Title: Device for intracellular transport in resonance FIELD OF THE INVENTION

This invention relates to a device for resonance intracellular transport. BACKGROUND STATE OF THE ART

In brief, it should be noted that hydroelectrophoresis, developed and implemented since 1989, is an evolution of the classic iontophoresis therapy. Hydroelectrophoresis was presented to the medical field with a better passage of ions and also with a passage of small molecules through the skin, by means of new bipolar waves, which improved transdermal transmission with respect to classic iontophoresis, by virtue of acquisition of these modified bipolar currents.

Figure 1 shows an example of a device for transdermal transport overall designated as 1.

In the example considered, device 1 comprises a wave generator 10 to which two electrodes 20 and 30 are connected by means of respective cables 12 and 14.

In particular, in the example considered, electrode 30 is made of a conductive material and can be of any shape, though a flexible metal lamina is preferable. Said flexible metal lamina can in fact be applied adapting itself to the anatomical shape of the body area of the patient on which this electrode is to be applied.

In the embodiment considered, the electrode 20 is a handpiece made in such a way as to contain an active principle to be administered by the transdermal route. For example, the active principle may be contained in a liquid or frozen solution, a gel or other. In general, the term "active principle" may include a drug, a product to treat skin blemishes, such as cellulitis or similar, or ions and/or molecules in general.

For example, Italian patent application FI99A000141 describes a wave generator that generates a special waveform that can be used for hydroelectrophoresis.

Italian patent applications FI98A000137 and FI99A000055, on the other hand, describe possible embodiments of the handpiece 20.

The particular waveform used, together with the gel formulation, allow the drug to penetrate the tissues as deeply as up to approximately 11 cm. This depth is greater than can normally be achieved with other electrophoretic methods (by just a few mm). Moreover, high local concentrations of the drug used can be achieved.

Another known document WO 00/74774 describes various embodiments, the device for transdermal transport can be connected to two electrodes, wherein one electrode is configured to contain an active principle to be administered by the transdermal and/or intradermal route. The device also comprises a wave generator, which generates a driving signal for the electrodes.

The driving signal includes a plurality of packets grouped in trains of packets and in groups of trains. In particular, each packet consists of a unidirectional signal resulting from the combination of a modulating signal, for example with a frequency of between 0.1 and 5 Hz, and a carrier signal, with a frequency of between 200 and 2000 Hz, for example. Moreover, each train of packets consists of a series of packets and each group of trains comprises a series of trains of packets. Specifically, in various embodiments, the trains of packets comprise packets with the same polarity and same duration, but at least a first packet has a carrier signal with a first frequency and at last a second packet has a carrier signal with a second frequency.

The wave generator reverses the polarity of the trains of packets after a given time interval. For example, in various embodiments, the wave generator reverses the polarity of each train of packets with respect to the polarity of the preceding train of packets.

One of the objects of this invention is to increase the therapeutic effect achieved with the known devices, by increasing the local and not systemic action of the molecules transported through the cell membrane.

This invention also aims to succeed in causing the molecules transported through the cell membrane to activate the cell's metabolism.

Essentially, an object of this invention is to describe a method and a device that will stimulate resonance transport, surpassing the normal transdermal and/or intradermal techniques, thereby essentially offering an advantageous method in terms of a plurality of innovative aspects.

Finally, this invention aims to increase local therapeutic action.

BRIEF SUMMARY OF THE INVENTION

These objects and others which shall become clear in the course of the description are achieved by means of an innovative method and device for the resonance transport that will be described hereunder.

It is considered very important in this case to provide an accurate definition of what the applicant means by "resonance": the term normally used would be "bioresonance", but that term has been used incorrectly over time. Therefore, the applicant hereby specifies that resonance in this case reverts to the technical definition provided below, which will be further supported by the bibliography annexed hereto. In fact, the "cellular resonance" technique, which is of interest here, is widely documented in science.

As such, resonance is to be understood herein as electromagnetic resonance, in other words emission, by means of an artificially generated electromagnetic field, of electromagnetic waves (EMW) that resonate with the same waves produced by the cells of the human body. By way of an illustrative example, think of a normal radio signal that the cell is able to decipher to respond to it adequately, thanks to the coherent nature of the signals.

In this way it is therefore possible to communicate with a body by giving information that is coherent with the normal functioning of the body: as though the body were a mobile telephone that rings when its coherent signal arrives, and the voice - i.e. other waves - is transferred on that wave. (See: M. Covelli ATTI XVI SNAMID National Congress, February 2003: Frohlich H. Biological coherence and response to external stimuli. Berlin, Heiderberg, Sprinder, 1988; A.R. Liboff "Cyclotron resonance in membrane transport" in A. Chiabrera et al. (Eds) Interactions between electromagnetic fields and cells, pp. 281-296, Plenum Press, 1985; many others in the bibliography provided)

Quotation: "It should be underlined that the molecular aggregation of living biological tissue occurs exclusively within a water molecule. Therefore, water is both a solvent for the molecules of the biological tissue and an environment in which they develop. Water clusters can be affected and modified by the coherent electromagnetic fields, (reference Masaru Emoto, Giuliano Preparata, Ricciardi, Bodo Kohler, Arcieri)." If we consider DNA and its classic double helical representation, we will notice that DNA, too, (Garyaev) has a resonance frequency of its own, which corresponds to the cellular resonance frequency. End of quotation -

