4D fabrication of shape-changing systems for tissue engineering: state of the art and perspectives.

In recent years, four-dimensional (4D) fabrication has emerged as a powerful technology capable of revolutionizing the field of tissue engineering. This technology represents a shift in perspective from traditional tissue engineering approaches, which generally rely on static-or passive-structures (e.g., scaffolds, constructs) unable of adapting to changes in biological environments. In contrast, 4D fabrication offers the unprecedented possibility of fabricating complex designs with spatiotemporal control over structure and function in response to environment stimuli, thus mimicking biological processes. In this review, an overview of the state of the art of 4D fabrication technology for the obtainment of cellularized constructs is presented, with a focus on shape-changing soft materials. First, the approaches to obtain cellularized constructs are introduced, also describing conventional and non-conventional fabrication techniques with their relative advantages and limitations. Next, the main families of shape-changing soft materials, namely shape-memory polymers and shape-memory hydrogels are discussed and their use in 4D fabrication in the field of tissue engineering is described. Ultimately, current challenges and proposed solutions are outlined, and valuable insights into future research directions of 4D fabrication for tissue engineering are provided to disclose its full potential.