Consumable hydrogels for ultrasound conduction, methods of obtaining and uses thereof

Abstract

In a first aspect, the invention relates to a consumable hydrogel for ultrasound conduction, characterized in that the hydrogel comprises at least one layer, and wherein each layer consists of 3-10% of polyvinyl alcohol (PVA) and 1-15% of 1, 2 propylene glycol and water. In a second aspect, the present invention relates to a process for the preparation of consumable hydrogels according to a first aspect of the present invention. Finally, the invention relates to the use of consumable hydrogels for ultrasound conduction and to the use of consumables as couplants for ultrasound medical devices.

Description

Technical Field

[0001] This invention belongs to the field of ultrasound equipment for medical diagnosis, triage, screening, and treatment monitoring, and more specifically to the field of hydrogel consumables for ultrasound conduction. Background Technology

[0002] Ultrasound is a longitudinal compression wave with a frequency greater than 20 kHz, which is useful for sample detection in the range of a few tenths of a MHz. Typically, ultrasonic equipment comprises a transducer or array of transducers that is acoustically in contact with the sample to be measured, and operates by generating an ultrasonic signal through the sample and then receiving reflected or backscattered signals containing information about the sample. Some systems, particularly unit transducer systems, are mechanized and involve the transducer displacing along a linear, pivoting, or circular trajectory to collect data from the volume of interest. However, in these systems, the transducer cannot directly contact the sample, as this could damage the transducer, and the collected data would be disrupted by friction between the moving transducer and the sample. For the proper operation of these systems, an aqueous medium is essential to allow the transducer to move freely and for the signal to propagate through the medium to the sample with reduced attenuation.

[0003] It is known in the art to use lenses for focusing in transducers. When attached to a planar transducer, lenses allow the acoustic beam to be focused; therefore, they cannot be considered coupling media because their use results in a loss of sensitivity due to large reflections at the interface between the transducer and lens materials. As a result, significant energy loss exists in the signal reaching the target volume, especially at high frequencies.

[0004] Furthermore, it is known that ultrasonic probes using a single transducer as a signal transmitter / receiver employ a fluid (typically water) as the means of signal propagation, immersing the transducer within a watertight chamber of the probe itself. In some configurations, the chamber walls are made of a solid material, and in others, a plastic membrane is used for the chamber or to seal it to prevent fluid leakage, while providing a very thin interface with low attenuation to the sample. Using a fluid as the coupling material has the following limitations:

[0005] - The risk associated with a fluid-filled waterproof chamber is that the fluid may leak, damaging not only the electronics and / or probe mechanism, but also the sample, or even worse, interfering with the patient; this risk is greatest when the transducer is displaced along the longitudinal axis (approaching and moving away from the target sample).

[0006] - The fluid is incompressible; this leads to an increase in pressure within the chamber during the transducer's longitudinal displacement, which challenges watertightness.

[0007] - The use of fluids leads to reflection and bubble problems, which are often associated with transducer scanning movement.

[0008] - To maintain fluid tightness, a solid material or plastic membrane is required, which leads to high signal loss at the interface between the fluid chamber and the sample; in fact, if a portion of the signal is to be transmitted to the target material (e.g., tissue), the ultrasound gel is still forced, thus creating another interface where the signal energy transmitted further is lost again; all of these losses are cumbersome if the interest is in small structures in the range of millimeters or micrometers (which often occurs when working at relatively high frequencies (e.g., greater than 10 MHz)).

[0009] In the prior art, patent CN107022161B relates to hydrogel materials for ultrasound conduction and their preparation methods, belonging to the technical field of hydrogel functional materials. The hydrogel material is made of polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, sodium polyacrylate, calcium chloride, tannin, nitrite, triethanolamine, polyethylene glycol, propylene glycol, and glycerin. However, the disclosed method for preparing the hydrogel involves the use of chemicals known to cause skin burns, such as phosphoric acid, which is therefore undesirable due to potential health risks upon contact with human tissue.

[0010] Furthermore, patent application CN101744761A describes a drug-loaded therapeutic ultrasound coupling gel, which belongs to the field of ultrasound therapy technology. The gel contains the following components in dosage percentages: 0.5-8% hydrophilic polymer material, 0.5-15% penetration enhancer, 2-10% humectant, 0.5-5% solubilizer, 0.5-5% conditioning agent, and water.

