US20180126677A1 - Extremely compliant yet tough hydrogel systems as ultrasound transmission agents - Google Patents

Extremely compliant yet tough hydrogel systems as ultrasound transmission agents Download PDF

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US20180126677A1
US20180126677A1 US15/846,301 US201715846301A US2018126677A1 US 20180126677 A1 US20180126677 A1 US 20180126677A1 US 201715846301 A US201715846301 A US 201715846301A US 2018126677 A1 US2018126677 A1 US 2018126677A1
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hydrogel
ultrasound transmission
transmission agent
sacrificial
kpa
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Xuanhe Zhao
Shaoting Lin
Hyunwoo Yuk
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Massachusetts Institute of Technology
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C71/00—After-treatment of articles without altering their shape; Apparatus therefor
    • B29C71/0009—After-treatment of articles without altering their shape; Apparatus therefor using liquids, e.g. solvents, swelling agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/42—Details of probe positioning or probe attachment to the patient
    • A61B8/4272—Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue
    • A61B8/4281—Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue characterised by sound-transmitting media or devices for coupling the transducer to the tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • C08J3/246—Intercrosslinking of at least two polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/22—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for
    • A61B17/225—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for for extracorporeal shock wave lithotripsy [ESWL], e.g. by using ultrasonic waves
    • A61B17/2251—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for for extracorporeal shock wave lithotripsy [ESWL], e.g. by using ultrasonic waves characterised by coupling elements between the apparatus, e.g. shock wave apparatus or locating means, and the patient, e.g. details of bags, pressure control of bag on patient
    • A61B2017/2253—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for for extracorporeal shock wave lithotripsy [ESWL], e.g. by using ultrasonic waves characterised by coupling elements between the apparatus, e.g. shock wave apparatus or locating means, and the patient, e.g. details of bags, pressure control of bag on patient using a coupling gel or liquid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/0058—Liquid or visquous
    • B29K2105/0061—Gel or sol
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2995/00—Properties of moulding materials, reinforcements, fillers, preformed parts or moulds
    • B29K2995/0037—Other properties
    • B29K2995/0078—Shear strength
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2300/00—Characterised by the use of unspecified polymers
    • C08J2300/14—Water soluble or water swellable polymers, e.g. aqueous gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2300/00—Characterised by the use of unspecified polymers
    • C08J2300/20—Polymers characterized by their physical structure
    • C08J2300/208—Interpenetrating networks [IPN]
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2333/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers
    • C08J2333/24—Homopolymers or copolymers of amides or imides
    • C08J2333/26—Homopolymers or copolymers of acrylamide or methacrylamide

