A consumable hydrogel for ultrasonic conduction and the method of obtention and use thereof

Abstract

In a first aspect, the invention refers to a consumable hydrogel for ultrasonic conduction characterized in that said hydrogel comprises at least one layer and wherein each layer consists of 3-10% of polyvinyl alcohol (PVA) and 1-15% of 1.2 propanediol and water. In a second aspect, the invention refers to a method of preparation the consumable hydrogel according to the first aspect of the invention. Finally, the invention refers to a use of the consumable hydrogel for ultrasound conduction and the use of the consumable as a coupling agent of an ultrasound medical device.

Description

[0001] DESCRIPTION

[0002] A CONSUMABLE HYDROGEL FOR ULTRASONIC CONDUCTION AND THE METHOD OF OBTENTION AND USE THEREOF

[0003] FIELD OF THE INVENTION

[0004] The invention belongs to the field of ultrasound devices for medical diagnosis, triaging, screening, treatment monitoring, and more particularly, a hydrogel consumable for ultrasonic conduction.

[0005] BACKGROUND OF THE INVENTION

[0006] Ultrasound waves are longitudinal compression waves of frequency greater than 20 KHz which, in the range of tenths of MHz, are useful for exploration of a sample. In general, ultrasound devices comprise a transducer or an array of transducers in acoustic contact with the sample to be interrogated, and work by generating an ultrasonic signal through said sample and then receiving reflected or backscattered signals containing information of said sample. Some systems, particularly single-element transducer ones, are motorised and displace the transducer in linear, pivotal or circular trajectories to collect data from a target volume of interest. In these systems, however, the transducer cannot be in direct contact with the sample as this could deteriorate the transducer while the collected data would be corrupted by the friction between the sample and the transducer in motion. For a correct operation of these systems, an aqueous medium is essential to allow the transducer to move freely and the signal to propagate through said medium at a reduced attenuation to the sample.

[0007] It is known in the state of the art the use of lenses in the transducer for focusing. Lenses allow acoustic beam focusing when attached to flat transducers and, therefore, they cannot be considered as coupling media because their use leads to sensitivity losses due to large reflections at the interfaces between the transducer and the lens materials. As a result, and particularly at high frequencies, there is significant loss of energy in the signal that reaches the target volume.

[0008] Furthermore, it is also known that ultrasound probes that use a single transducer as a signal transmitter I receiver, use a fluid, commonly water, as a means of propagating the signal, submerging the transducer in a watertight chamber in the probe itself. In some configuration the chamber walls are made of a solid material and in other configurations a plastic film is used for a chamber or to close the chamber to prevent the fluid from spilling out while providing a very thin and, consequently, low attenuation interface with the sample. The use of fluid as coupling material has the following limitations:

[0009] The risk associated with having a watertight chamber full of fluid, is that fluid could leak and not only damaging the electronics and I or the probe mechanism but also damaging I corrupting the sample or even worse disturbing the patient; this risk is maximal when the transducer displacement is in the longitudinal axis, approaching and separating from the target sample.

[0010] Fluids are not compressible; during a longitudinal displacement of the transducer this leads to an increased pressure in the chamber that challenges water tightness.

[0011] The use of fluids causes reflections and bubbles problems often associated to the scanning motion of the transducer.

[0012] To preserve fluid tightness either solid materials or plastic films are needed that imply high losses of signal at the interface between the fluid chamber and the sample; as a matter of fact, ultrasound gel is still mandatory if part of the signal is going to be transmitted to the target material, e.g. tissue, thus creating yet another interface in which the further transmitted signal energy is again lost; all these losses are impeding if small structures in the few millimetres or micron-range are of interest, which is often the case when working at relatively high frequencies, e.g. more than 10 MHz.

[0013] In the state of the art, the patent CN 107022161 B refers to hydrogel material for ultrasonic conduction and a preparation method thereof, belonging to the technical field of hydrogel functional materials. Wherein said hydrogel material is made of polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, sodium polyacrylate, calcium chloride, tannin, nitrite, triethanolamine, polyethylene glycol, propylene glycol, glycerin. However, this method of preparation the hydrogel disclosed comprises the use of known chemicals that cause skin burns such as phosphoric acid, and thus it is not desired due to the possible health risk when in contact with human tissue.

[0014] Furthermore, the patent application CN 101744761 A that depicts a medicament-carried therapeutic ultrasonic coupling gel agent belonging to the technical field of ultrasonic therapy. The gel agent comprises the following components in percentage by dosage: 0.5- 8 percent of hydrophilic polymer material, 0.5-15 percent of penetration enhancer, 2-10 percent of humectant, 0.5-5 percent of solubilizer, 0.5-5 percent of conditioner and water.

