A flexible, stretchable, adhesive multilayered gel pad displaying self-healing capacity and ultrasound transparency

Abstract

The present disclosure relates to a multilayered gel pad comprising a first layer having a first surface that is non-adherent to patient tissue; and a second layer having a second surface that is adapted to be adherent to a target surface; wherein the first and second surface are on opposite outer sides of the gel pad and wherein the first layer is self-healing to the second layer.

Description

[0001] A flexible, stretchable, adhesive multilayered gel pad displaying self-healing capacity and ultrasound transparency

[0002] Technical field

[0003] The present disclosure relates to a flexible, stretchable, adhesive multi-layered gel pad displaying self-healing properties and ultrasound transparency, and methods of manufacturing such gel pad.

[0004] Background

[0005] Ultrasound imaging is one of the most commonly used imaging techniques for diagnostic purposes. It uses high-frequency sound waves to create images and is a non-invasive and safe tool used in various medical specialties. Ultrasound imaging has the advantage of being painless and does not involve ionizing radiation, making it a preferred choice for many diagnostic and monitoring purposes. The effectiveness is influenced by factors such as the patient's body habitus, the operator's skill and the presence of air between the transducer and the tissue.

[0006] Since air has a much lower acoustic impedance than tissue, it can result in significant signal distortion when ultrasound waves encounter air. When ultrasound waves encounter air bubbles inside the liquid gel or a gel pad, they create strong echoes, which can obscure structures located deeper in the tissue. This shadowing effect can make it difficult to visualize and accurately assess tissues or organs beyond the air bubbles.

[0007] Air bubbles can produce artifacts in the ultrasound images, such as comet tail artifacts, which are bright streaks extending from the air bubble, which could lead to misinterpretation of the image. To minimize these issues, it is essential to ensure that there are no air bubbles trapped between the transducer and the tissue. Applying gel between the transducer and the tissue is the standard way of avoiding introducing air. Irregular surfaces, such as the knuckles of a hand or joints affected by arthritis are inheritably difficult to image and require skill and a sufficient amount of gel.

[0008] Acoustic impedance mismatch can contribute to poor image quality in ultrasound imaging. Acoustic impedance is a measure of how resistant a material is to the passage of sound waves, and it plays a critical role in ultrasound imaging. When ultrasound waves travel through the body, they encounter different tissues, structures, air and gel with varying acoustic impedance values. When ultrasound waves encounter a tissue interface with a significant acoustic impedance mismatch, such as between soft tissue and bone or air, some of the ultrasound waves are reflected back to the transducer, and some waves may be redirected in different directions. This creates artifacts and reduces the clarity of the image. Acoustic impedance mismatches can also lead to shadowing and attenuation of ultrasound waves, it can create areas of increased brightness or darkness on the image, making it challenging to visualize structures beyond the mismatched area.

[0009] Hence, it is necessary to minimize the reflection caused by the interfaces, by having a gel composition with an acoustic impedance which is close to that of the tissue to be imaged.

[0010] Ultrasound imaging currently requires highly trained staff to be present during the whole procedure. This is not always possible or desired to the extent that is required. Performing ultrasound examinations can be physically demanding, especially when scanning for extended periods. Robotic systems can help reduce operator fatigue and enhance ergonomics by taking over some of the manual tasks, such as holding and manipulating the ultrasound transducer. Robots can further provide precise and consistent control over the ultrasound transducer, which can help improve the quality and accuracy of ultrasound images. This is particularly beneficial for procedures that require a high level of precision.

[0011] Another advantage of robotic ultrasound systems is that they can be operated remotely. Which could be particularly useful in situations where an expert ultrasound operator is not physically present with the patient, such as in rural or underserved areas. Additionally, automated imaging could be used to reduce close physical contact between the operator and the patient during the imaging, which otherwise can be a problem, especially if the patient suffers from a contagious disease.

[0012] There is consequently a clear need to automate the ultrasound imaging process. However, applying the right amount of liquid gel in an even layer onto a patient requires skill and knowledge about imaging technique and the limitations of an ultrasound transducer. These are features that are difficult to automate. Further, imaging irregular surfaces, such as the knuckles of a hand or joints affected by arthritis, normally requires plenty of gel and that the ultrasound transducer is pushed hard against the tissue to achieve full contact in order to acquire good quality images. This can cause severe discomfort for the patient and alternatives would be beneficial.

[0013] Thus, there is a need for an ultrasound composition that functions on irregular surfaces, such as the knuckles of a hand, which can easily be attached and removed from to the transducer.

[0014] Summary

[0015] The present inventors have surprisingly realized that a multilayered gel pad having a first surface that is non-adherent to patient tissue, and a second surface that is adapted to be adherent to a target surface can advantageously be used to address the shortcomings of the gel pads of the prior art.

[0016] Thus, in a first aspect, the present disclosure relates to a multilayered gel pad comprising:

[0017] • a first layer having a first surface that is configured to be non-adherent to patient tissue, the first layer comprising:

[0018] - a first polymer comprising a repeating first subunit containing an amide group; and

[0019] - a second polymer comprising a repeating second subunit containing an aldehyde group;

[0020] • a second layer having a second surface that is configured to be adherent to a target surface, the second layer comprising:

[0021] - the first polymer;

[0022] - the second polymer; and

[0023] - a third polymer comprising a repeating second subunit containing an aldehyde group, an amine group and a phenolic group; wherein the first surface and the second surface are on opposite outer sides of the gel pad, and wherein the first layer and the second layer have self-healing properties. The third polymer in the second layer can be chosen from a variety of polymers that are functionalized with appropriate components to meet the defined structural and functional properties. For instance, the third polymer may be oxidized alginate functionalized with dopamine, or alternatively, it could be chitosan functionalized with dopamine. Other suitable examples include oxidized alginate functionalized with tyramine, hyaluronic acid functionalized with catechol, or silk fibroin functionalized with dopamine. Further variations may involve oxidized pectin functionalized with catechol, chitosan functionalized with catechol, alginate functionalized with caffeic acid, or pectin functionalized with dopamine. Additionally, oxidized hyaluronic acid functionalized with catechol can be used. These combinations provide a third polymer with repeating subunits containing aldehyde groups, amine groups, and a phenolic group.

[0024] In one example, the phenolic group of the third polymer is a catechol group, a pyrogallol group or a hydroquinone group, depending on the functionalization approach. Other possible phenolic groups for the third polymer include resorcinol, dopamine, or caffeic acid, each providing the necessary phenolic structure to support the gel’s adhesive and self-healing properties.

[0025] In certain embodiments, the third polymer is a functionalized base polymer. The base polymer may be selected from a range of biocompatible materials, including oxidized alginate, alginate, chitosan, oxidized chitosan, pectin, oxidized pectin, silk, oxidized silk, methacrylated silk, methacrylated alginate, keratin, aminated keratin, methacrylated keratin, methacrylated pectin, methacrylated chitosan, or aminated chitosan. Functionalization of the base polymers can be achieved by the introduction of the phenolic group.

[0026] In one example, the present disclosure relates to a multilayered gel pad, the multilayered gel pad comprising a first layer having a first surface that is non-adhesive, for example to patient tissue, and a second layer having a second surface that is adhesive to a target surface, wherein the first and second surface are on opposite sides of the gel pad and wherein the gel of the first layer and the gel of the second layer have self-healing properties.

[0027] In one example the first polymer of the multilayered gel pad comprise repeating first subunits, the first subunit comprise an amide group. The second polymer comprise a repeating second subunit, the second subunit comprise an aldehyde group. The third polymer comprise a repeating second subunit, the second subunit of the third polymer comprise an aldehyde group and may be functionalized with dopamine.

[0028] The gel pad has many advantageous properties, as disclosed herein, and can be applied to a wide range of applications.

[0029] The gel pad may for example be used as a tissue adhesive. Further, the gel pad may be used as a wound bandage for wound care applications. Yet further, the gel pad may be used as an implant / wearable, with for example theraregenerative (i.e. therapeutic and / or regenerative capacities), cyborganic and theranostic capacities. Even further, the gel pad may be arranged for adhering to and monitoring living tissue both in vitro and in vivo via imaging and / or electrically.

[0030] In a specific example, the presently disclosed gel pad is arranged for ultrasound imaging.

[0031] The gel pad may for example be arranged for ultrasound imaging using an ultrasound transducer, as such, the multilayered gel pad may comprise a first layer having a first surface that is non-adhesive to patient tissue, particularly skin tissue, and a second layer having a second surface that is adhesive to an ultrasound transducer, wherein the first and second surface are on opposite sides of the gel pad and wherein the gel of the first layer and the gel of the second layer have self-healing properties

[0032] An ultrasound gel pad with two distinctly different sides removes the need for using a liquid gel.

[0033] While the intrinsic properties of the two layers of the gel pad are distinct, the imaging properties are similar to that of a single layer, for example as a result of the self-healing properties of the multilayered gel pad.

[0034] The presently disclosed gel pad is adapted for automation, for example in a system comprising a transducer attached to a robotic arm, the robotic arm can for example move the transducer to pick up a gel pad, by contacting the transducer with a surface of the gel pad that is adhesive to the ultrasound transducer, thereby attaching the gel pad to the transducer. The use of an ultrasound gel pad removes the need for conventional ultrasound gel, and the ultrasound gel pad can easily be removed, once completion of the measurement.

[0035] The gel pad is arranged to adhere firmly to the transducer, yet it is possible to remove the gel pad in one piece. The presently disclosed ultrasound gel pad is thus arranged to be reversibly coupled to the ultrasound transducer.

[0036] In one example, the multilayered gel pad may comprise a first and a second layer that self-heal when they come into contact. The first layer may comprise a first and a second polymer. The second layer may comprise a the first and the second polymer as well as a third polymer. The first polymer could for example be a polymer comprising repeating subunits comprising amide groups, the second polymer could for example be a polymer comprising a repeating second subunit comprising aldehyde groups.

[0037] The third polymer could for example be a polymer comprising a repeating second subunit comprising an aldehyde group, an amine group and a phenolic group.

[0038] In a second aspect, the present disclosure relates to the use of a multilayered gel pad for ultrasound imaging. The multilayered ultrasound gel pad can be used for both manual and automated ultrasound imaging.

[0039] The multilayered ultrasound gel pad can be used for many different ultrasound applications such as to visualize abdominal tissues and organs; for bone sonometry to assess bone fragility; breast ultrasound, to visualize breast tissue; doppler foetal heart rate monitors or to visualize blood flow through a blood vessel, organs, or other structures; for echocardiogram, to view the heart; for foetal ultrasound; for ultrasound- guided biopsies, to collect a sample of tissue; for ophthalmic ultrasound, to visualize ocular structures; for ultrasound-guided needle placement in blood vessels or other tissues of interest.

[0040] Use of the gel pad typically involves attaching the adhesive side directly to an ultrasound transducer. The structural integrity and mechanical toughness of the gel pad allows for fully automated mounting and removal from the ultrasound transducer without the gel pad breaking. Having both an adhesive side and an opposite nonadhesive side the gel pad can replace the traditional use of both a gel pad and liquid gel. Attaching the gel pad directly to the ultrasound transducer instead of the patient allows for further automatization, since that step does not involve the patient, and may further simplify the procedure.