[0011] Patent application EP1671656A1 describes anhydrous biocompatible and bioexcretizable lubricants and ultrasonically coupled fluids or gels produced from formulations based on polyvinylpyrrolidone (PVP) and one or more diols and / or polyols (e.g., propylene glycol, glycerin, polyethylene glycol, and sorbitol).

[0012] Finally, patent application US2005074407A1 relates to biocompatible and bioexcretable lubricants and ultrasonically coupled fluids or gels containing a solution of polyvinylpyrrolidone and / or polyvinyl alcohol in water, to which a humectant (e.g., alkylene glycols and / or polyalkylene glycols) is added to achieve desired tactile and drying properties.

[0013] However, none of the aforementioned coupling materials solve the technical problem of maintaining the integrity of transmitted signals and energy through a moving unit transducer system. Such a solution must possess such high compressive strength that it allows deformation up to 50% of the material's maximum, thus permitting axial movement of the transducer, and importantly, it must have a high level of acoustic transmission properties to allow for minimal acoustic energy loss.

[0014] In this way, there is a need in this field for consumable materials that can be easily compressed, have shape memory and a high level of acoustic transmission, thereby allowing for minimal acoustic energy loss. Summary of the Invention

[0015] As outlined in the background section, a technical problem in the art is how to obtain consumable materials for mechanically driven ultrasonic transducers that are easily compressible and possess a high level of acoustic transmission. This problem is effectively solved by the present invention.

[0016] In a first aspect, the present invention relates to a consumable hydrogel for ultrasonic conduction, characterized in that the hydrogel comprises at least one layer, wherein each layer consists of 3-10% PVA and 1-15% 1,2-propylene glycol and water.

[0017] In the context of this invention, the term "consumable" refers to a hydrogel intended to be used up and then replaced. Therefore, this invention relates to consumable hydrogels for replacement within the chamber of an ultrasound device during each measurement, ensuring optimized consumable properties, that the transducer's focusing volume falls near or at the target volume, ensuring optimal acoustic coupling and sensitivity, and eliminating the risk of potential contamination from one target to another.

[0018] In the context of this invention, an ultrasound device is a means of measuring and quantifying circulating cells in a target superficial body fluid by means of high-frequency (e.g., ultrasound) transduction. This device can be used to detect circulating cells in an individual's body fluids without extracting a sample, and can be used as a screening, triage, and diagnostic tool, and for monitoring the effectiveness of treatments administered to individuals suffering from viral, protozoan, fungal, and / or bacterial diseases.

[0019] In the context of this invention, the term "phase" is also referred to as "layer".

[0020] In another preferred embodiment, the consumable hydrogel is a multiphase hydrogel consumable, meaning that it has one or more phases or layers whose compositions differ from each other.

[0021] 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-propylene glycol relative to the other layers.

[0022] In a second aspect, the present invention relates to a method for preparing the consumable hydrogel of the first aspect of the present invention.

[0023] In a third aspect, the present invention relates to the use of hydrogel consumables for ultrasonic conduction. Attached Figure Description

[0024] To complete the description and to better understand the invention, a set of accompanying drawings is provided. These drawings form an integral part of the specification and illustrate embodiments of the invention. They should not be construed as limiting the scope of the invention, but are merely examples of how the invention may be practiced. The drawings include the following figures:

[0025] Figure 1 A schematic diagram of consumable hydrogels with one layer and different sizes is shown: 1) 1.2g; 2) 3.5g; 3) 4.7g.

[0026] Figure 2 Schematic diagrams of two different types of consumable hydrogels are shown: 1) 3.5g monophase; 2) 3.5g biphase.

[0027] Figure 3 The image processing scheme used in this study is shown. Image A = original image; Image B = averaged control image; Image C = subtracted image; Image D = sobel image; and Image E = binarized image.

[0028] Figure 4 Schemes for experimental design were described to evaluate the performance of two consumables in compressing their size by more than 50% and fully recovering their shape over a time period of 1 to 10 seconds: (1) a single-phase and (2) a biphase 3.5 g consumable.

[0029] Figure 5 The decay results are shown. Decay (dB / cm) of consumables (hydrogels) with single-phase (left) and biphase (right) characteristics are presented. Statistical significance was determined by the Mann-Whitney U test. p<0.001).

[0030] Figure 6 shows the average signal intensities obtained using single-phase and two-phase consumables alone for different PS particle concentrations, such as A) 20 pp / μL, B) 50 pp / μL, C) 100 pp / μL, and D) 200 pp / μL (more than 75 images were used for each condition). Statistical significance was determined by the Mann-Whitney U test. p<0.001).