The intensities of the EM field are therefore very low (in the region of a few to a few hundred photons per second per square centimetre of emission surface). One of the sources is DNA; ultrafine or Threshold electromagnetic fields transmit essential information, such as the regulation of the biochemical reactivity of the membrane potentials (i.e. active transport of substances inside and outside the cell, nutrients from one side, waste from the other), transmission of nerve impulses (i.e. the electrical command signals, for example to the muscles, also to the heart), immunostimulation, growth regulation, biological rhythms, etc.". Bases of reference: F. A. Popp, "Recent Advances in biophoton research and its application", World Scientific, 1992; Blank Martin, Goodman Reba, "Do electromagnetic fields interact directly with DNA?" Bioelectromagnetics, 18:111 5, 1997; Gariaev P.P. Wave genetic code. Moscow, Izdatcenter, 1997; Gariaev P.P. Genetic structures as source and receiver of holographic information. Together with I.V. Prangishvili, G.G. Tertinshny and others.//Sensors and systems, 2000. No. 2(11). P2_8. And others in the bibliography).

A classic example of cellular resonance frequency used in medicine is NMR (nuclear magnetic resonance).

In particular, for the requirements of this invention, the principle of operation is the same: the human body is two-thirds water, and the quantity of water varies according to the tissues and any pathological conditions they may have. A strong external magnetic field makes the body's water molecules change energy state and excites the protons. When a radio wave of suitable frequency to resonate with the protons is passed, their energy changes and they return to their original conditions. The oscillations induced in the protons can be detected from externally by measuring the density of molecules in that point. When processed by a computer, this information will, finally, give an image of the organs explored by the machine; if tissues contain a lot of water, they appear very light, whereas if they contain little water, they are dark. With their work in the 1970s, the two Nobel Prize winners (Felix Bloch and Edward Purcell), one a chemist and the other a physicist, lay the foundations for application of this powerful examination instrument in humans (Raymond Vahan Damadian/ Paul Lauterbur biological effects of magnetic fields). The subject matter of this invention is therefore an innovative method for resonance cellular transport, associated with an innovative device for resonance intracellular transport.

The advantages and objects of this invention shall be achieved thanks to the innovative device for resonance intracellular transport wherein said device can at least be connected to two electrodes, wherein a first of said electrodes is configured to contain an active principle to be administered by the intracellular route, the device comprising at least one wave generator configured to generate at least one driving signal to be sent to said electrodes, wherein said driving signal comprises a plurality of packets grouped in trains of packets and in groups of trains and said wave generator is configured to reverse the polarity of said trains of packets; the device is configured to generate at least one driving signal having a first depth frequency of the carrier signal correlated to the depth of an organ or of a tissue to be treated, characterized in that the device is configured to generate at least one driving signal generated by said wave generator to drive a solenoid and at least one further signal to drive an ultrasound generator and is configured to generate at least other modulating signals to build waveforms comprising packets and trains of packets and groups of trains of packets and groups of groups of trains and to reverse the polarity of the latter signal, to obtain, at the same time, the emission of the full spectrum of resonance frequencies in the area to be treated, these frequencies being univocally defined by the device, to act exclusively on that area to be treated, said areas to be treated being reached through water channel transport.

Therefore, the at least one frequency/carrier signal is suitable for modulating a pulse that determines the depth of transfer of the active principle and the at least second frequency/modulating signal groups and modulates said pulse into at least four packets having the same pulse frequency.

The further modulated modulating signal modulates and groups the packets into trains, which can have the same or different pulse frequencies within a group of trains and the modulating signal groups and modulates the trains into groups of trains, and the modulating signal modulates and groups the groups of trains into groups of groups of trains and reverses the polarity of the group of trains with respect to the preceding group of trains, the latter preferably occurring every 2 minutes

This is in order to obtain the emission of the full spectrum of resonance frequencies of the area to be treated, these frequencies being univocally defined, as stated above and as shall be described hereunder, to act exclusively on the chosen area, therefore in a totally innovative and advantageous way, without dispersions in circulation.

In particular, said solenoid is suitable for generating an electromagnetic field able to make the water clusters coherent with the currents generated by electrophoresis.

Furthermore, the ultrasound generator breaks the bonds of the stratum corneum, thus creating more space between corneocytes (the cellular component of the stratum corneum), distancing them from one another, all this enabling more effective action.

Therefore, said wave generator or signal, already present in the known art, is advantageously innovatively modified here to produce waves of various forms, including sine, triangle and square waves, etc. with frequency of 0 to 2200 Hz and variable currents and voltages, and is built to generate several carrier signals at the same time, each carrier signal further characterised in that it modulates and groups the signals, or pulses, into packets, the packets into wave-trains, the wave trains into groups of trains, the groups of trains into further groups of trains, and is also made to be able to reverse the polarity of one or more signals.

An advantage of this solution is that the particular combination of trains of packets can be modulated so as to match the specific organ of the human body to be treated, on each occasion, reaching a given area with precision.

In particular, with said device combined with a handpiece which will be described hereunder, forming an adequate system, desired uniform transport is obtained, through the extremely accurate control of transport times at the selected depths. Consequently, the treatment guarantees better results overall, as the tissues are more inundated with molecules in a uniform way, thus preventing the dispersion of the transported products within the body.

