ULTRASOUND COUPLING MATERIAL

This application claims priority of U.S. provisional patent application No. 60/948,595, filed July 9, 2007, which is incorporated herein be reference in its entirety.

1.0 FIELD OF THE INVENTION

[0001] The present invention is generally directed to ultrasound coupling materials. In particular, the present invention is directed to ultrasound coupling materials that include at least one hydrogel, a viscosifying agent or a combination thereof and a hydrating fluid, wherein the hydrating fluid is introduced to the hydrogel, viscosifying agent or combination thereof to form a semi-solid ultrasound coupling material that does not compromise the image quality of the tissue being imaged or distort the tissue being imaged and minimizes patient discomfort since it can be easily removed and/or disposed of.

2.0 BACKGROUND

[0002] Ultrasound is a non-invasive means of imaging internal soft tissue and soft tissue structures, such as the gallbladder, liver, heart, kidneys, pancreas, bladder, thyroid gland, prostate, uterus and breast tissue. Ultrasound imaging can help in the diagnosis of a wide range of diseases and conditions. For example ultrasound can help detect breast cancer and measure the flow of blood in arteries to detect blockages. Ultrasound can also be used to monitor the growth and development of embryos in the uterus. [0003] During an ultrasound test, high-frequency sound waves, inaudible to the human ear, are transmitted through body tissues using an instrument called a transducer. The ultrasound waves are used to detect variations in tissue densities. The transducer then transmits the information to a computer that displays the information on a monitor. [0004] Since the ultrasound waves are poorly transmitted through air, the transducer is generally placed in direct contact with the patient's skin. Having the transducer directly applied to the skin can be uncomfortable and unhygienic for the patient. Moreover, the pressure applied to the skin by the contact and movement of the transducer can result in undesirable tissue distortion which can make diagnosis difficult and may even result in misdiagnosis.

[0005] In addition to placing the transducer in direct contact with the patient's skin a coupling fluid is usually applied to the patient's skin to occupy any remaining space

between the transducer and the patient's skin. Ultrasound coupling fluids are important in helping to ensure efficient transmission of ultrasound waves in and out of the body. Such coupling fluids are usually viscous, sticky pastes or gels that contain water soluble, non-cross-linked polymers. Traditionally, application and removal of such gels can be messy and unpleasant for the patient.

[0006] Accordingly, there is a need for ultrasound coupling materials that ensure efficient transmission of ultrasound waves in and out of the body. Ideally such coupling materials are easy to use and minimize patient discomfort. Additionally, there is a need for ultrasound systems that include ultrasound coupling materials and minimize or prevent tissue distortion.

3.0 SUMMARY

[0007] These and other objectives are addressed by the present invention. The ultrasound coupling materials of the present invention are designed to minimize patient discomfort while making removal and disposal of the ultrasound coupling material easier compared to currently available ultrasound coupling fluid formulations, which are commonly discontiguous gels or pastes that are difficult to remove. For example, many currently available ultrasound coupling fluid formulations must be washed-off or wiped- off in order to be removed. Additionally, the ultrasound coupling materials described herein allow for superior image quality and do not deter from or otherwise interfere with the image quality of the ultrasound images.

[0008] The present invention is directed to ultrasound coupling materials that behave initially like a fluid and ultimately become a semi-solid. While in the initial fluid phase, the ultrasound coupling materials described herein are able to fill any space between a transducer and tissue being imaged. After becoming a semi-solid, the ultrasound coupling materials described herein can be removed as one contiguous mass, allowing for easy removal and disposal of the coupling material. Thus, patient hygiene is improved and patient discomfort is reduced since the ultrasound coupling materials can be removed as one contiguous mass and do not need to be wiped-off or washed-off the patient's skin. Also, issues associated with cleaning and handling ultrasound coupling fluid formulations such as the need for mechanical or other types of seals to prevent leakage are eliminated or at least greatly reduced.

[0009] The ultrasound coupling materials described herein are also designed to be used with an applicator dome or other device which can help eliminate the need for the transducer to be in direct contact with the patient. The ultrasound coupling materials are also formulated such that the coupling materials do not deter from or interfere with the image quality of the ultrasound images and the properties of the ultrasound coupling material such as, but not limited to, propagation speed, acoustic impedance and attenuation, are similar to the properties of the tissue being imaged. [0010] The ultrasound coupling materials of the present invention include a viscosifying agent, a hydrogel or a combination of a viscosifying agent and a hydrogel and a hydrating fluid. The ultrasound coupling materials of the present invention are formulated by combining a viscosifying agent, hydrogel or the combination of a hydrogel and a viscosifying agent with a hydrating fluid. Upon introducing the hydrating fluid to the viscosifying agent, hydrogel or the combination of a hydrogel and a viscosifying agent, the ultrasound coupling material is in a fluid phase and is capable of flowing into and filling any space between a transducer and the tissue being imaged. Over time and during the ultrasound procedure, the ultrasound coupling material transforms into a semi-solid. Thus, once the ultrasound procedure is complete, the ultrasound coupling material can be removed from the patient and/or the ultrasound machine as one contiguous mass, making removal and disposal of the ultrasound coupling material easier. Also, patient discomfort is minimized since the semi-solid ultrasound coupling material is removed as one contiguous mass and the patient does not need to wipe-off or wash-off a paste or a gel from their skin.

[0011] In certain embodiments the ultrasound coupling materials described herein include a viscosifying agent and a hydrating fluid, wherein the hydrating fluid can include, among other materials, at least one multivalent ion. For example, the ultrasound coupling materials described herein can include a viscosifying agent such as an ionically charged polymer like sodium alginate, water, a divalent ion such as calcium, an insoluble calcium salt, a calcium sequestrant and a water soluble acid. [0012] In other embodiments the ultrasound coupling materials described here include a hydrogel and a hydrating fluid. In some embodiments the hydrogels used in the ultrasound coupling materials described herein include cross-linked hydrophilic polymers. For example, the ultrasound coupling materials of the present invention include cross-linked hydrophilic polymers such as polyacrylic acid, polyacrylamide or co-polymers thereof and a hydrating fluid.

[0013] In some embodiments, the ultrasound coupling materials described herein have a solids modulus of between about 10 dynes/cm ² and about 1000 dynes/cm ² once they become a semi-solid. Alternatively, once the ultrasound coupling materials have become a semi-solid the ultrasound coupling materials described herein can have a viscosity of between about 100 Pa. to 10,000 Pa.

[0014] The present invention is also directed to methods of making the ultrasound coupling materials of the instant application. In certain embodiments the methods of making an ultrasound coupling material described herein include the steps of providing a viscosifying agent comprising an ionically charged polymer, introducing a hydrating fluid comprising a soluble multivalent ion to the ionically charge polymer, and forming a semi-solid ultrasound coupling material.