[0041] The gel pad is specially adapted to image irregular surfaces since the gel pad has the ability to conform to irregular surfaces being both soft and flexible. The risk for discomfort or pain of the patient, by the application of a larger pressure onto the patient, is decreased since the presently disclosed gel pad is both soft and flexible.

[0042] In a third aspect, the present disclosure relates to a method of manufacturing a multilayered gel pad comprising casting a gel of the first layer and a gel of the second layer.

[0043] The gel pad may for example be manufactured by casting, the outcome of which can be dependent on timing of the different steps. Since the polymer polymerizing typically occurs immediately, the mixing of the components of the gel pad, may advantageously be done instantly to avoid bubbles formed during mixing to be trapped in the gel. Sonicating the still not completely polymerized first and gel of the second layer may be done in order to remove a significant part, such as the majority, of trapped air bubbles. In other examples of the present disclosure, the multi-layered gel pad may comprise nanoparticles that have the ability to reduce, such as to completely eliminate air bubbles in the final gel pad. The nanoparticles may for example be arranged to scavenge vapor of the remaining air bubbles trapped in the gel during the casting process, such as by different means as compared to sonication.

[0044] In a further example of the present disclosure, the multi-layered gel pad has self- healing properties making it superior to other multi-layered gel pads, for example wherein the layer-layer interface can affect the final imaging properties. The first layer and the second layer may be self-healing to each other. As such, the first layer may comprise one or more functional groups that spontaneously, or by external stimulation, form a bond to one or more functional groups of the second layer.

[0045] In one example, the multi-layered gel pad may comprise a first and a second alginate gel that is arranged to self-heal when they come into contact. The multi-layered gel pad may for example comprise a first and a second oxidized alginate-polyacrylamide based gel that is arranged to self-heal when they come into contact. In this way, the two gels are effectively turned into one, although having internal property variations, and thus removing imaging artifacts that for example can arise due to an imperfect interface between layers of an ultrasound gel pad.

[0046] In one example, polymerization takes place in a controlled atmosphere, for example of nitrogen gas, wherein the temperature can be below 10°C, preferably below 4°C.

[0047] Description of Drawings

[0048] The invention will in the following be described in greater detail with reference to the accompanying drawings. The drawings are exemplary and are intended to illustrate some of the features of the presently disclosed multilayered ultrasound gel pad and related methods, and are not to be construed as limiting to the presently disclosed invention.

[0049] Fig. 1 illustrates the gel pad assembly according to an embodiment of the present disclosure. The gel of the first layer and the gel of the second layer are mixed under a controlled N2 atmosphere, in an ice bath, up to 4°C (101, 104). The gel of the first layer and the second layer are sonicated for 5-10 seconds to remove the bubbles afterwards in order to avoid further air bubbles forming (102, 105), immediately and carefully, the gels are transferred to the one or more molds (103,106). The curing process starts and the gel of the first layer and second layer are kept under controlled N2 atmosphere in an ice bath up to 4°C, in order to further avoid bubble formation during the polymerization process (103, 106).

[0050] Fig. 2 illustrates an example of using the gel pad for multiple consecutive ultrasound measurements of a surface having a complex shape. The ultrasound transducer (201) is coupled to a second surface (206) a second layer (202) of the gel pad. The gel pad further comprises a first layer (203) comprising a first surface (205) that is nonadhesive. During use, the gel pad can be pressed against the tissue (204) and conforms to the irregular surface for improved imaging.

[0051] Fig. 3 shows a gel pad according to an embodiment of the present disclosure. The gel pad comprises two gels arranged into a first layer (302) and a second layer (301). The first layer having a first surface (305), and the second layer having a second surface (306). The first and second surfaces are arranged on opposite sides of the gel pad, and display distinct properties. Typically, the first surface is non-adhesive and / or has lubricating properties and the second surface is adhesive (306), such as to an ultrasound transducer. The first and the second layer have self-healing properties, which can result in the gel of the first layer and the gel of the second layers having a gradual transition in the composition and / or the properties across the interphase, and / or no clear interface between the two layers, as also shown in the close-up (303), wherein a gradual transition (304), such as of the composition and / or properties, between the first layer and the second layer is shown.

[0052] Fig. 4 shows gel pads according to different embodiments of the present disclosure. Specifically, a gel pad comprising air bubbles (Fig. 4A), for example due to not being placed under an ice bath and under a controlled nitrogen atmosphere during manufacture. However, preparation under an ice bath and under a controlled nitrogen atmosphere during manufacture resulted in no observable air bubbles in a single-layer gel pad when viewed from the top (Fig. 4B) and in a double-layer the side (Fig. 4C). The gel pads comprised of 125 mg oxidized alginate, 1% silica-based nanoparticles and 1000 mg acrylamide dissolved in 2800 mL water. The acrylamide phase was polymerized using potassium persulfate (KPS) and tetramethylethylenediamine (TEMED) and finalized with a second-layer with 3% oxidized-layer with dopamine.

[0053] Fig. 5 shows scanning electron micrographs of gel pads according to an embodiment of the present disclosure. Specifically, Fig. 5 shows a cross-section of the gel pad without nanoparticle inclusion in the first layer (Fig. 5A, Fig. 5B) and with 1% of hollow mesoporous silica nanoparticles included in the first layer (Fig. 5C, Fig. 5D). The second layer of both examples comprises 3% oxidized alginate functionalized with dopamine. Scale bars are 200 pm.

[0054] Fig. 6 shows size measurements of nanoparticles by dynamic light scattering. Fig. 6A shows silica-based nanoparticles, showing the particle size for solid silica nanoparticles (601), hollow mesoporous silica nanoparticles before the solid silica core removal (602) and hollow mesoporous silica nanoparticles after the solid silica core removal (603). Fig. 6B shows scanning electron microscopy of solid silica nanoparticles showing nanoparticles mono-dispersion.

[0055] Fig. 7 shows ultrasound images of joints using different gels: traditional water-based ultrasound gels (Fig. 7A, Fig. 7E); First and second layer gel pad without nanoparticles (Fig. 7B); First layer only gel pad without nanoparticles (Fig. 7F); First and second layer gel pad comprising 1% solid silica nanoparticles (Fig. 7C), First and second layer gel pad 1% hollow mesoporous silica nanoparticles (Fig. 7G); Aquaflex® pad (Fig. 7D, Fig. 7H).

[0056] Fig. 8 shows the characterization of the oxidized alginate. Molecular weight measurements of alginate and oxidized alginate (Fig. 8A), the oxidation degree alginate quantified by NMR (Fig. 8B), and FTIR measurements of alginate and oxidized alginate (Fig. 80).

[0057] Fig. 9 shows FTIR measurements of the first layer of the gel pad. This gel pad consists of 250 mg oxidized alginate, 0,1 ,2, or 4% silica-based nanoparticles and 1000 mg acrylamide dissolved in 2800 ml water and the acrylamide was polymerized using KPS and TEMED.

[0058] Fig. 10 shows FTIR measurements of the second layer of the gel pad. The gel pad comprises 250 mg oxidized alginate, 3% oxidized alginate functionalized with dopamine and 1000 mg acrylamide dissolved in 2800 ml water and the acrylamide were polymerized using KPS and TEMED.

[0059] Fig. 11 shows FTIR measurements of dopamine, oxidized alginate and oxidized alginate functionalized with dopamine.

[0060] Fig. 12 Fig. 12 shows a schematic overview of the polymerized network and major linkages in the gel of the second layer (1201), the interface self-healing zone between the two gels (1202) and the gel in the first layer (1203) (Fig. 12A). Further, Fig. 12B shows a schematic overview of the polymer networks and major linkages in the gel of the second layer (1205, 1206, 1207, 1208, 1210, 1211 , 1212), the self-healing zone (1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211 , 1212), and the gel of the first layer (1208, 1210, 1211 , 1212). The major linkages in the gel pad are hydrogen bonds, for example, between the hydroxyl groups present in the dopamine molecule, from the dopamine functionalised oxidized alginate (ALOX-Dop) and hydroxyl groups present on the surface of the nanoparticles (1204), or with other hydroxyl groups from adjacent ALOX-Dop (1206), or with amide functional groups of polyacrylamide (PAM) (1207).

[0061] Hydrogen bonds are also present between the linkage between PAM and ALOX chains (1208), such as with the carbonyl group (i.e. aldehyde) or the hydroxyl of the ALOX chains with hydrogen of PAM chains, as well as the hydrogen in the ALOX chain can interact with amide functional group. Hydrogen linkage can also be presented between ALOX chains (1210), with linkage involving hydrogen, carbonyl groups and hydroxyl groups; as well as, between PAM chains (1212) where the amide functional group can hydrogen bond with itself. Moreover, both PAM and ALOX chain can interact by hydrogen linkage with the hydroxyl group on the surface of the nanoparticles (1209). In the gel pad we also have pi-pi interaction between the dopamine molecules from the ALOX-Dop (1205), and dynamic covalent Shiff base bonds (1211) between PAM and ALOX chains.

[0062] Fig. 13 shows compression mechanical tests for the gel of the first layer, without and hollow mesoporous silica based nanoparticles (Np) in the formulation. Representative curves of compressive stress vs. strain for the gel of the first layer without silica based nanoparticles behavior (0% Np), and the gel of the first layer containing 1-4% of hollow mesoporous silica particles (1 %, 2% and 4% Np) (Fig. 13A).The compressive young modulus for 0% Np is around 39 kPa, 1% Np at 50 kPa, 2% Np at 40 kPa and 4% Np at 37 kPa (Fig. 13B). All displayed breaking points for all compositions are above 78% (Fig. 13C). Compressive strain values at 50 % for the compositions are shown here with values for 0% Np at 23 kPa, 1 % Np at 29 kPa, 2% Np at 22 kPa and 4% Np at 22 kPa (Fig. 13D). Compressive strain values at 80 % for the compositions are shown here with values for 0% Np at 226 kPa, 1 % Np at 251 kPa, 2% Np at 171 kPa and 4% Np at 238 kPa (Fig. 13D). The toughness for 0% Np was 24 kJ / m3, 32 kJ / m3for 1 % Np, 32 kJ / m3for 2% Np and 24 ± 2 kJ / m3for 4% Np (Fig. 13F).

[0063] Fig. 14 shows compression mechanical tests for the gel of the second layer performed after 24 hours of curing time. Representative curves of compressive stress vs. strain for the gel of the second layer with 1%, 2% or 3% of oxidized alginate functionalized with dopamine (Dop) (Fig. 14A).

[0064] The compressive young modulus for 1% Dop is 11 ± 5 kPa, for 2% Dop it is 7 ± 2 kPa and for 1 % Dop it is 4 ± 2 kPa (Fig. 14B).

[0065] All three gels had a breaking point of at least 79%, irrespective of their Dop % (Fig. 14C).

[0066] Compressive stress at 50% of strain, 1% Dop is 5 ± 1 kPa, 2% Dop is 3,5 ± 0,5 kPa and 3% Dop is 1 ± 0,2 kPa (Fig. 14D). Compressive stress at 80% of strain, 1% Dop is 30 ± 20 kPa, 2% Dop is 17 ± 3 kPa and 3% Dop is 9 ± 4 kPa (Fig. 14E).

[0067] The toughness for 1% Dop is 4 ± 1 ,5 kJ / m3, for 2% Dop it is 3 ± 0,3 kJ / m3and for 3% Dop it is 1 ± 0,4 kJ / m3(Fig. 14F).