Moreover, even more advantageously, application and transport times are reduced.

Furthermore, thanks to the solution described above, the device is able to reach depths of up to 10 cm and thicknesses of up to 3 cm.

In general, the depth and thickness to which molecules can be transported is determined by the frequency of the pulses described above, depending on the waveform and its envelope.

In particular, in this case, transport occurs via the water channel, unlike in previous methods that exploited the ion channel. When the ion channel is used, the molecules of the active principle encounter the cell's ion filters, which adversely causes reduced penetration and dispersion of the active principles in circulation. The result obtained was inferior and potentially caused an immune system response in the case of allergies.

The innovative device and method described herein, which instead takes advantage of the water channel on the outside of the cell membrane, significantly increases the amount of active principle actually reaching the area to be treated, with almost no (less than 5%) dispersion of the active principle in circulation. An exclusively localised, and not systemic, effect can be established.

In fact, no resonance modulating frequencies were present in the previous methods (repetition frequencies of the trains and repetition frequencies of the packets were not associated with a particular systemic effect or desired result, but were simply convenient, or arbitrary, choices); what is more, they provided for at least one pulse frequency within a train being different from the others, which compromised penetration and uniform transfer.

Ultimately, with reference to the abovementioned document WO2013/190489, which describes a previous method described by the same known applicant, which in that case provided for transdermal transport (a method that we aim to surpass with the resonance method described by this invention), which occurred according to modulation of the repetition frequencies of the packets and of the trains, those frequencies, unlike in the method described by this invention, were arbitrary. Another significant factor of the previous invention was the use of the ion channel to transport substances, whereas this invention uses the water channel, made possible also by the coherence of the agarose gel obtained thanks to the solenoid driven by the device and present on the handpiece. In fact, the previous invention had a transdermal transport method with significant dispersion of the transported active principles in circulation, for the reasons stated above.

That same known method expressly required that, within a train of packets, at least one packet had a different pulse frequency from the others: this type of specific implementation does not allow constant migration or uniform transfer of product in the area to be treated, due to the too short duration of the signal, for each individual depth frequency: if the second packet in a train has a different depth frequency to the first packet, the duration of the signal bringing out the migration of the first packet is too short; instead, by keeping the depth frequency within the train constant, the new device/method produces a longer duration for the depth of migration.

Technical studies have demonstrated that unparalleled results can be obtained in terms of the quantity of active principle transported and the transport time of the same, by keeping a minimum of four packets with the same frequency within a given train.

The known resonance frequencies set out below in table 1 are instead advantageously exploited in the invention described herein.

In this invention, on the other hand, the use of the resonance frequencies as described advantageously serves to stimulate the response of the relative cell receptors exclusively in the area to be treated, by applying the method of repetition of trains, packets, etc. described herein in detail. This makes it possible to essentially prevent dispersion in circulation, limiting it to a maximum of 5%.

Secondly, thanks to the coherence of the clusters in the solvent (agarose gel) thanks to the abovementioned solenoid, molecular transfer capacity has increased, resulting in faster treatment. The previous methods took 45 minutes to transport 30 ml of saline gel with a concentration of 2 grams of active principles, via the transdermal route, and 25% of that gel remained outside the dermis. In this case, this method is advantageously able to transfer 60 ml of agarose gel, with an active principle concentration of up to 15 grams, in a maximum of 24 minutes (with 5% remaining on the dermis). In particular, the ultrasound emitter envisages a non-linear sweep in emission frequency of between 20 and 40 kHz inclusive.

This particular frequency, or a non-linear sweep between 22.5 and 40 kHz, acts exclusively on the stratum corneum. More specifically, said frequency acts by breaking the bonds of the stratum corneum, thus creating more space between the corneocytes, distancing them from each other, all this enabling more effective action by the dispenser roller, as better explained below.

According to another aspect of this invention, the active principle is dissolved, as mentioned previously, in agarose-based gel.

More specifically, the solution used contains agarose with the possible addition of one or more other carrier substances.

The use of a saccharine glycoside gel, unlike in the known transdermal transport technique in which the gel has to be saline (as also in the aforementioned WO document), is a highly important aspect to transport substances for cosmetic and pharmacological use, as cells prefer feeding on sugar, so in the days following application, the cells of the treated body continue feeding and working, thus obtaining a long-lasting result.

Therefore, the gel is made up of water, in which agarose is dissolved, wherein the clusters (Definition of cluster: molecules of water that are held together by a hydrogen bond due to the attraction between the positive nucleus of the hydrogen and the negative atom of the oxygen) are made coherent with the currents delivered by electrophoresis and with the resonance frequencies of the tissue/organ to be treated, by an electromagnetic field generated by a solenoid (described hereunder) appropriately driven with a programmed device.

It should be noted that no device/method makes water clusters coherent for trans/intradermal transport; the latter is made possible thanks to what is described above in relation to the coherence of clusters, obtained thanks to the innovative device.

For non-ionisable or heavy substances (as in the case of chemotherapeutics), on the other hand, it is preferable to add an additional carrier to the agarose used to break down the stratum corneum barrier.

Returning to the device, according to an aspect of this invention, the first electrode comprises an ultrasound acoustic generator, wherein said acoustic generator is driven by means of said driving signal.