[0015] In other embodiments, the methods of making ultrasound coupling materials include the steps of providing a hydrogel, introducing a hydrating fluid comprising water to the hydrogel, and forming a semi-solid ultrasound coupling material. [0016] The present invention is also directed to systems for ultrasound imaging of soft tissue. Specific systems include, but are not limited to, systems for ultrasound diagnostics. In certain embodiments, the systems described herein include a transducer; an applicator dome having a first side and a second side, wherein the first side is in communication with the transducer and the second side is contoured to accept a breast; a viscosifying agent comprising an ionically charged polymer that is capable of being placed in the second side of the applicator; and a hydrating fluid, wherein upon introducing the hydrating fluid to the ionically charged polymer, a semi-solid ultrasound coupling material is formed.

[0017] In other embodiments the systems described herein can include a transducer; an applicator dome having a first side and a second side, wherein the first side is in communication with the transducer and the second side is contoured to accept a breast; a hydrogel that is capable of being placed in the second side of the applicator; and a hydrating fluid, wherein upon introducing the hydrating fluid to the hydrophilic cross- linked polymer, a semi-solid ultrasound coupling material is formed. [0018] Finally, the present invention is directed to kits that include components to make the ultrasound coupling materials of the present invention. For example, kits of the present invention include a hydrogel and a hydrating fluid, wherein the hydrating fluid includes water. Alternatively, the kits of the present invention include a

viscosifying agent such as an ionically charged polymer; and a hydrating fluid, wherein the hydrating fluid includes a multivalent ion.

4.0 BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 shows a flow chart depicting a method of making the ultrasound coupling materials of the present invention.

[0020] Figure 2 shows an ultrasound system that includes an embodiment of the ultrasound coupling materials described herein.

[0021] Figure 3 shows the creep of a hydrogel sample under 100 g of force.

[0022] Figure 4 shows the creep of hydrogel samples under 100 g of force between

50 and 60 seconds.

[0023] Figure 5 shows the stress relaxation of hydrogel samples.

[0024] Figure 6 shows the stress relaxation of hydrogel samples.

[0025] Figure 7 shows the stress relaxation of hydrogel samples.

[0026] Figure 8 shows the stress relaxation of an example of a ultrasound coupling material.

[0027] Figure 9 shows the stress relaxation of an example of an ultrasound coupling material.

5.0 DETAILED DESCRIPTION

5.1 DEFINITIONS

[0028] The phrase "fluid phase" as used herein can refer to the state of the ultrasound coupling material immediately after the hydrating fluid is introduced to the viscosifying agent, hydrogel or the combination of a viscosifying agent and a hydrogel, wherein the ultrasound coupling material behaves more like a fluid than a solid. [0029] The phrase "hydrating fluid" as used herein can mean a liquid such as a solution or a suspension that when added to a hydrogel, a viscosifying agent or a combination of a hydrogel and a viscosifying agent, a semi-solid ultrasound coupling material is formed.

[0030] The term "hydrogel" as used herein can mean a network of natural or synthetic polymers that are highly water absorbent.

[0031] The term "hydration ratio" means the wet weight of a hydrated hydrogel less the dry weight divided by the dry weight times 100%.

[0032] The term "hydrophilic" as used herein, describes a polymer or other compound that is capable of absorbing water or swelling in the presence of water, but is not necessarily soluble in water. Hydrophilic polymers contained in the ultrasound coupling materials of the present invention can be partially soluble in water.

[0033] The phrase "multivalent ion" as used herein means an element that has the ability to form more than one ion.

[0034] The word "semi-solid" as used herein can mean a material having qualities of a solid and a liquid and is highly viscous.

[0035] The phrase "viscosifying agent" as used herein can mean any agent that is capable of increasing the viscosity of the ultrasound coupling material.

[0036] The phrase "insoluble salt" as used herein can mean a salt that does not dissociate at pH 7.

[0037] The phrase "slow dissolving acid" as used herein can mean an acid that does not dissociate immediately upon contact with water.

[0038] As used herein, the terms "comprising," "comprises", "comprised of,"

"including," "includes," "included," "involving," "involves," "involved," and "such as" are used in their open, non-limiting sense.

5.2 ULTRASOUND COUPLING MATERIALS

[0039] The present invention is directed to ultrasound coupling materials that include a viscosifying agent, a hydrogel or a viscosifying agent and a hydrogel and additionally a hydrating fluid. The ultrasound coupling materials described herein can be used during an ultrasound procedure as coupling between an ultrasound transducer and the tissue being imaged. The ultrasound coupling materials described herein are formulated to behave initially like a fluid during transfer between the transducer and the tissue and, after filling the space between the transducer and the tissue, the material can transform into a semi-solid that can be removed as one contiguous mass following an ultrasound procedure. By transforming into a semi-solid that can be removed as one contiguous mass, issues associated with fluid handling, like the need for mechanical seals to prevent leaking or spillage are eliminated or at least reduced. Also, patient discomfort is reduced and/or clean-up is made easier, since the ultrasound coupling material can be removed and disposed of easily and the patient does not need to wipe or wash-off an ultrasound coupling paste or gel.

[0040] Additionally, the ultrasound coupling materials described herein are formulated so that the image quality of the ultrasound images is not compromised. The ultrasound coupling materials of the present invention are formulated such that the ultrasound properties of the coupling material such as, but not limited to, propagation speed, acoustic impedance and attenuation are close to that of the tissue being imaged. [0041] Once the ultrasound coupling materials described herein become a semi-solid the ultrasound coupling materials are stiff enough so that they can be removed from the ultrasound machine and/or the patient in one contiguous mass. However, the ultrasound coupling materials are not so stiff as to deform the tissue being imaged. In some embodiments, the ultrasound coupling materials described herein have a solids modulus of between about 10 dynes/cm ² and about 1000 dynes/cm ² once the ultrasound coupling materials become a semi-solid.

[0042] The ultrasound coupling materials described herein can have a viscosity of between 0.1 Pa and 10,000 Pa. In certain embodiments the ultrasound coupling materials described herein can have an initial viscosity between 0.1 Pa and 100 Pa, between 0.1 Pa and 50 Pa., between 1 Pa. and 20 Pa. Initial viscosity is the viscosity of the ultrasound coupling material immediately after the hydrogel, viscosifying agent or the hydrogel and the viscosifying agent and the hydrating fluid are combined and the ultrasound coupling material is a liquid. Once the ultrasound coupling material has become a semi-solid, in certain embodiments the ultrasound coupling material can have a viscosity of between 100 Pa. and 10,000 Pa., between 500 Pa. and 10,000 Pa., between 750 Pa. and 10,000 Pa., between 1,000 Pa. and 10,000 Pa., between 5,000 Pa. and 10,000 Pa. or between 1,000 Pa. and 5,000 Pa.

