A multiphysics model of photo-sensitive hydrogels in response to light-thermo-pH-salt coupled stimuli for biomedical applications

Highlights

• A model is developed for photo-sensitive hydrogels.

• The coupled effect of multiple stimuli is considered.

• Electrical and pH responses are investigated.

• The findings can inspire some biomedical applications.

Abstract

This paper aims to unveil the fundamental response mechanism of photo-sensitive hydrogels subject to light-thermo-pH-salt coupled stimuli, for their potential biomedical uses such as cell scaffolds and extracellular matrices, where biological activity largely depends on internal electrochemical changes. To mimic the microenvironment of biomolecules or cells, we focus on a spirobenzopyran-modified N-isopropylacrylamide hydrogel incorporating acrylic acid as a proton generator and develop a multiphysics model to characterize its behaviour within aqueous solution in response to light intensity, temperature, buffer pH, and salt concentration. The model allows for concurrent chemical reactions, ionic diffusion, electrostatic effects and large mechanical deformation, as well as interaction with the solution domain. Validation was performed by comparison with the published experimental results and showed good agreement. It is demonstrated by the simulation results that the photo-sensitive hydrogel exhibits a varied sensitivity to the external stimuli if incorporated with different molar ratios of acrylic acid. The electrical and pH response characteristics of the hydrogel, especially those in neutral solution, may inspire some potential biomedical applications, such as photo-controlled drug release and cell growth.

Introduction

Recently, photo-sensitive hydrogels have gained much popularity in the field of clinical and tissue engineering due to their distinctive advantages, including localized manipulation, exquisite modulation, and remote and wireless controllability, especially for cell culture. For example, by contrast with temperature, chemical, and mechanical force changes, it is easy to manipulate the individual cell adhesion via low-power irradiation [1] and even to kill cells selectively through photo-acid-generation [2], [3] within the photo-sensitive hydrogel-based extracellular matrix (ECM). The performance of a photo-responsive ECM or scaffold is closely related to the stimuli-responsive electrochemical behavior of the photo-sensitive hydrogel, which directly affects biological activity. For instance, cell adhesion is influenced by some properties of the ECM, such as water content, hydrophobicity, and mechanical strength [4], which might vary due to the photo-chemical reaction within the hydrogel. Meanwhile, cell growth largely depends on the surrounding temperature, pH and salt level. For example, glycosaminoglycans (GAGs) are often used to regulate numerous growth factors in the scaffold through their sulfation patterns which are highly determined by electrostatic interaction and the pH environment within the microenvironment [5]. Furthermore, some detectable responses like electrical impedance or conductivity can be employed to monitor cell behavior within the ECM [6]. Hence, a self-feedback system could be developed to improve the photo control system of photo-responsive ECMs or other bioelectronics, for when measurement of the electrical response signal becomes available. To this end, it is important to understand the fundamental response of photo-sensitive hydrogels subject to multiple coupled stimuli, especially the electrical response, for further exploration of their potential use in the biomedical field.

A literature review reveals that photo-sensitive hydrogels have been mostly synthesized by incorporating photo-sensitive groups (PSGs) into the thermo-responsive polymer N-isopropylacrylamide (pNIPAAm), such as spiropyran [7], [8], metal nanoparticles [9], chlorophyllin [10], and photoacid generators [11]. The phase transition temperature of pNIPAAm is near that of the human body, and thus, pNIPAAm-based photo-sensitive hydrogels have widespread biomedical applications, especially as photo-responsive cell culture surfaces [1]. Spiropyran is one of the most well-known and used PSGs, with a reversible conversion between hydrophobic closed-ring and hydrophilic open-ring isomers. Most importantly, this compound also responds to a wide range of stimuli apart from light, including temperature, pH, metal ions, and mechanical stress [12], [13], [14]. As such, many relevant studies have focused on the spiropyran-based pNIPAAm hydrogel (pSpNIPAAm gel) for its promising use in biological sensing [15]. For pSpNIPAAm gels, Sumaru et al. examined their hydration and dielectric states in response to multiple stimuli, including light irradiation, ambient temperature and buffer pH [7], [8], [16], [17], [18], [19]. A fascinating feature of pSpNIPAAm gels was their ability to undergo drastic dehydration under visual light even at 21 °C, while the equivalent dehydration state in the dark occurred at a temperature that was approximately 10 °C higher [7], [8]. However, the acidic environment is indispensable to this photo-induced dehydration [17], [19], [20]. To address this issue, a self-protonating photo-sensitive hydrogel was developed by incorporating an acrylic acid (AA) co-monomer into the pSpNIPAAm gel as the proton generator, such that it could even work in deionized water [20], [21]. Despite the widespread use of this novel photo-sensitive hydrogel in the area of photo-actuation [22], [23], [24], very few studies have been carried out on its electrochemical characteristics, inhibiting its extended application in bioelectronics. Furthermore, the above efforts were basically trial-and-error experiments.

Numerical simulation is a cost-effective approach to study the response mechanism of photo-sensitive hydrogel systems. Kuksenok et al. were the first research group to model pSpNIPAAm gels [25], [26], [27], and then, Dehghany and Xuan improved the model by considering the ionic migration and electrostatic field [28], [29]. However, the authors still failed to consider the solution domain and multiple concurrent reactions on fixed groups, especially protonation equilibrium. For this reason, these models were not accurate enough to predict the multi-stimuli-responsive behaviours of photo-sensitive hydrogels, especially the electrical and pH responses. Furthermore, to the best of our knowledge, no modelling work has been carried out on self-protonating photo-sensitive hydrogels.

This paper focuses on the response behaviour of the pSpNIPAAm hydrogel subjected to light-thermo-pH-salt coupled stimuli, where the light sensitivity depends on the photoisomerization of spiropyran, the temperature sensitivity depends mostly on the pNIPAAm backbone and partly on the thermal isomerization of spiropyran, and the pH and salt sensitivities depend mainly on the immobilized spiropyran and acrylic acids. A multi-effect-coupling photo-stimulus (MECp) model is developed to investigate its responses against the coupled effect of light intensity, temperature, buffer pH, and salt concentration. In the MECp model, multiple coupled effects are formulated regarding the hydrogel system, including the photo-chemical reaction, thermal isomerization, protonation equilibrium, ionic migration, electrostatic interaction, and large mechanical deformation. In addition, the model allows for the surrounding solution domain to capture the interaction between the polymeric network and buffer solution. Herein, for the first time, the characteristic analysis is performed on the electrical and pH responses of self-protonating photo-sensitive hydrogels immersed in neutral solution, following published procedures [5], [30], [31]. Through the MECp model, these studies unveil the multi-stimuli responsive mechanism of photo-sensitive hydrogels, which might provide insight into some biomedical applications.