Moreover, the device can have current or voltage control to keep the amplitude of the signal constant, given that different areas of the body can have different impedance during treatment. Consequently the device self- regulates to keep the flow of molecules transferred constant and at the same time to prevent any electric shocks due to a sudden change in the conditions.

According to a further aspect of this invention, the handpiece used with the device comprises a surface provided with knurling or grooves suitable to create microchannels in the stratum corneum of the epidermis.

Advantageously, said roller, thanks to the opportunely created grooves, produces microchannels that enable the gel to come into direct contact with the dermis by passing through the stratum corneum, thus cancelling out any resistance.

Even more advantageously, said handpiece has a "spray head" shape, so the gel coming out of the handpiece can be dosed in the quantity desired and at precise points; the shape of the spreading surface makes it possible to stop as long as desired or necessary on a given area, thus obtaining greater product transport precision in the areas where it is necessary.

Lastly, the handpiece comprises a dispenser with an essentially plane or convex surface, from which the said roller protrudes, where said plane or convex surface (or in any case of another shape suitable for the purpose) of the dispenser has an area of at least 5 cm ² , meaning the roller can stay still for a sufficient amount of time in the point where the product needs to be transported, which makes it different from commonly used handpieces. Also, this innovative surface also makes it possible to act in the corners of the handpiece, thus making it possible to reach body parts that were previously hard to access.

Moreover, in an innovative manner, it is possible to insert a solenoid into said handpiece, thanks to the shape of the latter, in order to direct the magnetic field in the handpiece all around in a consistent way.

Further characteristics and advantages of the invention can be inferred from the dependent claims.

BRIEF DESCRIPTION OF THE FIGURES

Further characteristics and advantages shall become evident by reading the following description provided by way of a non-limiting example, with the help of the figures shown in the tables annexed hereto, wherein:

- Figure 1 shows a generic device for resonance transport;

- Figure la shows a block diagram of a preferred embodiment of the device for resonance transport;

- Figures 2 to 9a show details of a signal useful for resonance intracellular transport according to this description;

- Figure 10 shows a handpiece for a device for resonance intracellular transport according to an aspect of the invention.

DETAILED DESCRIPTION OF SOME WAYS TO CARRY OUT THIS INVENTION

The following description illustrates various specific details aimed at allowing in-depth understanding of the embodiments. The embodiments may be carried out without one or more of the specific details, or with other methods, components, materials, etc. In other cases, known structures, materials or operations are not shown or described in detail, in order to prevent making various aspects of the embodiments unclear.

Reference to "an embodiment" within the context of this description means that a particular configuration, structure or characteristic described in relation to the embodiment is included in at least one embodiment.

Therefore, phrases such as "in an embodiment", which may be present in different places in this description, do not necessarily refer to the same embodiment. Furthermore, particular conformations, structures or characteristics may be appropriately combined in one or more embodiments.

The references used herein are for convenience purposes only and do not therefore define the scope of protection or the scale of the embodiments.

To facilitate a better understanding of the invention, some information shall be provided here, which is however known by technicians operating in the field, on the structure of the stratum corneum of the epidermis, which is made up of both the cellular component (i.e. corneocytes), and the space existing between them, which is rich in lipids with very important functions. The majority of these are: ceramides (which connect together corneocytes), cholesterol and free fatty acids that bind to both the corneocytes in the outermost layers and to those deeper down.

The stratum corneum can be informally compared to a brick wall, in which the stones represent the corneocytes and the mortar, the lipid-rich space between the cells.

Corneocytes are large flat cells which become bigger with age, as the epidermis is renewed more slowly and they remain longer in the area nearer the surface. During their migration to the outer layers, they take on keratin, bit by bit, and become corneocytes, forming the stratum corneum. Differentiation concludes with desquamation to make way for new cells.

The entire stratum corneum can be seen as the skin's external barrier: just one corneocyte protects between 1 and 20 basal cells under its area.

The outermost layers also contain large quantities of lipids produced by the sebaceous glands (triglycerides, wax esters and squalene).

To improve the connection between the cells and prevent them from sliding on top of each other, the corneocytes are secured to each other by protuberances called desmosomes.

The water content of the corneocytes is essential and is affected by ambient temperature and humidity level. The cells tend to become dehydrated if the surrounding air is very dry; if it has high moisture content, they can absorb a lot of water. In any case, the water cannot penetrate the stratum corneum in high quantities, due to the presence of the lipids between the cells. The integrity of the barrier is crucial for the skin's selective permeability. Some conditions such as psoriasis and atopic dermatitis destroy said barrier.

In general, even though a combination of all three mechanisms produces the best result, the mechanisms described above may also be used individually.

As mentioned previously, the invented device uses the following signal generated by a wave generator 10 and applied by means of connection cables 12 and 14 to two electrodes 20 and 30, wherein one of the two electrodes is designed to contain a carrier containing the active principle, all of which is better described below with reference to Figure 10.

