Patent Application
20230389868
This patent application claims priority from European patent applications no. 20217275.5 and no. 21155605.5 filed on 24 Dec. 2020 and on 05.02.2021, respectively, and Italian patent application no. 102021000032537 filed on 23 Dec. 2021, the entire disclosure of which is incorporated herein by reference.
The present invention concerns an electromedical system for the non-invasive diagnosis of neoplastic diseases.
Over the last decades, various technologies and correlated devices have been developed for investigating the properties of biological material.
For example, using computed tomography it is possible to generate a three-dimensional image through successive cross-sectional scans of the body. The majority of activities in the image reconstruction field are based on the use of X-rays and other narrow-beam penetrating radiations, for example gamma rays. The quantity measured and displayed is the absorption of X-rays in each elementary volume within the cross-section of interest.
Emission tomography differs from transmission tomography in that instead of radiating a selected section of the body with penetrating radiations and measuring the quantity discharged from the other side, the penetrating radiation emitted by a special radioactive chemical substance injected into the body is measured and an image of the area through which the emission beam passes is generated. In the case of medical investigations, X-ray tomography presents a health risk due to the effects of the ionizing emissions. Research and development in this field focus on increasingly sensitive sensors to reduce the dose released to the body.
Other image diagnosis methods use non-ionizing radiations. In ultrasound devices, for example, high frequency ultrasonic pulses are transmitted to the body and the images of the shape of the tissues are reconstructed by the reflected pulses (echo data). Although this technique uses non-ionizing radiations, it has some drawbacks: the main one is that the echo data often contain considerable noise and the limited definition is a constraint on its possible applications.
A complementary technique for mapping the electric properties of the biological material relates to impedance analysis using weak electric currents or microwave tomography techniques. Despite recent developments, also these techniques suffer from the same drawbacks as the ultrasound methods. The bioelectric mapping methods are mainly based on investigation of the dielectric constant and the conductivity of the biological material.
The conductivity can be obtained from measurements taken at different radio frequencies according to the quantity of imbalance created in a previously stable balanced system by means of a sensing coil. Some diagnostic devices function by measuring the variations of the electric constant and conductivity of the breast tissue. It is also possible to radiate target tissues or materials with electromagnetic radiations and to detect the scattered electromagnetic radiation, using techniques developed mainly for avionics and terrestrial radar systems, to extract the structural characterization of the target (in the time and/or frequency domain).
In the diagnostic field, some devices also make use of the fluorescent radiation stimulated in response to a primary electromagnetic excitation.
Another class of diagnostic techniques refers to systems based on nuclear magnetic resonance (NMR). NMR devices exploit the fact that the nuclei, typically single protons or hydrogen nuclei, have a small nuclear momentum and an associated spin angular momentum. The combined effect of the magnetic and spin momentums gives rise to precessions on the nuclei in the direction of an applied magnetic field. In NMR a magnetic gradient is applied to the sample under examination, where the nuclei tend to align in the direction of the static magnetic field, giving rise to mass magnetization of the sample. A further pulse is then used to perturb the magnetization and the repolarization takes place based on the spin-lattice relaxation time. The precession frequency, known as Larmor frequency, is typically detected between 10 and 100 MHz, and this requires the application of a high intensity magnetic field (0.2-2.5 Tesla). This is the biggest limit of the technique.
Using photon-phonon couplings, when the pulsed EM energy is absorbed by the biological tissue, it is known that part of the impulsive energy is converted into acoustic energy. Some devices have been developed to analyse this information to reconstruct the image of the biological tissue under examination. The absorption is correlated to the permittivity, conductivity and radiofrequency chosen to excite the material under examination.
In the brief and non-exhaustive review described above, all the techniques reported are characterized by the capacity to investigate specific physical responses of the biological target under examination. The physical response is usually obtained and measured at the expense of the increase in entropy of the system under examination. This side effect originates from exposure of the sample under examination to the energy emitted by the detection device (X-rays, static magnetic field, EM field, etc. . . . ). In some cases a fundamental criticality also emerges: for example in NMR, the additional increase in entropy can reduce or even cancel the capacity to obtain potentially important microscopic information. This is known in cases of nuclear quadrupole resonance, which are cancelled by the high static field of the NMR devices.