Definitions

  • This invention relates to a method for making a tough and compliant hydrogel with a low shear modulus that is extremely tough and robust.
  • hydrogels be both resilient and tough.
  • a particular use for such a hydrogel is as a transmission agent for ultrasound because resiliency allows it to conform to a body part. Resilience and toughness appear to be intrinsically contradictory properties but can be achieved according to the methods disclosed herein.
  • the method for making a tough and compliant hydrogel according to the invention includes combining a long chain polymer network to maintain high elasticity and a sacrificial chain polymer network to dissipate mechanical energy to form an interpenetrating hydrogel.
  • the interpenetrating hydrogel is prestretched to a prescribed multiple of its original length and then relaxed for multiple cycles. Thereafter, the pre-stretched hydrogel is soaked in a biocompatible medium to reach equilibrium swelling of the hydrogel. As a result, the shear modulus of the hydrogel is significantly reduced. To achieve extremely low modulus, multiple loading-unloading steps are performed to deplete most of the sacrificial polymer network to a controlled degree.
  • the long chain network may be selected from a group consisting of polyacrylamide, polyethylene glycol, poly (vinyl alcohol), poly (N-isopropyl acrylamide), and poly (2-hydroxyethyl methacrylate).
  • the sacrificial chain network may be selected from the group consisting of alginate, hyaluronic acid, collagen, agarose, gelatin, fibrin and chitosan.
  • the hydrogel made by the method of the invention may be used as an ultrasound transmission agent.
  • FIG. 1 is a schematic illustration of the steps performed according to the invention to transform a tough and stiff hydrogel into a tough and compliant hydrogel by pre-stretching the gel, relaxing and soaking it in a solvent such media or PBS.
  • FIG. 2 is a graph of modulus against pre-stretch. One can see that soaking the pre-stretched hydrogel in solvent can significantly reduce the shear modulus of the hydrogel from over 10 kPa to approximately 1 kPa.
  • FIG. 3 is a comparison graph of stress versus stretch for hydrogels with different treatments.
  • FIGS. 4 a and 4 b are photographs of the soft and tough hydrogel of the invention conformably attached to different regions of a human body.
  • FIGS. 5 a and 5 b are ultrasound images of a phantom object measured through conventional liquid hydrogel as shown in FIG. 5 a and the extremely compliant and tough hydrogel of the invention shown in FIG. 5 b.
  • hydrogels of the invention can be formed and printed into various shapes with different dimensions. As a result of their low rigidity and high robustness, the gels of the invention can be conformally attached to different regions of the human body. This aspect is important when the novel gel system of the invention is used as an ultrasound transmission agent.
  • materials from which the hydrogels are made according to the invention are from two types of polymers; one type of polymer maintains high elasticity of the hydrogel and the other type of polymer dissipates mechanical energy when the hydrogel is deformed.
  • the first type of polymers include polyacrylamide, polyethylene glycol, poly (vinyl alcohol), poly (N-isopropyl acrylamide), and poly (2-hydroxyethyl methacrylate).
  • the second type of polymers includes alginate, hyaluronic acid, collagen, agarose, gelatin, fibrin, and chitosan, which are generally capable of reversible crosslinking.
  • the first type of polymers are usually crosslinked by methods including free-radical polymerization, UV crosslinking, gamma irradiation, electron beam irradiation and freeze thawing.
  • the second type of polymers is usually crosslinked by methods including adding multivalent ions, changing ambient temperature and varying pH of the solution.
  • the chain length between two adjacent crosslinkings of the first type polymers is generally much longer than that of the second type polymers.
  • the volume concentration of the first type of polymers in the hydrogel can range from 5% to 40%, and that of the second type is usually lower than the first type, ranging from 0.15% to 10%. Therefore, the crosslinking density of the second type polymers is usually much larger than the first type polymers.
  • Tough hydrogels are fabricated by combining two types of polymer networks with different concentrations and crosslinking densities.
  • a matrix is used to guide the selection of different polymers.
  • Network for maintaining Network for dissipating energy short chain
  • Elasticity long chain
  • Alginate Hyalauronic Acid Collagen Agarose Gelatin Fibrin Chitosan Polyacrylamide Polyethylene glycol Poly (vinyl alcohol) Poly (N-isopropylacrylamide) Poly (2-hydroxyethyl methacrylate)
  • a pre-gel solution was prepared by mixing alginate (Sigma, A20330) and acrylamide (sigma, A8887) into a solution with one to five weight percent of alginate and 5-40 weight percent, of acrylamide.
  • the concentration of the N,N-methylenebisacrylamide needs to be very low (i.e., less than 4 ⁇ 10 ⁇ 4 g per 10 ml of the polymer solution) to enable the low modulus of the hydrogels in fixture steps.
  • the pre-gel solution After degassing the pre-gel solution in a vacuum chamber, we added calcium sulfate (Sigma, C3771) as the crosslinker for alginate and N,N,N′N′-tetramethylethylenediamine (Sigma, T7024-50M) as the crosslinking accelerator for polyacrylamide. Thereafter, the pre-gel solution was infused into molds of different shapes and was subjected to ultraviolet light for 60 minutes with 8 W power and 254 nm wavelength to fabricate the initial hydrogel.
  • calcium sulfate Sigma, C3771
  • N,N,N′N′-tetramethylethylenediamine Sigma, T7024-50M
  • the as-fabricated pre-gel hydrogels are relatively stiff with a shear modulus over 10 kPa and up to 100 kPa as shown in FIG. 2 .
  • the inventors have developed an innovative and practical method to reduce the modulus of the hydrogel while maintaining its high fracture toughness.
  • the extremely soft and tough hydrogel disclosed herein can be conformally attached to different regions of a human body.
  • the material can also conformally deform and wrap around ultrasound probes of various shapes.
  • the hydrogel is elastic and extremely tough, it will not flow or fracture as commonly used ultrasound gels do.
  • the shear modulus of the hydrogel is very low (approximately 1 kPa), it is expected to give excellent transmission efficiency for ultrasound.
  • the extremely compliant and tough hydrogel of the invention gives high quality ultrasound images.
  • conventional liquid hydrogel flows away or dehydrates after approximately one minute of measurement the novel compliant and tough hydrogel of the invention can last 30 minutes to hours.

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Abstract

A method for making a tough and compliant hydrogel. A precursor hydrogel is made of a first polymer selected to maintain high elasticity and a second polymer selected to dissipate mechanical energy. The precursor hydrogel is stretched to a multiple of its original length to form a pre-stretched hydrogel. The pre-stretched hydrogel is allowed to relax and is soaked in a biocompatible solvent to reach equilibrium swelling of the pre-stretched hydrogel whereby shear modulus of the hydrogel is reduced.