Figure la shows an example, in schematic form, of a particularly preferred embodiment of the device for resonance cellular transport innovatively described by this invention. In particular, said device comprises at least one wave generator 10' or signals already present in the known art, but in this embodiment, it has been innovatively created to produce waves of various forms, including sine, triangle, square waves, etc. with frequency of 0 to 2200 Hz and variable currents and voltages, and built to generate a number of carrier signals at the same time, each carrier signal further characterised in that it modulates and groups the signals, or pulses P, into packets, the packets into wave-trains Tr, the wave trains into groups of trains Tg, the groups of trains into further groups of trains, and also made to be able to reverse the polarity of one or more signals, by means of specific device programming. Furthermore, the device comprises a feeder 2 and signal amplifier 2a, designed to amplify the signal generated by generator 10' comprising also a condenser discharge system in order to prevent electric shock during the change in polarity of the signal; there is also a battery pack and corresponding charger 3a and 3b, and also an output stage 4 to drive a solenoid on the handpiece and relative amplification (the signal is picked up by the generator 10' and then amplified and regulated according to the solenoid that will be connected); an audible warning device 30 is also included, which is actuated by a square wave generated by the generator 10' when there is a change in polarity of the signal.

The device also comprises an ultrasound transducer driving stage 6 which will act as a function generator for a signal of between 20 kHz and 40 kHz inclusive, preferably 22.5 Kz and performs a non-linear frequency sweep from 22.5 to 40kz.

Furthermore, in an innovative manner, a circuit 8 is present, dedicated to reading the currents and voltages emitted: said circuit makes it possible to control the actual emission of the currents and enables the system to self- regulate its voltage and/or current depending on the changes in impedance in the human body. Impedance is generated by the body positioned between the two electrodes (one electrode is positioned in the handpiece - the spray head- and the other is the second electrode); the measurement is carried out by a dedicated feedback circuit in the device. Once the intensity has been set according to the patient's level of tolerance, the device shall keep said intensity (under current or voltage) constant, despite the changing impedance of the part. Circuit 8 sends the reading to stage 1 of the device and the latter automatically regulates the intensities in current or voltage.

This ensures uniform transport of molecules in the whole area to be treated and prevents any electric shocks in case of significant changes in impedance.

Lastly, the device comprises a wireless transmitter 31, for example WiFi and a 3G/4G connection module, GPRS UMTS, etc. able to connect the device itself to one or more networks to allow it to connect remotely to one or more data exchange terminals (e.g. for device recognition, gel consumption, etc.).

The signal driver typically has a current output, for example with maximum intensity of approximately 15-100 mA. However, the driver could also have a voltage output.

In various embodiments, the signal comprises a carrier signal with frequency of between 200 and 2000 Hz modulated in amplitude by means of a modulating signal with a frequency of between 0.1 and 5 Hz, preferably between 0.5 and 2 Hz.

For example, Figures 2a to 2f show examples of carrier signals 102, composed, in order, of: a rectified sinusoidal waveform, a positive sinusoidal waveform, a triangular waveform, a positive square waveform, a sawtooth wave and a series of pulses spaced at intervals apart. However, in general, the carrier signal has a waveform oscillating periodically between zero and a maximum amplitude value.

For example, in one embodiment, the carrier signal is a positive sine wave whose amplitude as a function of time t has the following equation:

f(t) = sin (ar f _p t) + l (l)

where f _p is the frequency of the carrier signal.

The modulating signal can also have different waveforms. For instance,

Figures 3a to 3d show examples of modulating signals 104 composed, in order, of: a sawtooth waveform, a triangular waveform, a rectified sinusoidal waveform and a trapezoidal waveform. Therefore, in general, the modulating signal 104 also has a waveform oscillating periodically between zero and a maximum amplitude value.

For example, in one embodiment, the modulating signal 104 is a rectified sinusoidal wave, whose amplitude as a function of time t is given by:

where f _m is the frequency of the modulating signal. For instance, in various embodiments, the modulating signal has a frequency f _m of between 0.1 and 5 Hz, preferably substantially equal to 0.5, 1 or 2 Hz.

Therefore, according to this description, a packet is created with a duration

Tpac corresponding to the duration of a period T _m of the modulating signal:

T _pac = T _m (3)

For instance, in various embodiments, the period of the modulating signal Tm is between 0.3 and 0.8 s, preferably between 0.4 and 0.6 s, preferably 0.5 s. For example, for a modulating signal with a rectified sinusoidal waveform, the period of the modulating signal T _m would correspond to l/(2f _m ), i.e. only to the period of a half-wave. For instance, if the period of the modulating signal Tm is equal to 0.5 s, then the rectified sine wave of the modulating signal 104 would have a frequency of 1 Hz.

For example, for the carrier signal according to equation (1) and the modulating signal according to equation (2), the packet would have the following waveform:

f(t) = |sin(2¾ - f _B - - (sin(¾r -† _p - t) + l) (4)

For instance, Figure 4 shows a possible embodiment of a signal comprising a sequence of two packets P.

In various embodiments, the polarity of these packets, which by definition are unidirectional, is periodically reversed. For example, in various embodiments, said polarity reversal is carried out after a time T _inv which corresponds to the time of a group of trains, or a time that corresponds to a multiple of the time of a group of trains: for example, approximately 2 minutes

where i is an integer greater than zero.

In particular, in various embodiments, groups of packets are formed, comprising a number of packets with a first polarity followed by the same number of packets i with reversed polarity, i.e. the duration T _gr of a group of packets is:

= 2 - T _lnv = 2 -i -T, (6) In various embodiments, the frequency f _p of the carrier signal remains constant for a group of packets.