[0015] The patent application EP1671656A1 describes a waterless in vivo biocompatible and bio- excretable lubricant and ultrasound coupling fluid or gel produced from formulations based on polyvinylpyrrolidone (PVP) and one or more glycols and / or polyols such as propylene glycol, glycerol, polyethylene glycol and sorbitol.

[0016] Finally, the patent application US2005074407A1 refers to a vivo biocompatible and bio- excretable lubricant and ultrasound coupling fluid or gel comprising polyvinylpyrrolidone and / or polyvinyl alcohol solutions in water to which humectants such as alkylene glycols and / or polyalkylene glycols are added to achieve desired tactile and drying characteristics.

[0017] However, none of these coupling materials described above solve the technical problem of preserving the integrity and energy of the transmitted signal by moving single-element transducer systems. Such solutions must have a compressive strength of such magnitude that allows its deformation up to a maximum of 50% of the material allowing the axial movement of the transducer and, importantly, have high level of acoustic transmission properties allowing minimal acoustic energy losses.

[0018] In this way, there is a need in this field of a consumable material able to be easily compressible that has shape memory and a high level of acoustic transmission allowing minimal acoustic energy losses.

[0019] BRIEF DESCRIPTION OF THE INVENTION

[0020] As it has been outlined in the background section, a technical problem present in the field is how to obtain a consumable material for mechanically-actuated ultrasound transducers able to be easily compressible with a high level of acoustic transmission. This problem is effectively addressed by the present invention.

[0021] In a first aspect, the invention refers to a consumable hydrogel for ultrasonic conduction characterized in that said hydrogel comprises at least one layer and wherein each layer consists of 3-10% of PVA and 1-15% of 1.2 propanediol and water.

[0022] In the context of the present invention, the term “consumable” refers to a hydrogel that is intended to be used up and then replaced. Therefore, the present invention is related to a consumable hydrogel that is replaced inside the chamber of the ultrasound device for use in each measurement, to guarantee consumable properties are optimal, the focal volume of the transducer will fall close or at the target volume, secure best acoustic coupling and sensitivity, and remove the risk of possible contamination from one target to another.

[0023] In the context of the present invention, the ultrasound device is a device used for measuring and quantifying circulating cells in superficial body fluids of a target by means of high- frequency (e.g., ultrasound) transduction. The device can be used for detecting circulating cells in the fluids of an individual without the necessity of extracting a sample thereof, being useful as a screening, triaging and diagnostic tool and for monitoring the effectiveness of a treatment administered to an individual suffering from a viral, protozoal, fungal and / or bacterial disease.

[0024] In the context of the present invention, the term “phase” it is also referred as “layer”.

[0025] In another preferred embodiment, the consumable hydrogel is a multiphasic hydrogel consumable, which means that has one or more phases or layers, whose composition is different from each other.

[0026] In a preferred embodiment, the consumable hydrogel comprises more than one layer and each layer optionally comprises a different amount of PVA and / or a different amount of 1 .2 propanediol with respect to the other layers.

[0027] In a second aspect, the invention refers to a method for preparing the consumable hydrogel of the first aspect of the invention.

[0028] In a third aspect, the invention refers to the use of the hydrogel consumable for ultrasound conduction.

[0029] BRIEF DESCRIPTION OF THE DRAWINGS

[0030] To complete the description and in order to provide for a better understanding of the invention, a set of drawings is provided. Said drawings form an integral part of the description and illustrate an embodiment of the invention, which should not be interpreted as restricting the scope of the invention, but just as an example of how the invention can be carried out. The drawings comprise the following figures: Figure 1 shows an illustration of the consumable hydrogel with one layer and with different sizes: 1) 1.2g; 2) 3.5g; 3) 4.7g.

[0031] Figure 2 shows an illustration of two different types of the consumable hydrogel 1) 3.5g single-phase; 2) 3.5g dual-phase.

[0032] Figure 3 shows a scheme of the image processing used in this study. Image A = original image; Image B = mean control image; Image C = subtracted Image; Image D = sobel image; and Image E = binarized image.

[0033] Figure 4 depicts a scheme of the experimental design used to evaluate the performance of compression of more than 50% of its size and fully recovery of its shape during a period of 1 to 10 seconds of both consumables: 1) single-phase and 2) dual-phase of the 3.5g consumable.

[0034] Figure 5 shows attenuation results. Attenuation (dB / cm) of the consumables (hydrogels) with a single-phase (left side) and with a dual-phase (right side). Statistical significance was determined by the Mann-Whitney U test (***p < 0.001).