The discovery of electric properties in biological tissues dates back to 1926 when it was realised that the dielectric characteristics of tumours are significantly different from those of healthy tissues when radiated by electromagnetic (EM) waves with a frequency around 20 KHz [1]. In particular, and interestingly, Fricke and Morse found that malignant tumours have a fairly high electrical capacity compared to benign lesions or healthy tissues. They reported the polarization effects of these biological systems and noted that the central (oldest) portion of the tumour has a lower electrical capacity compared to the actively growing edge (the capacity decreases with the age of the patient).
Estimation of the parameters of the Fricke-Morse model of the biological tissue is widely used in processing and analysis of bioimpedance data. More recent studies have confirmed that the dielectric properties of cells depend on their type and physiological state: MDA-231 human breast cancer cells, for example, have a mean specific capacity of the plasmatic membrane of 26 mF/m2, in contrast with the value of 11 mF/m2 observed for the T lymphocytes at rest [2].
Without embarking on a lengthy review of the results on this topic, we cite only the recent observation [3] that an EM signal, appropriately modulated, is able to induce self-assembly of the tubulin protein, whereas no effect is observed in spontaneous growth of the microtubules in absence of EM pumping (see the live visualization in [4] where the frequency interval is measured in which the protein mechanically folds and its structure electromagnetically vibrates). Equally interesting is the dielectrophoretic separation of the tumour cells from the blood [2], achieved by applying to the sample a non-homogeneous electric field (with a rotation frequency up to 140 MHz).
Both the above examples illustrate in particular the fact that in biological systems non-thermal effects occur when said systems interact with an applied EM field. A long series of experimental and theoretical studies also leads to the conclusion that cells electrically polarize when they are subjected to an oscillating electric field, which thus induces polarization (dipole) oscillations in biological systems.
It is also reported here, for the sake of awareness of the relevant scientific literature, that the dielectric properties of the cells are determined by the morphology of the cell surface, the dimensions of the cells and other biochemical factors. These effects can be included (within 10% of the real values, with a 90% confidence level) in the specific dielectric model referred to in [2].
Therefore, with appropriate boundary conditions, the problem of a biological disease can be analysed as an anisotropy with respect to a medium (the body) into which an exploratory electromagnetic field is penetrating.
In fact, the cells that form a living tissue communicate by means of gap junction contacts, which allow the passage of ions and other signalling molecules between the cells. This establishes the electric connections between the cells. The biological membranes form a system with high level of molecular integration, in which chemical, lipidic, structural protein and enzymatic components, interacting with one another, combine to form a fundamental and unitary structure.
The cells of the diseased tissues, in particular tumour cells, are characterised by different forms of atypia (metabolic, biochemical and cooperative behaviour), to which alterations of the pathogenic membrane contribute, both at the level of the subcellular vesicles and at the level of the cell surface. The surface is generally rich in electrostatic charges, which determine reciprocal attraction or repulsion: the tissue cells attract one another and remain cohesive due both to the presence of glycoproteic cementing substances and the action of ions neutralizing the surface charges that form a bridge between the cells. All the cells show an electronegative surface. In tumour cells, the electronegativity of the cell surface increases and this is connected to the increase in sialic acid. The electronegativity is not countered by the calcium ions, the importance of which is well known in adhesion. In tumours, the extracellular calcium content diminishes and is not able to facilitate the adhesion.
In addition to the adhesiveness, the fundamental role of the proteins in the cells should be mentioned. In fact, their job is to form and maintain the double lipid layer of the membrane, within which they are free to move by translations or rotations, according to the fluidity of the lipid layer. This property is markedly altered in the case of tumours.
Finding new targets for the study and understanding of tumour cells is one of the biggest challenges in current medical research. Specifically, predicting whether a tumour is inclined to progression or remission is a very important priority. For this purpose, various approaches have been attempted to anticipate the behaviour of the tumour cells before and after the beginning of treatment.
Another important point to consider is that, undoubtedly, during the progression of the tumour, changes occur not only in the macroscopic structure and viscoelasticity of the cells, but also in their internal microscopic dynamics. This happens because the alterations in cell morphology and packing naturally influence the pathways through which the organelles, the water and other biomolecules can move. Curiously, despite the consolidation of this idea and the fact that the cells contain mainly water molecules, very few studies have focused on the properties of the intra- and extracellular water, relating them to the behaviour of the tumour cells.
Given the nature of the cell medium, the modifications in the characteristics and properties of the water can be correlated with single or distinct movement types and this differentiation may be the key to explaining how and why water dynamics change within cells with different prognoses [5]. The possible differences can be traced back to the different ways in which the water can interact within the complex cell environment. While the weakly interacting water molecules show a behaviour similar to free water, scattering at 37° C. with a scattering coefficient of approximately 3×10−9 m2/s, the water molecules confined, for example, by folded proteins, cell membranes and organelles, show different properties since their mobility and therefore effective scattering is limited [6].