[0068] Fig. 15 shows the Lap-shear strength of the gel of the second layer comprising 1%, 2% or 3% oxidized alginate functionalized with dopamine (Fig. 15A).

[0069] Qualitative test of the gel of the second layer comprising 3% oxidized alginate functionalized with dopamine adhered to the ultrasound transducer (Fig. 15B). Lap-shear strength of a 3% dopamine functionalized oxidized alginate gel on to transducer, skin and metal surface (Fig. 15C). Control experiment using fibrin for adhesion is shown in Fig. 15D.

[0070] Fig. 16 shows acoustic characterization of a gel pad comprising 250 mg oxidized alginate and 1000 mg polyacrylamide in 2800 ml water where polymerization was initialized by KPS and TEMED. Velocity (m / s) (Fig. 16A) and Attenuation (dB / cm) (Fig. 16B) as a function of frequency (MHz).

[0071] Definitions

[0072] As used herein, the term self-healing refers to a composition that exhibits spontaneous formation of new bonds when old bonds are broken within a material or when two materials with self-healing properties come into contact with each other regardless of any prior bonds having been broken.

[0073] The term gel pad refers to a solid piece of hydrogel adapted for ultrasound imaging, for example as a replacement for a liquid ultrasound gel.

[0074] The term multilayered gel pad as used herein, refers to a gel pad comprising several layers having different properties, typically different intrinsic properties such as adhesiveness and / or lubricating properties. In specific examples, a first surface of the multilayered gel pad may be non-adhesive and / or lubricious, while a second surface, opposite of the first surface may be adhesive, such as to an ultrasound transducer. The term hydrogel is used as a collective name of gels comprising one or several different polymers and water as the main constituent.

[0075] As used herein, the term "non-adherent" refers to a surface property where the lap shear strength to another surface, such as a surface of patient skin, is below 0.5 kPa. This can allow for minimal attachment of a first surface, thereby ensuring easy removal and repositioning.

[0076] As used herein, the term "adherent" refers to a surface property where the lap shear strength to a target surface, such as the surface of an ultrasound transducer, is higher than 0.5 kPa. The lap shear strength can for example be in the range of 1-75 kPa, such as in the range of 2-70 kPa, such as in the range of 4-60 kPa, such as in the range of 4-50 kPa, such as in the range of 4-40 kPa, such as in the range of 6-35 kPa, such as in the range of 8-35 kPa. This can allow the second surface of the gel pad to provide stable attachment to the target surface, ensuring that it remains securely in place during use.

[0077] A vapor scavenger as used herein is an entity, such as a nanoparticle or a microparticle, that has the ability to remove air bubbles that are formed during the gel pad manufacturing process. A vapor scavenger, such as a nano particles have hydroxyl groups on the surface that are involved in hydrogen bonds with the dopamine molecule. The vapor scavenger may comprise one or more micro and I or nano cavities.

[0078] A mold is any container wherein a suitable hydrogel can be cast, it is preferably made from a non-sticky material, such as polypropylene, or polyester.

[0079] As used herein, the term "patient tissue" refers to biological material or bodily components of an individual, whether human or animal, including but not limited to cells, organs, bones, or any anatomical or physiological element of a patient's body. In specific examples, patient tissue refers to skin.

[0080] A self-healing polymer as used herein refers to a material designed to repair and regenerate itself when damaged or subjected to external stresses and includes intrinsic and extrinsic self-healing polymers, wherein intrinsic self-healing may for example rely on spontaneous bond formation, while extrinsic self-healing typically rely on an external stimuli such as heat-light or pressure. Self-healing polymers typically have the unique ability to recover their structural integrity and mechanical properties after experiencing cracks, scratches, or other forms of damage. Further, self-healing can be used to manufacture multilayered structures, as disclosed elsewhere herein.

[0081] A self-healing polymer by Schiff base reaction refers to a type of synthetic polymer that incorporates Schiff base chemistry as a mechanism for self-repair and regeneration when damaged. Schiff base reactions involve the formation of reversible covalent bonds between an amine group (typically from a primary amine) and a carbonyl group (for example from an aldehyde or ketone). These bonds can break and reform allowing for the polymer to repair itself when subjected to damage or stress.

[0082] In a self-healing polymer based on Schiff base reactions, the polymer matrix contains functional groups capable of undergoing Schiff base reactions. For example, a first layer may comprise one or more functional groups that are arranged to undergo said reactions with one or more functional groups of a second layer. When the polymer is damaged, these functional groups react with each other, forming new covalent bonds and thereby restoring the material's structural integrity. This repair process can be triggered by various environmental factors, such as changes in temperature, pH, or the presence of specific catalysts.

[0083] As used herein a nanoparticle is a particle having a dimension with a length of less than 1 pm, such as between 1 nm and 100 nm. Some nanoparticles, such as mesoporous nanoparticles (e.g. mesoporous nanosilicate), can remove / scavenge vapor, such as during manufacturing. Thus, nanoparticles arranged to remove vapor during manufacturing are also referred to as vapor scavengers.

[0084] Detailed description

[0085] In a first aspect, the present disclosure relates to a multilayered gel pad. For example the multilayered gel pad may comprise a first and a second layer. The multilayered gel pad may comprise a first layer having a first surface that is non-adherent, for example to patient tissue. Further, the multilayered gel pad may comprise a second layer having a second surface that is adherent to a target surface. The first and second surface can be on opposite sides of the gel pad. In specific examples, the first layer and the second layer have self-healing properties.

[0086] The first layer may contain a first polymer, which can include a repeating first subunit that contains an amide group. Additionally, the first layer may include a second polymer, which has a repeating second subunit containing an aldehyde group.

[0087] In certain embodiments, the second layer may contain the first polymer and the second polymer. Furthermore, the second layer may comprise a third polymer. The third polymer can include a repeating subunit comprising an aldehyde group, an amine group, and a phenolic group.

[0088] The first surface and the second surface may be located on opposite outer sides of the gel pad, allowing for differential adherence properties on each side. In various examples, both the first layer and the second layer possess self-healing properties.

[0089] The non-adhesive surface may be arranged to be lubricious, and may as such be arranged such that the first surface of the gel pad can glide over another surface.

[0090] The gel pad has many advantageous properties, as disclosed herein, and can be applied to a wide range of applications. The gel pad may for example be used as a tissue adhesive. Further, the gel pad may be used as a wound bandage for wound care applications. Yet further, the gel pad may be used as an implant / wearable, with for example theraregenerative (i.e. therapeutic and / or regenerative capacities), theranostic and cyborganic capacities. Even further, the gel pad may be arranged for adhering to and monitoring living tissue both in vitro and in vivo via imaging and / or electrically.

[0091] In a specific example, the presently disclosed gel pad is arranged for ultrasound imaging. In one embodiment of the present disclosure, the multilayered gel pad may therefore be arranged to be used for ultrasound imaging. As such, the gel pad may be arranged to transmit and / or convey ultrasound energy between an ultrasound transducer (also commonly referred to as an ultrasound probe) and patient tissue. The multilayered gel pad may comprise a first layer having a first surface that is non- adhesive, such as to patient tissue, such as skin tissue, and a second layer having a second surface that is adhesive to a target surface, such as a surface of an ultrasound transducer. Typically, the first and the second surface are on opposite sides of the gel pad. For example, an upper and a lower surface of the gel pad. The gel pad typically has self-healing properties, such that the first and the second layer can self-heal.

[0092] In one embodiment of the present disclosure, the gel pad may comprise a self-healed interface between the first layer and the second layer. The gel pad may for example be arranged such that the composition across the interface has a gradual transition, such as from a composition of the first layer to a composition of the second layer. A gradual transition between the first layer and the second layer may allow the multilayered gel pad to behave as a single unit. At the same time, the first layer may be adapted for being compressed against irregular surfaces, thus allowing for ultrasound imaging of irregular surfaces of a patient’s body. Additionally, or alternatively, the second layer, such as the second surface, may be arranged for being attached to the transducer.

[0093] In one embodiment of the present disclosure, the first layer is self-healing to the second layer. For example, the interface between the first layer and the second layer may be self-healing. As such, the interface between the first layer and the second layer may have been formed by self-healing of said layers. As such, components of the first layer may spontaneously, such as under room temperature, form bonds to components of the second layer.

[0094] The second layer may be thin, such as between 0.0001-10 mm, for example 1-5 mm. The second layer may be as thin as possible, while sufficiently thick to enable adhesion to an ultrasound transducer. The first layer, on the other hand, may be sufficiently thick to give rise to sufficient structural integrity for the ultrasound imaging to be performed.

[0095] In one embodiment of the present disclosure, the first layer and / or the second layer comprises or consists of a hydrogel.

[0096] Hydrogels are safe for the patient to use on the skin or other tissues, as it does not cause any allergic reactions. It is comfortable, does not smudge and leaves skin clean after imaging since the structural integrity of the gel keeps the gel pad intact during imaging due to their high mechanical toughness.

[0097] In one embodiment of the present disclosure, the hydrogel of the multilayered gel pad comprises a first and a second polymer; or a first, a second and a third polymer.

[0098] In one embodiment of the present disclosure, the hydrogel of the multilayered gel pad comprises a first and a second layer, wherein the first layer comprises a first and a second polymer; and the second layer comprises a first, a second and a third polymer. In one embodiment of the present disclosure, the first polymer is polyacrylamide, sodium acrylate, methacrylamide, acrylic acid, poly(methyl methacrylate), polyvinyl acetate, polyacrylamide-co-acrylic acid, hydrolyzed polyacrylamide, poly-acrylamido-2- methylpropane sulfonate, poly(acrylamide-co-diallyldimethylammonium) or poly(acrylamide-co-N,N,N-trimethyl-2-((1-oxo-2-propenyl)oxy)) gelatin or aminated gelatin.

[0099] In one embodiment of the present disclosure the second polymer is alginate, oxidized alginate, chitosan, oxidized chitosan, pectin, oxidized pectin, silk, oxidized silk, methacrylated silk, methacrylated alginate, keratin, aminated keratin, methacrylated keratin, methacrylated pectin, methacrylated chitosan, aminated chitosan, polyacrylic acid, poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), Polyaniline, Poly(N-isopropylacrylamide), Polyvinyl Alcohol (PVA), Polyacrylic Acid (PAA), glycerol, cellulose, methacrylared cellulose or nano-cellulose.

[0100] In one example, the phenolic group of the third polymer is a catechol group, a pyrogallol group or a hydroquinone group, depending on the functionalization approach. Other possible phenolic groups for the third polymer include resorcinol, dopamine, or caffeic acid, each providing the necessary phenolic structure to support the gel’s adhesive and self-healing properties.

[0101] In certain embodiments, the third polymer is a functionalized base polymer. The base polymer may be selected from a range of biocompatible materials, including oxidized alginate, alginate, chitosan, oxidized chitosan, pectin, oxidized pectin, silk, oxidized silk, methacrylated silk, methacrylated alginate, keratin, aminated keratin, methacrylated keratin, methacrylated pectin, methacrylated chitosan, or aminated chitosan. Functionalization of the base polymers can be achieved by the introduction of the phenolic group.

[0102] In one embodiment of the present disclosure the third polymer is oxidized alginate functionalized with dopamine. Thus, in one example the first polymer is polyacrylamide, the second polymer is oxidized alginate, and the third polymer is dopamine- functionalized oxidized alginate.

