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Page 2 of 23 Du et al. Soft Sci 2024;4:35 https://dx.doi.org/10.20517/ss.2024.31

[3]
content, excellent biocompatibility, and tunable physicochemical structures and properties . These unique
characteristics make stimuli-responsive hydrogels ideal for developing soft actuators. These actuators can
employ diverse structural and functional designs to modify their physicochemical properties, detect
environmental stimuli, undergo shape changes and movement processes, adapt to complex environments,
and meet functional requirements under varying conditions .
[4]
The properties of stimuli-responsive hydrogel actuators are promising in the biomedical field, particularly
in on-demand drug delivery . These actuators possess mechanical and soft material properties, and their
[5]
excellent biocompatibility makes them superior to similar products in biomedical applications . Their
[6]
structural similarity to the extracellular matrix (ECM) allows for safe and effective integration into the
human physiological environment, adapting to diverse and complex conditions and facilitating drug
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acquisition and release . Hydrogels have a porous network structure that can load drugs within the gel,
with pore size adjustable by altering the hydrogel’s crosslinking density . Stimuli-responsive hydrogel
[8]
actuators can contract, swell, and decompose by responding to external stimuli, enabling the controlled
release of drugs to deliver the optimal dose to the target area at the appropriate time . Furthermore, the
[9]
drug delivery effect of hydrogel actuators can be precisely controlled in time and space, meeting various
treatment needs, enhancing treatment efficacy, reducing adverse side effects, and ultimately achieving the
goal of disease treatment.

This paper reviews the various types of external stimuli to which stimuli-responsive hydrogel actuators can
respond, outlines their performance and application pathways, and highlights their biomedical applications
in skin therapeutics and beyond [Figure 1].

TYPES OF STIMULI-RESPONSIVE HYDROGELS
Natural systems constantly respond and adapt to changes in their environment. Inspired by nature and
bionics, various soft actuators have been designed and developed. Among them, hydrogel actuators
demonstrate significant potential in drug delivery and biomedical engineering, owing to their resemblance
to soft biological tissues, high water content, flexibility, and biocompatibility. Because hydrogel actuators
can achieve specific responses to different stimuli, they are well-suited for applications in various
biomedical engineering fields. Studies have shown that when biological tissues are affected by trauma or
disease, their pH, temperature, enzyme levels, and other states change. As a “smart” stimuli-responsive
material, hydrogel actuators can respond to various environmental stimuli, including pH, electricity,
temperature, and light [Table 1]. The specific structure of stimuli-responsive hydrogel actuators allows for
controllable target deformation and function [Figure 2], making them advantageous in drug delivery and
disease therapy.

pH-responsive hydrogel actuators
Altered pH values are closely linked to many physiological processes. Under normal conditions, the pH
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ranges from gastric acid (pH 1-3) to the duodenum (pH 6) and the jejunum and ileum (pH 6-7.5) . In
abnormal conditions, such as inflammation, bacterial infection, wound healing, tumors, and other
pathological environments, pH levels change correspondingly. pH-responsive hydrogels contain easily
hydrolyzed units, including carboxyl, sulfonate, and amino moieties, which dissociate or protonate
according to the environmental pH, leading to changes in electrostatic interactions and ultimately altering
the volume of the hydrogel . These hydrogels can exhibit swelling and deswelling deformation
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characteristics in response to pH changes under different physiological conditions, making them highly
applicable in the biomedical field. pH-responsive hydrogel actuators can be classified as cationic or anionic
based on their functions . Their swelling mechanisms include changes in hydrophobic properties,
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