Development of chitosan/β-glycerophosphate/glycerol hydrogel as a thermosensitive coupling agent
Introduction
Focused ultrasound is a form of thermal therapy capable of destroying diseased tissues by protein denaturation at supra-physiological temperatures (Lin et al., 2012), with the trade-off being occasional cases of skin burns when tissues are overheated (ter Haar & Coussios, 2007). Fortunately, such a side effect can be prevented with an instant warning signal based on real-time temperature measurements. Common temperature sensors include a thermocouple, thermometer, and infrared thermometer. However, these are awkward additions to this form of therapy, and each has its own limitations. For example, a thermocouple and thermometer can only monitor temperature at one spot a time. Their sensing areas are limited and difficult to move during therapy. On the other hand, while an infrared thermometer can show the surface temperature for a wide area, it needs an additional and expensive read-out system (Medberry, Tottey, Jiang, Johnson & Badylak, 2012).
One potential method of warning on overheating is directly changing the transparency of the coupling agent employed during therapy. Coupling agents are often used to promote the conduction of ultrasound between air and human tissues. The simplest coupling agent is water due to its high transmission coefficient and low reflection coefficient. The operation time of water can be extended by adding hydrophilic compounds, such as glycerol, to slow down evaporation. Coupling agents can contain a wide range of components. For example, Vaseline is one kind of petrolatum with a high transmission like water (Casarotto, Adamowski, Fallopa & Bacanelli, 2004) and KY gel is a common and aqueous lubricant composed of water and glycerol (Poltawski & Watson, 2007). Finally, Biofreeze is an alcoholic hydrogel adding glycerol and menthol to provide the lubricant (Cage et al., 2012).
Since none of agents outlined above can warn overheating, this study proposes a thermosensitive hydrogel composed of chitosan (CS), β-glycerophosphate (β-GP), and glycerol. CS is biodegradable, biocompatible, and non-toxic. Its polymer chains have numerous hydrophilic groups. β-GP is an organic and non-toxic compound approved by the Food and Drug Administration, while glycerol is a commonly used hydrophilic lubricant. CS/β-GP/glycerol is a transparent solution below the sol-to-gel temperature, but it becomes an opaque and turbid gel above this temperature. The transparency reduction is able to serve as an overheating signal.
In this work, we tune the compositions of the hydrogel such that the sol-to-gel transition temperature agrees with the supra-physiological temperature. The resulting hydrogel is able to give out a real-time overheating warning. The thermal and other physical properties of the proposed hydrogel are examined to assess its capabilities. First, the chemical structures of the CS/β-GP/glycerol hydrogel are analyzed using Fourier transform infrared spectroscopy. Second, the light transmission of the samples is measured to identify the sol-to-gel transition temperature of CS/β-GP/glycerol hydrogel with different compositions. Finally, the acoustic impedance (Z), attenuation coefficient (α), and ultrasound transmission of the optimized hydrogel are also evaluated.
Section snippets
Materials
CS have positively charged amine group (NH3+). The protonation (NH2 + H+ → NH3+) generates when CS is dissolved in weak acid solution (Berger et al., 2004). CS is composed of glucosamine and derived by deacetylation of chitin. The positively charged NH3+ groups provide CS with many excellent properties, including bacteriostasis and biocompatibility, as well as promoting cell growth.
GP has α- and β-type, but β-GP has a more compact structure and shows more steric hindrance than α-type with its
Chemical analysis by FTIR
Fig. 1 shows the FTIR spectra of the benchmark (0.5% CS, 5% β-GP, and 25% glycerol) at 25, 45, and 65 °C in the range of 950–4000 cm−1. The sol-to-gel temperature is 53 °C, such that the spectrum at 65 °C differs from those at 25 and 45 °C. There are several characteristic peaks of CS at the small wavenumber region. The peaks at 1030 cm−1 and 1115 cm−1 are both broad, and they indicate the CO stretching vibration. The peak associated with the COC band at 1195 cm−1 could be the reference peak from the d
Conclusions
This work successfully developed a thermosensitive hydrogel composed of CS, β-GP and glycerol. This hydrogel has a tunable sol-to-gel temperature from 35 to 56 °C, which can be controlled by changing the composition. Optimized formula of the hydrogel is 0.5% CS, 5% β-GP, and 25% glycerol. This hydrogel has high acoustic impedance (Z = 1.8 Mrayl) close to that of human skin, and its attenuation coefficient (α = 4.0 Np/m) is much lower than that of human skin. The hydrogel’s ultrasound transmission
Acknowledgements
The work is supported by the Ministry of Science and Technology (MOST) in Taiwan under grants No. MOST-103-2923-E-006-008-MY2, MOST-104-3113-E-006-002, and MOST-104-2628-E-006-008-MY2. The authors thank Dr. Chih-Chung Huang and Mr. Cho-Chiang Shih for their help during the final stages of this work.
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