[0043] Alternatively, in some embodiments the ultrasound coupling materials described herein have a Gel Integrity Index of about 0.5 kg/mm to about 2500 kg/mm, about 10 kg/mm to about 2500 kg/mm, about 10 kg/mm to about 2000 kg/mm, about 10 kg/mm to about 1000 kg/mm, about 50 kg/mm to about 750 kg/mm, about 50 kg/mm to about 500 kg/mm or about 100 kg/mm to about 500 kg/mm once they become a semisolid.

[0044] The amount of time for the ultrasound coupling material to fill the space between a transducer and the patient and become a semi-solid can vary. Ideally, the ultrasound materials should fill the space between the transducer and the patient and become a semi-sold quickly so that the patient can be imaged as quickly as possible. However, the ultrasound coupling materials should fill the space between the transducer

and the patient and become a semi-solid at a rate in which air or other materials that can have a deleterious effect on the image quality are not introduced, or only minimally introduced, into the ultrasound coupling material. The ultrasound coupling materials described herein may become a semi-solid after one minute or longer after the hydrogel, viscosifying agent or the hydrogel and the viscosifying agent and the hydrating fluid are combined. In certain embodiments, the ultrasound coupling materials of the present invention become a semi-solid after 1 min., 2 min., 3 min., 4 min., 5 min., 6 min., 7 min., 8 min., 9 min. or 10 min. In other embodiments, the ultrasound coupling materials of the present invention become a semi-solid between 15 sec. and 3 min., or between 30 sec. and 3 min., or between 30 sec. and 2 min., or between about 30 sec. and 1 min. [0045] In other embodiments, when the ultrasound coupling materials of the present invention are tested using the Creep Test and placed under a 100 g force, the total deformation of the ultrasound coupling materials of the present invention can be between 0 mm and 10 mm. As a semi-solid, the total deformation of the ultrasound coupling materials can be between 3 mm and 7 mm.

[0046] In certain embodiments, the hydrogel coupling materials of the present invention include a viscosifying agent and a hydrating liquid. In certain other embodiments, the ultrasound coupling materials of the present invention can include an ionically charged polymer, such as a viscosifying agent and an aqueous solution that includes a multivalent ion, an insoluble salt, an acid and a sequestrant, as a hydrating fluid. For example, sodium alginate can be used as a viscosifying agent which then can be mixed with a hydrating fluid that includes calcium ions, a calcium salt such as calcium hydrogen phosphate, a calcium sequestrant such as sodium pyrophosphate and an acid such as citric acid. Not wanting to be limited to any one theory, the inventors believe that in such an embodiment, the sodium salts of alginic acid are cross-linked by the addition of divalent ions, such as calcium. Moreover, the addition of calcium salts, an acid and a calcium sequestrant increase the homogeneity of the semi-solid ultrasound coupling material.

[0047] In other embodiments the ultrasound coupling materials of the present invention can include a hydrogel and a hydrating liquid. In such embodiments the hydrogel is a cross-linked hydrophilic polymer and the hydrating fluid is an aqueous solution that can include an acid or a base. For example, in certain embodiments the cross-linked hydrophilic polymer is a co-polymer of polyacrylic acid and polyacrylamide and the hydrating fluid is water. In some embodiments the co-polymer

of polyacrylic acid and polyacrylamide is treated with or includes a mild acid or surfactant before being hydrated with the hydrating fluid.

[0048] In still other embodiments the ultrasound coupling materials described herein include a hydrogel, a viscosifying agent and a hydrating fluid. For example, an ultrasound coupling material of the present invention can include a cross-linked hydrophilic polymer such as a polyacrylic acid polyacrylamide co-polymer, sodium alginate as a viscosifying agent and a hydrating fluid which includes water, an acid such as citric acid and, optionally, a preservative. In some embodiments, the hydrophilic cross-linked polymer can be treated with a surfactant and can be mixed with a salt that can provide a multi-valent ion, such as, but not limited to dicalcium phosphate anhydrous.

5.2.1 VISCOSIFYING AGENT

[0049] The ultrasound coupling materials described herein can include a viscosifying agent. The viscosifying agent can be any agent that increases the viscosity of the ultrasound coupling materials of the present invention. The choice of a viscosifying agent depends upon factors such as the desired viscosity and stiffness of the ultrasound coupling materials. Suitable viscosifying agents may include, but are not limited to, colloidal agents (e.g., clays, polymers, and guar gum), emulsion forming agents, diatomaceous earth, starches, biopolymers, synthetic polymers, or mixtures thereof.

[0050] Suitable viscosifying agents often are hydratable polymers that have one or more functional groups. These functional groups include, but are not limited to, hydroxyl groups, carboxyl groups, carboxylic acids, derivatives of carboxylic acids, sulfate groups, phosphate groups, propionate groups, and amino groups. In certain embodiments of the present invention, viscosifying agents may be used that comprise hydroxyl groups and/or amino groups. In certain embodiments of the present invention, the viscosifying agents may be biopolymers, and derivatives thereof, that have one or more of these functional groups or monosaccharide units. Viscosifying agents can have a charge, such as an ionic charge or they can be neutral. Examples of viscosifying agents with ionic charges include ionically charged polymers.

[0051] Suitable viscosifying agents include, but are not limited to, sugars, such as sucrose, glucose, maltose, dextrose and fructose, hydric alcohols, such as sorbitol, mannitol, xylitol and maltitol, galactose, mannose, glucoside, xylose, arabinose,

glucuronic acid, or pyranosyl sulfate; polymers such as polydextrose, xanthan gum, welan gums, guar gum, hydroxypropyl guar, carboxymethyl hydroxypropyl guar, sodium alginate, carrageenan; cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, polyvinylpyrrolidone (PVP), maltodextrin, carbomer, polyvinyl alcohol, polyethylene glycol (PEG), polyethylene oxide, carboxymethylcellulose (CMC) and hydroxyethyl cellulose (HEC). [0052] Additionally, synthetic polymers that contain the above-mentioned functional groups may be used. Examples of such synthetic polymers include, but are not limited to, poly(acrylate), poly(methacrylate), poly(ethylene imine), poly(acrylamide), poly(vinyl alcohol), and poly(vinylpyrrolidone). Other suitable viscosifying agents include chitosans, starches and gelatins. Suitable clays include kaolinites, montmorillonite, bentonite, hydrous micas, attapulgite, sepiolite, and the like, as well as synthetic clays, such as laponite. Surfactants discussed in Section 5.2.2 can also be used as viscosifying agents.