Description

  • This application is a continuation of U.S. application Ser. No. 14/970,704, filed Dec. 16, 2015 and entitled EXTREMELY COMPLIANT YET TOUGH HYDROGEL SYSTEMS AS ULTRASOUND TRANSMISSION AGENTS; which claims priority to U.S. provisional application No. 62/095,243 filed on Dec. 22, 2014, and entitled EXTREMELY COMPLIANT YET TOUGH HYDROGEL SYSTEMS AS ULTRASOUND TRANSMISSION AGENTS, the contents of which are incorporated herein by reference.
    • BACKGROUND OF THE INVENTION
  • This invention relates to a method for making a tough and compliant hydrogel with a low shear modulus that is extremely tough and robust.
  • It is desirable to have hydrogels be both resilient and tough. A particular use for such a hydrogel is as a transmission agent for ultrasound because resiliency allows it to conform to a body part. Resilience and toughness appear to be intrinsically contradictory properties but can be achieved according to the methods disclosed herein.
    • SUMMARY OF THE INVENTION
  • The method for making a tough and compliant hydrogel according to the invention includes combining a long chain polymer network to maintain high elasticity and a sacrificial chain polymer network to dissipate mechanical energy to form an interpenetrating hydrogel. The interpenetrating hydrogel is prestretched to a prescribed multiple of its original length and then relaxed for multiple cycles. Thereafter, the pre-stretched hydrogel is soaked in a biocompatible medium to reach equilibrium swelling of the hydrogel. As a result, the shear modulus of the hydrogel is significantly reduced. To achieve extremely low modulus, multiple loading-unloading steps are performed to deplete most of the sacrificial polymer network to a controlled degree.
  • The long chain network may be selected from a group consisting of polyacrylamide, polyethylene glycol, poly (vinyl alcohol), poly (N-isopropyl acrylamide), and poly (2-hydroxyethyl methacrylate). The sacrificial chain network may be selected from the group consisting of alginate, hyaluronic acid, collagen, agarose, gelatin, fibrin and chitosan. The hydrogel made by the method of the invention may be used as an ultrasound transmission agent.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a schematic illustration of the steps performed according to the invention to transform a tough and stiff hydrogel into a tough and compliant hydrogel by pre-stretching the gel, relaxing and soaking it in a solvent such media or PBS.
  • FIG. 2 is a graph of modulus against pre-stretch. One can see that soaking the pre-stretched hydrogel in solvent can significantly reduce the shear modulus of the hydrogel from over 10 kPa to approximately 1 kPa.
  • FIG. 3 is a comparison graph of stress versus stretch for hydrogels with different treatments.
  • FIGS. 4a and 4b are photographs of the soft and tough hydrogel of the invention conformably attached to different regions of a human body.
  • FIGS. 5a and 5b are ultrasound images of a phantom object measured through conventional liquid hydrogel as shown in FIG. 5a and the extremely compliant and tough hydrogel of the invention shown in FIG. 5 b.
    • DESCRIPTION OF THE PREFERRED EMBODIMENT
  • We have invented a method and material system to make new hydrogels that have a shear modulus as low as 1 kPa but are extremely tough and robust. The extraordinary properties of the hydrogels are achieved through the mechanisms of delayed stiffening and mechanical dissipation. The hydrogels of the invention can be formed and printed into various shapes with different dimensions. As a result of their low rigidity and high robustness, the gels of the invention can be conformally attached to different regions of the human body. This aspect is important when the novel gel system of the invention is used as an ultrasound transmission agent.
  • In general, materials from which the hydrogels are made according to the invention are from two types of polymers; one type of polymer maintains high elasticity of the hydrogel and the other type of polymer dissipates mechanical energy when the hydrogel is deformed. The first type of polymers include polyacrylamide, polyethylene glycol, poly (vinyl alcohol), poly (N-isopropyl acrylamide), and poly (2-hydroxyethyl methacrylate). The second type of polymers includes alginate, hyaluronic acid, collagen, agarose, gelatin, fibrin, and chitosan, which are generally capable of reversible crosslinking.
  • The first type of polymers are usually crosslinked by methods including free-radical polymerization, UV crosslinking, gamma irradiation, electron beam irradiation and freeze thawing. The second type of polymers is usually crosslinked by methods including adding multivalent ions, changing ambient temperature and varying pH of the solution. The chain length between two adjacent crosslinkings of the first type polymers is generally much longer than that of the second type polymers. In addition, the volume concentration of the first type of polymers in the hydrogel can range from 5% to 40%, and that of the second type is usually lower than the first type, ranging from 0.15% to 10%. Therefore, the crosslinking density of the second type polymers is usually much larger than the first type polymers. The possible combinations of different polymers to form tough hydrogels are summarized in the matrix shown in Table 1.