[0031] Figure 7 The percentage of pixels with signal is shown at different PS concentrations (average value is shown for each condition).

[0032] Figure 8 The original images of in vivo uveitis patients obtained in a proprietary image visualization application are shown. Measurements were performed on different patients with different SUN grades using a 20 MHz single-element piezoelectric transducer and 4.7 g of biphase consumables at a gain of 42 dB: 1) SUN = 0, 2) SUN = 0.5, 3) SUN = 1, 4) SUN = 2, and 5) SUN = 4. SUN is an abbreviation for the standardized nomenclature of uveitis.

[0033] Figure 9 The decay of 1,2-propanediol with different percentages was depicted, including 5% PVA.

[0034] Figure 10 shows a schematic diagram of the core-shell arrangement of the consumable hydrogel. Figure 10.a) Side view; Figure 10.b) Top view. Detailed Implementation

[0035] In a first aspect, the present invention relates to a consumable hydrogel for ultrasonic conduction having at least one phase, wherein each phase comprises 3-10% polyvinyl alcohol (PVA) and 1-15% 1,2-propylene glycol and water.

[0036] In a preferred embodiment, the water is MQ water. In the context of this invention, MQ water refers to MilliQ-water, which is water purified using the Millipore Milli-Q laboratory water system, as is generally known in the art. In the context of this invention, the room temperature is between 20-22°C, preferably 21°C.

[0037] In the context of this invention, the term "phase" is also referred to as "layer".

[0038] In the context of this invention, a consumable hydrogel for ultrasonic conduction having one phase or layer is also referred to as a one-phase consumable hydrogel.

[0039] In a preferred embodiment, the consumable hydrogel for ultrasound conduction comprises at least two phases or layers, meaning that the consumable hydrogel comprises N+1 layers and N is at least 1.

[0040] Therefore, in a preferred embodiment, the consumable hydrogel of the present invention is a multiphase or multilayer consumable hydrogel.

[0041] Furthermore, in embodiments where the hydrogel comprises N+1 layers, the composition of each layer differs from that of the other layers, which in the context of this invention means that the amount of PVA and 1,2-propylene glycol contained in each layer differs from that in other layers of the consumable object of this invention.

[0042] In certain embodiments, the consumable hydrogel comprises polyvinyl alcohol (PVA). In a preferred embodiment, the intermediate molecular weight of PVA is between Mw 130,000 and Mw 145,000. In another preferred embodiment, the PVA is highly hydrolyzed. Therefore, the PVA is hydrolyzed by at least 95% to ensure the most effective physical crosslinking possible. In a preferred embodiment, the PVA is hydrolyzed by 95-99%. In a more preferred embodiment, the PVA is hydrolyzed by 95%, 96%, 97%, 98%, or 99%.

[0043] In embodiments of the present invention, a consumable hydrogel with more than one layer comprises a horizontal, vertical, or core-shell layer arrangement.

[0044] In the context of this invention, a horizontal arrangement refers to an arrangement of layers parallel to a horizontal axis. Additionally, in a preferred embodiment, this horizontal arrangement has an inclination of ±10% relative to the horizontal axis.

[0045] In the context of this invention, vertical arrangement refers to an arrangement of layers having an inclination of 90° (±10%) relative to the horizontal axis.

[0046] In the context of this invention, a core-shell arrangement refers to a consumable hydrogel comprising a core and at least one additional layer surrounding the core.

[0047] In a preferred embodiment, at least one layer of the consumable hydrogel contains 3-10% PVA. In a preferred embodiment, at least one layer of the consumable hydrogel contains 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0048] In certain embodiments, the consumable hydrogel contains propylene glycol (1,2-propanediol) in each phase, which is commonly used in various pharmaceutical formulations as a humectant, solvent, or co-solvent and preservative. It is generally considered a non-corrosive and relatively non-toxic substance. It is also widely used in cosmetics and food.

[0049] In a preferred embodiment, at least one layer of the consumable hydrogel comprises 1-15% 1,2-propanediol. In a preferred embodiment, 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% 1,2-propanediol.

[0050] In a more preferred embodiment, the consumable hydrogel for ultrasound conduction comprises:

[0051] - The first layer (L1) consists of 3-4% PVA, 2-15% 1,2-propylene glycol, and water; and

[0052] - The second layer (L2) consists of 5-10% PVA and 2-15% 1,2-propanediol and water.