[0053] Additionally, in some embodiments more than one viscosifying agent can be co-blended with another viscosifying agent. For example, sodium alginate can be co- blended with other materials such as gums, starches and polysaccharides, to alter the properties of the ultrasound coupling materials described herein.

[0054] The concentration of the viscosifying agent can be altered to affect the clarity and the stiffness of the ultrasound coupling material. The viscosifying agent is present in the ultrasound coupling materials of the present invention in an amount sufficient to provide a desired degree of stiffness for ease of handling. Viscosifying agents can be about 0.1 % to 99% of the total weight of the ultrasound coupling materials. In certain embodiments, the viscosifying agent is between about 0.1% to 50%, between about 0.1% to 25%, between about 0.1% to 20%, between about 0.1% to 10%, between about 0.1% to 5%, between about 0.1% to 2%, between about 0.1% to 0.3%, or between about 0.1% to 0.25% of the total weight of the ultrasound coupling material.

5.2.2 HYDROGELS

[0055] In certain embodiments the hydrogel coupling materials described herein include a hydrogel and a hydrating fluid. A hydrogel can be defined as a network of natural or synthetic polymers that are insoluble or only partially insoluble in water and highly water absorbent. Suitable polymers can be at least partially soluble in aqueous solutions, such as water, buffered salt solutions, or aqueous alcohol solutions.

[0056] Suitable hydrogels that can be used in the ultrasound coupling materials described herein are formed when an organic polymer (natural or synthetic) is cross- linked via covalent, ionic, or hydrogen bonds to create a three-dimensional open-lattice structure which entraps water molecules to form a hydrogel. Such hydrogels are synthesized so that they contain a large degree of interconnected pores. [0057] Suitable highly porous hydrogels can absorb and hold many times their own mass in water or hydrating fluid, in many cases more that one hundred times, and are capable of swelling at extremely fast rates, preferably in a matter of minutes. Additionally, the hydrogels will not significantly alter the geometry of the tissue with which they come in contact while hydrating. However, the swollen hydrogels can remain stiff enough for handling purposes while retaining desirable ultrasonic properties. In certain embodiments, the hydration ratio of the hydrogels suitable for use in the ultrasound coupling materials described herein is between about 50 to 150. In certain embodiments, the hydration ratio is 50, 75, 100, 125, or 150.

[0058] In certain embodiments, suitable hydrogels that can be used in the ultrasound coupling materials described herein can be characterized as contiguous masses, wherein the polymers of the hydrogel are touching or connected in an unbroken sequence. Such hydrogels are distinguished from other hydrogel materials that are free-flowing powders consisting of a collection of discreet particles.

[0059] Examples of materials which can be used to form a hydrogel include, but are not limited to, synthetic and naturally occurring hydrophilic cross-linked polymers, polysaccharides and proteins. Examples of polysaccharides include celluloses such as methyl cellulose, dextrans, and alginate. Examples of proteins include gelatin and hyaluronic acid. Examples of hydrophilic cross-linked polymers include both biodegradable and non-degradable polymers, such as polyvinyl alcohol, polyacrylamide, polyacrylic acid, co-polymers of polyacrylamide and polyacrylic acid, polyphosphazines, polyacrylates, polyethylene oxide, and polyalkylene oxide block copolymers ("Poloxamers™") such as Plronics™ or Tetronics™ (polyethylene oxide- polypropylene glycol block co-polymers).

[0060J Suitable polymers can have charged side groups. Examples of polymers with acidic side groups are polyphosphazenes, polyacrylic acids, poly(meth)acrylic acids, polyvinyl acetate, and sulfonated polymers, such as sulfonated polystyrene. Copolymers having acidic side groups formed by reacting acrylic or methacrylic acid and vinyl ether monomers or polymers can also be used. Examples of acidic groups are

carboxylic acid groups, sulfonic acid groups, halogenated (preferably fluorinated) alcohol groups, phenolic OH groups, and acidic OH groups.

[0061] Examples of basic side groups are amino and imino groups. Examples of polymers with basic side groups that can be used are polyvinyl amines, polyvinyl pyridine, polyvinyl imidazole, polyvinylpyrrolidone and some imino substituted polyphosphazenes. The ammonium or quaternary salt of polymers can also be used. Additionally, alginate can be ionically cross-linked with divalent cations, in water, at room temperature, to form a hydrogel matrix.

[0062] Preferred hydrogels include porous polymer networks composed of hydrophilic cross-linked polymers such as methyl cellulose, dextrans, agarose, polyvinyl alcohol, hyaluronic acid, polyethylene oxide and polyoxyalkylene polymers ("poloxamers"), polyacrylic acid and polyacrylamide and co-polymers thereof. [0063] Methods for the synthesis of the polymers described above are known to those skilled in the art. Cross-linked hydrogels can be synthesized by reacting monomers with other monomers or polymers in the presence of a crosslinker and/or a catalyst to produce an interpenetrating network. The degree of cross-linking can be varied to alter the physical properties of the resulting hydrogel. The ratio of monomers, such as acrylic acid to acrylamide, can also be altered to modify the crosslink density and the porosity of the hydrogel.

[0064] Additionally, the hydrogels can be combined with or treated with a surfactant to increase hydration rates. Suitable surfactants include ionic and non-ionic surfactants. For example suitable surfactants include, but are not limited to, Triton surfactants, Tween and Span surfactants, Pluronic™ surfactants (poly(ethylene oxide)- poly(propylene oxide)-poly(ethylene oxide) tri-block co-polymers), Silwet™ surfactants, sodium dodecyl sulfate, albumin, gelatin, or combinations thereof. Surfactants of special interest are Pluronic™ F 127 or PF 127. Preferably, non- foaming or anti-foaming surfactants are used due to the fact non-foaming surfactants are less likely to allow air to be incorporated into the ultrasound coupling materials, which would interfere with image quality. Suitable non-foaming surfactants include non- foaming nonionic surfactants such as sucrose esters, e.g., sucrose cocoate, sucrose stearate and mixtures thereof. Foaming surfactants can be used to the extent that they do not allow air to be incorporated into the ultrasound coupling materials. Additionally, if a foaming surfactant is used an anti-foaming agent such as, but not limited to, cetyl alcohol can be used.

[0065] The hydrogels may be titrated with fluids of different pH to alter the swelling properties of the hydrogel. For example, a cross-linked polyacrylic acid-co- polyacrylamide hydrogel can be treated with a mild acid to partially or fully protonate the acrylic acid residues and reduce the degree to which the hydrogel swells. Suitable acids and bases are discussed in Section 5.2.3 below.