The variation in the scattering coefficient can influence, also significantly, the response of the tissues when exposed to an electromagnetic field, explaining how the phenomenon of electromagnetic interaction differs as the cell prognosis differs, and can therefore represent a new vehicle for specific information transduction.
In general, different events are known at cell membrane level, such as:
These phenomena lead to the conclusion that the onset of disease causes new degrees of freedom in terms of the electronic and ionic charges involved in the cell exchange dynamics.
Furthermore, the detachment of the cells from the tumour and the association of the tumour cells with the bone are strongly influenced by the cell-cell cohesion and the cell-substrate adhesion, attributes that give the tumours quantifiable biophysical properties. These properties are the elasticity of the tumour (a measurement of the capacity of a tumour to deform in response to an applied stress), the viscosity of the tumour (an indication of the cell motility within the tumour) and the compactness of the tumour (a dynamic and complex manifestation of the cell-cell cohesion and cell-substrate adhesion). These phenomena are essential for investigating the biophysical and biomolecular changes that accompany the malignant progression of the tumour.
Various adhesion factors have been studied as markers for the presence of cancer.
By way of example, hyaluronic acid (HA), a glycosaminoglycan, regulates cell adhesion and migration. Hyaluronidase (HAase), an endoglycosidase, breaks down the HA into small angiogenic fragments. Using an assay similar to the enzyme-linked immunosorbent assay, an increase in HA levels (3-8 times) was found in prostate cancer tissues (CaP) compared to normal tissues (NAP) and benign tissues (BPH) [7]. The majority (75-80%) of HA in prostate tissues was found in the free form. The primary CaP fibroblasts and the epithelial cells secrete 3-8 times more HA than the respective NAP and BP cultures. Only the CaP epithelial cells and the established CaP lines secreted HAasi and the secretion increased with the tumour stage and the metastases.
A stromal and epithelial pattern of expression of HA and HYAL1 was observed in the CaP tissues. While the high HA colouring was observed in the stroma associated with the tumour, the HYAL1 colouring in the tumour cells increased with the tumour stage and the metastases.
While HA with higher or intermediate molecular weight was found in all the tissues, the HA fragments were found only in the CaP tissues. In particular, the high-quality CaP tissues, that showed high levels of HA and HYAL1, contained fragments of angiogenic HA. The stromal-epithelial expression of HA and HYAL1 can promote angiogenesis in CaP and can serve as an electrically charged vector for the electromagnetic interaction.
Obviously the greater freedom of movement of these available charges, typical in a pathological condition (rotary motion, ionic currents), can be used to investigate the biophysical state of the tissues by means of an electromagnetic interaction.
When irradiated by an electromagnetic field, the molecules such as the water and the proteins aim to form a line along the polarization of the field, to minimize the potential energy of the dipoles.
From the spectroscopic analysis, the rotary motion of the water molecules bound to macro-molecules has resonance in frequencies between 100 and 1000 MHz and could be used to provide a signal with high information content. The technological problem is its transduction since it has an extremely weak intensity.
While conventional biology is based mainly on the microstructure of the biological material, namely the cellular or molecular structure as in molecular biology or microbiology offered by physical-chemical concepts, biological material has recently been recognized as an electromagnetic aggregate and a complex electric network system. Therefore, a variety of new mechanical, electromagnetic and electrodynamic effects are described in the latest literature also in cumulative terms; not only for the electrical properties and functioning of the biological material itself, but also for the interactions of the external electromagnetic fields with the biological material as a coherent whole considering cooperative effects.
In the physical world, the structure and properties of material can be described in two ways: description of particles (atom, molecules and/or elementary particles) for microstructures and continuum (medium or fluid) for macrostructures. In the same way, the structure and properties of biological material can also be described in two ways: descriptions with cells, molecules and elementary “Biologically Closed Electric Circuits” for the microstructures and description of the continuum (fluid) for the macrostructures.
A need is therefore felt in the sector for non-invasive diagnoses to determine neoplastic diseases.
The object of the present invention is to provide an electromedical system for the non-invasive diagnosis of neoplastic diseases.
According to the present invention, an electromedical system is provided as claimed in the attached claims.