[0103] In one embodiment of the present disclosure the third polymer comprises an aldehyde group, an amine group and a phenolic group. The third polymer, as used in the multilayered gel pad disclosed herein, can be characterized by a repeating second subunit comprising an amine group, an aldehyde group, and a phenolic group. The phenolic group can provide strong adhesive properties, and can be particularly advantageous for adhesion in aqueous or high- moisture environments commonly encountered in biomedical applications. For example, catechol — a phenolic group known for its strong affinity to both organic and inorganic surfaces — mimics natural adhesive qualities found in marine organisms, such as mussels. This can enable the gel pad to adhere securely to biological tissues and synthetic surfaces, such as medical devices or ultrasound transducers.

[0104] The phenolic group may alternatively be selected from gallol, hydroquinone, resorcinol, or caffeic acid. These groups can typically impart adhesive strength by forming hydrogen bonds and metal chelates, allowing for customized selection based on the required bonding strength and compatibility with specific target environments. In addition to enhancing adhesion, these groups may improve the gel’s resistance to displacement, particularly in moist conditions.

[0105] The aldehyde group in the third polymer facilitates covalent crosslinking with amine- containing compounds, thereby enhancing the hydrogel’s mechanical integrity and self- healing properties. This robust crosslinking provides structural stability, enabling the gel pad to maintain adhesion and resilience even through repeated use.

[0106] The amine group within the third polymer may further support biocompatibility and gel stability. Through additional crosslinking and hydrogen bonding interactions, the amine group can contribute to the gel pad’s durability when exposed to mechanical stresses, such as during application to or removal from surfaces. The combination of an amine group, an aldehyde group, and a phenolic group within the third polymer can produce a synergistic effect, effectively addressing limitations seen in prior art gel pads, such as limited adhesion in moist conditions, reduced durability under stress, and restricted self-healing capabilities.

[0107] The first polymer can be polyacrylamide, sodium acrylate, methacrylamide, acrylic acid, poly(methyl methacrylate), polyvinyl acetate, poly(acrylamide-co-acrylic acid), hydrolyzed polyacrylamide, poly(acrylamido-2-methylpropane sulfonate), poly(acrylamide-co-diallyldimethylammonium), or poly(acrylamide-co-N,N,N-trimethyl- 2-((1-oxo-2-propenyl)oxy)). In one embodiment of the present disclosure, the hydrogel of the multilayered gel pad comprises polyacrylamide.

[0108] In one example, the first polymer is the polymer of the highest wt. % of the hydrogel. The first polymer may be arranged to bind water in a sufficiently high amount and form a complex interpenetrating network with the second polymer. In some examples, the polymer is arranged to bind to the second polymer, via both hydrogen bonds and dynamic covalent bonds. In some examples by a so-called Schiff-base interaction.

[0109] In one embodiment of the present disclosure, the hydrogel of the multilayered gel pad comprises nanoparticles, such as nanoparticles arranged for chemically interacting with the network of the gel pad, such as with the network of the first layer and / or the second layer.

[0110] In one embodiment of the present disclosure, the first layer and / or the second layer comprises ionic liquids, such as iron chloride, lithium chloride and / or calcium chloride. By varying the concentration and type of the ionic liquids, it may be possible to tune properties of the first and / or the second layer. For example the adhesiveness. Alternatively or additionally, it may be possible to tune properties such as the self- healing properties, the conductivity, and / or the mechanical properties.

[0111] As such, the first layer and / or the second layer may comprise nanoparticles. For example, the first and / or second layer may comprise solid nanosilicate particles, hollow mesoporous nanosilicate particles, carbon-nanotubes, graphene nanoparticles, 2D transition metal carbides, carbonitrides, nitrides, MXenes, nanoclays such as bentonite, kaolinite, hectorite, halloysite, montmorillonite, silica-based nanoparticles, polysaccharide based nanoparticles, alginate-based nanoparticles, acrylamide-based nanoparticles, ZrC>2, Iron oxide-based, TiCh-based nanoparticles, quantum dots and / or metal organic framework (MOF).

[0112] In one embodiment of the present disclosure, the first polymer of the first layer and of the second layer has a molecular weight in the range of 10-600 kDa, such as 70-80 kDa. In one example, the manufacturing of the hydrogel of the multilayered gel pad may be carried out such that the acrylamide monomers are polymerized into large polymers, i.e. the first polymer, that interact with the second polymer, oxidized alginate, and the third polymer, dopamine functionalized oxidized alginate. Depending on the different gel compositions of the first and the second layer, polyacrylamide polymers of different average sizes can be formed.

[0113] In one embodiment of the present disclosure, the first layer comprises polyacrylamide, oxidized alginate and optionally a vapor scavenger.

[0114] In one embodiment of the present disclosure, the second layer comprises polyacrylamide, oxidized alginate and oxidized alginate functionalized with dopamine and optionally a vapor scavengers.

[0115] In one embodiment of the present disclosure, the first and / or the second layer comprises one or more vapor scavengers. Alternatively, or additionally, said first and / or second layer comprises one or more nanoparticles that are not vapor scavengers.

[0116] Oxidized alginate has a higher number of active functional groups, such as aldehyde groups, compared to alginate. These functional groups can react with amines or hydrazides, thus forming self-healing hydrogels. In specific examples of the present disclosure, oxidized alginate can be preferred over (non-oxidized) alginate.

[0117] The interactions between oxidized alginate and dopamine occur primarily due to the amide bond formation between carboxylate group present in oxidized alginate and amine group present in the dopamine. However, as disclosed elsewhere herein, the present disclosure can comprise additional or alternative first, second, and / or third polymers.

[0118] In one embodiment of the present disclosure, the ratio, in dry weight, between the second polymer and the first polymer of the first layer is in the range 10-500:1000, such as in the range 20-400:1000, such as in the range 20-375:1000, such as in the range 25-350:1000, such as 62.5-250:1000. In one embodiment of the present disclosure, the ratio, in dry weight, between the first polymer, the second polymer, and the third polymer, of the second layer is in the range 1000:10-500:0.15-40, such as in the range 1000:10-500:0.25-30, such as in the range 1000:15-400:0.25-30, such as in the range 1000:15-400:0.25-20, such as in the range 1000:20-400: 0.25-20, such as in the range 1000:20-400: 0.25-17.5, such as in the range 1000:20-350: 0.25-17.5, such as in the range 1000:20-350: 0.25-17.5, such as in the range 1000:40-350: 0.25-17.5, such as in the range 1000:50-350: 0.25-17.5, such as in the range 1000:75-325: 0.25-17.5, such as in the range 1000:100-300: 0.25-17.5, such as in the range 1000:100-300: 0.5-10, such as in the range 1000:100-300: 0.75- 10, such as in the range 1000:100-300: 1-9.

[0119] Decreasing the second polymer content in the hydrogel typically increases the hardness and compressibility of the gel, while at the same time decreasing the self- healing capacity. The hydrogel may therefore become less adhesive and cost less to produce. Increasing the second polymer content typically decreases the hardness and compressibility, increases the self-healing capacity and the adhesiveness, while in general making the hydrogel less affordable.

[0120] Decreasing the third polymer content typically increases the hardness and compressibility, decreases the self-healing capacity and the adhesiveness while in general making the hydrogel more affordable. However, increasing the third polymer content typically decreases the hardness and compressibility, becoming ultra-soft hydrogels, increases the self-healing capacity, the adhesiveness and the initiator contents, while in general making the hydrogel less affordable.

[0121] In one embodiment of the present disclosure the second polymer the multilayered gel pad in the first and the second layer has a molecular weight of between 20-60 kDa.

[0122] In one embodiment of the present disclosure, the second polymer of the first and the second layer has a molecular weight of between 20-60 kDa.

[0123] In one embodiment of the present disclosure third polymer of second layer of the multilayered gel pad has a molecular weight between 5-60 kDa. In one embodiment of the present disclosure the second polymer functionalized with dopamine of second layer of the multilayered gel pad has a molecular weight between 5-60 kDa.

[0124] In one embodiment of the present disclosure, the third polymer of the second layer has a molecular weight between 20-60 kDa.

[0125] In specific examples, the third polymer is a functionalized variant of the second polymer. For example, the third polymer can be oxidized alginate functionalized with dopamine. The incorporation of functional groups into the third polymer can in general act to increase the average molecular weight. The interactions between the initial polymer of the third polymer, e.g. oxidized alginate, and the functionalized group, e.g. dopamine, are typically due to the amide bond formation between carboxylate groups present in the initial polymer and amine groups present in the functional group.

[0126] In one embodiment of the present disclosure, the second polymer of the first and the second layer has a degree of oxidation between 50% and 60%, preferably between 54% and 55%.

[0127] Changing the oxidation degree of the second polymer, changes the self-healing and mechanical properties of the gel as well as adhesiveness. The preferred degree of oxidation between 54% and 55% produces a gel pad with desired properties.

[0128] In one embodiment of the present disclosure, the water content of the first layer is at least 72%, such as in the range of 72% and 79%.

[0129] In one embodiment of the present disclosure, the water content of the second layer is at least 70%.

[0130] The water content of the first and second layer typically affects the physical properties of the gel such as rigidity. A gel pad of a preferred water content can easily be compressed and conform to irregular surfaces and can as such be used instead of a liquid gel during imaging.

[0131] In general, a water content as high as possible is preferred in the first layer. However, a high water-content could increase the adhesiveness and affect the compressibility, which must be taken into consideration when modifying the composition of the first layer. For the second layer it is preferred to decrease the water content since the functional group of the third polymer, e.g. dopamine, can act to slow down the gelation, which will affect the mechanical properties.

[0132] In one embodiment of the present disclosure, the gel pad, such as the interface between the first layer and the second layer, is self-healing.

[0133] In one embodiment of the present disclosure, the first layer and the second layer are formed such that no defined interface is distinguishable, particularly, the first layer and the second layer form a self-healed region. In this way, improved ultrasound imaging properties can be achieved.

[0134] In one embodiment of the present disclosure, the interface between the first layer and the second layer has a smooth transition in the compositions of the first and second layers across said interface.

[0135] In one embodiment of the present disclosure, the multilayered gel pad has a sufficiently high structural integrity such that the gel pad can be detached from an ultrasound transducer without being damaged, such as breaking. The gel pad may thus be arranged to be detachably coupled to an ultrasound transducer, and may be easily detached from the transducer, for example following completion of a measurement.

[0136] The multilayered gel pad preferably has a structural integrity that allows the transducer to be moved around on the skin without disintegrating during imaging. This also allows for automation, for example by a robotic arm, which may be arranged to attach the ultrasound gel pad to the transducer and carry out the imaging of a subject without human intervention. The structural integrity of the gel pad may also be such that the gel pad can be attached and detached from the transducer several times, such as up to five times.

[0137] In one embodiment of the present disclosure, the imaging quality for images obtained with the gel pad on uneven surfaces is higher or equal to that of images obtained with a liquid gel only or gel pads of the prior art. The composition and manufacturing method of the present invention results in a gel pad that minimizes, such as eliminates, artifacts during imaging, such as shadows of bright streaks in the image. The self-healing property of the gel prevents reflection at the interface between the first and the second layer.

[0138] In one embodiment of the present disclosure, the variation in acoustic impedance of the multilayered gel pad is at most 10%, such as the most 5%, wherein the acoustic impedance of the multilayered gel pad is constant.