For example, Figure 5 shows a possible embodiment of a group of packets PG, comprising a packet with positive polarity P+ followed by a packet with negative polarity P-.

Therefore, in the embodiment considered, the polarity is reversed after each half-wave of the modulating signal 104, which means that modulating signal 104 behaves like a normal sine signal, not a rectified one:

f(t) = sin(2¾ - f _e t) - lsin(2ff f _p t) + 1) (7)

Moreover, the inventors observed that the penetration depth of the active principle depends mainly on the frequency of the carrier signal. Specifically, the penetration depth p can be approximated using the following equation:

(2000 Hz - † _p )

p = — cm (8)

180

i.e. the frequency f _p of the carrier signal can be calculated according to the penetration depth p required:

180 · p ^'

2000 Hz (9)

cm

For instance, Figure 6 shows a table with 23 typical depths, identified using the letters from A to Z, with the corresponding penetration depth p measured in cm and the respective frequency f _p of the carrier signal measured in Hz.

In particular, the inventors observed that treatment efficiency can be improved, by creating a sequence of signals with different carrier frequencies

For example, in various embodiments, a train of packets T _r is created, comprising a sequence of a plurality of packets P, wherein the frequency f _p of the carrier signal of each packet P is reduced, thereby encouraging the active principle to move downwards in depth.

For instance, Figure 7 shows an embodiment of a train of packets T _r comprising four packets Pi, P ₂ , P3, and P ₄ .

These trains of packets are periodically repeated in various embodiments. Moreover, in various embodiments, the frequency f _m of the modulating signal remains constant for the entire train of packets. Therefore, in the embodiment considered, the duration of a train of packets T _tr is:

T _tr = ^{4 ■} Tpac (10)

For example, if the packet has a duration T _pac of 0.5 s, the train would have a duration T _tr of 2 s.

Therefore, in the currently preferred embodiment, the wave generator 10 is configured to generate a signal that comprises trains of packets Tr, wherein each train of packets Tr comprises a plurality of packets P. In particular, the packets P consist of a unidirectional signal resulting from the combination of a modulating signal 104 and a carrier signal 102. Moreover, while the frequency f _p of the carrier signal remains constant for a packet P, the frequencies of the carrier signals f _p of the packets P within a train of packets Tr are all the same as each other.

As mentioned previously, in the currently preferred embodiment, the train of packets Tr comprises four packets P.

In various embodiments, these trains of packets Tr are used to form groups of trains.

For instance, Figure 8 shows a possible embodiment of a group of trains TG.

In particular, in the embodiment considered, each group of trains TR comprises a plurality of trains Tr followed by a pause Ttg off preferably lasting between 0.1 and 5s, in which the signal is constant, for example at zero. Therefore, the trains are transmitted for a duration:

» ^{= k} tr (11)

where k is an integer greater than one, equal to the number of trains Tr in a group of trains TG, and the entire duration of a group of trains T _tg is

^tg - ^tg _ on ⁺ ^tg _ off ~ ^ ^' ^tr ⁺ ^tg _off (12)

For example, in the currently preferred embodiment, the group of trains TG comprises four trains Tri, Tr ₂ , Tr ₃ and Tr ₄ , i.e. k = 4, and the length of the pause Ttg off is 1 s. Therefore, in the embodiment considered, the duration Ttg on of a group of trains TG would be 9 s. In this case, too, it may be envisaged that the polarity of the trains Tr included within a group of trains TG is reversed at the end of a group of trains TG, or rather at the end of a set time, for example 2 mins, or 120s. In fact, the inventors observed that reversal in the packets as shown in Figure 5 only slightly improves the result, and that efficiency increases considerably only with polarity reversal in the trains and groups of trains. Therefore, in the currently preferred embodiment, the packets within a train Tr have the same polarity.

For example, Figure 9 shows a particularly preferred embodiment showing details of pulses Pll, P12, P13 and P14 contained in the train Trli. Pulses P21... etc.. contained in the train Trl ₂ are also shown, as well as pulses P31... etc.. contained in the train Trl ₃ , and pulses P41... etc.. contained in the train Trl ₄ .

Pulse trains Trli, Trl ₂ , Trl ₃ and Trl ₄ form a first group of trains TGi.

The subsequent groups of trains, not shown here, for example TG ₂ , TG ₃ and TG ₄ can have the same polarity as the first group of trains TGi, or reversed polarity between subsequent groups of trains TG ₂ , TG ₃ and TG ₄ .

Therefore the polarity of the second group of trains TG ₂ is reversed, for instance, for the four subsequent trains of packets Tr2i, Tr2 ₂ , Tr2 ₃ , Tr2 ₄ contained in said second group of trains TG ₂ ; (to simplify matters, said trains of packets are not shown here but can be clearly inferred from the description of the preceding figures).

According to a particularly preferred example, the polarity of the groups of trains is reversed every 120s. Consequently, the first four trains of packets Trli, Trl ₂ , Trl ₃ and Trl ₄ have the same waveform and the second four trains of packets Tr2i, Tr2 ₂ , Tr2 ₃ , Tr2 ₄ have the same waveform as the first group of packets, but with reversed polarity.

Note that within a given train of packets Pll, P12, P13 and P14, the carrier signal frequencies fpll, fpl2, fpl3 and fpl4 are the same, as is the case for fp21, fp22 and so on.