The present invention will now be described in detail with reference to the attached figures to allow a person skilled in the art to produce it and use it. Various modifications to the embodiments described will be immediately evident to the persons skilled in the art and the generic principles described can be applied to other embodiments and applications without thereby departing from the scope of the present invention, as defined in the attached claims. Therefore, the present invention must not be considered limited to the embodiments described and illustrated but must be given the widest scope in accordance with the characteristics described and claimed.
Where not defined otherwise, all the technical and scientific terms used here have the same meaning commonly used by persons of ordinary experience in the field pertaining to the present invention. In the case of conflict, the present description, including the definitions provided, will be binding. Furthermore, the examples are provided for purely illustrative purposes and as such must not be considered limiting.
In particular, the block diagrams included in the figures attached and described below are not be understood as representations of the structural characteristics, namely constructional limitations, but must be interpreted as a representation of functional characteristics, that is, intrinsic properties of the devices and defined by the effects obtained, namely functional limitations and which can be implemented in various ways, therefore such as to protect the functionalities of the same (possibility of functioning).
In order to facilitate understanding of the embodiments described here, reference will be made to some specific embodiments and a specific language will be used to describe the same. The terminology used in the present document has the purpose of describing only particular embodiments and is not intended to limit the scope of the present invention.
The new extraction method subject of the present description is aimed at obtaining, by non-invasive electromagnetic means and without the use of ionizing radiations, information useful for understanding and analysis of the state of the biological tissues and refers, considering the above introductory premise, also, but not only, to the phenomenon of “synchronization”.
The history of synchronization dates back to the 17th century when the Dutch scientist Christian Huygens reported his observations on the behaviour of two pendulum clocks which he had just invented, which synchronized with each other by means of a vibrational mechanical coupling. This invention significantly increased timekeeping accuracy and helped him to tackle the problem of longitude determination.
In the mid-19th century, in his treatise ‘The Theory of Sound”, Lord Rayleigh described an interesting phenomenon of synchronization of acoustic systems: ‘When two organ pipes of the same pitch stand side by side, complications arise which frequently create problems in practice. In an extreme case, the pipes can reduce each other to silence. Even when the reciprocal influence is moderate, it may still go so far as to cause the pipes to play in absolute unison in spite of inevitable small differences”. Therefore, Rayleigh observed not only mutual synchronization when two distinct but similar pipes begin to play in unison, but also the correlated effect of damping of the oscillation when the coupling causes suppression of the oscillations of interacting systems.
In many natural situations, interactions are present between several oscillators. If two oscillators (whether mechanical or otherwise) can modify their rhythms, a large number of systems can also do so.
Apart from the possible variety of dynamic systems and coupling geometries between oscillators, an essential aspect of the overall behaviour of a group of interacting oscillators is the transition from a disorderly state to a situation of synchronization (more orderly state), when the intensity of the coupling between the systems exceeds the critical threshold. The Kuramoto model [8] constitutes a simplified description of the dynamics of a group of interacting oscillators, where the mechanism of birth and maintenance of the synchronization is described.
In its original version, it presents as a population of N oscillators with phase θi(t) having natural frequencies ωi distributed according to a probability density g(ω), and coupled proportionally to the sine of the phase differences:
The factor 1/N guarantees good behaviour of the model in the thermodynamic limit N→∞, while K represents the coupling intensity. Clearly, for K=0 the oscillators evolve each according to its natural frequency, ωi.
The equation therefore describes the dynamics of the population of oscillators coupled on any topology. It is used, for example, as a model of the dynamics of electrical distribution networks, or of biological systems interacting at various levels.
The present invention is based on the availability of an electronic architecture in which an active oscillator, agile in frequency in its operating band (i.e. free), acts as an active stimulus relative to the more or less complex group of oscillators that form an integral part of the biological material to be examined. The operating band of the active oscillator shall be commensurate with the specific characteristic frequencies ωi of the oscillators to be synchronized. The coupling vector between the active oscillator and the interacting oscillators consists of the electromagnetic field of stimulus.
One of the most critical aspects for correct functioning of the method and the device is the use of both:
It is also evident that if the coupling vector is to be the electromagnetic field, the oscillating elements of the network must have prerogatives such as to interact with the stimulus field of the active oscillator. In fact, the field will act mainly on ionic charges and dipole moments belonging to the biomolecular structures.
The active source must be free to interact with the elementary constituents of the biological medium to create a specific coupling pattern, linked to the principle of minimization of the energy of the global eigenstate that describes the coupled system formed of the active external source and the passive network of the oscillators.
We will see below that during the stimulus (pump) conditions, the oscillating material will behave in a very particular manner relative to the probe field.