  • TABLE 1
    Tough hydrogels are fabricated by combining two types of polymer networks with different concentrations and
    crosslinking densities. A matrix is used to guide the selection of different polymers.
    Network for maintaining Network for dissipating energy (short chain)
    Elasticity (long chain) Alginate Hyalauronic Acid Collagen Agarose Gelatin Fibrin Chitosan
    Polyacrylamide
    Polyethylene glycol
    Poly (vinyl alcohol)
    Poly (N-isopropylacrylamide)
    Poly (2-hydroxyethyl methacrylate)
  • An example protocol for making a specific hydrogel with polyacrylamide and alginate is now described. A pre-gel solution was prepared by mixing alginate (Sigma, A20330) and acrylamide (sigma, A8887) into a solution with one to five weight percent of alginate and 5-40 weight percent, of acrylamide. We then added N,N-methylenebisacrylamide (Sigma, 146072) as the crosslinker for polyacrylamide and ammonium persulphate (Sigma, 248614) as photo initiator for polyacrylamide. The concentration of the N,N-methylenebisacrylamide needs to be very low (i.e., less than 4×10−4 g per 10 ml of the polymer solution) to enable the low modulus of the hydrogels in fixture steps. After degassing the pre-gel solution in a vacuum chamber, we added calcium sulfate (Sigma, C3771) as the crosslinker for alginate and N,N,N′N′-tetramethylethylenediamine (Sigma, T7024-50M) as the crosslinking accelerator for polyacrylamide. Thereafter, the pre-gel solution was infused into molds of different shapes and was subjected to ultraviolet light for 60 minutes with 8 W power and 254 nm wavelength to fabricate the initial hydrogel.
  • The as-fabricated pre-gel hydrogels are relatively stiff with a shear modulus over 10 kPa and up to 100 kPa as shown in FIG. 2. The inventors have developed an innovative and practical method to reduce the modulus of the hydrogel while maintaining its high fracture toughness. With reference first to FIG. 1, we first pre-stretch the hydrogel for a prescribed time to a multiple of its original length (i.e., λr1=2˜10) and then relax for multiple cycles. We then soak the pre-stretched hydrogel in a biocompatible solvent such as PBS or media over a period of time to reach equilibrium swelling of the hydrogel. We then stretched the hydrogel again to a ratio higher than the first pre-stretch (i.e., λr2>λr1) and then relax for multiple cycles. As a result, the shear modulus of the hydrogel will be significantly reduced as shown in FIG. 2. For example, when the ratio of the second stretch λr2>7, the shear modulus of the hydrogel is reduced to approximately 1 kPa. Although the resultant hydrogel has a very low shear modulus, it is still very tough as indicated by the stress versus strain curve of the hydrogel under loading and unloading. With reference to FIG. 3 it can be seen that the pre-stretched and soaked hydrogel still provides very high stretchability (over 11 times) and significant mechanical dissipation indicated by the hysteresis loop. The combination of high stretchability and mechanical dissipation give high fracture toughness to the resulting compliant hydrogel.
  • As shown in FIGS. 4a and 4b , the extremely soft and tough hydrogel disclosed herein can be conformally attached to different regions of a human body. The material can also conformally deform and wrap around ultrasound probes of various shapes. In addition, because the hydrogel is elastic and extremely tough, it will not flow or fracture as commonly used ultrasound gels do. Furthermore, since the shear modulus of the hydrogel is very low (approximately 1 kPa), it is expected to give excellent transmission efficiency for ultrasound. As shown in FIGS. 5a and 5b , the extremely compliant and tough hydrogel of the invention gives high quality ultrasound images. However, whereas conventional liquid hydrogel flows away or dehydrates after approximately one minute of measurement, the novel compliant and tough hydrogel of the invention can last 30 minutes to hours.
  • Additional information concerning this invention may be found in Lin et al., “Designing Extremely Resilient and Tough Hydrogels via Delayed Dissipation”, Extreme Mechanics Letters 1 (2014) 70-75. Reference may also be made to international publication number WO2013/103956. The contents of both of these references are incorporated herein by reference.
  • It is recognized that modifications and variations of the invention will be apparent to those of ordinary skill in the art and it is intended that all such modifications and variations be included within the scope of the appended claims.