[0066] Also, the hydrogel network may be used to stabilize other species, such as ionic species, that may interact synergistically with fluids and other material imbibed into the hydrogel porous network. For example, the hydrogels described herein can include salts such as insoluble calcium salts that can react with viscosifying agents like sodium alginate in the hydrating fluid. Wetting agents can also be combined with the hydrogels described herein. Suitable wetting agents are discussed in Sections 5.2.3. [0067] Hydrogels can be about 0.1 % to 99% of the total weight of the ultrasound coupling materials. In certain embodiments, the hydrogels are between about 0.1% to 50%, between about 0.1% to 25%, between about 0.1% to 20%, between about 0.1% to 10%, between about 0.1% to 5%, between about 0.1% to 2%, between about 0.1% to 0.3%, or between about 0.1% to 0.25% of the total weight of the ultrasound coupling material. In other embodiments, hydrogels can be about 0.1 %, 0.25%, 0.3% or 1.3% of the total weight of the ultrasound coupling materials.

5.2.3 HYDRATING FLUIDS

[0068] Hydrating fluids are liquids that once added to the viscosifying agent, hydrogel or the combination of a hydrogel and a viscosifying agent, cause the ultrasound coupling material to become a semi-solid. In most instances the hydrating fluids include water. Depending on the viscosifying agent or hydrogel being hydrated as well as the desired characteristics of the ultrasound coupling material, the hydrating fluid can contain other materials such as multivalent ions, insoluble salts, sequestrant agents, wetting agents, acids, bases or a combination thereof.

5.2.3.1 Hydrating Fluids to be Used with Viscosifying Agents

[0069] Hydrating fluids to be used with viscosifying agents in the ultrasound coupling materials of the present invention include water and a multivalent ion. Multivalent ions are elements that can form more than one ion. Examples of multivalent ions include, but are not limited to, alkaline earth metal ions, Group IHA metal ions, Group IVA metal ions, Al ⁺³ , Sn ⁺⁴ , Pb ⁺⁴ , Ti ⁺³ , Cr ⁺³ , Mn ⁺³ , Fe ⁺³ , Ni ⁺² , Cu ⁺² , Co ⁺³ , Ir ⁺³ , CO ₃ ^'2 , PO ₄ ^'3 , SO ₃ ^"2 , S ^"2 , Te- ² , Se ^'2 , N ^"3 , P ^"3 , O ₂ ^"2 , and mixtures thereof. Suitable

multivalent anions include elements and multi-atom complexes capable of carrying a (- 2) or higher charge such as multi-atom ions, such as sulfate, hydrogen phosphate, and oxalate. Other examples of multivalent ions include titanium(III), chromium(III), manganese(III), iron(III), cobalt(III) iridium(IV), and phosphate, Te ^"2 , S ^" , HaSO ₄ ^"2 , MnO ₄ ^"2 , Ca(OH) ₄ ^"2 , Mg(OH) ₄ ^"2 , Hg(OH) ₄ ^"2 , V ₂ O ₇ ^"4 , and Mn(OH) ₄ ^"2 ; halide complexes capable of carrying a (-2) or higher charge, such as Co(X) ₄ ^"2 , Cu(X) ₄ ^"2 , Fe(X) ₄ ^"2 , Th(X) ₆ ^{" 2} , and Ti(X) ₆ ^" , where X is fluoride, chloride, bromide, or iodide; and mixtures thereof. [0070] Preferred multivalent ions include multivalent cations. Suitable multivalent cations include, but are not limited to metals capable of carrying a +2 or higher charge, such as Ba ⁺² , Ca ⁺² , Cd ⁺² , Co ⁺² , Cu ⁺² , Fe ⁺² , Hg ⁺² , Mg ⁺² , Mn ⁺² , Ni ⁺² , Pb ⁺² , Zn ⁺² , Pd ⁺² , Sn ⁺² , Sr ⁺² , V ⁺² Pb ⁺⁴ , Pu ⁺⁴ , Sn ⁺⁴ , Th ⁺⁴ , U ⁺⁴ , and Zr ⁺⁴ ; divalent and higher metal oxides, such as UO ₂ ⁺² and VO ⁺² ; divalent and higher metal hydroxides, such as AlOH ⁺² , TiOH ⁺² , Ti(OH) ₂ ⁺² , and MnOH ⁺² ; divalent and higher cationic metal halides, such as AlX ⁺² , Pb(X) ₂ ⁺² , Ti(X) ₂ ⁺² , and MnX ⁺² , where X is fluoride, chloride, bromide, or iodide; and mixtures thereof.

[0071] Hydrating liquids can also include at least one insoluble salt. Suitable insoluble salts include, but are not limited to, calcium salts like calcium carbonate, calcium phosphate, dicalcium phosphate anhydrous, calcium sulfate; lithium salts like lithium carbonate, lithium citrate, lithium sulfate; cesium salts like cesium carbonate, cesium chloride, cesium nitrate; barium salts like barium sulfate, barium carbonate; magnesium salts like magnesium carbonate, and magnesium stearate; aluminum salts like aluminum silicate; or combinations thereof.

[0072] Hydrating liquids can also include at least one sequestrant. Suitable sequestrants include, but are not limited to, sodium pyrophosphate, sodium citrate or a multidentate ligand such as, but not limited to, ethylenediamine tetraacetic acid (EDTA). [0073] Hydrating liquids can further include at least one wetting agent or surfactant. Wetting agents and surfactants can be non-foaming or foaming, however, non-foaming wetting agents and surfactants are preferred since they are less likely to allow air to be incorporated into the ultrasound coupling materials. Additionally, wetting agents and surfactants can be ionic or anionic. Suitable wetting agents and surfactants for the ultrasound coupling materials include, but are not limited to, those surfactants discussed in Section 5.2.2 and polyoxyethylene derivatives of sorbitan esters, such as, polysorbate 20 and polysorbate 80; lecithin; polyoxyethylene and polyoxypropylene ethers; sodium deoxycholate, sodium diocyl sulphate or a combination thereof.

[0074] Hydrating fluids can also include an acid or a base. Suitable bases include, but are not limited to, sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumerate, and combinations thereof. Suitable acids include, but are not limited to, hyaluronic acid, citric acid, formic acid, acetic acid, N-acetylglycine, acetylsalicylic acid, fumaric acid, glycolic acid, iminodiacetic acid, itaconic acid, lactic acid, maleic acid, malic acid, nicotinic acid, 2-pyrrolidone-5-carboylic acid, salicylic acid, succinamic acid, succinic acid, ascorbic acid, aspartic acid, glutamic acid, glutaric acid, malonic acid, pyruvic acid, sulfonyldiacetic acid, benzoic acid, epoxysuccinic acid, adipic acid, thiodiacetic acid and thioglycolic acid. Suitable acids can also include slow dissolving acids such as fumaric acid, isooctanoic acid and isomers thereof, and adipic acid. The amount of the sequestrant and the acid can be adjusted to control the time it takes the ultrasound coupling material to transform from its initial liquid phase to a semi-solid.