[0035] Figure 6 shows mean signal intensity obtained with single-phase and dual-phase consumables alone, for different PS particles concentration as such A) 20 pp / / zL, B) 50 pp / jizL, C) 100 pp / jtzL and D) 200 pp / yzL (more than 75 images used per condition). Statistical significance was determined by the Mann-Whitney U test (***p < 0.001).

[0036] Figure 7 illustrates the percentage of pixels with signal at different PS concentrations (the average for each condition is shown).

[0037] Figure 8 shows original images obtained in a proprietary image visualization application for in vivo uveitis patients. Measurements performed with a 20 MHz single-element piezoelectric transducer, and a dual-phase consumable of 4.7g at 42 dB of gain for different patients with different SUN grade: 1) SUN=0, 2) SUN=0.5, 3) SUN=1 , 4) SUN=2 and 5) SUN=4. Being SUN the acronym of standardization of uveitis nomenclature.

[0038] Figure 9 depicts the attenuation with different percentage of 1 ,2-Propanediol, with 5% PVA.

[0039] Figure 10 shows an illustration of a core-shell layer disposition of the consumable hydrogel. Fig. 10. a) Side view; Fig.10. b) Top view.

[0040] DETAILED DESCRIPTION OF THE INVENTION

[0041] In a first aspect, the invention refers to a consumable hydrogel for ultrasonic conduction that has at least one phase and wherein each phase comprises 3-10% of polyvinyl alcohol (P A) and 1-15% of 1.2 propanediol and water.

[0042] In a preferred embodiment, the water is MQ water. In the context of the present invention MQ water refers to MilliQ - water, which is a water purified using a Millipore Milli-Q lab water system, as generally known in the state of art. In the context of the present invention, the room temperature is between 20-22°C, preferably 21 °C.

[0043] In the context of the present invention, the term “phase” it is also referred as “layer”.

[0044] In the context of the present invention, the consumable hydrogel for ultrasonic conduction that has one phase or layer it is also referred as one-phase consumable hydrogel.

[0045] In a preferred embodiment, the consumable hydrogel for ultrasonic conduction comprises at least two phases or layers which means that the consumable hydrogel comprises N+1 layers and N is at least 1 .

[0046] Therefore, in a preferred embodiment, the consumable hydrogel object of the invention is multiphasic or multi-layered consumable hydrogel.

[0047] Furthermore, in the embodiment wherein the hydrogel comprises N+1 layers, the composition of each layer is different from the other layers, which in the context of the present invention means that the amount of PVA and 1 .2 propanediol that comprises each layer is different from the other layer of the consumable object of the invention.

[0048] In a particular embodiment, the consumable hydrogel comprises the polyvinyl alcohol (PVA). In a preferred embodiment, the PVA has a medium molecular weight between Mw 130,000 to Mw 145,000. In another preferred embodiment, the PVA is a very high hydrolyzed. Therefore, the PVA is at least 95% hydrolyzed, in order to guarantee the most efficient physical crosslink possible. In a preferred embodiment, the PVA is from 95 to 99% hydrolyzed. In a more preferred embodiment, the PVA is 95%, 96%, 97%, 98% or 99% hydrolyzed.

[0049] In an embodiment of the invention, the consumable hydrogel of more than one layer comprises a horizontal, vertical or core-shell layer disposition.

[0050] In the context of the present invention, the horizontal disposition refers to a disposition of the layer parallel to a horizontal axis. Additionally, in a preferred embodiment, this horizontal disposition has a ± 10% of inclination in respect to the horizontal axis.

[0051] In the context of the present invention, the vertical disposition refers to a disposition of the layer which has a 90° (± 10%) of inclination in respect to the horizontal axis.

[0052] In the context of the present invention, the core-shell layer disposition refers to a consumable hydrogel that comprises a core, and at least one additional layer surrounding the core.

[0053] In a preferred embodiment, the at least one layer of the consumable hydrogel comprises 3- 10% of PVA. In a preferred embodiment, the at least one layer of the consumable hydrogel comprises 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.

[0054] In a particular embodiment, the consumable hydrogel comprises in each phase propylene glycol (1 ,2-propanediol) commonly employed in various pharmaceutical preparations as a humectant, solvent or cosolvent, and preservative. It is usually considered to be a noncorrosive and comparatively non-toxic substance. It is also utilized widely in cosmetics and foods.

[0055] In a preferred embodiment, the at least one layer of the consumable hydrogel comprises 1- 15% of 1.2-propanediol. In a preferred embodiment, the at least one layer of the consumable hydrogel, comprises 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14% or 15% of 1.2-propanediol.