[0139] Acoustic impedance is a physical property of a medium that describes how it resists the propagation of acoustic (sound) waves. It is defined as the product of the density (p) of the medium and the speed of sound (c) in that medium. The unit of measurement for acoustic impedance is the rayl (kg / (m2s)). While acoustic impedance differences at tissue boundaries lead to a wanted (partial) reflection of ultrasound waves, enabling the generation of an image, unwanted acoustic impedance differences, such as in a gel pad, can act to introduce image artifacts and / or decrease the image quality.

[0140] As the amount of reflection and transmission depends on the impedance mismatch, acoustic matching minimizes the reflection and maximizes the transmission of ultrasound waves.

[0141] In one embodiment of the present disclosure, the first layer and / or the second layer of the gel pad comprises vapor scavengers for removing and / or entrapping vapor. Some nanoparticles, such as mesoporous nanoparticles (e.g. mesoporous nanosilicate), can remove / scavenge vapor. For example, the vapor scavengers may be arranged to remove or entrap vapor during manufacturing of the gel pad.

[0142] In one embodiment of the present disclosure, the vapor scavengers have an average diameter of less than 200 nm, preferably in the range of 20-110 nm.

[0143] In one embodiment of the present disclosure, the concentration of vapor scavenger nanoparticles is less than 4%, such as in the range of 1-2%.

[0144] In one embodiment of the present disclosure, the first layer comprises the vapor scavengers. In other examples, the second layer comprises the vapor scavengers. In yet other examples, both the first and the second layer comprise the vapor scavengers. Vapor scavengers may be nanoparticles arranged to minimize vapor trapped in the gel, for example during manufacturing, such as mixing. Since the polymer crosslinking is, in general, a rapid process, once the initiator has been added it is typically vital to thoroughly mix the gel components immediately. However, because of the rapid crosslinking / polymerization, small air bubbles may become trapped in the formed layer. Such air bubbles may act to distort the ultrasound image and can thereby obscure anatomical structures deeper in the tissue.

[0145] As mentioned elsewhere herein, a high as possible water content of the gel of the first layer may be preferred. However, a high-water content can also act to increase the adhesiveness and affect the compressibility. However, a gel pad comprising vapor scavengers can have a higher water content without the adhesiveness and compressibility being affected. Thus, the vapor scavengers also enable a higher water content, while maintaining the adhesiveness and the compressibility unaffected.

[0146] Additionally, the vapor scavengers can act to improve the self-healing property of the gel pad since the vapor scavengers typically add hydroxyl groups and hydrogen bonds to the system.

[0147] In one embodiment of the present disclosure, the first layer has a compressive Young’s modulus in the range of 1-90 kPa, such as in the range of 10-80 kPa, such as in the range of 20-75 kPa, such as in the range of 20-70 kPa, such as in the range of 20-65 kPa, and the second layer has a compressive Young’s modulus in the range of 1-20 kPa, such as in the range of 1-15 kPa, such as in the range of 1-10 kPa, such as in the range of 1-8 kPa.

[0148] In one embodiment of the present disclosure, the first layer has a compressive Young’s modulus of 43 ± 16 kPa and the compressive second layer has a Young’s modulus of 4 ± 2 kPa.

[0149] In one embodiment of the present disclosure, the lap shear strength of the second surface to the ultrasound transducer material is in the range of 1-75 kPa, such as in the range of 2-70 kPa, such as in the range of 4-60 kPa, such as in the range of 4-50 kPa, such as in the range of 4-40 kPa, such as in the range of 6-35 kPa, such as in the range of 8-35 kPa. In one embodiment of the present disclosure, the lap shear strength of the second surface of the gel pad to the ultrasound transducer material is in the range of 8-34 kPa, such as 12-18 kPa.

[0150] In one embodiment of the present disclosure the lap shear strength of the first layer to patient tissue such as skin, is 0.5k Pa or less.

[0151] In one embodiment of the present disclosure, the acoustic velocity of the first layer is 1650 - 1670 m / s, such as 1661.8 m / s.

[0152] In one embodiment of the present disclosure, the acoustic impedance of the first layer is 1.90 - 1.920, such as 1.911 MPa.s.m-1 (Mrayl)

[0153] Preferably, the acoustic velocity and acoustic impedance of the gel pad matches the tissue to be imaged as far as possible as this will result in less ultrasound waves being reflected back to the transducer. A good match between the gel pad and the tissue will in general produce images of high quality with few artifacts.

[0154] In one embodiment of the present disclosure the lap shear strength between the multilayered gel pad and the ultrasound transducer is 8-34 kPa, such as when the material of the ultrasound transducer, to which the gel pad may adhere, may comprise polymer silicone rubber, polyimide film and / or copper film.

[0155] In an alternative embodiment of the present disclosure the lap shear strength between the second surface and the material to which it is arranged to be adherent to, such as polymers such as silicone, rubber, polyimide, metals such as copper, steel, brass or titanium, tissue such as bone, skin, muscle and heart, is 8-34 kPa.

[0156] The lap shear strength of the gel of the second layer is adapted to adhere to the surface of common ultrasound transducers on the market.

[0157] Another aspect of the present disclosure relates to a gel pad comprising the first layer of the multilayered gel pad as disclosed elsewhere herein. Thus, the gel pad may comprise a surface that is non-adhesive to patient tissue. Yet another aspect of the present disclosure relates to a gel pad comprising the second layer of the multilayered gel pad as disclosed elsewhere herein. Thus, the gel pad may comprise a surface that is adhesive to the ultrasound transducer.

[0158] Yet another aspect of the present disclosure relates to a method of manufacturing a multilayered gel pad.

[0159] In one embodiment of the present disclosure, the first layer is cast first, and the second layer is subsequently cast on top of the first layer.

[0160] In one embodiment of the present disclosure, the second layer is cast first, and the first layer is subsequently cast on top of the second layer.

[0161] In one embodiment of the present disclosure, the first and the second layers are cast simultaneously and assembled after they have solidified.

[0162] Typically, the self-healing properties of the first and the second layer result in the casting order becoming irrelevant. When the first and the second layer come into contact with each other the self-healing process starts.

[0163] In one embodiment of the present disclosure, the method comprises: a) Forming a first layer by mixing a first polymer, such as polyacrylamide, and a first second polymer, such as oxidized alginate, in a controlled environment, such as under nitrogen gas at a temperature in the range of 0-10°C, such as 0-4°C, followed by sonication and immediate transfer to a mold for polymerization to take place, thereby generating a polymerized first layer; b) Forming a second layer by mixing a second first polymer, such as polyacrylamide, a second polymer, such as oxidized alginate, and a third polymer, such as oxidized alginate functionalized with dopamine, in a controlled environment, such as under nitrogen gas a temperature in the range of 0-10°C, such as 0-4°C, followed by sonication, and immediate transfer of said second layer on top of the polymerized first layer, and allowing for polymerization of the second layer; c) Self-healing the first and second layer by having the first and second layer being in contact at a temperature in the range of 0-10°C, such as 0- 4°C for at least 30 minutes.

[0164] In one embodiment of the present disclosure, the resulting ultrasound gel pad comprises a second surface adapted for adhering to a transducer surface, and a first surface opposite of said second surface having a low adhesiveness to tissue.

[0165] In one embodiment of the present disclosure, the still liquid second layer is, after sonication, transferred onto the polymerized first layer.

[0166] In one embodiment of the present disclosure, the method is performed at a temperature in the interval 0-10°C, preferably up to 4°C.

[0167] In one embodiment of the present disclosure, the first and the second layers are sonicated prior to polymerizing and casting.

[0168] In one embodiment of the present disclosure, increasing the oxidation degree of the second polymer, such as oxidized alginate, increases the self-healing properties of the first and / or second layer.

[0169] In one embodiment of the present disclosure, increasing the oxidation degree of the second polymer, such as oxidized alginate, increases the adhesiveness of the second layer.

[0170] In one embodiment of the present disclosure, decreasing the oxidation degree of the second polymer, such as oxidized alginate, decreases the Young’s modulus of the first and second layer.

[0171] In one embodiment of the present disclosure, the first layer is prepared, under a N2 controlled atmosphere up to 4°C by: a) dissolving the second polymer, such as oxidized alginate, in a minimum amount of water; b) adding 0.1-4% nanoparticles, such as Silica-based nanoparticles; c) adding acrylamide and mixing until it dissolves; d) adjusting the pH to 3.5-4, preferably by adding (0.1 M) NaOH, and mix; e) adding potassium persulfate dissolved in water and mix; f) adding TEMED, mixing, sonicating and casting the gel immediately in a controlled N2 atmosphere up to 4°C.

[0172] In one embodiment of the present disclosure, the second layer is prepared by: a) dissolving oxidized alginate and oxidized alginate functionalized with dopamine in a minimum amount of water; b) adding acrylamide and mixing until it dissolves; c) adjusting the pH to 3.5-4, preferably by adding (0.1 M) NaOH, and mix; d) adding ammonium persulfate dissolved in water and mix; e) adding TEMED, mixing, sonicating and casting the gel immediately in a controlled N2 atmosphere up to 4°C.

[0173] In one embodiment of the present disclosure, the oxidized alginate is prepared by: a) dissolving sodium-alginate in water; b) adding sodium periodate and stir the solution for 20h at room temperature in the dark; c) adding ethylene glycol; d) perform dialysis on the oxidized alginate; e) freeze-dry the oxidized alginate.

[0174] Examples

[0175] Example 1 - Alginate oxidation

[0176] 4 g of sodium alginate is slowly added to 400 ml MQ H2O, the mixture is agitated for 2h until it is fully dissolved. Sodium periodate is added until the final concentration is 50 mM. The mixture is agitated in the dark at RT for 20h. 6 ml of ethylene glycol (MW 2000) is added, and the mixture is stirred for another hour until it is transferred to a 3500 MWCO dialysis bag. The dialysis continues for three days, and the water is changed twice per day. The resulting oxidized alginate is freeze dried.

[0177] Example 2 - Preparation of a gel pad comprising the first and the second first hydrogel. The first hydrogel is prepared by mixing 125 mg of oxidized alginate and 125 pl of a 10mg / ml silica-based nanoparticle stock solution for 10 minutes in 2,675 ml MQ H2O. 1 g acrylamide is added, the mixture is vortexed and stirred for 10 minutes. 250 pl 0.1 M NaOH is added, and the mixture is vortexed and stirred intensively for 1-2 minutes. 10 mg potassium persulfate is added, and the mixture is vortexed and stirred intensively for 1-2 minutes. 15 pl TEMED is added, and the mixture is vortexed immediately followed by sonication for 10 seconds and direct transfer to mold for casting.

[0178] The second hydrogel is prepared by mixing 242,5 mg oxidized alginate and 7,5 mg (3%) dopamine functionalized oxidized alginate for 10 minutes in 2,4 ml MQ H2O. 1 g acrylamide is added, the mixture is vortexed and stirred for 10 minutes. 250 pl 0.1 M NaOH is added, and the mixture is vortexed and stirred intensively for 1-2 minutes. 375 pl of a 9,82 ml / ml stock solution of ammonium persulfate is added and the mixture is vortexed and stirred intensively for 1-2 minutes. 22,5 pl TEMED is added, and the mixture is vortexed immediately followed by sonication for 10 seconds and direct transfer to mold for casting.