[0053] In the context of this invention, a consumable hydrogel having two phases for ultrasonic conduction is referred to herein as a biphase consumable hydrogel. In a more preferred embodiment, the biphase consumable hydrogel comprises 40%-60% (w / w) of a first layer and 40%-60% (w / w) of a second layer. In another embodiment, the volume ratio of L1 to L2 is 40%-60% (w / w).

[0054] Figure 2-2 The preferred embodiment of the consumable hydrogel is described in which the consumable hydrogel comprises a first layer 1 (L1) and a second layer (L2).

[0055] In a preferred embodiment of the invention, the biphasic consumable hydrogel comprises 40%-60% (w / w) of a first layer (L1), more preferably 45-55% (w / w) of a first layer (L1). In another preferred embodiment, the biphasic consumable hydrogel comprises 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, or 55% (w / w) of a first layer (L1).

[0056] In a preferred embodiment of the invention, the biphasic consumable hydrogel comprises 40%-60% (w / w) of a second layer (L2), more preferably 45-55% (w / w) of a second layer (L2). In another preferred embodiment, the biphasic consumable hydrogel comprises 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, or 55% (w / w) of a second layer (L2).

[0057] In a preferred embodiment, the second phase (L2) contains 5-10% PVA. In a preferred embodiment, the second layer (L2) contains 5%, 6%, 7%, 8%, 9%, or 10% PVA.

[0058] In a preferred embodiment, each phase of the consumable hydrogel, the first layer (L1) and the second layer (L2), contains 1-10% 1,2-propanediol. In a preferred embodiment, each phase of the consumable hydrogel contains 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% 1,2-propanediol.

[0059] The inventors have developed this biphasic consumable hydrogel, whose main advantages to be highlighted are lower signal attenuation compared to monophasic consumable hydrogels, while having a first layer (L1) for better adhesion and coupling to different patient skin morphologies, but also having the stiffness of a second layer (L2) to allow for easy handling of biphasic consumables.

[0060] By using this composition, the inventors discovered that the consumable hydrogel exhibits good flexibility and resistance, thereby enhancing the acoustic coupling between the device and the patient's body during ultrasound measurements. Furthermore, the hydrogel exhibits a low attenuation level and therefore demonstrates excellent ultrasound signal transmission capabilities.

[0061] Therefore, consumable hydrogels possess the following technical properties:

[0062] - When a compressive strength of less than 10 N, preferably between 3 N and 7 N, and more preferably between 4 N and 6 N is applied, it has the ability to produce more than 50% material deformation, thereby allowing axial movement of the transducer;

[0063] - It exhibits a high level of acoustic transmission, allowing for minimal acoustic energy loss. This is evidenced by the inventors' ability to demonstrate that the hydrogel according to the first aspect of the invention has an acoustic energy loss of 0.02-0.07 dB / mm at 20 MHz.

[0064] A second aspect of the present invention is a method for preparing consumable hydrogels, comprising the following steps:

[0065] i) Mix water with 1,2-propanediol in the receiver;

[0066] ii) Add PVA to the mixture from step i);

[0067] iii) Heating the mixture obtained in step ii) at a temperature between 90°C and 125°C;

[0068] iv) Cool the solution obtained in step iii) to a temperature between 45°C and 80°C and stir to obtain a homogeneous solution;

[0069] v) Add the solution obtained in step iv) to the template;

[0070] vi) Freeze the template at a temperature between -25°C and -20°C for 15-25 hours to obtain a frozen one-layer (L1) hydrogel.

[0071] In a more preferred embodiment, the method for preparing a consumable hydrogel includes the following steps:

[0072] i) Mix MQ water with 1-15% by weight of 1,2-propanediol in a receiver at 100-500 rpm, preferably 250 rpm, for 1 to 5 minutes, preferably 3 minutes.

[0073] ii) Add 3-10% by weight of PVA to the mixture obtained in step i) and mix at 100-500 rpm, preferably 250 rpm, for 4 to 10 minutes, preferably 5 minutes;

[0074] iii) Heat the mixture obtained in step ii) at a temperature between 90°C and 125°C for 0.5 to 5 hours;

[0075] iv) Cool the solution obtained in step iii) on a hot plate to a temperature between 45°C and 80°C, preferably 50°C, and stir for 25 to 45 minutes to obtain a homogeneous solution;

[0076] v) Add the solution obtained in step iv) to the template;

[0077] vi) Freeze the template at a temperature between -25°C and -20°C for 15-25 hours to obtain a frozen one-layer (L1) hydrogel.