[0056] In a more preferred embodiment, the consumable hydrogel for ultrasonic conduction comprises: a first layer (L1) consisting of 3-4% PVA and 2-15% 1 .2 propanediol and water; and a second layer (L2) consisting of 5-10% PVA and 2-15% 1.2-propanediol and water. In the context of the present invention, the consumable hydrogel for ultrasonic conduction that has two phases, it is mentioned in this document as dual-phase consumable hydrogel. In a more preferred embodiment, the dual-phase consumable hydrogel comprises 40%- 60% (w / w) of the first layer and 40%-60% (w / w) of the second layer. In another embodiment, the volume ratio of L1 with respect to L2 is of 40%-60% (w / w).

[0057] This preferred embodiment wherein the consumable hydrogel comprises a first layer 1 (L1) and a second layer (L2), is depicted in Figure 2-2.

[0058] In a preferred embodiment of the invention, the dual-phase consumable hydrogel comprises 40%-60% (w / w) of the first layer (L1), more preferred 45 - 55% (w / w) of the first layer (L1). In another preferred embodiment, the dual-phase consumable hydrogel comprises 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% or 55% (w / w) of the first layer (L1).

[0059] In a preferred embodiment of the invention, the dual-phase consumable hydrogel comprises 40%-60% (w / w) of the second layer (L2), more preferred 45 - 55% (w / w) of the second layer (L2). In another preferred embodiment, the dual-phase consumable hydrogel comprises 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%, 53%, 54% or 55% (w / w) of the second layer (L2).

[0060] In a preferred embodiment, the second phase (L2) comprises 5-10% of PVA. In a preferred embodiment, the second layer (L2) comprises 5%, 6%, 7%, 8%, 9%, or 10% of PVA.

[0061] In a preferred embodiment, each phase of the consumable hydrogel, the first layer (L1) and the second layer (L2), comprises 1-10% of 1.2-propanediol. In a preferred embodiment, each phase of the consumable hydrogel, comprises 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of 1.2-propanediol.

[0062] The inventors have developed this dual-phase consumable hydrogel which its main advantages to be highlighted are a lower attenuation of the signal compared with a singlephase consumable hydrogel, while having a first layer (L1) to better adhere and couple with the different patient skin’s morphologies but also the stiffness of the second layer (L2) allowing to handle the dual-phase consumable easily.

[0063] By using this composition, the inventors found that the consumable hydrogel exhibits great flexibility and resistance, whence it enhances the acoustic coupling between the device and the patient body during the measurement performed by ultrasound. On the other hand, this hydrogel exhibits a low attenuation level, and consequently, excellent ultrasonic signal transmission capabilities.

[0064] Therefore, the consumable hydrogel comprises the following technical properties:

[0065] - it has a capacity of yielding more than 50% of deformation of the material allowing axial movement of the transducer when a compressive strength of less than 10N, preferably, between 3N - 7N, and more preferable between 4N to 6N is applied;

[0066] - has a high level of acoustic transmission allowing minimal acoustic energy losses. Proof of this, is that the inventors were able to verify that the hydrogel, according to the first aspect of the invention, has an acoustic energy loss between 0.02-0.07 dB / mm for 20MHz.

[0067] It is a second aspect of the invention the method for preparing the consumable hydrogel that comprises the following steps: i) mixing water with 1 ,2-Propanediol in a recipient; ii) adding PVA to the mixture of step i); iii) heating the mixture obtained in step ii) at a temperature between 90°C - 125°C; iv) cooling the solution obtained in step iii) to a temperature between 45°C to 80°C, and steering, to obtain a homogeneous solution; v) adding the solution obtained in step iv) into a template; vi) freezing the template at a temperature between -25°C to -20°C during 15-25 hours to obtain a frozen one-layer (L1) hydrogel.

[0068] In a more preferred embodiment, the method for preparing the consumable hydrogel that comprises the following steps: i) mixing MQ water with 1-15 wt. % of 1 ,2-Propanediol in a recipient for a period from 1 to 5 minutes, preferably 3 minutes, at a 100-500rpm, preferably at 250rpm; ii) adding 3-10 wt. % of PVA to the mixture obtained in the step i) and mixing for a period from 4 to 10 minutes, preferably 5 minutes, at a 100-500rpm, preferably at 250rpm; iii) heating the mixture obtained in step ii) at a temperature between 90°C - 125°C for period between 0,5 to 5 hours; iv) cooling the solution obtained in step iii) until a temperature between 45°C to 80°C, preferably 50°C in a hotplate and steering, for a period between 25 a 45 min, to obtain a homogeneous solution; v) adding the solution obtained in step iv) into the template; vi) freezing the template at a temperature between -25°C to -20°C during 15-25 hours to obtain a frozen one-layer (L1) hydrogel.

