3D/4D printed bio-piezoelectric smart scaffolds for next-generation bone tissue engineering

Piezoelectricity in native bones has been well recognized as the key factor in bone regeneration. Thus, bio-piezoelectric materials have gained substantial attention in repairing damaged bone by mimicking the tissue's electrical microenvironment (EM). However, traditional manufacturing strategies still encounter limitations in creating personalized bio-piezoelectric scaffolds, hindering their clinical applications. Three-dimensional (3D)/four-dimensional (4D) printing technology based on the principle of layer-by-layer forming and stacking of discrete materials has demonstrated outstanding advantages in fabricating bio-piezoelectric scaffolds in a more complex-shaped structure. Notably, 4D printing functionality-shifting bio-piezoelectric scaffolds can provide a time-dependent programmable tissue EM in response to external stimuli for bone regeneration. In this review, we first summarize the physicochemical properties of commonly used bio-piezoelectric materials (including polymers, ceramics, and their composites) and representative biological findings for bone regeneration. Then, we discuss the latest research advances in the 3D printing of bio-piezoelectric scaffolds in terms of feedstock selection, printing process, induction strategies, and potential applications. Besides, some related challenges such as feedstock scalability, printing resolution, stress-to-polarization conversion efficiency, and non-invasive induction ability after implantation have been put forward. Finally, we highlight the potential of shape/property/functionality-shifting smart 4D bio-piezoelectric scaffolds in bone tissue engineering (BTE). Taken together, this review emphasizes the appealing utility of 3D/4D printed biological piezoelectric scaffolds as next-generation BTE implants.