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Page 14 of 23 Du et al. Soft Sci 2024;4:35 https://dx.doi.org/10.20517/ss.2024.31

undergoes a sol-gel transition at body temperature, allowing it to fill small tissue voids of various shapes,
such as those caused by periodontitis. The experimental results show that the hydrogel supports repeated
and long-term administration, effectively terminating inflammation and promoting periodontal tissue
regeneration.

The limitation of periodontal disease lesions makes injectable hydrogel actuators more competitive, as they
can fill various small tissue pores. Therefore, future research should focus on further improving the
degradation efficiency and ratio of hydrogel actuators to achieve rapid and complete degradation while
meeting the therapeutic cycle.

Psoriasis
Psoriasis is a chronic autoimmune skin disorder influenced by both genetic and environmental factors. It is
marked by excessive keratinocyte proliferation, the infiltration of inflammatory cells in the epidermis, and
the formation of lesions with silvery scales . The pathogenesis of psoriasis involves complex mechanisms,
[116]
with the overactivation of the adaptive immune system via the CARD14 gene being a leading
explanation . Many current psoriasis treatments have side effects; however, since 90% of cases are mild to
[117]
moderate and predominantly localized, topical treatments remain the most commonly employed
therapeutic approach . Hydrogel actuators not only fulfill the requirements for psoriasis treatment but
[118]
also offer more targeted and effective therapies based on the severity and specific needs of the patient.

Noddeland et al. developed enzyme-responsive hydrogels for the treatment of psoriasis by delivering the
[101]
anti-inflammatory drug tofacitinib citrate [Figure 4E]. When the enzyme-responsive hydrogel interacts
with matrix metalloproteinase-9 (MMP-9), alterations in the concentration and structure of the multi-arm
PEG within the hydrogel can modify its physical and mechanical properties. This interaction induces
swelling and structural changes in the hydrogel, which in turn leads to drug release. Additionally, by fine-
tuning specific formulation parameters, drug release can be further optimized to address the personalized
treatment needs of individual patients.

Jiang et al. developed a thermoresponsive hydrogel, “ProGel-Dex”, which is administered through
[100]
intradermal injection, using dexamethasone as a model drug [Figure 4F]. Its therapeutic efficacy and
safety in the treatment of psoriasis were validated in a mouse model of psoriasis. ProGel-Dex is in liquid
form at 4 °C, but once injected into the body, it forms a solid hydrogel, enabling sustained drug release at
the pathological site. The unique thermoresponsive phase transition property of ProGel-Dex allows it to
remain effective for one to four months, significantly extending the treatment duration.

Due to the complex pathogenesis and types of psoriasis, most experiments using hydrogel actuators for
psoriasis treatment are based on acute inflammation models. Further research is needed to address the
chronic and complex pathophysiology of psoriasis in humans.

Other diseases
Cancer treatment
In recent years, cancer has remained one of the leading causes of death. Chemotherapy, the main treatment
[119]
for cancer, has significant drawbacks, including poor stability and systemic toxicity . Stimuli-responsive
hydrogel actuators offer a promising alternative for drug delivery. These hydrogels exhibit controlled
volume or phase changes in response stimuli, allowing for precise control of drug release location and
duration. Implantable or injectable hydrogels encapsulate drugs to target the tumor’s surrounding or
internal environment, ensuring targeted delivery to the tumor site . This approach aims to achieve better
[120]