[0069] In a preferred embodiment, the method comprises a further step after step vi) of removing the template from the freezer and letting one-layer (L1) hydrogel thaw at room temperature for 30-45min.

[0070] In a more preferred embodiment, the method for preparing the consumable hydrogel comprises a further step of removing the one-layer (L1) hydrogel from the template.

[0071] In a preferred embodiment of the invention, when the consumable hydrogel comprises more than one layer, the method for preparing the consumable hydrogel comprises the following steps: i) providing a frozen one-layer (L1) hydrogel obtained by the method according to the second aspect of the invention, ii) injecting in the template on top of the one-layer hydrogel a mix consisting of 3- 10% of PVA and 1-15% of 1.2 propanediol and water to obtain a further hydrogel layer; iii) freezing the template at a temperature between -25°C to -20°C for a period of 15- 25 hours; wherein the added layer comprises a different amount of PVA and / or different amount of 1.2 propanediol than the previous layer to obtain a hydrogel with an additional layer (L2), and optionally, repeat this process to obtain hydrogels with Ln layers, wherein n is an integer over 2.

[0072] In a preferred embodiment, the method for preparing the consumable comprises a further step after step viii) of removing the template from the freezer consumable hydrogel thaw at room temperature for 30-45min.

[0073] In a more preferred embodiment, the method for preparing the consumable comprises a further step of removing the consumable hydrogel from the template.

[0074] In a preferred embodiment, the step iii) comprises heating the mixture obtained in step ii) by an autoclave at a temperature of 121°C for a period between 0.5 - 1 hour, preferably 0.5 hour. In another preferred embodiment, the step a-iii) and b-iii) comprises heating the mixture obtained in step ii) at a temperature between 90°C - 125°C, preferably 95°C-110°C and more preferably 95°C, and for a period between 3 - 6 hours, preferably 4-5 hours and more preferably 4 hours.

[0075] In a preferred embodiment, the mixtures obtained in steps i), ii), are performed by a magnetic steerer and a magnetic steerer bar and is removed from the recipient before the mixture is heated inside the autoclave.

[0076] In a particular embodiment, if bubbles appear on the solution obtained in step iii), the sub- the method comprises an additional step wherein the bubbles are removed from the solution obtained in step iii) by the use of a vacuum chamber.

[0077] In another preferred embodiment, the step iv) cooling the solution obtained in step iii) until a temperature between 50°C to 80°C, preferably 50°C is performed in a hotplate with steering until the a-i) solution is homogeneous.

[0078] In another aspect of the invention, the consumable hydrogel obtained by the method object of the invention is preserved until it is used by immersion in a container with an antimicrobial solution of 0.005% Chlorhexidine in MQ water at a temperature between 4°C to 10°C, more preferably, between 5°C to 8°C.

[0079] In the present invention, the dimensions of the consumable material can be adapted depending on the application for which it is to be used. The method of obtaining the consumable hydrogel would also allow, with the appropriate templates, to develop consumables with geometries that adapt to several ultrasonic transducer and chamber configurations.

[0080] Finally, another aspect of the present invention refers to the use of the hydrogel consumable for ultrasound conduction.

[0081] Furthermore, the present invention refers to the use of the consumable hydrogel as a coupling agent of an ultrasound medical device.

[0082] In a more preferred embodiment, the consumable hydrogel is used as coupling agent housed in a chamber of an ultrasound probe. In a more preferred embodiment, the consumable hydrogel is used as coupling agent in the ultrasound probe disclosed in the patent application P202330177.

[0083] The consumable hydrogel is arranged inside the chamber of the ultrasound medical device, allowing its position between the ultrasound transducer and a superficial body fluid of a target, during a measurement. In a preferred embodiment, the target refers to an individual, subject or patient whose treatment is monitored with the ultrasound medical device, the target being either a person, an animal, a recipient containing a sample or directly a sample.

[0084] In the scope of this invention, the term “superficial body fluid” refers to fluid of a target that is substantially transparent from the acoustic point of view for the ultrasonic waves, such that the concentration changes of the cells flowing within them are significant.

[0085] In a more preferred embodiment wherein the sample is a superficial body fluid selected from the group consisting of serous body fluid, urine and aqueous humour.

[0086] In a more preferred embodiment, the serous fluid is selected from the group consisting of cerebrospinal fluid, synovial fluid, peritoneal fluid, pericardial fluid, pleural fluid, amniotic fluid and aqueous humor.

