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High-performance Shape-memory Hydrogel Microcoils as Permanent Embolic Agents

 Research

Aneurysm is a bulging disease of the arterial wall, and the thinning of blood vessel wall after bulging increases the risk of vessel rupture, leading to uncontrolled bleeding, thus severely threatening to life at any time. Transcatheter arterial embolization (TAE) has been widely used to treat aneurysms because of its minimal invasiveness. In the treatment of large aneurysms, the commercial metal coils cannot be stacked closely in the cavity because of their high stiffness, and there is a risk of recanalization. As a kind of intelligent soft wet material with memory function, shape memory polymer hydrogels have potential applications as implantable minimally invasive scaffolds and biosensors due to their soft tissue-like properties. However, the vast majority of thermo-sensitive shape memory hydrogels are too soft and have a modulus much lower than megapascals, which can easily deform and block the catheter during transcatheter delivery, making the administration unsuccessful. In addition, the trigger temperatures of most shape memory hydrogels reported are far beyond body temperature. It is also difficult to fix a small diameter of coil which could generate large resilience force. The other challenge is that the high-strength hydrogels reported so far lacked X-ray imaging function, and could not be in situ tracked during operation or after surgery. All these shortcomings seriously limited their clinical applications. 

Recently, Professor Liu Wenguang’s team from School of Materials Science and Engineering of Tianjin University has created a high-modulus and high strength body temperature triggered shape memory hydrogel with X-ray imaging function, and further developed a novel shape memory microcoil which with Dr. Feng Xuequan’ team from Tianjin First Central Hospital. They achieved successful embolization of pig’s renal arterial vessels with this smart high-strength hydrogel microcoil for the first time. The gel network consisted of dipole-dipole interaction of polyacrylonitrile/hydrogen bonding physical interaction of polyacrylamide and the chemical crosslinking of long-chain polyethylene glycol dimethacrylate. The results of wide-angle X-ray diffraction and small-angle X-ray scattering suggested that the crystalline hydrophobic microdomains formed by the dipole pairs were crucial for swelling stability in water environment and modulus of the hydrogels. Dynamic mechanical analysis showed that the Young's modulus of gel reached as high as 16 MPa due to strong physical crosslinking at room temperature. When the temperature was raised to body temperature, the gel modulus dropped to 270 kPa owing to the disruption of dipole-dipole/hydrogen bonding interactions. Remarkably, body temperature-driven shape memory effect could be achieved and the shape of the gel could be recovered as fast as 4 s. Considering that copolymerization of iodine-containing monomers may adversely affect the shape memoryeffect, the team endowed the gel with X-ray imaging function by a simple barium sulphate deposition method. The experimental results showed that the adsorption of barium sulphate has little effect on the shape memory effect and the mechanical property of the hydrogels. 


Figure 1. (A) Photos depicting the thermoreversible softeningstiffening transition. (B) Schematic illustration of the fabrication of radiopaque TAE hydrogel coils. (C) The SM procedure of the hydrogel coil in an unconfined environment. (D) In vitro shape recovery of the hydrogel coil from initial straight strip, which was delivered through a catheter into the glass tube immersed in 37 °C water. 

In order to explore the effect of embolization in vivo, the team preformed a radiopaque gel into a microcoil which were straightened at an elevated temperature, and fixed at a low temperature; then the straight hydrogel strip was delivered to the pig’s renal artery by an interventional catheter under protection of cooled saline. Upon contact with "warm blood", the gel strip rapidly transformed into a coil. Delivering several coils in succession could efficiently embolize the renal artery. At 12 post operation, the hydrogel coil remained very stable in the blood vessels, and no recanalization phenomenon was observed. Anatomical and staining results showed that the kidneys in the embolized area became necrotic. This self-imaging shape memory coil is expected to open a new avenue to treat aneurysm. 


Figure 4. The SM effect of radiopaque hydrogel coils in vivo and their embolism assessment. (A) Schematic illustration of the TAE process. The stiff straight hydrogel strips passed through a transcatheter in sequence pushed by a guide wire under the protection of cooled saline solution to be delivered into the targeted renal artery. Upon contacting blood, the strips converted into microcoils rapidly and got entangled, leading to blocking of the blood. (B) Angiograms of the delivery of radiopaque hydrogel coils (yellow dots indicated the contour of the microcoils formed) into the target renal artery: hydrogel coils twisted rapidly upon contacting warm blood. (C) Angiographic images obtained at different time intervals after embolization; red circles indicated the position of hydrogel coils. (D) Gross examination of the embolized and normal kidneys at 4, 8, and 12 weeks after surgery. Scale bar = 2 cm. 

This outcome was recently published in Adv Funct Mater 2018 DOI: 10.1002 / adfm.201705962. The first author is Ph.D. student Zhang Yinyu. The work is financially supported from the National Natural Science Funds for Distinguished Young Scholar (Grant No. 51325305) and National Natural Science Foundation (Grant No. 21274105). 

By: School of Materials Science and Engineering

Editor: Qin Mian