[0179] Example 3 - Casting of multi-layered ultrasound gel pad.

[0180] The first hydrogel is mixed in controlled conditions; under a nitrogen atmosphere and in an ice bath (101). The first hydrogel is sonicated for 5-10 seconds to remove the bubbles (102), it is subsequently and carefully transferred to the mold before the curing process starts and continuously kept in controlled conditions in order to avoid further bubbles forming during the polymerization process (103). The silica-based nanoparticles in the gel of the first layer absorb and remove vapor unable to escape the hydrogel. Once the first hydrogel is solid and cross-linked the second hydrogel is cast on the top of the first hydrogel following the same procedure as for the first hydrogel (104, 105, 106) (Fig. 1).

[0181] Example 4 - Scanning Electron Microscopy (SEM).

[0182] Morphological structures of the gel pads were investigated using a FEI Quanta 200 ESEM FEG Scanning Electron Microscope (USA) equipped with a field emission gun, a scanning electron microscope (FEI Quanta 200 ESEM FEG). It was operated with 5, 10, 30 kV and emission current at 5 mA. In order to avoid structure collapsing, the gel pads were surrounded by milli-Q water then transferred to -80°C and kept overnight, lyophilized for 24 hours and snap cross-sectioned by using N2 liquid. Samples were placed in carbon conductive tapes, and sputter-coated using gold (10 nm) by Quorum coater Q150T (Quorum Technologies, UK).

[0183] The first and the gel of the second layers become a single gel pad unit, without phase separation or formation of an interface. The addition of silica-based nanoparticles cannot not be seen in the gel pad. However, it does improve the self-healing properties of the first and the gel of the second layer because of the additional hydroxyl groups and hydrogen bonds (Fig. 5A-D).

[0184] Scanning electron microscopy of solid silica nanoparticles showing nanoparticles mono-dispersion (Fig. 6B).

[0185] Example 5 - Mechanical characterization of the gel pad.

[0186] Mechanical tests were performed by Instron (model 5967, U.K.) mechanical tester equipped with a 500 N load cell, under a 0.5 mm / min compression rate. The hydrogels dimensions (diameter and height) were measured by using a digital caliper. The compressive young modulus was calculated from the slope of the stress-strain curve at 15-25% strain region. The breaking points and the compression stress at specific strain (specifically, at 50% strain and at 80% strain) were also reported. The toughness was computed as the area under the stress-strain curve.

[0187] The mechanical characterizations of the first hydrogel shows that not only does the silica-based nanoparticles have the ability to minimize bubble production, but can indeed also result in a firmer gel (Fig. 13A-F)

[0188] Decreasing the oxidized alginate functionalized with dopamine content increases the hardness and compressibility, decreases the self-healing capacity and increases the lap shearing while at the same time reduces the production cost. While increasing the content of oxidized alginate functionalized with dopamine content decreases the hardness and compressibility, produces ultra-soft hydrogels, increases the self-healing capacity and increases the adhesiveness (Fig. 14A-F).

[0189] Example 6 - The lap-shear strength test for the second layer.

[0190] The adhesiveness of the hydrogels was investigated by following a standard lap-shear test method (ASTM F2255) using Instron (model 5967, U.K.) with 500 N load cell. At a speed of 10 mm / min, the measurements were performed using ultrasound transducers. Once the specimens were placed between the surface pieces, they were slightly compressed to ensure that all surfaces were covered. The lap-shear strength test for the second layer is analyzed for varying dopamine concentration (FIG15A), while (Fig. 15B) shows the adhesion to the ultrasound transducer, coated with 3% dopamine). (Fig. 15C) shows the lap-shear strength tests for the second layer with 3% dopamine functionalized oxidized alginate on different surfaces. It was observed that the ultrasound transducer exhibited adhesion strengths around 15 kPa for porcine skin, around 65 kPa for bone, and on the metal surface around 89 kPa. While the control-fibrin glue (Fig. 15C) showed very weak adhesiveness on porcine skin, while on metal and plastic it was around 2.7 kPa and 18 kPa for bone. Thus, the second layer was in average superior to commercially available fibrin. For skin anything about 20 kPa will create patient discomfort and anything below 5 kPa will not adhere properly. Hence, anything above 20 kPa creates sufficient adhesion to the transducer.

[0191] Example 7 - Analysis of alginate oxidation.

[0192] The oxidation degree alginate was determined by NMR to be 54.53 % (Fig. 8B). The molecular weight was determined of both the pristine alginate and the oxidized alginate, observing a drop from around 150 kDa to 20 kDa (Fig. 8A). The chemical structure of the oxidized alginate was analyzed in depth by FTIR (Fig. 8C). It was observed that pristine alginate exhibited a wide band centered at 3325 cm-1indicative of hydroxyl group stretching modes, accompanied by a minor intensity peak at 2924 cm-1stemming from -CH2 groups. Two prominent high-intensity peaks at 1596 cm-1and 1404 cm-1were attributed to asymmetric and stretching modes of carboxylate groups, while a range of vibrations between 1100-1000 cm-1denoted C-O-C stretching modes arising from glycoside bonds. Verification of alginate oxidation was confirmed by the appearance of a new C=O group resulting from aldehyde moieties, evident at 1731 cm-1. Additionally, the intensity of peaks corresponding to C-O-C stretching at 1080 and 807 cm-1displayed attenuation, indicative of alginate chain cleavage during the oxidation process.

[0193] Example 8 - FTIR analysis of oxidized alginate functionalized with dopamine.

[0194] FTIR analysis was performed on both dopamine and oxidized alginate to ascertain the interaction between oxidized alginate and dopamine (Fig. 11).

[0195] The FTIR spectra of dopamine identifies significant peaks at 3325 cm-1(associated with NH stretching), 3200 cm-1(linked to OH stretching), 3027 cm-1(aromatic CH stretching), 1609 cm-1(pertaining to NH bending), 1491 cm-1(indicative of aromatic C=C stretching), and 1273 cm-1(attributed to C-N stretching).

[0196] Following the modification of the oxidized alginate, shifts were detected in the dopamine-related peaks within the FTIR spectra. The aromatic C=C stretching peak shifted to 1509 cm-1, and the CN stretching peak shifted to 1280 cm-1. A new peak 1669 cm-1is related to the C=O group due to the amide bond formation between carboxylate group present in oxidized alginate and amine group present in the dopamine However, the C=O group at 1731 cm-1, originating from aldehyde moieties, remained observable in the dopamine functionalized oxidized alginate spectra. This observation underscores that the Schiff base reaction between the amine and aldehyde groups are insignificant. FTIR results indicate amide bond formation between carboxylate group present in oxidized alginate and amine group present in the dopamine are the main coupling mechanism between dopamine and oxidized alginate.

[0197] Example 9 - FTIR analysis of the first layer.

[0198] Important peaks were observed corresponding to acrylamide at 3333, 3164 cm-1(NH2 stretching), 1664 cm-1(C=O stretching), 1603 cm-1(NH2 bending), 1418 cm-1(CN stretching), and 980 cm-1(C=C bending). After reacting the oxidized alginate with acrylamide, the C=O peak belonging to aldehyde moieties at 1731 cm-1disappeared in the FTIR spectrum of oxidized alginate 0% nanoparticles.

[0199] In addition, the shift in the position of the peak from 1664 cm-1(corresponding to C=O stretching in acrylamide) to 1645 cm-1, coupled with an increase in intensity, indicates the formation of a C=N bond due to the Schiff-base reaction. The disappearance of the C=C peak at 980 cm-1confirmed the acrylamide polymerization. The acrylamide polymerization is also confirmed by the disappearance of the C=C peak at 980 cm-1. The incorporation of 1% silica-based nanoparticles did not induce noticeable shifts in the FTIR spectra, primarily owing to the low silica-based nanoparticle concentration in the gel pad. However, with an increasing concentration of nanoparticles in the gel pad (2% and 4%), noticeable Si-0 stretching at 949 cm-1and Si-O-Si stretching at 1065 cm-1were observed (Fig. 9).

[0200] Example 10 - FTIR analysis of the second layer.

[0201] The FTIR spectra of the second layer confirmed a Schiff base reaction between aldehyde and amine groups by the presence of a C=N bond at 1651 cm-1. The disappearance of the C=C peak at 980 cm-1also confirmed acrylamide polymerization. Overall, the dynamic formation of C=N bonds, acrylamide polymerization, and the incorporation of nanoparticles in the second layer were confirmed by the FTIR analysis (Fig. 10).

[0202] Items

[0203] 1. A multilayered gel pad comprising:

[0204] • a first layer having a first surface that is non-adherent to patient tissue; and

[0205] • a second layer having a second surface that is adapted to be adherent to a target surface; wherein the first and second surface are on opposite outer sides of the gel pad and wherein the first and the second layer have self-healing properties.

[0206] 2. The multilayered gel pad according to any one of the preceding items, wherein the target surface is made of one or more polymeric materials, an organic material, such as cells or tissues, and a metal.

[0207] 3. The multilayered gel pad according to any one items 1-2, wherein the gel pad is an ultrasound gel pad.

[0208] 4. The multilayered gel pad according to any one items 1-2, wherein the gel pad is a tissue adhesive.

[0209] 5. The multilayered gel pad according to any one items 1-2, wherein the gel pad is a wound bandage, such as for wound care applications.

[0210] 6. The multilayered gel pad according to any one items 1-2, wherein the gel pad is an implant / wearable with theraregenerative, theranostic and cyborganic capacities.

[0211] 7. The multilayered gel pad according to any one items 1-2, wherein the gel pad is arranged for adhering to living tissue, and for monitoring living tissue, such as both in vitro and in vivo, by imaging and / or electrically.

[0212] 8. The multilayered gel pad according to any one items 1-2, wherein the gel pad is a hemostatic. 9. The multilayered gel pad according to any one of the preceding items, wherein the gel pad has a self-healing interface between the first layer and the second layer, and wherein the composition of said interface has a gradual transition, such as from a composition of the first layer to a composition of the second layer.

[0213] 10. The multilayered gel pad according to any one of the preceding items, wherein the interface between the first and the second layer of the gel pad is self- healing, such as wherein the interface between the first layer and the second layer has been formed by self-healing of said layers.

[0214] 11 . The multilayered gel pad according to any one of the preceding items, wherein the first and / or second layer comprises or consists of a hydrogel.

[0215] 12. The multilayered gel pad according to any one of the preceding items, wherein the first and / or the second layer comprises gelatin, aminated gelatin, dopamine, alginate, oxidized alginate, chitosan, oxidized chitosan, pectin, oxidized pectin, silk, oxidized silk, methacrylated silk, methacrylated alginate, keratin, aminated keratin, methacrylated keratin, methacrylated pectin, methacrylated chitosan, aminated chitosan, polyacrylic acid, poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), Polyaniline, Poly(N-isopropylacrylamide), Polyvinyl Alcohol (PVA), Polyacrylic Acid (PAA), glycerol, cellulose, methacrylared cellulose, nano-cellulose, polyacrylamidesodium acrylate, methacrylamide, acrylic acid, poly(methyl methacrylate), polyvinyl acetate, polyacrylamide-co-acrylic acid, hydrolyzed polyacrylamide, poly-acrylamido-2- methylpropane sulfonate, poly(acrylamide-co-diallyldimethylammonium) or poly(acrylamide-co-N,N,N-trimethyl-2-((1-oxo-2-propenyl)oxy)).