[0087] In this way, the consumable hydrogel, is replaced for use in each patient, to guarantee consumable properties are optimal, the focal volume of the transducer will fall close or at the target volume, secure best acoustic coupling and sensitivity, and remove the risk of possible contamination from one patient to another. In a particular embodiment of the invention, the softer phase of the consumable hydrogel, which comprises the first layer (L1) that comprises 3-4% PVA and 1-10% 1.2 propanediol, is always in contact with the patient, to provide a better coupling, and the harder phase of the consumable hydrogel which comprises the second layer (L2) 5-10% PVA, 1-10% 1.2 propanediol, it is always in contact with the transducer, being more resistant to the constant linear or pivotal movement of the transducer.

[0088] In the context of the invention, the hydrogel consumable refers to a coupling material that fills the space between the ultrasound transducer and a target.

[0089] This fact has the extra advantage that allows extra reduction of signal attenuation since there is no fluid chamber wall (solid or film) in the signal pathway from the transducer to tissue. In addition, the use of conventional ultrasound gel is neither essential not detrimental given that the hydrogel consumable is the coupling medium itself.

[0090] In the context of the present invention, the target is an individual, subject or patient whose treatment is monitored with an ultrasound probe, the target being either a person, an animal, a recipient containing a sample or directly a sample.

[0091] The use of templates for the method for preparing the consumable hydrogel allows reproducibility of the consumable in different shapes, sizes and scalability of the production of it. In a preferred embodiment, the template used for preparing the consumable hydrogel has the shape of the chamber where the transducer of an ultrasound medical device is housed and therefore, the consumable is shaped such that it allows its placement within the chamber and in direct contact with the transducer, that may be mechanically moved, as a part of the medical device. This always provides, a perfect coupling of the consumable with the transducer. And the coupling with the skin of the patient will only happen when the user gently positions the medical device against in the area of interest.

[0092] In particular embodiments, the consumable hydrogel is removable and can be replaced after each use or measurement.

[0093] In a particular embodiment, the inventors have demonstrated that an improved coupling and lower attenuation are relevant to better see the cells, for example, in the case of Uveitis screening or treatment monitoring.

[0094] Thus, the consumable hydrogel is an advantageous alternative to other coupling material such as water that it usually used in the state of art, and therefore, avoids the use of fluids from spilling out of the chamber, reducing cross-contamination and ensuring proper performance.

[0095] The main advantages of the consumable hydrogel object of the invention and its use are: Better transmission of the signal reducing the reflection at interfaces;

[0096] Minimum absorption of energy: throughout the material, because 75-96% of the consumable is water; and no chamber wall is needed to prevent chamber fluid to spill out of the chamber since the coupling material is in direct contact with the target sample or tissue;

[0097] Higher deposition of energy on the tissue;

[0098] Minimum diffraction of the wave; Good mechanical coupling with the tissue avoiding the use of other standard ultrasound gels in contact with the tissue;

[0099] Clean and easy use;

[0100] Improves usability by avoiding having to fill with water and seal the cavity where the transducer is housed in each use, as the coupling material is solid and easy to handle.

[0101] No need to use a water chamber which may create air bubbles and cannot be compressed;

[0102] Eliminates the risk associated with having a watertight chamber full of water, which can generate water leaks damaging the electronics and I or the probe mechanism as well as disturbance of the patient;

[0103] Maintains both the ability to move the transducer axially and without losing coupling or offering resistance to the rotation of the mechanism, as it is an easily compressible and shape memory material.

[0104] The consumable hydrogel lasts longer than a commercially available ultrasound gels that tends to evaporate fast, requiring several additions of fresh ultrasound gel during their use in the transducer for at least 30min, since it is stable for that period of time;

[0105] The consumable is a solid material, preventing it to slip outside the chamber, which could possibly happen with the use of the common ultrasound gel that can slip to unwanted places, such as into the eyes of the patient during a measurement.

[0106] - The use of ultrasound coupling gel between the consumable and the target (e.g., human tissue) is not essential to accomplish a high-level of signal transmission to the target tissue / medium.

[0107] EXAMPLES

[0108] This invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope thereof.

[0109] Conclude about the performance of the dual-phase consumable in comparison with the single-phase consumable, to better visualize the polystyrene (PS) particles (pp).

[0110] Methods

[0111] It was tested:

[0112] • Fresh single-phase consumables of 3.5g of 5% wt. PVA and 5% wt. 1.2 propanediol and water, and

[0113] • Fresh dual-phase consumables comprising: o 50% of L1 : 1 ,75g of PVA (3% wt.) and 1 .2 Propanediol (5% wt.) and water; o 50% of L2: 1 ,75g of PVA (5% wt.) and 1 .2 Propanediol (5% wt.) and water.

