ES2575731B1 - Synthetic model of biological tissues for the evaluation of wireless transmission of electromagnetic waves - Google Patents

Abstract

Synthetic model of biological tissues for the evaluation of wireless transmission of electromagnetic waves. # The present invention relates to synthetic models or phantoms of tissue and biological organs composed mainly of sodium chloride and acetonitrile in solution or embedded in a polymer matrix and for use to test the possible effects of electromagnetic waves on living beings, particularly in the frequency range of 0.5 to 18 GHz.

Description

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Synthetic model of biological tissues for the evaluation of the wireless transmission of electromagnetic waves

DESCRIPTION

The present invention relates to synthetic models of tissue and biological organs composed mainly of sodium chloride and acetonitrile in solution or embedded in a polymer matrix and its use to test the possible effects of electromagnetic waves in living beings, particularly in the range of frequencies from 0.5 to 18 GHz.

STATE OF THE TECHNIQUE

There is a growing interest in using telecommunications devices, either as oral administration capsules or as implantable medical sensors or monitoring systems, of short or long life, to record biological information from inside the organism and be able to transmit it to the outside, in order to make a clinical diagnosis or adjust the medical treatment before a chronic pathology with greater precision. For this, said devices communicate wirelessly by sending electromagnetic waves through the body, which behaves as a means of transmission. In order to develop and test devices of this type before marketing, it becomes necessary, at a certain point, animal and human experimentation.

To avoid resorting to animal or human experimentation (what is usually called in vivo tests), a synthetic model (called phantom or phantom in Spanish) has been developed that is based on mixtures of different components whose concentrations are adjusted to simulate different tissues humans and organs, and that in part avoids having to resort to those of in vivo trials.

The phantom consists of a liquid mixture, which can be contained in the container with the shape and dimensions of interest, for example those of the organ that mimics, or it can be contained a conformable gel with the shape and dimensions of interest, capable of housing liquids or mixtures thereof in the polymeric crosslink.

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JP2012110563A describes a phantom for evaluation of the influence of electromagnetic wave discharge on an implanted medical device. The liquid used has a dielectric constant similar to that of the human body and is used to fill the phantom to a position higher than the medical device.

JP2006251012A refers to a phantom equivalent to a living body, used to investigate the influence of electromagnetic waves of domestic electronic devices, such as cell phones, television, etc., on the human body. The phantom comprises a specific weight of electrolytes and water absorbing polymers. The advantage of phantom stability in wide wave frequency ranges is mentioned.

Document KR20000015490A discloses a human phantom and a human phantom cell of the brain, skull, and muscle tissue, to assess the electromagnetic effect.

JPH0546074A describes a biological liquid for the electrical simulation of the body comprising an electrolytic solution and a polar organic compound sealed in a container with specific electromagnetic transmittance (at least 0.9). The organic compound preferably comprises a monovalent or polyhydric alcohol. The liquid allows the dielectric constant to be maintained over a wide range, accurately simulating the characteristics of the human body.

Although phantoms have been developed for organs such as muscle, brain, skin or adipose tissue, they have not been achieved for liver, heart, pancreas, colon or cartilage. In addition, taking into account the amplitude of frequencies in the electromagnetic radiation of the different devices that surround us, it is necessary to have adequate phantoms to determine the repercussions of certain frequency ranges on biological tissues.

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DESCRIPTION OF THE INVENTION

The inventors have developed a synthetic model of biological or organ tissues based on an aqueous solution of NaCl, acetonitrile and a solvent whose concentrations are adjusted to simulate different human and organ tissues, in terms of their electromagnetic properties, relative permittivity and conductivity Dielectric and conductivity. This model offers several advantages: to avoid it in part having to resort to animal or human experimentation to test wireless devices that are expected to be used as implantable sensors or monitoring systems, experiments will be better controlled and the dependence of the signal with the individual be avoided. under study.

This model would be of application in the ex vivo evaluation (without using animal or human models) of the propagation of electromagnetic waves of developed or developing devices or systems, both for the communication towards the outside of the body from the inside, and from external use, in the UWB (ultrawide band) frequency band comprising 0.5 to 18 GHz.