The description in frequency of the collective behaviour of the biological oscillators (see also
It is shown that when an internal oscillation with frequency ω0 is perturbed by an external oscillation with force F0 and frequency W much lower than coo, with the increase in F0 the internal oscillation undergoes a series of quasi-periodic and irregular or non-periodic states until it is completely synchronized. At that moment, the internal oscillation has synchronized its original frequency with the new frequency W set from the outside and oscillates with a fixed amplitude F0. The phenomenon depends heavily on W and F0.
It should be noted that during the time t necessary for complete synchronization of the internal oscillation with the new values of W and F0 set externally, there are moments in which the internal oscillatory phenomenon reaches quasi-periodic and non-periodic states. At the end of the synchronization process, when the internal oscillation has settled in frequency and intensity on the externally set values, a new oscillatory order is reached, in the sense that the molecular process on which the external radiation has acted continues in an orderly manner, but with new frequency and intensity values (see example in
In the models of F. Kaiser there are other interactive possibilities between external and internal oscillations (graph A of
The non-linear and parametric processes are central in the wave propagation mode in complex environments. They are at the centre of numerous applications in high frequency optics and acoustics.
In the case of optics, the possibility of generating a phase conjugation through processes such as four-wave mixing, so as to create a “phase-conjugate mirror” (see
It is important to note that the effect of the pump waves is equivalent to a time modulation of the refractive index with frequency double that of the signals used.
Recently the possibility of obtaining the phase conjugation on acoustic waves in a liquid through the induction of Faraday instability [10] has been discovered and demonstrated. In this case, the pumping occurs mechanically with one single vibrational source, which shakes the liquid so as to compete with the force of gravity.
This document discloses the capacity of the biological media to behave like phase-conjugate mirrors, when subjected to an electromagnetic pump stimulus.
In the extracellular spaces, there is a large amount of water in which many ions are dissolved. When the frequency of the external pumping field causes a charge anisotropy (separation of positive ions from negative ions), caused by the fact that the different signs are accelerated in opposite directions, intense local electrostatic forces are generated that try to somehow reabsorb the spatial anisotropy.
The high frequency oscillations, in cases where the separation between positive ions and negative ions is no longer negligible, induce in the biological medium a space-time modulation of the local permittivity, similar to a plasma oscillation.
In the case of the present invention, an electromedical system 1 for the non-invasive diagnosis of neoplastic diseases is used to activate the phase conjugation in the biological medium (namely the patient).
The steps to activate the phase conjugation in the biological medium are therefore the following:
The electromagnetic pump signal constitutes, in the present invention, the parametric excitation of the biological tissue which is comparable to a state of Faraday instability. If the tissue is outside its state of homeostasis, the periodic oscillation of the stimulus induces its coherent destabilization, like the Faraday instability for a liquid interface (see for example
If the frequency of the electromagnetic probe signal is equal to the modulation frequency of the dielectric permeability, which is equal to half the frequency of the electromagnetic pump signal, then the interaction of the signals involved gives rise to an idler beam in response, reversed in time and in the wave vector.
We have therefore disclosed that the biological material in a disordered state, therefore far from homeostasis, synchronized by an electromagnetic pump signal, acts like a phase-conjugate mirror relative to a second incident beam, giving rise to a third response beam reversed in time and in the propagation direction.
The response waves refocus on any initial emission source, thus allowing, according to an inverse and non-invasive procedure, external evaluation and measurement of a specific property of the material under examination, namely that of being in a state of non-homeostasis.
It is well known that tumour cell membranes have different electrochemical properties and a different distribution of the electric charges compared to normal tissues [11]. The homeostasis of tissues in which a tumour neoformation is present is completely lost, and as such it is possible to analyse it by means of the method and the electromedical system 1 of the present invention.
Among the many variations compared to healthy cells, tumour cells have lower potassium concentrations and sodium and (above all) water content higher than normal cells [12-14]. Consequently, cancer cells show a greater permittivity, interacting differently from normal cells when an external EM field is applied. This characteristic is exploited by conventional imaging systems that use exploratory electromagnetic fields (microwave tomography).
The present invention does not use the principles of radio-wave tomography.
The electromedical system 1 for applying the method described above consists essentially of an electromagnetic source unit 2, a receiving unit 3, a multi-band and multi-channel antenna 4 and a software installed on a computer for processing (processing unit 5) the data, appropriately connected to one another (see
In other words, an electromedical system 1 for the non-invasive diagnosis of neoplastic diseases is described which comprises the electromagnetic source unit 2, the receiving unit 3, the multi-band and multi-channel antenna 4 and the processing unit 5 provided with a data processing software.