[0114] These consumables were also tested, in vitro, by using a setup mimicking the eyelid, cornea and anterior chamber of an eye, created in house with a phantom. The phantom was used to mimic the human eyelid (attenuation 9,1 dB / cm) with cornea. The aqueous humour, with and without inflammation / infection (uveitis) present in the anterior chamber of the eye was replicated artificially with aqueous PS particles solutions of 0, 20, 50, 100 and 200 pp / pL. The PS beads mimic the cells that can be found in the anterior chamber of the eye in an inflammatory / infectious disease such as uveitis. Furthermore, to mimic the signal that comes from the lens, an artificial hydrogel was also created in house with 10% PVA.

[0115] In order to quantitatively assess the quality of the images under each condition, the mean signal value and the percentage of pixels with signal for every image was computed. To do so, all samples and control images were initially processed using the same pre-processing methods. A mean control image was generated for each experiment by calculating the mean value for each pixel over all the control images within each experiment. Then from all sample images it was subtracted the mean control for each corresponding pixel. Furthermore, a Sobel filter with a kernel of size 3 was applied. Next, the Sobel image was binarized using a specific lower threshold for each concentration in order to obtain a mask that allowed identifying and isolating the particle traces present in each image. Finally, the mean signal value was computed as the mean of the absolute value of the pixels in the subtracted image that were binarized using the mask and, thus, represent a particle trace.

[0116] The measurements were performed with a 20 MHz single-element piezoelectric transducer.

[0117] Furthermore, only if the acoustic impedances of the two media are identical can the transfer of ultrasonic energy be 100%. The energy reflected (ER) can be calculated as exemplified in equation (eq.) 1.

[0118] EQ.1 For such reason, the acoustic impedance (Z) was calculated for the hydrogels with 5% PVA + 5% 1.2-propanediol and for 3% PVA + 5% 1.2-propanediol. For these measurements, fresh hydrogels were prepared in triplicate for each condition with an added mass of hydrogel precursor of 6.5g inside a petri dish of 29 mm of diameter.

[0119] Equipment

[0120] In this study consumables of 3.5g were prepared with PVA (Sigma Aldrich, 563900-1 KG) and 1.2-propanediol (Sigma Aldrich, 82280-1 L). PS beads of 5pm (Merck, 79633-5ML-F) solutions were used to mimic the cells in the anterior chamber of the eye during an infection, like uveitis.

[0121] Results

[0122] The attenuation of 10 single-phase and 10 dual-phase consumables, freshly prepared are showed in Figure 5.

[0123] These attenuation values obtained for the single-phase and dual-phase with a mean value of 0.48 and 0.32 dB / cm, respectively, were expected since half of the dual-phase consumable is done with only 3% of PVA, so less polymer and more water are in the composition of this hydrogel, in comparison with the single-phase, and for such reason the attenuation was lower.

[0124] Furthermore, regarding the acoustic impedance results, once again, as expected the inventors obtained an impedance for the 3% PVA hydrogel (Zh-3 = 1.43 Kg / m2s) similar to the calculated water impedance in our conditions (Zw = 1.44 Kg / m2s) and lower, as expected, from the impedance of the 5% PVA hydrogel (Zh-5 = 1.50 Kg / m2s). Both hydrogels, contained 5% 1.2-propanediol.

[0125] As per below, in Figure 6, it is shown the results obtained when using a single-phase consumable or a dual-phase consumable to visualize the different PS solutions (20, 50, 100 and 200 pp / zL) under a phantom of 9,1 dB / cm of attenuation. In Figure 6, it is showed the results of the mean intensity values obtained from the PS particles.

[0126] As showed in Figure 6, the dual-phase consumable allowed to see the PS particles with higher intensity for all the different concentrations either at 42 or 48 dB of gain, with statistical significance, clearly indicating the advantage of using this consumable design to better detect particles in suspension, which may also relate with a better visualization of the cell in serous fluids in vivo.

[0127] Also, in accordance with the above mentioned, the percentage of pixels with signal increases, as expected, with the increase of the concentration of PS particles (Figure 7). Nevertheless, an increase of pixels with signal was appreciated when acquiring images with the dual-phase, indicating a better PS particle detection performance, than the single-phase consumable. The only exception is found with 20 pp / ^L, where there is no statistical difference between the single-phase and dual-phase consumable at 42 dB of gain. However, when at 48dB, and at 20 pp / ^L, the single-phase consumable has shown to better perform the dual-phase counterpart. A possible explanation for these results is the fact that at very low concentration as it is the case with 20 pp / / zL, the dual-phase despite making the PS particles more visible in terms of intensity (as shown in Figure 6) it also increases the noise in the area of interest, which at 48dB of gain it becomes even more relevant, which may hinder the observation of the few particles in suspension. However, at 42dB of gain, or at higher PS particles concentration it is no longer the case and the dual-phase matches or outperforms the single-phase consumable.