In various embodiments, the groups of trains TG are repeated for a certain duration that corresponds to the duration of treatment. For example, for typical applications, treatment duration is between 10 and 40 minutes, preferably 20 minutes.

It should be noted that the "resonance" frequencies are due to the repetition frequency of the packets, to the repetition frequency of the trains Tr and to the repetition frequency of the groups of trains TG,, where, as specified previously, each group of trains TG, comprises a plurality of trains of packets transmitted for a duration tg on followed by a pause Tt _{g 0} ff-

The length of the pauses (T _tg _ ₀ ff) between groups of trains is preferably between 0.1 and 5 s inclusive.

See Table 1 below, as an example, in which burst frequency is used to indicate the frequency of the carrier signal fp:

TABLE 1

More specifically, the device described is configured to generate a driving signal having a first depth frequency of the carrier signal 102 correlated with the depth of an organ to be treated and at least a second depth frequency correlated with the thickness of said organ.

Figure 9a, on the other hand, defines the pulses, packets, trains and trains of trains in terms of signal, so as to define the actions performed by the innovative device 1. Specifically, carrier signal 201 defines the pulses, the aforesaid modulating signal 104 is further modulated as appropriate: in particular, a signal 104' modulates and groups the pulses into packets P, a modulating signal 104" modulates and groups the packets P into trains Tr, which can have the same or different pulse frequencies within a group of trains Tg and the signal 104"" modulates and groups the groups of trains into groups of groups of trains and can reverse the polarity. The modulating signal shall always be labelled 104 and shall accordingly take on the characteristics described. The captions 104', 104", 104"' and 104"" shall only be used to define the various packets of signals (and/or of trains, etc.) in schematic form, as described in the figure. Note that said signals are emitted at the same time to cover, as mentioned, the emission of the full spectrum of resonance frequencies of the area to be treated, those frequencies being univocally defined by the device in accordance with specific tables taken from scientific data, to act exclusively on said area to be treated.

The inventors observed that with this wave generator - in itself generic and programmable - various treatment programs can be created.

For example, the user can select the most suitable treatment program based on the organ to be treated.

First of all, the depth of action is selected, by choosing from the depths of action from A to Z set out in the table described above with reference to Figure 6.

In a second step, the thickness of the organ to be treated is selected, where the thickness that can be selected ranges from a minimum of 0.5 cm to a maximum of 3 centimetres.

First Example.

Let us suppose we want to treat a muscle at a depth of 2 cm, for a thickness of 3 cm. Consequently, the initial depth corresponds to the train Trl= G.

The final depth corresponds to the train Tr4=N. The choice of resonance frequency varies according to the type of tissue to be treated.

Furthermore, the software of the device is configured to complete the intermediate trains with the intermediate depths, i.e. (Tr2=J) + (Tr3= L).

The final train of packets will therefore be TG=(G+J+L+N). The packets forming a train always have the same carrier frequency fp. Second Example.

Let us suppose we want to treat a bone at a depth of 5 cm for a thickness of 1 cm. Consequently, the initial depth corresponds to the train N. The final depth corresponds to the train P.

The software controlling the device is configured to complete the intermediate trains with the intermediate depths, i.e. O.

However, given that there are 4 trains, in that case the software will always double the deepest frequency.

The final train will therefore be N+O+P+P.

Essentially, the pulses IM are grouped into at least four packets pll-pl2- pl3-pl4 with the same pulse frequency (f _P ll-fpl2-fpl3-f _p 14) to form a train TR1 where the repetition frequency of the packets is correlated with the area to be treated and in this case corresponds to the highest and/or maximum frequency, which is between 2Hz and 25.9 Hz inclusive (Table 1), while the second train TR2 has the same packet repetition frequency but the pulse frequency for all the packets of TR2 can be equal to trl or different and corresponding to the second depth frequency, and so on for T3 and TR4.

In general, the trains are grouped into groups of at least four trains, where the repetition frequency of the trains corresponds to the second resonance frequency, which is between 0.4 and 2.8 Hz inclusive. The repetition frequency of the groups of trains occurs with a variable pause which in this case lasts 0.5 seconds. Each group of trains therefore comprises a plurality of trains of packets followed by a pause, where the length of the pause is correlated to the precise area to be treated.

The length of the pauses between groups of trains is preferably between 0.1 and 5 s inclusive.

Figure 10 shows a handpiece 200 for a device for resonance intracellular transport, according to an aspect of the invention, where said handpiece is provided with a cover 230 and a bottom part 240 as well as with a solenoid 280.

Moreover, the first electrode 20 of the device comprises an ultrasound acoustic generator 210, wherein said acoustic generator 210 is driven by means said driving signal and supported by the handpiece 200 itself.

The ultrasounds can be generated by means of a piezoelectric transducer with the following characteristics:

· Oscillation frequency between 20 and 40 kHz, preferably 20 - 25 kHz.

Power supply voltage 12 - 24 V

• Maximum current supply 400 - 200 mA

Power 2.5 - 3.5 W/cm ²

The first electrode 20 of the device may additionally comprise a magnetic transducer, wherein said magnetic transducer is driven by means of said driving signal.

By magnetic transducer, we mean a solenoid 280 placed inside the handpiece 200, with the following characteristics.