[0078] In a preferred embodiment, the method includes an additional step following step vi), namely, removing the template from the freezer and allowing a layer (L1) of hydrogel to thaw at room temperature for 30-45 minutes.

[0079] In a more preferred embodiment, the method for preparing the consumable hydrogel includes an additional step of removing a layer (L1) of hydrogel from the template.

[0080] In a preferred embodiment of the present invention, when the consumable hydrogel comprises more than one layer, the method for preparing the consumable hydrogel includes the following steps:

[0081] i) Provide a frozen one-layer (L1) hydrogel obtained by the method according to the second aspect of the invention,

[0082] ii) Inject a mixture of 3-10% PVA and 1-15% 1,2-propylene glycol and water into a template on top of a layer of hydrogel to obtain an additional hydrogel layer;

[0083] iii) Freeze the template at a temperature between -25°C and -20°C for 15-25 hours;

[0084] The added layer contains a different amount of PVA and / or a different amount of 1,2-propylene glycol than the preceding layer to obtain a hydrogel with an additional layer (L2), and

[0085] Optionally, the process can be repeated to obtain a hydrogel with Ln layers, where n is an integer greater than 2.

[0086] In a preferred embodiment, the method for preparing the consumable includes an additional step after step viii), namely, removing the template consumable hydrogel from the freezer and thawing it at room temperature for 30-45 minutes.

[0087] In a more preferred embodiment, the method for preparing the consumable includes an additional step of removing the consumable hydrogel from the template.

[0088] In a preferred embodiment, step iii) comprises heating the mixture obtained in step ii) in a pressure vessel at a temperature of 121°C for 0.5-1 hour, preferably 0.5 hours. In another preferred embodiment, steps a-iii) and b-iii) comprise heating the mixture obtained in step ii) at a temperature between 90°C and 125°C, preferably 95°C-110°C, and more preferably 95°C, for 3-6 hours, preferably 4-5 hours, and more preferably 4 hours.

[0089] In a preferred embodiment, the mixture obtained in steps i) and ii) is processed by a magnetic stirrer and a magnetic stirring rod and removed from the receiver, after which the mixture is heated in a pressure vessel.

[0090] In a particular embodiment, if bubbles appear on the solution obtained in step iii), the method includes an additional step in which the bubbles are removed from the solution obtained in step iii) by using a vacuum chamber.

[0091] In another preferred embodiment, step iv) is performed on a hot plate to cool the solution obtained in step iii) to a temperature between 50°C and 80°C, preferably 50°C, and the solution is stirred until ai) the solution is homogeneous.

[0092] In another aspect of the invention, the consumable hydrogel obtained by the method of the invention is preserved before use by immersing it in a container having an antimicrobial solution of 0.005% chlorhexidine in MQ water at a temperature between 4°C and 10°C, more preferably between 5°C and 8°C.

[0093] In this invention, the size of the consumable material can be adapted to the application in which it is to be used. The method for obtaining the consumable hydrogel will also allow for the development of consumables with geometries adapted to a variety of ultrasonic transducer and chamber configurations by using appropriate templates.

[0094] Finally, another aspect of the invention relates to the use of hydrogel consumables for ultrasonic conduction.

[0095] Furthermore, this invention relates to the use of consumable hydrogels as coupling agents in ultrasound medical devices.

[0096] In a more preferred embodiment, the consumable hydrogel is used as a coupling agent housed within the chamber of the ultrasound probe. In an even more preferred embodiment, the consumable hydrogel is used as a coupling agent in the ultrasound probe disclosed in patent application P202330177.

[0097] A consumable hydrogel is disposed within the chamber of an ultrasound medical device, allowing it to reside between the ultrasound transducer and the superficial bodily fluid of the target during measurement. In a preferred embodiment, the target refers to an individual, subject, or patient whose treatment is being monitored by the ultrasound medical device; the target may be a human, animal, a receiver containing a sample, or the sample itself.

[0098] Within the scope of this invention, the term "superficial body fluid" refers to a fluid of a target that is substantially transparent from an ultrasonic acoustic point of view, such that the concentration of cells flowing therein varies significantly.

[0099] In a more preferred embodiment, the sample is a superficial body fluid selected from serous fluids, urine, and aqueous humor.