5.2.3.2 Hydrating Fluids that can be Used with Hydrogels

[0075] Hydrating fluids that can be used with hydrogels include water. Additionally, similar to the hydrating fluids that can be used with viscosifying agents, the hydrating fluids that can be used with hydrogels can also include acids, bases, wetting agents, surfactants or a combination thereof. Suitable acids, bases, wetting agents and surfactants are discussed in Section 5.2.3.1.

[0076] Also, hydrating fluids that can be used with hydrogels can include a viscosifying agent. Suitable viscosifying agents, such as alginates are discussed in Section 5.2.3.1.

5.2.4 ADDITIONAL MATERIALS

5.2.4.1 Shape Memory Materials

[0077] Additionally, the ultrasound coupling materials of the present invention can include materials that increase the stiffness of the ultrasound coupling materials and allow the ultrasound coupling materials to have "shape memory" meaning the ultrasound coupling material forms to and retains the shape of tissue being imaged, such as a breast, even after the ultrasound coupling material is no longer in contact with the tissue. [0078] Polymer latex particles such as monodispersed, surface-modified polystyrene particles can be included in the ultrasound coupling materials of the present invention.

Such particles can range in size from about 100 nm to several tens of microns. The polymer latex polymers can form close-packed particle arrays that further serve to stiffen the ultrasound coupling materials and allow them to have shape memory. In certain embodiments, a hydrogel network can be prepared in the presence of monodispersed, surface-modified polystyrene polymers.

5.2.4.2 Preservatives

[0079] The ultrasound coupling materials described herein can further include at least one preservative. Suitable preservatives can include, but are not limited to, sodium azide, sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphate.

5.2.4.3 Scents

[0080] In certain embodiments of the present invention, the ultrasound coupling material described herein can be scented. Scented materials can include essential oils or microencapsulated scented compositions. Scents in the ultrasound coupling materials described herein may be selected for an aromatherapy effect, such as providing a relaxing or invigorating mood. As such, any material that exudes pleasant or otherwise desirable odors can be used as a scent.

[0081] The ultrasound coupling materials can have any of the following scents: root beer, cola, vanilla, chocolate, mint, peanut butter, apple, orange, grapefruit, peach, cinnamon, ocean, cut grass, carrot, butterscotch, strawberry, banana, blueberry, bubblegum, lavender, rose, pepper, clove, coffee, tea, oregano, pumpkin pie, raspberry, vinegar, dill, pineapple, sour apple, almond, licorice, cotton candy, popcorn, cherry, pine, apple pie, candy corn, caramel, cherry pie, gingerbread, licorice, marshmallow, lemon, lime, honey, coconut, grape, pina colada, floral, lilac, baby powder, perfume, suntan oil, jasmine, anise, and eucalyptus.

5.2.4.4 Colors

[0082] Additionally, the ultrasound coupling materials of the present invention can be clear or colored. When the ultrasound coupling materials are colored they can be translucent, i.e. allow light to transmit through the ultrasound coupling material, or opaque i.e. do not allow light to transmit through the ultrasound coupling material. The ultrasound coupling materials described herein can be any color including, but not limited to, red, orange, yellow, green, blue, purple, black, white, brown or any shade variant thereof.

[0083] In certain embodiments, the ultrasound coupling material can be more that one color. Also, in certain embodiments the individual components of the ultrasound coupling material can be colored. Each individual component of the ultrasound coupling material can be the same or a different color. For example, the viscosifying agent can be yellow and the hydrating fluid can be blue and upon mixing the viscosifying agent and the hydrating fluid the ultrasound coupling material can become green. [0084] Preferably, the coloring in the ultrasound coupling material does not leach out, stain or otherwise mark the patient.

6.0 METHODS OF MAKING

[0085] The present invention is also directed to methods of making ultrasound coupling materials. In certain embodiments, the present invention includes methods of making an ultrasound coupling material that includes the following steps: providing a cross-linked hydrophilic polymer; introducing a hydrating fluid comprising water; and forming a semi-solid ultrasound coupling material.

[0086] In other embodiments the present invention includes methods of making an ultrasound coupling material that includes the following steps: providing a viscosifying agent comprising an ionically charged polymer; introducing a hydrating fluid comprising a soluble multivalent ion; and forming a semi-solid ultrasound coupling material.

[0087] Figure 1, is a flow diagram that depicts a method of manufacturing the ultrasound coupling materials of the present invention. As shown in Figure 1, a hydrogel is formed by mixing monomers, at least one cross-linker, a porogen, a surfactant, water and a viscosifier. A porogen is an excipient that introduces pores into the hydrogel. Porogens can introduce pores into the hydrogel by chemical decomposition of the porogen or physical removal of the porogen. Porogens that are capable of chemical decomposition generally decompose into gas and additional bi- products, such porogens include sodium bicarbonate, carbon and nitrogen. Porogens that can be physically removed from the hydrogel include salts and sugars that are insoluble in the hydrogel.

[0088] As shown in Figure 1, monomers such as acrylic acid (AA) and acrylamide (Am) are combined with a cross-linker such as bisacrylamide, a porogen such as sodium bicarbonate, water and a surfactant and/or viscosifying agent such as Pluronic™ F 127. The mixture is heated until the desired hydrogel is formed. To clean and de-areate the

hydrogel, the hydrogel is first washed with a water-ethanol mixture. The ratio between water and ethanol can be between 70/30 ethanol/water to 95/5 ethanol water. The water/ethanol wash removes residual reactants and reaction bi-products which could cause oxidation and yellowing of the hydrogel. Residual bicarbonate can also cause bubble inclusion if the hydrating fluid is acidic. Such bubbles could be detrimental to ultrasound image quality.