In a first aspect, the present invention relates to a synthetic model of biological tissues formed by a solution comprising:

- a salt selected from sodium chloride, potassium chloride or sodium bromide in a proportion of 0 to 5% by weight with respect to the total,

- acetonitrile in a proportion of 10 to 70% by weight with respect to the total,

- at least one polar solvent in a proportion between 30 to 90%.

The proportions of each of the components are calculated and added so that the sum of these reaches 100%.

In the synthetic model of the present invention any salt that dissociates into ions can be used when dissolved in a polar solvent, although preferably said salt is sodium chloride.

In a preferred embodiment, the synthetic model of the invention is formed by a liquid mixture comprising:

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- sodium chloride, potassium chloride or sodium bromide, in a proportion of 0 to 5% by weight with respect to the total,

- acetonitrile in a proportion of 10 to 60% by weight with respect to the total,

- at least one polar solvent, in a proportion of between 40 to 90%.

In a preferred embodiment, said solutions that form the model may be contained in a polymeric gel of natural or synthetic origin. The polymers used can be of the acrylate, acrylamide, hydroxyacrylate, alginate, chitosan, hyaluronic acid or other non-degradable family to avoid deterioration over time. These materials are obtained by conventional radical polymerization, from the monomer or monomers corresponding to the polymer in question, in the presence of an initiating reagent of said polymerization reaction (benzoyl peroxide, or benzolna, for example) and a crosslinker (ethylene glycol dimethacrylate, for example), in the mold suitable for the tissue or organ to simulate. Other few crosslinked gels with high affinity for water, conventionally used as phantoms, such as gelatin or agar, could also be used to soak them in the liquid mixture.

In another preferred embodiment, the polar solvent is selected from water, ethanol or acetone.

In another preferred embodiment, the model comprises a biocidal agent that is incorporated into the mixture of acetonitrile or the polymer gel in which said mixture is embedded, in order to prolong the life of the model avoiding bacterial proliferation. These biocides can be of biological or chemical origin. In a more preferred embodiment, the biocidal agent is sodium azide.

Another aspect of the invention relates to the use of the synthetic model as described above for the simulation of the behavior of biological tissues in the frequency band of 0.5 to 18 GHz.

The mathematical treatment carried out on the data obtained with the coaxial probe with an exhaustive battery of solutions in which the concentration of each of its components has been systematically varied, allows obtaining the

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Optimal formulation to prepare phantoms ‘à la carte’, with the optimal chemical composition to simulate the tissue or organ of interest: muscle, liver, or others.

The hypothesis that with these systems analogs of human tissues or organs can be obtained from the electromagnetic point of view is based, on the one hand, (a) on the results obtained using a coaxial communications probe, attesting that the permittivity spectrum Real and imaginary relative of the prepared liquid mixtures conforms to that described in the literature for various human tissues (muscle, heart, pancreas, colon, liver, cartilage) in the frequency range between 0.5 and 18 GHz, and on the other hand that (b) it is possible to obtain gels with the shape and dimensions of interest by polymerization in the appropriate mold, and (c) it is possible to incorporate liquid mixtures into these polymer networks capable of swelling in the presence of them.

Another aspect of the invention relates to the method of obtaining the synthetic model described above comprising the following steps:

a) preparation of the liquid mixture by adding the components as described above and

b) mixing and stirring the solution prepared in (a), in a closed bottle.

In a preferred embodiment, this process comprises adding a biocide to the liquid mixture at the time of its preparation.

The solutions (liquid mixtures) are prepared from the concentrations established in the formulation, by weighing. That is, with the mass of solution to be prepared and the mass concentrations of each component, the mass of each component to be used is calculated first. Each quantity is then weighed on a precision balance and incorporated into a glass jar that is then closed and kept under stirring, using a magnetic stirrer, for one hour to ensure the correct mixing of all components.

In a preferred embodiment, when the model comprises the polymer gel in which the solution containing acetonitrile is then incorporated, the method of obtaining the synthetic model comprises the following steps:

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a) preparation of a reactive mixture comprising at least one final polymer forming monomer, an initiator and a cross-linking agent, and subsequent agitation of this mixture;

b) polymerization of the reaction mixture in a mold;

c) preparation of the liquid mixture by adding the components as described above, and subsequent mixing and stirring of said mixture, and

d) immersion of the product obtained in (b) once demoulded in the liquid mixture obtained in (c) for swelling until equilibrium (when it is no longer able to absorb more liquid).