The electromagnetic source unit 2 forms the active generation and transmission part of the electromedical system 1. The electromagnetic source unit 2 is configured to generate and radiate the electromagnetic pump, probe and test and reference signals.
In particular, according to the appropriate configurations, the signals can be emitted by physically separate radio frequency antennae and generators or the signal radiating and/or generating parts can be shared. The electromagnetic source unit 2 gives rise to several spectral and spatial field components, which have specific roles and functions. In terms of radiation characteristics, the near field components act in an essentially reactive manner with the oscillators of the biological network and act as a pump stimulus. The radiative field (probe field) components, interacting with the material subjected to pumping, interact electromagnetically with the oscillating material, set in coherent motion by interaction with the electromagnetic pump signal.
In particular, the electromagnetic source unit 2 can comprise a pump antenna and a probe antenna to emit the electromagnetic pump signal and the electromagnetic probe signal respectively.
Any modulations can be superimposed on the radiated signals, normally in continuous wave (CW), in order to implement adaptive techniques in the search for the best pump synchronism frequency. The frequency of the electromagnetic pump signal can vary preferably, but not necessarily, in discrete sub-bands in the range from 300 MHz to 2800 MHz. The frequencies of the probe and the test and reference electromagnetic signal will be consequently bound to the above bands, since the probe frequency is equal to half the pump frequency.
To simultaneously and effectively obtain scanning on several bands, harmonic generators (of the electromagnetic source unit 2) can be used, in which the various fundamental and harmonic bands can have a pump and probe role, also interchangeable.
In other words, the electromagnetic source unit 2 can comprise harmonic generators to generate the electromagnetic pump signal and the electromagnetic probe signal.
The signal generation must guarantee a frequency agility, which is a function of the separation in frequency between pump source and biological oscillator. Typically the value of 20% with respect to the nominal frequency value is required, so as to tune in and synchronise with the frequencies of the passive biological oscillators. This frequency agility can be obtained by means of free oscillators, or by means of scans in frequency controlled through analog and/or digital techniques.
The amplitude of the signals transmitted in the area of contact with the biological tissue lies preferably, but not necessarily, in the range between 2 V/m and 20 V/m. The amplitude of the level can be used as a synchronization parameter. The synchronization is linked to non-linear phenomena.
In further detail, the electromagnetic source unit 2 comprises antennae, in particular to emit the electromagnetic pump signal and the electromagnetic probe signal.
Preferably, the antennae of the electromagnetic source unit 2 have an impedance matching in the bands of use to allow a correct level of radiation, equal to a return loss of −20 dB.
The receiving unit 3 is configured to receive and measure in amplitude and phase the signals generated by the electromagnetic source unit 2, captured by the multi-band and multi-channel antenna 4.
The multi-band and multi-channel antenna 4 operates as a spatial and spectral filter by means of its radiant configuration of an array of independent and decoupled elements, appropriately distributed in space, such as to map the field distribution received.
A fibre optic link 6 (of the electromedical system 1) connects the electromagnetic source unit 2 to a local oscillator of the receiving unit 3, thus allowing coherent field reception in terms of amplitude and phase. Command and control signals also travel on the optical fibre 6 between the receiving unit 3 and the electromagnetic source unit 2.
The receiving unit 3 must allow reception of the signals correlating them in space and time, and the demodulation of said signals if necessary. Modulation of the test and reference signal can be deliberately imparted by the electromagnetic source unit 2, but could also be linked to phenomena such as microdoppler phenomena superimposed on the test and reference signal, and suggesting oscillatory dynamics within the biological medium, carriers of information on the state of homeostatic order or disorder of the tissues. Analysis of the superimposed modulations is considered important for any identification of the main biomolecular aggregates (proteins, bound water, ions, etc.) composing the synchronised biological oscillators.
The multi-channel and multi-frequency reception must take place in real time and simultaneously on all the channels or, if switching systems are used, the switching must be sufficiently rapid to allow spatial mapping of the signals in phase and amplitude, such that the latency time for the reading is negligible with respect to the physical variations of the signal to be received. Consequently, the switchings and readings of the signals must be carried out with an overall period of less than 0.04 seconds for each measurement frame.
The computer (the processing unit 5), by means of the software, allows the amplitudes of the signals measured by the receiving unit 3 to be displayed on a screen in real time.