[0089] Hydrogel pores are then filled with a material that occupies the voids in the hydrogel without completely hydrating the hydrogel, such as polyethylene glycol (PEG). For example, once the hydrogel is washed and sterilized, the hydrogel is transferred to a 80/20 PEG/water bath to prehydrate and de-aerate. This is essentially a pressing process to occlude entrained air and exchange residual water/ethanol. The water in the bath serves to keep the hydrogel partially hydrated to avoid brittleness. A low molecular weight PEG (Mw -400) is preferred since it is a liquid at room temperature and is infinitely soluble in water. Therefore, it serves to aid the de-aeration process and acts to facilitate hydration of the hydrogel during an ultrasound procedure. [0090] To further stabilize the hydrogel, the hydrogel can then be dipped in a bath of heated higher molecular weight PEG ( Mw-1000) to overcoat and seal the hydrogel. Dipping the hydrogel into the heated PEG bath further serves to occlude entrained air and, on removal, encapsulates the hydrogel with a waxy overcoat. Such a process can yield a thin sheet of hydrogel that contains a small amount of water to give it flexibility and a small amount of a highly soluble infiltrant and a coating that facilitates hydration when the sheet is placed into the hydrating fluid. Such a process allows the hydrogel to be placed into 40 ⁰ C water using 2.5g hydrogel / 10OmL of water and be fully hydrated and bubble-free in 2-3 minutes. The filled and pressed hydrogel is then packaged. [0091] Also, as shown in Figure 1, a hydrating fluid is formed by mixing water and at least one viscosifying agent. In the embodiment shown in Figure 1, the viscosifying agent is a combination of alginate and saccharides. The mixture is then degassed, sterilized and packaged.

7.0 ULTRASOUND SYSTEMS

[00921 The present invention is also directed to systems for ultrasound imaging of soft tissue. Examples of soft tissue include, but are not limited to, internal organs such as, the gallbladder, liver, heart, kidneys, pancreas, bladder, thyroid gland, prostate and uterus. An example of soft tissue also includes, but is not limited to, breast tissue. In

certain embodiments the present invention includes a system for ultrasound imaging that includes an ultrasound coupling material described herein and an apparatus for ultrasound imaging.

[0093] In certain embodiments the present invention is directed to ultrasound diagnostic systems. The ultrasound coupling materials are designed to be used as a part of an ultrasound diagnostic system that include an ultrasound coupling material described herein and an apparatus for ultrasound diagnosis such as the apparatus described in United States patent publication no. 2004/0254464.

[0094] In certain embodiments, the present invention includes ultrasound diagnostic systems that include a transducer; an applicator, such as a dome, comprising a first side and a second side, wherein the first side is in communication with the transducer and the second side is contoured to accept a breast; a hydrophilic cross-linked polymer that is capable of being placed in the second side of the applicator; and a hydrating fluid, wherein upon introducing the hydrating fluid to the hydrophilic cross-linked polymer, a semi-solid ultrasound coupling material is formed.

[0095] In other embodiments the present invention includes ultrasound diagnostic systems that include a transducer; an applicator, such as a dome, comprising a first side and a second side, wherein the first side is in communication with the transducer and the second side is contoured to accept a breast; a viscosifying agent comprising an ionically charged polymer that is capable of being placed in the second side of the applicator; and a hydrating fluid, wherein upon introducing the hydrating fluid to the hydrophilic cross- linked polymer, a semi-solid ultrasound coupling material is formed. The ultrasound coupling materials used in the systems described herein are capable of filling the space between the tissue being imaged which in certain embodiments is a breast, and the applicator. Additionally, the ultrasound coupling materials are capable of filling the space between the tissue being imaged which in certain embodiments is a breast, and the applicator while not causing any tissue distortion.

[0096] Ultrasonic transducers may be designed in various ways, and the present invention is not limited to any particular transducer design but rather may be advantageously applied to adapt many different types of transducers. Transducer arrays may be curved, with the front surface typically concave, and the individual piezoelectric elements may be substantially square blocks such as described in U.S. Pat. No. 5,042,492 to Dubut. Concave arrays may also be constructed with annular elements, such as that described in U.S. Pat. No. 4,537,074 to Dietz. Combining several linear

arrays to produce an electronically scanned ultrasonic "pencil" beam from crossed flat acoustic beams is described in U.S. Pat. No. 5,797,845 to Barabash et al. More recently, a new type of acoustic transducer has been developed in which silicon micromachining techniques are used to fabricate suspended membranes that are excited capacitively, as described in detail by Ladabaum et al., Surface Micromachined Capacitive Ultrasonic Transducers, IEEE Trans, on Ultrasonics, Ferroelectrics, and Freq. Control, Vol. 45, No. 3, May 1998.

[0097] To achieve good acoustic coupling between the transducer and the object under examination, the ultrasound coupling materials described herein can be placed between the transducer and the patient to eliminate any air space and replace it with an interface whose acoustic impedance is better matched to the tissue being imaged. As shown in Figure 2, an ultrasound coupling material 16 can be disposed in an applicator device in the form of a dome 11 located between the transducer 12 and the patient 13 (indicated by dashed lines). The ultrasound coupling material 16 prevents the applicator dome from coming into direct contact with the patient. The applicator dome 11 is designed to receive the breast 15 during examination, and the ultrasound coupling material 16, fills the volume between the dome and the breast. The applicator dome 11 may be provided in several different sizes to accommodate a wider range of patient-to- patient variations, thereby allowing for variations in patient anatomy. [0098] As shown in Figure 2, the ultrasound coupling materials are used with applicator dome 11, however, the ultrasound coupling materials described herein can be used with other applicators of different shapes and sizes. For example, the ultrasound coupling materials described herein can be used with an applicator bag that can be stored flat and later filled with the ultrasound coupling materials described herein. In another embodiment, the applicator bag can also be inflated to better conform to the tissue being imaged.

[0099] Optionally, an opening can be provided in the applicator so that the hydrating fluid can enter the applicator through the opening and hydrate the hydrogel, viscosifying agent or the combination of a hydrogel and a viscosifying agent, once the hydrogel, viscosifying agent or a combination of a hydrogel and a viscosifying agent have been placed in the applicator and the applicator has been fitted to the patient.

8.0 ARTICLES OF MANUFACTURE AND KITS

[00100] Ultrasound coupling materials described herein can be combined with packaging materials and sold as articles of manufacture and kits. The articles of manufacture may be combined with packaging material, such as containers including, but not limited to, packets, bottles, jars and pouches, that contain one or more of the components of the ultrasound coupling materials described herein. For example, the viscosifying agent, hydrogel or a combination of a viscosifying agent and a hydrogel can be packaged in one container and the hydrating fluid may be packaged in a second container.

[0100] In certain embodiments, prior to packaging, the hydrogels described herein are evacuated and filled, meaning all or almost all of the air is evacuated from the hydrogel and the voids of the hydrogel are then filled with a non-hydrating material that prevents air from penetrating the hydrogel but, at the same time, does not completely hydrate the hydrogel. Suitable materials can include PEG or other water soluble polymers, wetting agents or surfactants. Examples of such processes are discussed in Section 6.0. This step helps prevent air from being incorporated into the ultrasound coupling materials which, as mentioned before, will compromise the image quality of the ultrasound images.