[0216] 13. The multilayered gel pad according to any one of the preceding items, wherein the first and / or the second layer comprises ionic liquids, such as iron chloride, lithium chloride, and / or calcium chloride.

[0217] 14. The multi-layered gel pad according to any of the preceding items, wherein the first layer and / or the second layer comprise nanoparticles including solid nanosilicate particles, hollow mesoporous nanosilicate particles, carbon- nanotubes, graphene fillers, 2D transition metal carbides, carbonitrides, nitrides, Mxenes, nanoclays such as bentonite, kaolinite, hectorite, silver nanoparticles, gold nanoparticles, halloysite, silica-based nanoparticles, polysaccharide based nanoparticles, alginate-based nanoparticles, acrylamide-based nanoparticles, ZrC>2, Iron oxide-based, TiCh-based nanoparticles, quantum dots, montmorillonite and / or metal organic framework (MOF).

[0218] 15. The multilayered gel pad according to any one of the preceding items, wherein the first layer and / or the second layer comprises polyacrylamide.

[0219] 16. The multilayered gel pad according to item 15, wherein the polyacrylamide of the first layer and / or of the second layer have a molecular weight in the range of 10-600 kDa.

[0220] 17. The multilayered gel pad according to any one of the preceding items, wherein the first layer comprises polyacrylamide, oxidized alginate and vapor scavengers, such as nanoparticles arranged to scavenge vapor.

[0221] 18. The multilayered gel pad according to any one of the preceding items, wherein the second layer comprises polyacrylamide, oxidized alginate and oxidized alginate functionalized with dopamine and optionally vapor scavengers, such as nanoparticles arranged to scavenge vapor.

[0222] 19. The multilayered gel pad according to any one of the preceding items, wherein the ratio between the oxidized alginate and polyacrylamide of the first layer is in the range 10-500:1000, such as in the range 20-400:1000, such as in the range 20-375:1000, such as in the range 25-350:1000, such as 62.5-250:1000.

[0223] 20. The multilayered gel pad according to any one of the preceding items, wherein the ratio between the polyacrylamide, the oxidized alginate and the oxidized alginate functionalized with dopamine of the second layer is in the range 1000:10-500:0.15-40, such as in the range 1000:10-500:0.25-30, such as in the range 1000:15-400:0.25-30, such as in the range 1000:15-400:0.25-20, such as in the range 1000:20-400:0.25-20, such as in the range 1000:20-400:0.25-17.5, such as in the range 1000:20-350:0.25-17.5, such as in the range 1000:20-350: 0.25-17.5, such as in the range 1000:40-350:0.25-17.5, such as in the range 1000:50-350:0.25-17.5, such as in the range 1000:75-325:0.25-17.5, such as in the range 1000:100-300:0.25-17.5, such as in the range 1000:100-300:0.5-10, such as in the range 1000:100-300:0.75-10, such as in the range 1000:100- 300:1-9.

[0224] 21. The multilayered gel pad according to any one of the preceding items, wherein the oxidized alginate functionalized with dopamine of the second layer has a molecular weight between 5-60 kDa.

[0225] 22. The multilayered gel pad according to any one of the preceding items, wherein the oxidized alginate of the first and the second layer has a molecular weight of between 20-60 kDa.

[0226] 23. The multilayered gel pad according to any one of the preceding items, wherein the oxidized alginate of the first and the second layer has a degree of oxidation between 50% and 60%, preferably between 54% and 55%.

[0227] 24. The multilayered gel pad according to any one of the preceding items, wherein the water content of the first layer is at least 70%, such as in the range of 72% and 79%.

[0228] 25. The multilayered gel pad according to any one of the preceding items, wherein the water content of the second layer is at least 70%.

[0229] 26. The multilayered gel pad according to any one of the preceding items, wherein the gel pad, such as the interface between the first layer and the second layer, is self-healing.

[0230] 27. The multilayered gel pad according to any one of the preceding items, wherein the first layer and the second layer are formed such that no defined interface is distinguishable, particularly, the first layer and the second layer form a selfhealed region that does not distort the ultrasound imaging properties. 28. The multilayered gel pad according to any one of the preceding items, wherein the interface between the first and the second layer has a gradual transition in the compositions of the first and second layers across said interface.

[0231] 29. The multilayered gel pad according to any one of the preceding items, wherein the multilayered gel pad has a structural integrity sufficient such that it can be removed from the target surface without breaking.

[0232] 30. The multilayered gel pad according to any one of the preceding items, wherein the gel pad is adapted for ultrasound imaging of uneven surfaces.

[0233] 31. The multilayered gel pad according to any one of the preceding items, wherein the variation in acoustic impedance between the first layer and the second layer is at most 10%, such as the most 5%, wherein the acoustic impedance of the multilayered gel pad is constant.

[0234] 32. The multilayered gel pad according to any one of the preceding items, wherein the first layer and / or the second layer pad comprises vapor scavengers, such as nanoparticles arranged for entrapping vapor, such as during manufacturing of the gel pad.

[0235] 33. The multilayered gel pad according to item 32, wherein the vapor scavengers have an average diameter less than 200 nm, preferably 20-110 nm.

[0236] 34. The multilayered gel pad according to any one of items 32-33, wherein the concentration of the vapor scavengers is less than 4%, such as 1-2%.

[0237] 35. The multilayered gel pad according to any one of the preceding items, wherein the first layer has a compressive Young’s modulus in the range of 1-90 kPa, such as in the range of 10-80 kPa, such as in the range of 20-75 kPa, such as in the range of 20-70 kPa, such as in the range of 20-65 kPa, and the second layer has a compressive Young’s modulus in the range of 1-20 kPa, such as in the range of 1-15 kPa, such as in the range of 1-10 kPa, such as in the range of 1-8 kPa. 36. The multilayered gel pad according to any one of the preceding items, wherein the first layer has a compressive Young’s modulus of 43 ± 16 kPa and the compressive second layer has a Young’s modulus of 4 ± 2 kPa.

[0238] 37. The multilayered gel pad according to any one of the preceding items, wherein the lap shear strength of the second surface to the target material, such as an ultrasound transducer material, is in the range of 1-75 kPa, such as in the range of 2-70 kPa, such as in the range of 4-60 kPa, such as in the range of 4-50 kPa, such as in the range of 4-40 kPa, such as in the range of 6-35 kPa, such as in the range of 8-35 kPa.

[0239] 38. The multilayered gel pad according to any one of the preceding items, wherein the lap shear strength of the second surface of the gel pad to the target material, such as an ultrasound transducer, is in the range of 8-34 kPa, such as 12-18 kPa.

[0240] 39. The acoustic velocity of the first layer of the gel pad according to any one of the preceding items is 1650 - 1670 m / s, such as 1661.8 m / s.

[0241] 40. The acoustic impedance of the first layer of the gel pad according to any one of the preceding items is 1.90 - 1.920, such as 1.911 Mpa s nr1(Mrayl).

[0242] 41. The multilayered gel pad according to any one of the preceding items, wherein the target material comprises or consists of a material selected from the group including polymer silicone rubber, polyimide film and / or copper film.

[0243] 42. A gel pad comprising the first layer of the multilayered gel pad according to any one of items 1-41.

[0244] 43. A gel pad comprising the second layer of the multilayered gel pad according to any one of items 1-41.

[0245] 44. Use of the multilayered gel pad according to any of items 1-41 for ultrasound imaging. 45. Use of the multilayered gel pad according to any of items 1-41 as a tissue adhesive.

[0246] 46. Use of the multi-layered gel pad according to any of the items 1-41 as a wound bandage for wound care applications

[0247] 47. Use of the multi-layered gel pad according to any of the items 1-41 as an implant / wearable with theraregenerative, theranostic, and cyborganic capacities.

[0248] 48. Use of the multi-layered gel pad according to any of items 1-41 for adhering to, and monitoring, living tissue, such as both in vitro and in vivo, by imaging and / or electrically.

[0249] 49. The multilayered gel pad according to any one items 1-41, wherein the gel pad is a hemostatic.

[0250] 50. A method of manufacturing a multilayered gel pad, according to any one of items 1-41.

[0251] 51. The method of manufacturing a multilayered gel pad according to item 50, wherein the method comprises casting the first layer and the second layer.

[0252] 52. The method of manufacturing a multilayered gel pad according to any one of items 50-51 , wherein the first layer is cast first, and the second layer is subsequently cast on top of the first layer.

[0253] 53. The method of manufacturing a multilayered gel pad according to any one of items 50-52, wherein the second layer is cast first, and the first layer is subsequently cast on top of the second layer.

[0254] 54. The method of manufacturing a multi-layered gel pad according to any one of items 50-53, wherein the first and the second layers are cast simultaneously and assembled after they have solidified. 55. The method of manufacturing a multilayered gel pad according to any one of items 50-54 comprising:

[0255] • forming a first layer by mixing a first polyacrylamide and a first oxidized alginate in a controlled environment, such as under nitrogen gas at a temperature in the range of 0-10°C, such as 0-4°C, and adding nanoparticles, KPS (initiator) and TEMED followed by sonication and immediate transfer to a mold for curing to take place, thereby generating a polymerized first layer;

[0256] • forming a second layer by mixing a second polyacrylamide, a second oxidized alginate and an oxidized alginate functionalized with dopamine, in a controlled environment, such as under nitrogen gas a temperature in the range of 0-10°C, such as 0-4°C, and adding nanoparticles, ammonium persulfate (APS, initiator) and TEMED and followed by sonication, and immediate transfer of said second layer on top of the curing first layer, and allowing for polymerizing of the second layer;

[0257] • self-healing the first and second layer by having the first and second layer being in contact at a temperature in the range of 0-10°C, such as 0-4°C for at least 30 minutes in N2 atm.

[0258] 56. The method of manufacturing a multilayered gel pad according to any one of items 50-55, wherein the still liquid second layer is, after sonication, transferred onto the cured first layer.

[0259] 57. The method of manufacturing a multilayered gel pad according to any one of items 50-56, wherein the method is performed at a temperature in the range 0- 10°C, preferably in the range between 0-4°C.

[0260] 58. The method of manufacturing a multilayered gel pad according to any one of items 50-57, wherein the first and the second layers are sonicated prior to polymerizing and casting.

[0261] 59. The method of manufacturing a multilayered gel pad according to any one of items 50-58, wherein increasing the oxidation degree of the oxidized alginate increases the self-healing properties of the first and / or second layer. 60. The method of manufacturing a multilayered gel pad according to any one of items 50-59, wherein increasing the oxidation degree of the oxidized alginate increases the adhesiveness of the second layer.

[0262] 61. The method of manufacturing a multilayered gel pad according to any one of items 50-60, wherein decreasing the oxidation degree of the oxidized alginate decreases the Young’s modulus of the first and second layer.

[0263] 62. The method of manufacturing a multilayered gel pad according to any one of items 50-61 , wherein the first layer is prepared, under a N2 atmosphere, such as a N2 controlled atmosphere, of up to 4°C by: a) dissolving oxidized alginate in a minimum amount of water; b) adding 0.1-4% Silica-based nanoparticles; c) adding acrylamide and mixing until it dissolves; d) adjusting the pH to 3.5-4, preferably by adding (0.1 M) NaOH, and mix; e) adding potassium persulfate dissolved in water and mix; f) adding TEMED, mixing, sonicating and casting the gel immediately in a controlled N2 atmosphere up to 4°C.