The diagnosis of the state of homeostasis is carried out based on the signals which, by means of the biological phase conjugation mechanism, demonstrate the presence of said state by measurement of the interference detected. Appropriate selection rules and algorithms that combine the analysis of the various signals are fundamental for discriminating the significant thresholds and interference levels. This concept is schematically illustrated also in
The logic of the electromedical system 1 is based on the interfering electromagnetic interaction between test and reference signal and the phase-conjugate signal, obtained from interaction of the electromagnetic probe signal with the collective and cooperative type effects induced by the electromagnetic pump signal.
The coherent radiation beam coming from the transmitter of the present electromedical system 1 locally excites the dipole resonant oscillations so as to convey the transport of energy in the biological system.
In the case of tumour metabolism, a transition of the system occurs to a state of parametric Faraday instability (see also
Under the action of the radiation of the invention, the guided parametric instability behaves like a biological phase-conjugate mirror, and its activation is identified and quantified by means of the mapping of the field received from the antenna 4 (see also
The receiving unit 3 is connected to the array of independent antennae which, with their arrangement, allow analytical reconstruction of the incident wavefront, coming from the interaction of the fields of the electromedical source unit 2 with the biological tissues. A holographic algorithm allows the qualitative information on the state of health of the tissues to be presented graphically on a display 15 and in real time; said information can then be quantified by means of a subsequent post processing phase, correlating on the database of the experimental data already stored. The machine learning and classification phases are part of the post-processing subsystem.
By way of non-limiting application example of the method and system, we describe the procedures according to the invention for the extraction of information on the homeostasis of prostate tissues.
The examination is non-invasive, and as such can be performed directly on the patient without the risk of side effects. The patient stands in front of the array of antennae 4, at a distance of between 110 and 160 centimetres from them. Once all the reception and transmission devices relative to the electromagnetic source unit 2 and the receiving unit 3 have been connected and activated, as in the configuration of
The representation of the wavefront received from the array represents a measurement of the phase conjugation level obtained within the tissues stimulated.
The electromedical system 1 for the non-invasive diagnosis of neoplastic diseases is essentially composed, as already described, of the electromagnetic source unit 2, the receiving unit 3, the multi-band and multi-channel antenna and the software installed on a computer for data processing (processing unit 5), appropriately connected and interacting with one another.
The electromagnetic source unit 2 forms the active generation and transmission part of the system: from this unit the pump, probe and test and reference signals are generated and radiated.
In the present implementation, the electromagnetic source unit 2 is contained in a handpiece (probe 8), so that it can be held in the hand and used for scanning the area under examination. In particular, the probe 8 is configured to be placed in contact with the area of the patient under examination during the scan.
The electromagnetic source unit 2 includes a free oscillator 9 able to generate an RF signal at fundamental frequency, at a UHF band frequency, and its harmonics. The handpiece (the probe 8) also contains the power-supply circuits (with relative high-capacity lithium batteries 10) and control circuits (for example, to monitor correct operation of the oscillator and the battery charge status) in addition to a high-speed fibre optic transmitter 19, which takes a part of the signal of the oscillator 9 and transmits it in optical fibre 6. The probe 8 also includes circuits for management of the lithium battery charge using an external power-supply 11 at 5V (for example, a standard USB). In particular, the probe 8 also comprises a battery charger 17.
On the handpiece (on the probe 8) there are four control buttons 12: A, B, C, D. The pressing of a key must be notified together with information on which key has been pressed; for this purpose the line enabling the optical carrier on the fibre will be used. The “key pressed” event and the “key number” information is transmitted by a codified modulation of the optical signal. This modulated signal can also transmit other information on the operating status of the probe 8 and the battery charge level.
The receiving unit 3 includes three receiving channels 21 to simultaneously receive the signal transmitted by the probe 8 at the fundamental frequency and at the second and third harmonic. Each receiving channel 21 includes an amplifier 13, a radiofrequency filter 14 and an I/Q mixer, with low-pass filter in output, to receive the component in phase and in quadrature of the signal received with respect to the one transmitted, and therefore allow amplitude and phase measurement.
The local oscillator signal is generated for each of the receiving channels 21 starting from the test and reference signal received via optical fibre 6 from the probe 8, by means of appropriate amplifiers 13 and filters 14 (fundamental frequency F1) and also multipliers ×2 (frequency F2) and ×3 (frequency F3). In this way the signal received and the local oscillator signal are intrinsically at the same frequency and the output of the I/Q mixer is represented by a direct voltage proportional to the amplitude of the signal received, multiplied respectively by the sine and the cosine of the phase difference between signal received and reference signal.