[0100] In a more preferred embodiment, the serous fluid is selected from cerebrospinal fluid, synovial fluid, peritoneal fluid, pericardial fluid, pleural fluid, amniotic fluid, and aqueous humor.

[0101] In this way, the consumable hydrogel is replaced for each patient to ensure optimized consumable properties, the transducer's focusing volume will fall near or at the target volume, ensuring optimal acoustic coupling and sensitivity, and eliminating the risk of potential contamination from one patient to another. In a particular embodiment of the invention, the softer phase of the consumable hydrogel, which is always in contact with the patient to provide better coupling, comprises a first layer (L1) containing 3-4% PVA and 1-10% 1,2-propylene glycol, and the harder phase of the consumable hydrogel, which is always in contact with the transducer and more resistant to constant linearity or pivoting movement of the transducer, comprises a second layer (L2) containing 5-10% PVA and 1-10% 1,2-propylene glycol.

[0102] In the context of this invention, hydrogel consumables refer to coupling materials that fill the space between an ultrasonic transducer and a target.

[0103] This fact has the added advantage of allowing for a further reduction in signal attenuation, since there are no fluid chamber walls (solid or membrane) in the signal path from the transducer to the tissue. Furthermore, since the hydrogel consumable itself is the coupling medium, the use of conventional ultrasound gel is neither necessary nor harmful.

[0104] In the context of this invention, "target" refers to an individual, subject, or patient being monitored by an ultrasound probe, and the target may be a person, animal, receiver containing a sample, or the sample itself.

[0105] The use of templates in the method for preparing consumable hydrogels allows for the reproducibility of consumables in different shapes, sizes, and with scalability in their production. In a preferred embodiment, the template for preparing the consumable hydrogel has the shape of a chamber that accommodates a transducer of an ultrasound medical device, and thus the consumable is shaped to allow it to be placed within the chamber and in direct contact with the transducer, which is mechanically movable as part of the medical device. This always provides perfect coupling between the consumable and the transducer. Furthermore, coupling with the patient's skin will only occur when the user gently positions the medical device over the region of interest.

[0106] In certain implementations, the consumable hydrogel is removable and can be replaced after each use or measurement.

[0107] In certain embodiments, the inventors have demonstrated that improved coupling and lower attenuation are relevant for better cell observation, for example, in uveitis screening or treatment monitoring.

[0108] Therefore, consumable hydrogels are an advantageous alternative to other coupling materials (such as water, which is typically used in the prior art), and thus avoid the use of fluids that overflow from the chamber, reduce cross-contamination, and ensure proper performance.

[0109] The main advantages of the consumable hydrogel objects and their uses of the present invention are:

[0110] - Better signal transmission, reduced reflections at the interface;

[0111] - Minimal energy absorption: throughout the material, since 75-96% of the consumable is water; and no chamber walls are needed to prevent chamber fluid from overflowing, as the coupling material is in direct contact with the target sample or tissue;

[0112] - Higher energy deposition in the tissue;

[0113] -Minimum wave diffraction;

[0114] - It has good mechanical coupling with tissues, avoiding the use of other standard ultrasound gels that come into contact with tissues;

[0115] - Clean and easy to use;

[0116] Usability is improved by avoiding the need to fill and seal the cavity housing the transducer with water every time it is used, since the coupling material is solid and easy to handle.

[0117] - It does not require the use of a water chamber that can generate air bubbles and cannot be compressed;

[0118] - Eliminates the risks associated with watertight chambers filled with water, which can leak and damage electronics and / or probe mechanisms, as well as interfere with the patient;

[0119] - It maintains the ability to move the transducer axially without losing coupling or providing tolerance to the rotation of the mechanism because it is a material that is easily compressed and has shape memory properties.

[0120] - Consumable hydrogels last longer than commercially available ultrasonic gels, which tend to evaporate rapidly, requiring multiple additions of fresh ultrasonic gel during at least 30 minutes of use in a transducer, as they are stable during that time period.

[0121] - Consumables are made of solid material to prevent them from slipping out of the chamber, which can happen when using common ultrasound gels that can slip into unwanted places, such as into a patient's eye during a measurement.

[0122] - Using ultrasound coupling gel between consumables and targets (e.g., human tissue) is not necessary to achieve high levels of signal transmission to the target tissue / medium.

[0123] Example

[0124] The invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention in any way.

