Low-temperature-field-assisted fabrication of cross-scale tissue engineering scaffolds

In tissue engineering (TE), tissue-inducing scaffolds are a promising solution for organ and tissue repair owing to their ability to attract stem cells in vivo, thereby inducing endogenous tissue regeneration through topological cues. An ideal TE scaffold should possess biomimetic cross-scale structures, similar to that of natural extracellular matrices, at the nano- to macro-scale level. Although freeform fabrication of TE scaffolds can be achieved through 3D printing, this method is limited in simultaneously building multiscale structures. To address this challenge, low-temperature fields were adopted in the traditional fabrication processes, such as casting and 3D printing. Ice crystals grow during scaffold fabrication and act as a template to control the nano- and micro-structures. These microstructures can be optimized by adjusting various parameters, such as the direction and magnitude of the low-temperature field. By preserving the macro-features fabricated using traditional methods, additional micro-structures with smaller scales can be incorporated simultaneously, realizing cross-scale structures that provide a better mimic of natural organs and tissues. In this paper, we present a state-of-the-art review of three low-temperature-field-assisted fabrication methods—freeze casting, cryogenic 3D printing, and freeze spinning. Fundamental working principles, fabrication setups, processes, and examples of biomedical applications are introduced. The challenges and outlook for low-temperature-assisted fabrication are also discussed.