EXTREMELY COMPLIANT YET TOUGH HYDROGEL SYSTEMS AS ULTRASOUND TRANSMISSION AGENTS
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.
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 INVENTIONThis 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 INVENTIONThe 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.
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.
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
As shown in
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
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.
Type: Application
Filed: Dec 19, 2017
Publication Date: May 10, 2018
Inventors: Xuanhe Zhao (Allston, MA), Shaoting Lin (Cambirdge, MA), Hyunwoo Yuk (Allston, MA)
Application Number: 15/846,301