Claims (22)

1. An ultrasound transmission agent comprising:
a tough and compliant hydrogel comprising a long chain polymer network and a sacrificial chain polymer network,
wherein the hydrogel is provided with a low shear modulus and a high fracture toughness,
and wherein the hydrogel is conformable to various shapes.
2. The ultrasound transmission agent of claim 1, wherein the hydrogel has a shear modulus below 10 kPa.
3. The ultrasound transmission agent of claim 1, wherein the hydrogel has a shear modulus of about 5 kPa or less.
4. The ultrasound transmission agent of claim 1, wherein the hydrogel has a shear modulus of about 1 kPa or less.
5. The ultrasound transmission agent of claim 1, wherein the long chain network is selected from the group consisting of polyacrylamide, polyethylene glycol, poly (vinyl alcohol), poly (N-isopropyl acrylamide), and poly (2-hydroxyethyl methacrylate).
6. The ultrasound transmission agent of claim 1, wherein the sacrificial chain network is selected from the group consisting of alginate, hyaluronic acid, collagen, agarose, gelatin, fibrin and chitosan.
7. The ultrasound transmission agent of claim 1, wherein the volume concentration of the long chain network in the hydrogel ranges from 5% to 40%, and the volume concentration of the sacrificial chain network ranges from 0.15% to 10%.
8. The ultrasound transmission agent of claim 1, wherein the volume concentration of the sacrificial chain network is lower than the volume concentration of the long chain network.
9. The ultrasound transmission agent of claim 1, wherein polymers of the long chain network are crosslinked by free-radical polymerization, UV crosslinking, gamma irradiation, electron beam irradiation and/or freeze thawing.
10. The ultrasound transmission agent of claim 1, wherein polymers of the sacrificial chain network are crosslinked by adding multivalent ions, changing ambient temperature and/or varying pH of the solution.
11. The ultrasound transmission agent of claim 1, wherein the hydrogel has a shear modulus of about 1 kPa or lower, and can be stretched over 11 times its original length without fracture or flow.
12. The ultrasound transmission agent of claim 1, wherein the hydrogel conforms to various regions of a body and/or is conformable to wrap around ultrasound probes of various shapes without flow or fracture.
13. An ultrasound transmission agent comprising a tough and compliant hydrogel comprising a long chain polymer network and a sacrificial chain polymer network, wherein the hydrogel is formed by (a) combining the long chain polymer network and the sacrificial chain polymer network to form an interpenetrating hydrogel; (b) stretching the interpenetrating hydrogel a first time to a multiple of its original length to form a pre-stretched hydrogel; (c) allowing the pre-stretched hydrogel to relax; (c) soaking the relaxed hydrogel in a biocompatible solvent to reach equilibrium swelling of the hydrogel; (d) stretching the interpenetrating hydrogel a second time to a second multiple of its original length wherein the second multiple is greater than the first multiple, whereby shear modulus of the hydrogel is reduced.
14. The ultrasound transmission agent of claim 13, wherein the multiple of its original length is in the range of 2-10.
15. The ultrasound transmission agent of claim 13, wherein the shear modulus of the hydrogel is reduced from over 10 kPa to about 5 kPa or below.
16. The ultrasound transmission agent of claim 13, wherein the shear modulus of the hydrogel is reduced from over 10 kPa to about 1 kPa or below.
17. The ultrasound transmission agent of claim 13, wherein the long chain polymer network is selected from the group consisting of polyacrylamide, polyethylene glycol, poly (vinyl alcohol), poly (N-isopropyl acrylamide), and poly (2-hydroxyethylmethacrylate).
18. The ultrasound transmission agent of claim 13, wherein the sacrificial chain polymer network is selected from the group consisting of alginate, hyaluronic acid, collagen, agarose, gelatin, fibrin and chitosan.
19. The ultrasound transmission agent of claim 13, wherein the volume concentration of the long chain network in the hydrogel ranges from 5% to 40%, and the volume concentration of the sacrificial chain network ranges from 0.15% to 10%.
20. The ultrasound transmission agent of claim 13, wherein the volume concentration of the sacrificial chain network is lower than the volume concentration of the long chain network.
21. The ultrasound transmission agent of claim 13, wherein the hydrogel has a shear modulus of about 1 kPa or lower, and can be stretched over 11 times its original length without fracture or flow.
22. The ultrasound transmission agent of claim 13, wherein the hydrogel conforms to various regions of a body and/or is conformable to wrap around ultrasound probes of various shapes without flow or fracture.
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