[0125] Example 1:

[0126] Purpose

[0127] The performance of dual-phase consumables compared to single-phase consumables is summarized to better visualize polystyrene (PS) granules (pp).

[0128] method

[0129] Tested:

[0130] 3.5g of fresh single-phase consumable consisting of 5% PVA, 5% 1,2% propylene glycol, and water.

[0131] Fresh biphasic consumables, which include:

[0132] 50% L1: 1.75 g of PVA (3 wt%) and 1,2 propylene glycol (5 wt%) and water;

[0133] 50% L2: 1.75 g PVA (5 wt%) and 1,2-propylene glycol (5 wt%) and water.

[0134] These consumables were also tested in vitro using a device that mimics the eyelids, cornea, and anterior chamber of the eye, created internally with phantoms. The phantoms were used to mimic human eyelids with a cornea (attenuation 9.1 dB / cm). Aqueous humor present in the anterior chamber of the eye, both with and without inflammation / infection (uveitis), was artificially replicated using aqueous solutions of 0, 20, 50, 100, and 200 pp / μL of aqueous PS beads. The PS beads mimic cells found in the anterior chamber of the eye in inflammatory / infectious diseases such as uveitis. Furthermore, an artificial hydrogel was created internally with 10% PVA to mimic signals from the lens.

[0135] To quantitatively evaluate image quality under each condition, the average signal value and the percentage of pixels with the signal were calculated for each image. For this purpose, all sample and control images were initially processed using the same preprocessing method. An average control image was generated for each experiment by calculating the average of each pixel in all control images for each experiment. The average control image was then subtracted from all sample images for each corresponding pixel. Furthermore, a Sobel filter with a kernel size of 3 was applied. Next, the Sobel images were binarized using a specific lower threshold for each concentration to obtain a mask that allowed for the identification and isolation of particle trajectories present in each image. Finally, the average signal value was calculated as the average of the absolute values ​​of the pixels in the subtracted images binarized using the mask, and thus represents the particle trajectory.

[0136] Measurements were performed using a 20 MHz unit piezoelectric transducer.

[0137] Furthermore, ultrasonic energy transfer is 100% only when the acoustic impedances of the two media are the same. The reflected energy (ER) can be calculated as shown in Equation (eq.) 1.

[0138] EQ.1

[0139] For this reason, the acoustic impedance (Z) of hydrogels with 5% PVA + 5% 1,2-propanediol and 3% PVA + 5% 1,2-propanediol was calculated. For these measurements, fresh hydrogels were prepared in triplicate in 29 mm diameter petri dishes with an added mass of 6.5 g of the hydrogel precursor for each condition.

[0140] equipment

[0141] In this study, 3.5 g of consumables were prepared using PVA (Sigma Aldrich, 563900-1KG) and 1,2-propanediol (Sigma Aldrich, 82280-1L). A solution of 5 μm PS beads (Merck, 79633-5ML-F) was used to mimic cells in the anterior chamber of the eye during infections such as uveitis.

[0142] result

[0143] Figure 5 The degradation of 10 freshly prepared single-phase consumables and 10 two-phase consumables is shown in the figure.

[0144] These attenuation values ​​(average values ​​of 0.48 dB / cm and 0.32 dB / cm, respectively) obtained for the monophase and biphase are expected, since half of the biphase consumables are made with only 3% PVA, and therefore the hydrogel has less polymer and more water in its composition compared to the monophase, and for this reason, the attenuation is lower.

[0145] Furthermore, regarding the acoustic impedance results, once again as expected, the inventors obtained the water impedance calculated under our conditions (Zw = 1.44 kg / m). 2 The impedance of the s) hydrogel is similar and, as expected, lower than that of the 5% PVA hydrogel (Zh-5 = 1.50 kg / m). 2 The impedance of 3% PVA hydrogel (Zh-3 = 1.43 kg / m) 2 Both hydrogels contain 5% 1,2-propanediol.

[0146] As described below, Figure 6 shows the results obtained when using single-phase or two-phase consumables to visualize different PS solutions (20, 50, 100, and 200 pp / μL) at a phantom decay of 9.1 dB / cm. Figure 6 also shows the results for the average intensity values ​​obtained from the PS particles.

[0147] As shown in Figure 6, for all different concentrations, whether at a gain of 42 dB or 48 dB, the biphasic consumable allows PS particles to be seen with greater intensity, which is statistically significant and clearly demonstrates the advantages of using this consumable design for better detection of particles in suspensions. This may also be related to better visualization of cells in serous fluids in vivo.