Any band disturbances present, also at a frequency very near the measurement frequency, cause an oscillating signal at output of the I/Q mixer and can be eliminated by means of a low-pass low-frequency filtering stage.
The antenna 4 comprises dipole elements 7 (indicatively, but not exclusively, 9, 32, 64 or 128 elements), receiving in broadband and having reduced dimensions (indicatively, but not exclusively, a few centimetres) and allows measurement of the electromagnetic field generated by the probe 8 which interacts with the district or organ of the patient under examination at different points on a surface positioned at a given distance, indicatively between 1 m and 2 m.
The receiving elements 7 of the antenna 4 can be passive broadband elements (for example, biconical dipoles or Vivaldi antennae) or elements resonating at one of the frequencies received, typically the probe frequency (for example, inductively or capacitively charged dipoles). These elements are decoupled from the signal cable by means, for example, of ferrite balun.
The receiving elements 7 of the antenna 4 can also be composed of active elements (such as, for example, very small dipoles with respect to the wavelength with an integrated broadband amplifier). In this case it is possible to achieve adequate measurement sensitivity with very small receiving elements and therefore measure the signal received on the measurement surface with a reduced spacing between the measurement points (for example, from ⅕ to 1/10 wavelength).
With particular reference to
The input switch (switch device 19) also allows insulation of the input of the receiving unit 3 from the antennae 4 and also connection of it to an internal signal generator to perform zero-setting and calibration of the I/Q mixers of the three receiving channels 21.
The broadband signal coming from the selected antenna 4 is then separated into the three main components (fundamental, second and third harmonic) by means of a separator filter 20 (diplexer) (of the receiving unit 3) and sent to the three receiving channels 21.
With particular reference to
Furthermore, in order to improve the sensitivity of the receiving unit 3 it is also possible to take averages between several successive measurements. Indicatively, at the A/D conversion speed indicated above, 256 averages per antenna 4 and receiving channel 21 allow more than 20 measurements per second to be taken on an antenna 4 complete with 128 receiving elements 7.
Furthermore, the controller 18 also periodically takes the zero-setting and calibration measurement of the receiving channels 21, measurement of the frequency of the signal received from the probe 8 and measurement of the internal temperature of the I/Q mixers (for any correction of their temperature response).
All the data measured and in particular the data of the signals read for each of the elements of the antenna 4 and for the three frequency bands are then transmitted to the computer (processing unit 5) for the subsequent processing operations, presentation and storage of the results (in a memory 16). The data are transmitted to the computer (processing unit 5) by means of LAN network and TCP/IP protocols.
The firmware of the controller 18 of the receiving unit 3 is set so that the receiving unit 3 can work completely independently from the controller 18. The firmware of the receiving unit 3 carries out cyclically and in sequence the zero-setting and calibration measurements, the temperature measurement and measurement of the signals received from all the elements 7 of the antenna 4.
All the data measured of each single measurement cycle are then transmitted in a single data package with appropriate coding to minimize the dimensions and the load of the LAN network. The coding used and the speed of the LAN network (indicatively 100 Mbps or higher) are more than adequate for transmission of all the data measured with the maximum number of antenna elements scheduled in real time during the measurement.
The low-level operations in the receiving unit 3 are carried out by the hardware devices interfaced with the microprocessor of the receiving unit 3, therefore it is natural and appropriate for these operations to be managed locally by the internal microprocessor.
The operations at a higher hierarchical level are carried out by a code that runs on the embedded operating system (Linux) or by a code that runs on PC/external console. In the second case it is easier to make modifications to the software and therefore, having estimated the impact on the throughput, this second option, not necessary but expedient, was chosen.
In short, the functions implemented on the microprocessor of the receiving unit 3 comprise one or more of the following:
The processing unit 5 comprises:
The measurement phase can be driven remotely by means of four buttons that use the optical fibre transmission channel. This allows the operator to:
The software is able to display on screen, by means of indication provided by graph, icons and specific text messages, the presence of malfunctions in the system in the event of:
The correct operation of the electromedical system 1 is highlighted by graphic messages and icons.
The main characteristics of the system configuration are therefore one or more of the following:
| Number | Date | Country | Kind |
|---|---|---|---|
| 20217275.5 | Dec 2020 | EP | regional |
| 21155605.5 | Feb 2021 | EP | regional |
| 102021000032537 | Dec 2021 | IT | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2021/062292 | 12/24/2021 | WO |