In the case of gels, polymer networks are prepared first. This is done using the polymer monomer in question, an initiator of the polymerization reaction and a crosslinking agent (to avoid the subsequent dissolution of the polymer). They are mixed in the established proportions, and after stirring for an hour the mixture is arranged in a mold with the shape of the organ or tissue that we are interested in recreating. The polymerization reaction is carried out and then traces of residual monomer are removed by washing in ethanol or ethanol / boiling water in several steps. Finally, the polymer is dried using a watt desiccator to guarantee the elimination of the washing solvent. Then, to obtain the phantom, the xerogel would be submerged for swelling until equilibrium in the liquid mixture with the established formulation, until reaching the swelling equilibrium, that is, until sufficient time passes so that no more liquid is absorbed.

Throughout the description and claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will emerge partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.

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BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. It shows the relative permittivity of 0.5 to 18 GHz of the muscle phantom compared to Gabriel's model and with a 1M solution of sucrose. Real part: dielectric constant (left), imaginary part: loss factor (right).

FIG. 2. It shows the relative permittivity of 0.5 to 18 GHz of the heart phantom compared to Gabriel's model. Real part: dielectric constant (left), maginary part: loss factor (right).

FIG. 3. It shows the relative permittivity of 0.5 to 18 GHz of the pancreas phantom compared to Gabriel's model. Real part: dielectric constant (left), imaginary part: loss factor (right).

FIG. 4. Shows the relative permittivity in the UWB band of the colon phantom compared to Gabriel's model. Real part: dielectric constant (left), imaginary part: loss factor (right).

FIG. 5: Shows the relative permittivity of 0.5 to 18 GHz of the liver phantom compared to Gabriel's model. Real part: dielectric constant (left), imaginary part: loss factor (right).

FIG. 6: It shows the relative permittivity of 0.5 to 18 GHz of the carthage phantom compared to Gabriel's model. Real part: dielectric constant (left), imaginary part: loss factor (right).

FIG. 7: Shows the relative permittivity in the UWB band of the liver gel phantom compared to Gabriel's model. Real part: dielectric constant (left), imaginary part: loss factor (right).

FIG. 8: Shows the relative permittivity in the UWB band of the heart gel phantom compared to Gabriel's model. Real part: dielectric constant (left), imaginary part: loss factor (right).

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EXAMPLES

The invention will be illustrated below by tests carried out by the inventors, which shows the effectiveness of the product of the invention.

First, some of the synthesized liquid phantoms are shown as an example:

EXAMPLE 1

In Figure 1, the graphs corresponding to the phantom of the muscle are shown, which is the tissue considered as most important from the point of view of imitating, since it represents a very voluminous part of the body and is where more sensors will probably be implanted in a future. The composition of this phantom is 54.98% wt acetonitrile (Scharlab), 1.07% wt NaCl (99% purity; Panreac) in deionized water; The mixture was prepared as described above. The spectrum was obtained using an open ended coaxial probe. He has been represented alongside Gabriel's model [C. Gabriel, “Compilation of the Dielectric Properties of Body Tissues at RF and Microwave Frequencies” Environ. Heal., No. June, p. 21, 1996. S. Gabriel, R. W. Lau, and C. Gabriel, “The dielectric properties of biological tissues: II. Measurements in the frequency range 10 Hz to 20 GHz "Phys. Med. Biol., Vol. 41, pp. 2251-2269, 1996.], in this case in the range between 0.5 and 18 GHz, to appreciate the level of approximation and together with a 1M solution of sucrose, which is the solution adopted so far in most publications to mimic the muscle.The approximation achieved with the proposed phantom is almost perfect, much better than that obtained with a solution of sucrose.