[0264] 63. The method of manufacturing a multilayered gel pad according to any one of items 50-62, wherein the second layer is prepared by: a) dissolving oxidized alginate and oxidized alginate functionalized with dopamine in a minimum amount of water; b) adding acrylamide and mixing until it dissolves; c) adjusting the pH to 3.5-4, preferably by adding (0.1 M) NaOH, and mix; d) adding ammonium persulfate dissolved in water and mix; e) adding TEMED, mixing, sonicating and casting the gel immediately in a controlled N2 atmosphere up to 4°C.

[0265] 64. The method of manufacturing a multilayered gel pad according to any one of items 50-63, wherein the oxidized alginate is prepared by: a) dissolving sodium-alginate in water; b) adding sodium periodate and stir the solution for 20h at room temperature in the dark; c) adding ethylene glycol; d) perform dialysis on the oxidized alginate; e) freeze dry the oxidized alginate.

Claims

Claims1. A multilayered gel pad comprising:• a first layer having a first surface that is configured to be non-adherent to patient tissue, the first layer comprising: i. a first polymer comprising a repeating first subunit containing an amide group; and ii. a second polymer comprising a repeating second subunit containing an aldehyde group;• a second layer having a second surface that is configured to be adherent to a target surface, the second layer comprising: i. the first polymer; ii. the second polymer; and iii. a third polymer comprising a repeating second subunit containing an aldehyde group, an amine group and a phenolic group; wherein the first surface and the second surface are on opposite outer sides of the gel pad, and wherein the first layer and the second layer have self-healing properties.

2. The multilayered gel pad according to claim 1 , wherein the first and / or the second layer comprises or consists of a hydrogel.

3. The multilayered gel pad according to any one of the preceding claims, wherein the gel pad has a self-healing interface between the first layer and the second layer, and wherein the composition of said interface has a gradual transition, such as transitioning from a composition of the first layer to a composition of the second layer.

4. The multilayered gel pad according to any one of the preceding claims, wherein the interface between the first and the second layer of the gel pad is self- healing, such as wherein the interface between the first layer and the second layer has been formed by self-healing contact of said layers.

5. The multilayered gel pad according to any one of the preceding claims, wherein the interface between the first and the second layer has a gradual transition in the compositions of the first and second layers across said interface.

6. The multilayered gel pad according to any one of the preceding claims, wherein the first polymer has a molecular weight in the range of 10-600 kDa.

7. The multilayered gel pad according any one of the preceding claims, wherein the first polymer of the first and / or second layer has a molecular weight in the range of 70-80 kDa.

8. The multilayered gel pad according to any one of the preceding claims, wherein the second polymer of the first and the second layer has a molecular weight of between 20-60 kDa.

9. The multilayered gel pad according to any one of the preceding claims, wherein the third polymer of the second layer has a molecular weight between 5-60 kDa.

10. The multilayered gel pad according to any one of the preceding claims, wherein the ratio between the second and the first polymer of the first layer is in the range 10-500:1000, such as in the range 20-400:1000, such as in the range 20- 375:1000, such as in the range 25-350:1000, such as 62.5-250:1000.

11. The multilayered gel pad according to any one of the preceding claims, wherein the ratio between the first, the second and the third polymer of the second layer is in the range 1000:10-500:0.15-40, such as in the range 1000:10-500:0.25-30, such as in the range 1000:15-400:0.25-30, such as in the range 1000:15- 400:0.25-20, such as in the range 1000:20-400:0.25-20, such as in the range 1000:20-400:0.25-17.5, such as in the range 1000:20-350:0.25-17.5, such as in the range 1000:20-350: 0.25-17.5, such as in the range 1000:40-350:0.25-17.5, such as in the range 1000:50-350:0.25-17.5, such as in the range 1000:75- 325:0.25-17.5, such as in the range 1000:100-300:0.25-17.5, such as in the range 1000:100-300:0.5-10, such as in the range 1000:100-300:0.75-10, such as in the range 1000:100-300:1-9.

12. The multilayered gel pad according to any one of the preceding claims, wherein the degree of oxidation of the second and third polymer is between 50% and 60%, preferably between 54% and 55%.

13. The multilayered gel pad according to any one of the preceding claims, wherein the water content of the first layer is at least 70%, such as in the range of 72% and 79%.

14. The multilayered gel pad according to any one of the preceding claims, wherein the water content of the second layer is at least 70%.

15. The multilayered gel pad according to any one of the preceding claims, wherein the first polymer is polyacrylamide, sodium acrylate, methacrylamide, acrylic acid, poly(methyl methacrylate), polyvinyl acetate, polyacrylamide-co-acrylic acid, hydrolyzed polyacrylamide, poly-acrylamido-2-methylpropane sulfonate, poly(acrylamide-co-diallyldimethylammonium), or poly(acrylamide-co-N,N,N- trimethyl-2-((1-oxo-2-propenyl)oxy)).

16. The multilayered gel pad according to any one of the preceding claims, wherein the second polymer is oxidized alginate, alginate, chitosan, oxidized chitosan, pectin, oxidized pectin, silk, oxidized silk, methacrylated silk, methacrylated alginate, keratin, aminated keratin, methacrylated keratin, methacrylated pectin, methacrylated chitosan, or aminated chitosan.

17. The multilayered gel pad according to any one of the preceding claims, wherein the third polymer comprises a base polymer functionalized with the phenolic group, wherein the base polymer is oxidized alginate, alginate, chitosan, oxidized chitosan, pectin, oxidized pectin, silk, oxidized silk, methacrylated silk, methacrylated alginate, keratin, aminated keratin, methacrylated keratin, methacrylated pectin, methacrylated chitosan, or aminated chitosan.

18. The multilayered gel pad according to any one of the preceding claims, wherein the phenolic group is catechol, gallol, hydroquinone, pyrogallol, resorcinol, phloroglucinol, tannic acid, ellagic acid, an / or quercetin.

19. The multi-layered gel pad according to any of the preceding claims, wherein the first layer and / or the second layer further comprises a vapor scavenger.

20. The multi-layered gel pad according to any one of the preceding claims, wherein the vapor scavenger is solid nanosilicate particles, hollow mesoporous nanosilicate particles, carbon-nanotubes, graphene fillers, 2D transition metal carbides, carbonitrides, nitrides, Mxenes, nanoclays such as bentonite, kaolinite, hectorite, halloysite, and / or montmorillonite, and / or metal organic framework (MOF).

21. The multi-layered gel pad according to any one of the preceding claims, wherein the vapor scavenger is a mesoporous nanoparticle.

22. The multilayered gel pad according to any one of the preceding claims, wherein the vapor scavengers have an average diameter less than 200 nm, preferably 20-110 nm.

23. The multilayered gel pad according to any one of the preceding claims, wherein the concentration of the vapor scavengers is 4% or less, such as within the range of from 1 % to 2%.

24. The multilayered gel pad according to any one of the preceding claims wherein the first and / or the second layer comprises ionic liquids, such as iron chloride, lithium chloride, and / or calcium chloride.

25. The multilayered gel pad according to any one of the preceding claims, wherein the target surface is made of one or more polymeric materials, an organic material, such as cells or tissues, and a metal.

26. The multilayered gel pad according to any one of the preceding claims, wherein the variation in acoustic impedance between the first layer and the second layer is at most 10%, such as the most 5%, wherein the acoustic impedance of the multilayered gel pad is constant.

27. The multilayered gel pad according to any one of the preceding claims, wherein the first layer has a compressive Young’s modulus in the range of 1-90 kPa, such as in the range of 10-80 kPa, such as in the range of 20-75 kPa, such as in the range of 20-70 kPa, such as in the range of 20-65 kPa, and the second layer has a compressive Young’s modulus in the range of 1-20 kPa, such as in the range of 1-15 kPa, such as in the range of 1-10 kPa, such as in the range of 1-8 kPa.

28. The multilayered gel pad according to any one of the preceding claims, wherein the first layer has a compressive Young’s modulus of 43 ± 16 kPa and the second layer has a compressive Young’s modulus of 4 ± 2 kPa.

29. The multilayered gel pad according to any one of the preceding claims wherein the first layer has a lap shear strength to patient tissue, such as skin, of 0.5 kPa or less.

30. The multilayered gel pad according to any one of the preceding claims, wherein the lap shear strength of the second surface to the target material, such as an ultrasound transducer material, is in the range of 1-75 kPa, such as in the range of 2-70 kPa, such as in the range of 4-60 kPa, such as in the range of 4-50 kPa, such as in the range of 4-40 kPa, such as in the range of 6-35 kPa, such as in the range of 8-35 kPa.

31. The multilayered gel pad according to any one of the preceding claims, wherein the lap shear strength of the second surface of the gel pad to the target material, such as an ultrasound transducer, is in the range of 8-34 kPa, such as 12-18 kPa.

32. The multilayered gel pad according to any one of the preceding claims, wherein the acoustic velocity of the first layer of the gel pad is 1650 - 1670 m / s.

33. The multilayered gel pad according to any one of the preceding claims, wherein the acoustic impedance of the first layer of the gel pad is 1.90 - 1.920 Mpa s ■rm1(Mrayl).

34. Use of the multilayered gel pad according to any preceding claims for ultrasound imaging.

35. Use of the multilayered gel pad according to any one of claims 1-33 as a tissue adhesive.

36. Use of the multi-layered gel pad according to any one of claims 1-33 as a wound bandage for wound care applications.

37. Use of the multi-layered gel pad according to any one of claims 1-33 as an implant / wearable with theraregenerative, theranostic, and cyborganic capacities.

38. Use of the multi-layered gel pad according any one of claims 1-33 for adhering to, and monitoring, living tissue, such as both in vitro and in vivo, by imaging and / or electrically.

39. Use of the multi-layered gel pad according any one of claims 1-33 as a hemostatic.

40. A method of manufacturing a multilayered gel pad as defined in claims 1-33, wherein the first layer is prepared, under a N2 atmosphere, such as a N2 controlled atmosphere, of up to 4°C by: a) dissolving oxidized alginate in a minimum amount of water; b) adding 0.1-4% Silica-based nanoparticles; c) adding acrylamide and mixing until it dissolves; d) adjusting the pH to 3.5-4, preferably by adding (0.1 M) NaOH, and mix; e) adding potassium persulfate dissolved in water and mix; f) adding TEMED, mixing, sonicating and casting the gel immediately in a controlled N2 atmosphere up to 4°C.

41. The method of manufacturing a multilayered gel pad as defined in claims 1-33 and / or according to claim 40, wherein the second layer is prepared by: a) dissolving oxidized alginate and oxidized alginate functionalized with dopamine in a minimum amount of water;b) adding acrylamide and mixing until it dissolves; c) adjusting the pH to 3.5-4, preferably by adding (0.1 M) NaOH, and mix; d) adding ammonium persulfate dissolved in water and mix; e) adding TEMED, mixing, sonicating and casting the gel immediately in a controlled N2 atmosphere up to 4°C.

42. The method of manufacturing a multilayered gel pad as defined in claims 1-33 and / or according to claims 40-41 , wherein the first layer is cast first, and the second layer is subsequently cast on top of the first layer; or wherein the second layer is cast first, and the first layer is subsequently cast on top of the second layer; or wherein the first and the second layers are cast simultaneously and assembled after they have solidified.

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