[0128] Conclusions

[0129] • The dual-phase consumable attenuated less that the single-phase with statistical significance determined by the Mann-Whitney U test.

[0130] • The acoustic impedance (Z) of a 3% PVA consumable (1.43 Kg / m2s) is very similar to the calculated water impedance in our conditions (1.44 Kg / m2s) and lower, as expected, from the 5% PVA hydrogel (1.50 Kg / m2s).

[0131] • The dual-phase in vitro allows to see the PS particles at different concentrations (20, 50, 100 and 200 pp / juL) with higher intensity.

[0132] • At 42 dB of gain, the dual-phase and the single-phase equally performs in detecting the number of particles for a concentration of 20 pp / / zL. However, for higher concentrations such as 50, 100 and 200 pp / / zL, the dual-phase consumable outperforms the single-phase consumable, detecting more particle traces, by pixels quantification.

[0133] • In vivo results, obtained with the dual-phase consumable, in uveitis patients clearly showed cells inside the anterior chamber of the eye. Remarkably, in one of the cases was impossible to detect these cells by the conventional state of the art methodology, the slit lamp, due to an ocular condition preventing the passage of light into the anterior chamber.

Claims

CLAIMS1 A consumable hydrogel for ultrasonic conduction characterized in that said hydrogel comprises at least one layer and wherein each layer consists of 3-10% of polyvinyl alcohol (PVA) and 1-15% of 1.2 propanediol and water.2.- The consumable hydrogel according to claim 1 , characterized in that said hydrogel comprises more than one layer and each layer optionally comprises a different amount of PVA and / or a different amount of 1.2 propanediol with respect to the other layers.3.- The consumable hydrogel according to claim 2, characterized in that said hydrogel comprises: a first layer (L1) consisting of 3-4% PVA and 2-15% 1 .2 propanediol and water; and a second layer (L2) consisting of 5-10% PVA and 2-15% 1.2-propanediol and water.4.- The consumable hydrogel according to claim 3, characterized in that a volume ratio of L1 with respect to L2 is of 40%-60% (w / w).5.- The consumable hydrogel according to any one of claims 1-4, wherein the PVA is at least 95% hydrolyzed.6.- The consumable hydrogel according to any one of claims 2-5, characterized in that said hydrogel of more than one layer comprises a horizontal, vertical or core-shell layer disposition.7.- A method for preparing the consumable hydrogel disclosed in claim 1 , comprising the following steps: i) mixing water with 1 ,2-Propanediol in a recipient; ii) adding PVA to the mixture of step i); iii) heating the mixture obtained in step ii) at a temperature between 90°C - 125°C; iv) cooling the solution obtained in step iii) to a temperature between 45°C to 80°C, and steering, to obtain a homogeneous solution; v) adding the solution obtained in step iv) into a template; vi) freezing the template at a temperature between -25°C to -20°C during 15-25 hours to obtain a frozen one-layer (L1) hydrogel.8.- A method for preparing the consumable hydrogel disclosed in any one of claims 2-5, comprising the following steps: i) providing a frozen one-layer (L1) hydrogel obtained by the method of claim 6, ii) injecting in the template on top of the one-layer hydrogel a mix consisting of 3- 10% of PVA and 1-15% of 1.2 propanediol and water to obtain a further hydrogel layer; iii) freezing the template at a temperature between -25°C to -20°C for a period of 15- 25 hours; wherein the added layer comprises a different amount of PVA and / or a different amount of 1.2 propanediol than the previous layer to obtain a hydrogel with an additional layer (L2), and optionally, repeat this process to obtain an hydrogel with Ln layers, wherein n is an integer over 2.9.- Use of the consumable hydrogel of any one of claims 1 - 6, for ultrasound conduction.10.- The use according to claim 9, as a coupling agent of an ultrasound medical device.11.- The use according to claim 9 or 10, wherein the consumable hydrogel is located between an ultrasound transducer and a target.12.- The use according to claim 11 , wherein the target is a person, an animal, a sample or a recipient containing a sample.13.- The use according to claim 12, wherein the sample is a superficial body fluid selected from the group consisting of serous body fluid, urine and aqueous humour.14.- The use according to claim 13, wherein the serous body fluid is selected from group consisting of cerebrospinal fluid, synovial fluid, peritoneal fluid, pericardial fluid, pleural fluid and amniotic fluid.

Images