EXAMPLE 2

Heart phantom, another tissue with a high water content and properties similar to those of muscle, was prepared with 49.94% wt acetonitrile, 1.58% wt NaCl in deionized water. Figure 2 shows the curves of the dielectric constant and the phantom loss factor, again compared to the heart muscle spectra according to Gabriel, and in the frequency range between 0.5 and 18 GHz.

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In this case, a steeper slope than the muscle in the real part was obtained, but the maximum deviation produced is one unit in the real part at the initial and final measured frequencies, being the identical loss factor.

EXAMPLE 3

The pancreas phantom was prepared as an aqueous solution of 44.49% wt acetonitrile and 1.09% wt NaCl. Phantom and tissue spectra according to Gabriel are shown in Figure 3, again between 0.5 and 18 GHz.

The approximation of the synthetic model to the real behavior of the tissues is high, since the real part follows the same trend in the broth and there is only a deviation of about one unit, which is within the range of the variation produced by temperature changes , so it is not significant. The loss factor has a curve practically identical to Gabriel's model, so the approximation in this part is even better than the real one.

EXAMPLE 4

The colon phantom was obtained, on the one hand, with a mixture of 52.29% wt acetonitrile and 1.42% wt NaCl in deionized water, or even better, with a mixture 48.5% wt acetonitrile, 1,165% wt NaCl and 2.5% wt ethanol (Scharlab) in deionized water. Both spectra are shown in Figure 4 along with that of the colon according to Gabriel.

With ethanol, the phantom curve is more similar to that of the real tissue without significantly affecting the dielectric constant values or the loss factor. In spite of being a small amount of ethanol, the broth that it produces in the curve of the real part is significant, because its relaxation frequency is much lower both to that of water and to that of acetonitrile. By adding more significant amounts of ethanol, values that are not possible can be achieved by limiting the solutions to water, acetonitrile and salt.

Acetonitrile and ethanol reduce the dielectric constant of water at all frequencies, although ethanol does so in a greater way. While reducing the value of the real part, acetonitrile reduces the slope and ethanol increases it, so that in this sense they have opposite behaviors. NaCl lowers

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curves without modifying the slope, although its influence is rather centered on the imaginary part. In the imaginary part they also have different behaviors. While acetonitrile lowers water losses at all frequencies, ethanol increases them and their incorporation at high rates can cause maximum losses to occur within the UWB range. NaCl increases the loss factor only at the first frequencies studied, converging at one point to the highest, in which the salt does not exert any influence. The only way to regulate losses at high frequencies is, therefore, by varying the proportion of acetonitrile.

EXAMPLE 5

The liver phantom was obtained with a mixture of 51% wt acetonitrile, 0.95% wt NaCl and 17% wt ethanol in deionized water. Its spectrum is shown in Figure 5 along with that of liver according to Gabriel, between 0.5 and 18 GHz.

In the real part, the same slope as Gabriel's model was not achieved, although with a very high approach level and a minimum deviation at all frequencies The solution would have been to add more acetonitrile, which lowers the values and reduces the slope, but that would have lowered the loss factor at high frequencies, which is not of interest.

EXAMPLE 6

Among the tissues with high water content that cannot be modeled using acetonitrile, water and sodium chloride only, the cartilage was also found, having dielectric constant values much lower than water and with a steep slope impossible to reproduce with the use of acetonitrile only. In this case, an important concentration of ethanol was necessary to achieve this slope. Carthage phantom was obtained with a mixture of 41% wt acetonitrile, 1% wt NaCl and 30% wt ethanol in deionized water. Its spectrum is shown in Figure 6 along with that of cartilage according to Gabriel, between 0.5 and 18 GHz.

In the real part of the permittivity there is a deviation of the phantom with respect to the real tissue around a unit, but respecting the broth that occurs with the frequency that is the same in both curves. This represents approximately one

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deviation of 2.5% at 3 GHz and 3.5% at 8.5 GHz. As in the case of the liver, an approach is intentionally lost in the real part to reproduce extraordinary levels of imitation of the imaginary part, where they are adjusted notably both the trend of the curve and the values at all frequencies.

