usually caused by trauma, injuries and accidents of various kinds that determine tissue degeneration, inflammation and, therefore, pain. The multiplicity of agents damaging the body responds with a unique defense mechanism, inflammation, and repair the injured tissue activates mechanisms more or less specific. At the cellular level, the inflammatory state leads to a lowering of the membrane potential which, in turn, causes a reduction of the normal activity of the cell involved, and a reduction of its metabolism.

Reduces the normal transfer of nutrients from outside, through the specific mechanisms of exchange, which, first of all, the sodium potassium pump, and reduces the elimination of waste substances toxic to the cell. Gradually, the cell becomes depleted of oxygen, is enriched with toxins, and so is less than the production of ATP (adenine triphosphate).

Figure 2 The diagram shows the relationship between the concentration inside the cell Na + ions and the potential trans-membrane associated, since they are related to the health status of the cell. The device Papimi ® increases the TMP (Trans Membrane Potential) and decreases Natremia (concentration of Na-).

All cellular functions depend on the continued availability of energy derived from catabolism of organic molecules during the process of cellular respiration, the energy released is stored in the form of molecules of ATP (adenosine triphosphate). ATP is the energy reserves, readily available for all metabolic functions of the cell.

The electromagnetic field generated by the device PAP IMI device is to act directly at the cellular level, exploiting the natural ability of biological structures interact with electromagnetic fields. It is essentially to create resonances, as is now known, each substance has its own characteristic electromagnetic spectrum, and any substance interacts with electromagnetic waves is so non-specific (for example through the transfer of energy) and specifically (interactions based on the particular resonance frequency range).

Figure 3 The diagram shows the relationship between the concentration of intracellular K + and Na + ions, since they are connected to the trans-membrane potential and health status of the cells. The device Papimi ® pushes the curve from the area in the lower right to upper left area, where he represented the condition of young and healthy cells.

The membrane potential has a close relationship with the state of health of the cells. Under physiological conditions this potential assumes a certain value which, depending on the type of cell is between -70 and -90 mV. This potential must be kept constant because the cell remains in physiology.

So happens that, for certain frequencies, the wave emitted by the device is able to interact, resonating with the electromagnetic field produced by the cell. In addition, the cell membrane, by its very nature, conveys well the electromagnetic field.

The effect of electromagnetic pulse has features that allow you to restore the membrane potential, altered by the pathological state. Moreover, precisely due to its composition, the wave penetrates into the cell by stimulating mitochondrial activity, cellular respiration and ATP production.

Therefore, at the cellular level, it has a dual effect: stimulation of bio-electric nature, because it restores the normal membrane potential was altered by the disease, and stimulation of natural bio-chemistry, because the impulse is able to penetrate inside the cell, which is to restore the physiology.

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Lightning Bolts within Cells

Lightning Bolts within Cells

A new nanoscale tool reveals strong electric fields inside cells.

Using novel voltage-sensitive nanoparticles, researchers have found electric fields inside cells as strong as those produced in lightning bolts. Previously, it has only been possible to measure electric fields across cell membranes, not within the main bulk of cells. It's not clear what causes these strong fields or what they might mean. But now that it's possible to measure them, researchers hope to learn about disease states such as cancer by studying these electric fields.

The cell electric: Encapsulated in a polymer shell just 30 nanometers across, voltage-sensitive dyes (red) emit red and green light when illuminated with blue light. These encapsulated dyes make it possible to measure electric fields inside cells.
Raoul Kopelman, University of Michigan

University of Michigan researchers led by chemistry professor Raoul Kopelman encapsulated voltage-sensitive dyes in polymer spheres just 30 nanometers in diameter. When illuminated with blue light, the voltage-sensitive dyes emit a mixture of red and green light; the exact frequency of light emitted is influenced by the strength of local electric fields, allowing the researchers to measure those fields. Testing these nanoparticles in the internal fluid of brain-cancer cells, Kopelman found electric fields as strong as 15 million volts per meter, perhaps five times stronger than the field found in a lightning bolt.

"They have developed a tool that allows you to look at cellular changes on a very local level," says Piotr Grodzinski, director of the National Cancer Institute Alliance for Nanotechnology in Cancer. Traditional techniques for studying disease at the level of tissues average out differences between cells. Grodzinski says that many developments in cancer research over the past few years have been "more reactive," working toward developing diagnostics for catching the disease in its earlier stages and for better predicting to which drugs patients will respond. Despite how far cancer treatments have come, the way that cancer progresses at the cellular level is still not very well understood. With a better understanding, researchers hope to further improve diagnostics and personalized care. "This development represents an attempt to start using nanoscale tools to understand how disease develops," says Grodzinski.