[0148] Furthermore, as described above, with the increase of PS particle concentration, the percentage of pixels with signal increases as expected. Figure 7 However, when images were acquired using the biphase consumable, an increase in the number of pixels with a signal was observed, indicating better PS particle detection performance than the monophase consumable. The only exception was at 20 pp / μL, where there was no statistically significant difference between the monophase and biphase consumables at a gain of 42 dB. However, at 48 dB and 20 pp / μL, the monophase consumable showed superiority over the biphase consumable. A possible explanation for these results is that at very low concentrations, such as 20 pp / μL, while the biphase makes PS particles more visible in terms of intensity (as shown in Figure 6), it also increases noise in the region of interest, which becomes even more relevant at a gain of 48 dB, potentially hindering the observation of small amounts of particles in the suspension. However, this is no longer the case at a gain of 42 dB or at higher PS particle concentrations, and the biphase consumable matches or outperforms the monophase consumable.

[0149] in conclusion

[0150] The attenuation of biphase consumables is less than that of monophase consumables, which is statistically significant as determined by the Mann-Whitney U test.

[0151] The acoustic impedance (Z) of the 3% PVA consumable (1.43 kg / m²s) is very similar to the calculated water impedance (1.44 kg / m²s) under our conditions, and is as expected lower than that of the 5% PVA hydrogel (1.50 kg / m²s).

[0152] Biphasic in vitro observations at different concentrations (20, 50, 100, and 200 pp / μL) allowed for the observation of PS particles with higher intensity.

[0153] At a gain of 42 dB, both biphase and monophase consumables performed similarly in detecting particle numbers at a concentration of 20 pp / μL. However, for higher concentrations, such as 50, 100, and 200 pp / μL, the biphase consumable outperformed the monophase consumable, detecting more particle trajectories through pixel quantization.

[0154] In vivo results obtained using biphasic consumables in patients with uveitis clearly showed the cells within the anterior chamber of the eye. It is noteworthy that in one case, due to ocular conditions that prevent light from entering the anterior chamber, these cells could not be detected using conventional, existing techniques (slit-lamp).

Claims

1. A consumable hydrogel for ultrasound conduction, characterized in that, The hydrogel comprises at least one layer and wherein each layer consists of 3-10% polyvinyl alcohol (PVA) and 1-15% 1.2 propanediol and water.

2. The consumable hydrogel of claim 1, wherein, The hydrogel comprises more than one layer and each layer optionally comprises different amounts of PVA and / or different amounts of 1.2 propanediol relative to the other layers.

3. The consumable hydrogel of claim 2, wherein, The 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 of claim 3, wherein, The volume ratio of L1 to L2 is 40-60% (w / w).

5. The consumable hydrogel according to any one of claims 1-4, wherein the PVA is hydrolyzed at least 95%.

6. The consumable hydrogel according to any one of claims 2-5, wherein, The hydrogel of more than one layer comprises horizontal, vertical or core-shell layer arrangement.

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 receptacle; ii) adding PVA to the mixture of step i); iii) heating the mixture obtained in step ii) at a temperature between 90-125°C; iv) cooling the solution obtained in step iii) to a temperature between 45-80°C and stirring to obtain a homogenous solution; v) adding the solution obtained in step iv) to a mold; vi) freezing the mold at a temperature between -25 to -20°C for 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 a mixture consisting of 3-10% PVA and 1-15% 1.2 propanediol and water in a mold on top of the one layer hydrogel to obtain an additional hydrogel layer; iii) freezing the mold at a temperature between -25 to -20°C for 15-25 hours; wherein the added layer comprises different amounts of PVA and / or different amounts of 1.2 propanediol than the previous layer to obtain a hydrogel with an additional layer (L2), and optionally, repeating the process to obtain a hydrogel with Ln layers, wherein n is an integer greater than 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 couplant for an ultrasound medical device.

11. The use according to claim 9 or 10, wherein the consumable hydrogel is positioned between an ultrasound transducer and a target.

12. The use according to claim 11, wherein the target is a human, an animal, a sample or a receptacle 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 fluids, urine and aqueous humor.

14. The use according to claim 13, wherein the serous body fluid is selected from the group consisting of cerebrospinal fluid, synovial fluid, peritoneal fluid, pericardial fluid, pleural fluid and amniotic fluid.

Images