EXAMPLE 7

The liver can also be mimicked with a solid phantom (or phantom gel), in this example using polyacrylamide (PAM). First, 0.125% wt cross-linked PAM was prepared. For this purpose, the acrylamide monomer (Scharlau), N, N'-methylenebisacrylamide (NMBA) (Sigma-Aldrich) was mixed in an ISO glass jar, in order to obtain a polymeric network, and ammonium persulfate (PSA ) (Avocado) as the initiator of the polymerization reaction. PSA breaks homoltically in the presence of UV light and forms free radicals that attack the double bond between acrylamide carbons. This mixture was kept under stirring, on a magnetic stirrer, in a closed bottle for 1 h. The polymerization was carried out in this case in a transparent flat glass mold of 2 mm internal thickness, with a hole through which the reaction mixture was introduced. The hole was plugged and the polymerization was carried out in an ultraviolet oven for 24 hours, followed by a post-polymerization in a forced convection oven at 90 ° C for another 24 hours. Then, and after demolding, the materials were washed in boiling ethanol for 2 days, changing the ethanol every 8 h. In this way the unpolymerized residues were removed. Finally, they were punched with a diameter of 12 mm.

The glass transition temperature of the PAM is 165 ° C, this means that at room temperature and in the xerogel state it will behave like glass. For this reason, and because the change to the vitreous state is very abrupt and the material will probably break it, the PAM gels did not dry out. The materials were swollen to equilibrium in a solution of 35% wt acetonitrile and 0.75% wt NaCl, which was renewed several times to ensure the elimination of ethanol. Figure 7 shows the dielectric constant and the loss factor. Both the real and the imaginary part of the phantom follow the trend of Gabriel's curves, with a minimal deviation in both parts.

EXAMPLE 8

Figure 8 shows the graphs of the solid phantom corresponding to the heart, prepared again from PAM crosslinked 0.125% wt and swollen in an aqueous solution with 19.5% wt of acetonitrile and 1.25% wt of NaCl . The 5 values are very similar to those of Gabriel in both parts of the relative permittivity, the deviation that occurs in the dielectric constant at high frequencies being only relevant, although in no case is it greater than unity.

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Claims (13)

5 10 fifteen twenty 25 30 35 1. Synthetic model of biological tissues formed by a solution comprising: ■ an inorganic salt that is selected from sodium chloride, potassium chloride or sodium bromide, in a proportion of 0 to 5% by weight with respect to the total, ■ acetonitrile in a proportion of 10 to 70% by weight with respect to the total, ■ at least one polar solvent in a proportion between 30 and 90% by weight with respect to the total. 2. Synthetic model according to claim 1 wherein the inorganic salt is sodium chloride. 3. Synthetic model according to any of the preceding claims wherein the acetonitrile is in a proportion of between 10 to 60%. 4. Synthetic model according to any of the preceding claims wherein the polar solvent is selected from water, ethanol or acetone. 5. Synthetic model according to any of the preceding claims which further comprises a biocidal agent. 6. Synthetic model according to the previous claim where the biocidal agent is sodium azide. 7. Synthetic model according to any of the preceding claims wherein the solution is contained in a polymeric gel of natural or synthetic origin. 8. Synthetic model according to the previous claim wherein the polymer gel is selected from the acrylamide family, acrylic acid, hydroxyacrylates, gelatin, agar-agar, alginate, chitosan or hyaluronic acid. 9. Use of the synthetic model according to any one of claims 1 to 8 for the simulation of the behavior of biological tissues in the frequency band of 0.5 to 18 GHz. 10. Method for obtaining the synthetic model according to any of claims 1 to 4 comprising the following steps: a) preparation of a liquid mixture by adding the components according to claim 1, and 5 b) mixing and stirring the solution prepared in (a), in a closed bottle. 11. Procedure for obtaining the synthetic model according to claim 10, which also comprises the following steps: c) preparation of a reactive mixture comprising at least one monomer forming the final polymer, an initiator and an agent crosslinking, and subsequent stirring of this mixture; d) polymerization of the reaction mixture in a mold; and e) immersion of the product obtained in (d) after its demoulding in the liquid mixture obtained in (b) for its swelling until equilibrium. fifteen 12. Method according to claim 10 or 11, which comprises adding a biocide to the liquid mixture at the time of its preparation. 13. Method according to claim 12, wherein the biocide is sodium azide.