• Diameter of the cable 0.35 mm Self-sealing

· Solenoid diameter 8 cm

• Solenoid thickness 3 mm

• Coil 50

• Resistance 25 Ohm

Said solenoid 280 is driven with the same frequencies emitted for resonance.

Power supply voltage, for example 5 V

• Current supply, for example max. 100 mA

Solenoid 280 is ring-shaped and built into the handpiece 200, generating a magnetic field all around in a coherent way.

The handpiece 200 comprises an electrification chamber 205 entirely made of a metal material to contain an active principle to be administered.

The active principle contained in the electrification (or ionisation) chamber 205 of handpiece 200 is dissolved in agarose-based gel as well as potentially in another carrier, too.

In this design, a saccharine glycoside gel is used, unlike in the case of classic transdermal transport solutions, where the gel is required to be saline.

Said solution is crucial for transporting substances for cosmetic and pharmacological use, or in general chemical substances, taking advantage of the fact that the cells prefer feeding on sugar, so in the days following application, the treated cells continue feeding, thus obtaining a long-lasting result.

For non-ionisable or heavy substances, on the other hand, (such as chemo) a further agarose-based carrier is added to break down the barrier of the stratum corneum to allow those substances to be transported.

Furthermore, the handpiece 200 comprises a roller 220 provided with knurling or grooves suitable to create microchannels in the stratum corneum of the epidermis.

The microchannels enable the gel to come into direct contact with the dermis by passing through the stratum corneum, thus cancelling out any resistance.

The handpiece 200 also comprises a dispenser 250 provided with a plane surface from which the roller 220 protrudes.

The plane surface of the dispenser 250 has an area of at least 5 cm ² .

An advantage of this vast plane surface is that it also makes it possible to act in the corner of the handpiece, thus increasing the area of effectiveness of the handpiece.

It should be noted that, thanks to the invention, part of the product is metabolised immediately thanks to the opening of the cell receptors as a result of the effect of resonance, while the other part of the product is left deposited in the mesenchyme as a nutritional reserve, for which reason the action will continue to be effective even up to 72 hours after.

Specifically, it is also possible to summarise the combined action of the device and handpiece as follows, by describing a working method:

- dissolving of substances to be transported in an aqueous gel, specifically, agarose gel;

- dispensing of the gel using the handpiece;

- transformation by a magnetic field produced by said solenoid to make the water clusters forming the agarose gel coherent with the currents delivered for electrophoresis and with the resonance frequencies of a tissue to be treated;

- gel deposition by gravity in the electromagnetic chamber;

- ionisation of the gel in said chamber;

- uptake of the gel by the roller, which turns and deposits it in the dermis;

- generation of mechanical action (by means of an ultrasound transducer present on the handpiece and driven by the device) to break the lipid bond of the corneocytes, thus preparing and promoting the creation of microchannels (micro tunneling) produced by the knurling and microneedles (size 2/3 micron) present on the dispenser roller;

- transport (through resonance modulated currents by means of pulses/packets/trains/groups of trains/groups of groups of trains, according to said layout) of the compound molecules present in the agarose gel saturated with active principles linked molecularly as explained previously.

Thanks to these modulations, transport occurs via the water channel and not the ion channel. The method involves the sending of currents with multiple cellular resonance frequencies at the same time.

We wish to emphasise that the known art does not provide for specific repetition and modulation frequencies and is also different in the composition of packets, where at least one of the packets within a train must have a different pulse frequency and the frequency of the packets and trains, just like their duration, is not related in a targeted way.

This method, associated with the direct use of the innovative device and handpiece, sends pulses with frequency correlated with depth (see table)

(Fr = frequency; pr = depth formula Fr=(2000-180)*Pr).

- The pulses are grouped into packets, with a minimum of 4 per train, with a repetition frequency correlated to the area to be treated (table 1 column 3)

- Each train is composed of 4 packets with the same pulse frequency and therefore the same depth of transfer. - The trains are grouped into groups of trains, with a minimum of 4 per group of trains, and the trains repeat with a frequency correlated to the area to be treated (table 1 column 2)

Uniform transfer through the thickness is obtained thanks to the increased duration of the train with the same transfer depth frequency (pulse).

- transfer of the oppositely charged compound molecules by reversing the polarity of the currents by means of the signal generator.

We wish to emphasise that this method advantageously makes it possible to transfer 60 ml of agarose gel saturated in active principles with a weight of 75g into the selected tissue in 15 minutes without dispersion in circulation and exclusively localised in the selected tissue. As noted, in the known art, 20 ml of saline gel not saturated with active principles is transferred in 1 hour and in the best case in 45 minutes, by the transdermal route, therefore making it also systemic, with dispersion in circulation.

To conclude, this invention demonstrates the use of resonance, which exploits cellular communication by means of electromagnetic waves, as informational energy that enters electromagnetic resonance with the tissues and cells, which, through the DNA and the membranes, are electromagnetic emitters. Being open systems, or rather conditioned by environmental and endogenous (mind-body) stimuli, living beings can easily depart from biological vibrational harmony. In such cases, it becomes necessary to provide tested frequencies for the individual systems, or rather frequencies used and tested for treatments as described above.

Of course, changes or improvements may be added to the invention as described herein, without going beyond the scope of the invention as claimed below for this reason.

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