[0101] In certain embodiments, the evacuated and filled hydrogels are then vacuumed packed into packets or pouches to minimize volume of the article of manufacture and prevent air from being incorporated into the hydrogel. [0102] Hydrating fluids can be premixed and stored in any suitable container such as a bottle. Alternatively, the hydrating fluids can be packaged in multiple components and be mixed just prior to being combined with the hydrogel. The components of ultrasound coupling materials or ultrasound coupling materials themselves may be provided in a pre-packaged form in quantities sufficient for single or multiple uses. [0103] Kits can include components to make the ultrasound coupling materials of the present invention. For example kits of the present invention include a hydrophilic cross-linked polymer; and a hydrating fluid, wherein the hydrating fluid includes water. Alternatively, the kits of the present invention include a viscosifying agent such as an ionically charged polymer; and a hydrating fluid, wherein the hydrating fluid includes a multivalent ion. A label or instructions describing how the composition can be combined and used with ultrasound imaging systems, as well as, with patients may be

included in such kits. Such instructions may, in some embodiments, be printed on the packaging materials themselves.

9.0 EXAMPLES

9.1 Example 1

[0104] The effect of hydration on hydrogels was tested on polyacrylic-co- polyacrylamide hydrogels. The polyacrylic-co-polyacrylamide hydrogels were synthesized according to the formulation in Table 1. Table 1

[0105] Samples were made by first combining acrylic acid, acrylamide and bisacrylamide with sodium bicarbonate, N ₅ N ₅ N', N '-tetramethylene diamine, water and PF 127. The mixture was allowed to react for about 1 minute. The resulting hydrogel was rinsed of residual reactants and reaction bi-products, and dried with ethanol.

[0106] Seven hydrogel samples were hydrated with various amounts of water. Table 2 shows the hydration ratios of the seven samples. Table 2

9.1.1 Creep Test

[0107] Sample 3 was tested for mechanical strength using the Creep Test. The Creep Test shows the ability of the hydrogel to retain absorbed water. The greater the distance the more the hydrogel holds under a given stress. Figure 3 shows the results of the Creep Test preformed on Sample 3 after initial hydration i.e. when the water and hydrogel material are first combined (Initial test) and 10 minutes after the water and the hydrogel material were combined (After 10 min. equilibration). As shown in Figure 3, the total deformation (shown as distance in mm) for the initial test was greater than that after the hydrogel and water mixture were allowed to equilibrate for 10 minutes. Figure 4 shows the deformation of Samples 1, 3, 5 and 7 between 50 and 60 seconds after initial hydration (initial test) and 10 minutes after the water and the hydrogel material were combined (After 10 min. equilibration).

9.1.2 Stress-Relaxation Test

[0108] The seven samples were also tested using the Stress-Relaxation Test. This test shows the ability of the hydrogel to resist applied stress. The higher the value, the stiffer and stronger the hydrogel is and the hydrogel's ability to resist damage during manufacturing and handling is improved. Figure 5 shows the results of the Stress- Relaxation Test preformed on Sample 2 both once the water and hydrogel were initially mixed (Initial test, Sample 2) and 10 minutes after the water and the hydrogel material were combined (After 10 min., Sample 2) and on Sample 6 once the water and hydrogel

were initially mixed (Initial test, Sample 6). As shown in Figure 5, Sample 2, 10 minutes after the water and the hydrogel material were combined, required the most force before breaking and was the stiffest out of the three samples tested. Figures 6 and 7 show the results of the Stress-Relaxation Test on all seven samples once the hydrogel and water were initially mixed (Figure 6) and 10 minutes after the water and the hydrogel material were combined (Figure 7). Samples 2-6 with a hydration ratio between about 75-150 showed desired stiffness that would allow it to resist stress and damage but at the same time conform to tissue and not cause deformation of the tissue.

9.2 Example 2

[0109] Ten ultrasound coupling material samples comprising different hydrating fluids were synthesized and tested using the Stress-Relaxation Test. Polyacrylic-co- polyacrylamide hydrogels were synthesized according to the formulation in Table 1. Hydrogels were synthesized by first combining acrylic acid, acrylamide and the bisacrylamide with the sodium bicarbonate, N,N,N',N'-tetramethylene diamine, water, and PF 127. The mixture was allowed to react for about 1 minute. The resulting hydrogel was rinsed of residual reactants and reaction bi-products, and dried with ethanol.

[0110] Hydrating fluids were formulated as shown in Table 3. Table 3

[0111] Either 0.3 g or 1.3 g of the polyacrylic-co-polyacrylamide hydrogel was hydrated with the hydrating fluids shown in Table 3. The hydrogels were hydrated at room temperature using the hydrating fluids to achieve a hydration ratio of 100.

Samples were hydrated in an appropriately sized beaker and allowed to equilibrate for several minutes.

9.2.1 Stress-Relaxation Test

[0112] Figure 8 shows the results of the Stress-Relaxation test of all ten samples at maximum force and equilibrium force. As shown in Figure 8, Samples 4, 5 and 7 showed the greatest resistance to stress. Figure 9 show the results of the Stress- Relaxation test of Samples 3 and 7. As compared to Sample 3, Sample 7 shows a greater resistance to stress and is a stiffer ultrasound coupling material.

9.3 Example 3

[0113] Hydrogels were synthesized according to the formulation in Table 4. Table 4

[0114] To make the hydrogel of Formulation 1, sodium bicarbonate and water were mixed and added to a heat reaction flask. Acrylamide, acrylic acid, bisacrylamide, PFl 27, N,N,N',N'-tetramethylene diamine and ammonium persulfate were mixed in a separate container and then added to the heat reaction flask containing the sodium bicarbonate solution to produce a hydrogel.

[0115] To make the hydrogel of Formulations 2 and 3, sodium bicarbonate, dicalcium phosphate anhydrous and water were mixed and added to a heat reaction

flask. Acrylamide, acrylic acid, bisacrylamide, PF 127, N,N,N',N'-tetramethylene diamine and ammonium persulfate were mixed in a separate container and then added to the heat reaction flask containing the sodium bicarbonate solution to produce a hydrogel. [0116] Hydrating fluids were synthesized according to the formulation in Table 5. Table 5

[0117] The polyacrylic-co-polyacrylamide hydrogels of Formulations 1, 2 and 3 were each hydrated with the Hydrating Fluid 1 and Hydrating Fluid 2 as shown as Table 6. The hydrogels were hydrated at room temperature using the hydrating fluids to achieve a hydration ratio of 100. Samples were hydrated in an appropriately sized beaker and allowed to equilibrate for several minutes.

[0118] The description and examples contained herein is for purposes of illustration and not for purposes of limitation. Changes and modifications may be made to the embodiments of the description and still be within the scope of the invention. Furthermore, obvious changes, modifications or variations will occur to those skilled in the art. Also, all references cited above are incorporated herein, in their entirety, for all purposes related to this disclosure.