Jerry S.H. Lee, a nanotechnology project manager also at the National Cancer Institute, says that Kopelman's research bolsters the set of nanoscale tools that scientists are developing to probe cells' physical properties, such as special microscopic probes for measuring cell stiffness. (See "The Feel of Cancer Cells.") In the past decade, researchers have improved cancer diagnosis by examining protein markers and genetic signatures. Now they're "thinking of how nanotechnology can make tools to look at additional signatures" like electric fields, says Lee.

Voltage-sensitive dyes are not new. For decades, neuroscientists have used them to measure voltages across cell membranes in studies of how nerve cells generate and respond to electrical charges. But Kopelman says that it's not possible to control the placement of these dyes in cells. They are hydrophobic and aggregate in cell membranes, so it has not been possible to use them to study the cytosol, the bulk of the interior of the cell. Kopelman also says that these dyes might be reacting with enzymes and other molecules in cells. His encapsulated dyes aren't hydrophobic and can operate anywhere in the cell, not just in membranes. Because it's possible to place his encapsulated dyes in a cell with a greater degree of control, Kopelman likens them to voltmeters. "Nano voltmeters do not perturb [the cellular] environment, and you can control where you put them," he says.

The existence of strong electric fields across cellular membranes is accepted as a basic fact of cell biology. Maintaining gradients of charged molecules and ions allows for many cellular functions, from control over cell volume to the electrical discharges of nerve and muscle cells.

The fact that cells have internal electric fields, however, is surprising. Kopelman presented his results at the annual meeting of the American Society for Cell Biology this month. "There has been no skepticism as to the measurements," says Kopelman. "But we don't have an interpretation."
Daniel Chu of the University of Washington in Seattle agrees that Kopelman's work provides proof of concept that cells have internal electric fields. "It's bound to be important, but nobody has looked at it yet," Chu says.

Grodzinski says that an interesting application of the voltmeters will be to examine whether there's a difference in electrical signals between healthy and diseased cells, and whether different disease stages might have characteristic electrical signatures. To gauge the viability of the technique, researchers will need to "start tying it to biology by studying cell lines from the clinic," says Grodzinski. "This is a first demonstration."


Source: http://www.technologyreview.com/Biotech/19841/page1/


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Physiological effects of using Papimi Device

PHYSIOLOGICAL EFFECTS

• The analgesia achieved by the release of the endorphin of enkephalin, which acts as an inhibitor of pain.
• The regulation of membrane permeability to ions Na and K. When the cell membrane is disrupted, the electromagnetic and electric fields polarize the cells and provide them the energy they need to re-establish the electrostatic balance, by restoring the sodium-potassium pump to its normal levels. In this way, the magnetic fields help in the reduction of inflammation and edema and as a result the cell functions normally again.
• The regulation of glucide, lipid and protein metabolism, which are the effect of the beneficial influence of the sympathetic and the parasympathetic system.
• The balance of hormone secretion.
• The strengthening of the immune system by increasing the number of leukocytesτων,platelets and gamma globulin.
• The increase of collagen, due to the reduction of the adenylic acid (AMP).
• The reduction of osteoclasts.
• The increase of calcification, osteoblasts and prostaglandin.
• The improvement of blood flow and oxygen absorption(oxygenation).
• Binding free radicals.
• Positive results in the restoration of traumatic situations of the muscles and chronic locomotor system disorders.
• Anti-inflammatory effect.
• The increase of metabolism and biological activity of he cells.

     So far, no adverse effect by the application of Magnetic Fields has been reported and the results are only positive. Finally, the fact that magnetotherapy does not cause temperature raise of the exposed tissues must be underlined.

How The Papimi Device Works

The elements that make up the human body, according to the influence on these by magnetic fields are divided into:
 

1. Diamagnetic elements: elements that are affected little by the magnetic fields. Such elements are healthy cell membranes.
2. Paramagnetic elements: these elements are affected by the magnetic field and can be converted into magnetic dipoles orientated in the same direction of the field.
3. Ferromagnetic elements: these elements are mostly located near the bones of the base of the head, the pituitary, the pineal gland and central nervous system. Characterized by the presence in these of regions where the magnetic dipoles have a common orientation. These elements gain strong magnetic properties when found in a field, which are retained when the field no longer exists.
    

     When there is a disorder in the body, there are large amounts of paramagnetic elements in it, while a potential difference is created between a sick and a healthy region. Most of paramagnetic elements occur because some diamagnetic elements convert into paramagnetic ones. By applying magnetic fields, a balance of paramagnetic elements is achieved and therefore the rehabilitation of diseases.

     The pulsed magnetic field (nanopulses) penetrates the body evenly, unaffected and alters rapidly, it is generated and disappeared in minimum time. According to Faraday's law about induction,  a quenching magnetic field leaves behind in its place a circular electric field. In that way, deep inside a tissue electric nanopulses are generated. Nanopulses affect the intracellular traffic of ions, i.e. increase the permeability of cell membranes. The result is a reduction of swelling and pain, the rapid removal of products of metabolism, increasing oxygen supply locally, and regional movement nerves regain their proper function.