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Page 20 of 33 Ren et al. Soft Sci. 2026, 6, 6

Reproduced with permission from Ref. [34] . Copyright 2025, Wiley-VCH; (G) 3D laser lithography scaffold with β-cyclodextrin adamantane
chemistry for reversible chemically actuated cell stretching. Reproduced with permission from Ref. [134] . Copyright 2020, American
Association for the Advancement of Science; (H) 4D printed humidity-actuated seed-like soft robot from biodegradable hygroscopic
polymers for autonomous reshaping and soil interaction. Reproduced with permission from Ref. [135] . Copyright 2023, Wiley-VCH. 4D: Four-
dimensional; TPP: two-photon polymerization; 3D: three-dimensional; RH: relative humidity.

Zhang et al. introduced an acoustically activated micromachine that used preprogrammed soft hinges with
different stiffness [130] . Under an acoustic field, the hinges concentrated acoustic energy through intensified
oscillation and delivered millisecond folding with selectable morphologies by adjusting acoustic power
[Figure 7B]. Building on this concept, Xiao et al. developed an acoustically actuated hydrogel micromachine
with variable stiffness hinges that oscillated strongly under ultrasound and produced transformations within
500 ms . The folding was preprogrammed to convert between letters and characters, and a 174 μm wide
[33]
microrobot navigated narrow channels at about 800 μm/s [Figure 7C]. Extending acoustic control to spatially
selective and forceful operation, Hao et al. proposed a focused ultrasound-induced phase transition strategy
that inflated internal volumes to generate Newton-level forces with millimeter-scale addressability [132] . A
proof-of-concept robot is proposed for transporting liquid cargo and performing biopsy and patching
[Figure 7D].

Ultrasound provides remote, noninvasive and deep penetration control, and is capable of operating in
opaque media with rapid response. However, Precise localization and directional control are challenging due
to scattering and attenuation of acoustic fields in heterogeneous tissues, and the necessity to manage thermal
side effects to meet safety constraints.

Chemical stimuli
Chemically, actuation in 4D printing converts interactions between molecules and external chemical
environments into controllable shape changes. Typical triggers include pH, ionic strength changes, solvent
exchange, humidity, and specific ions or ligands [Figure 7E] [119] . They alter bond equilibria to modify
network connectivity and stiffness. Geometric shapes and chemical stimuli must be selected together, as
diffusion and reaction kinetics determine the response rate. Thin films, high porosity, and spatial patterning
can accelerate reaction progress and enable directional driving. These principles have been well
demonstrated in stimulus-responsive hydrogels and polymers .
[133]

Cao et al. developed a biomimetic micro-hinged actuator driven by stimuli-responsive hydrogel muscles .
[34]
A pseudo-rigid body model described large folding while maintaining high stiffness. The hinge arrays
produced by multi-step TPP enable multi-degree-of-freedom and programmable shape deformation [Figure
7F]. Hippler et al. introduced a chemical actuation strategy using β-cyclodextrin and adamantane
photoresist [134] . 3D laser lithography created composite scaffolds, and adding soluble competitive guests
under physiological conditions triggered reversible expansion to stretch cells and then return to the initial
state [Figure 7G]. To harness ambient cues for untethered operation, Cecchini et al. designed a humidity-
actuated seed-like soft robot using biodegradable hygroscopic polymers patterned by 4D printing [135] .
Environmental moisture changes drove reversible reshaping and soil interaction, enabling the robot to
generate approximately 30 μN m of torque, about 2.5 mN of extensional force, and lift objects weighing
about 100 times its own mass [Figure 7H].

Compared to physical fields, chemical stimuli are more readily accessible as they do not require specialized
equipment, exhibit biocompatibility in many formulations, and can be easily integrated with microfluidics
for localized delivery. Chemical stimulation requires sufficient interaction between chemicals and responsive
materials, leading to key challenges such as diffusion-limited rates (typically ranging from minutes to hours),
the need for sustained contact and reagent management, byproduct accumulation and leaching, and precise
spatiotemporal control.