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Du et al. Soft Sci 2024;4:35 https://dx.doi.org/10.20517/ss.2024.31 Page 5 of 23

actively controlled, electro-responsive hydrogel actuators offer the advantage of highly controllable
actuation states and adjustable actuation degrees. They can easily, remotely, and repeatedly generate
stimulation signals, meeting therapeutic needs for in vivo applications and adjustable release. The most
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common way to achieve this is by introducing conductive polymer structures into the hydrogel scaffold .
This enables electro-responsive hydrogel actuators to respond to electrical signals while maintaining high
hydrophilicity, biocompatibility, and the ability to deliver different molecules. The highly cross-linked
polymer network of hydrogel actuators possesses mechanical properties similar to biological tissues, and the
highly porous structure can store drugs. When an electrical signal is applied, the hydrogel aperture
increases, and the hydrogel network expands. The expansion and collapse of the hydrogel actuator provide a
switching system for drug release, meeting the need for intermittent and prolonged administration for
medical conditions such as cancer, diabetes, and chronic pain. By adjusting the voltage, current density, and
pulse conditions applied to the hydrogel actuator, on-demand drug release can be achieved. With the
development of flexible electronics, even in vivo implantation is possible.

Glucose-responsive hydrogel actuators
As the primary energy source for normal physiological activities, glucose levels are typically regulated by a
strict feedback mechanism . The human pancreas controls the release of endogenous insulin by
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monitoring glucose levels in the body. In diabetic patients, this feedback regulation system becomes
imbalanced, affecting insulin secretion. Glucose-responsive hydrogels can recognize and respond to various
glucose molecules, such as phenylboronic acid (PBA), glucose oxidase (GOx), and glucose-binding
molecules (GBM) . These three mechanisms have been extensively researched. Therefore, glucose-
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responsive hydrogel actuators hold significant potential for insulin delivery. For instance, in diabetes, these
hydrogel actuators can identify glucose molecules in the external environment, thereby altering their
physicochemical structure and properties to facilitate insulin release and supplementation.

Enzyme-responsive hydrogel actuators
Enzymes are widely found in various human tissues and can directly reflect the body’s health status. Due to
their high sensitivity and selectivity in living organisms, enzyme-responsive hydrogel actuators have
attracted considerable attention . Drugs loaded in the hydrogel can initiate an enzymatic response under
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the recognition of a specific enzyme, releasing the drug to the corresponding target site. Enzyme-responsive
hydrogels exhibit low swelling at low pH, which can protect protein drugs from digestion by proteolytic
enzymes in the stomach. Existing enzyme-responsive hydrogels include enzyme reaction hydrogel
nanoparticles (NPs), magnetic hydrogels, drug reaction hydrogels, and hydrogels for dual protein
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delivery . These hydrogel actuators can be used in a wide range of biomedical engineering applications,
such as wound healing, protein delivery, and antimicrobial scaffolds.

Light-responsive hydrogel actuators
Based on different wavelengths and energy levels, light stimulation sources can be divided into natural light,
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ultraviolet (UV) light, near-infrared (NIR) light, and infrared light . Due to its rapid, non-contact, and
sensitive characteristics, light stimulation has significant application potential in the biomedical field. Light-
responsive hydrogels are categorized into two types: (i) hydrogels containing photoisomerization/
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photoionizing chromophores and (ii) hydrogels containing photothermal agents . They can also be
classified into UV-responsive hydrogels and visible light-responsive hydrogels based on the light
stimulation sources. Visible light is particularly advantageous due to its accessibility, safety, and low cost.
Light-responsive hydrogels can change their properties through three mechanisms in response to external
light stimuli. First, photosensitive groups grafted onto the hydrogel initiate a response and deformation after
absorbing photons with sufficient energy. Second, photoactive molecules within the hydrogel produce ions
that react with the hydrogel network or alter its osmotic pressure, causing expansion. Finally, hydrogel