Stimuli-responsive hybrid materials for 4D

There is an existing need to develop 3D tissue models which correctly recapitulate healthy and diseased states. The most commonly used techniques focus on simplistic 2D cell culture techniques, themselves incapable of transmitting the complexity of multi-tissue arrangements, and archaic and unnecessary animal models which fail to reproduce species-dependent aspects. The advances in materials science and engineering approaches have opened the possibility to realistically design and even print, in 3D, complex tissue arrangements, aiming to reach full-scale organ printing. Significant improvements have been noted on the spatial and temporal scale, with excellent resolution and overall size being achieved, in addition to models with extensive lifespans. The application of 3D printing to achieve such models has been extensively reviewed. However, there remains an important lack of integration of physical and mechanical cues to achieve tissue responsiveness, aimed to mimic physiological conditions that occur frequently. With this in mind, we have conducted an extensive review of the literature related to stimuli-responsive materials compatible with 3D (bio)printing techniques. Such materials, often termed hybrid materials due to the combination of organic matrices with inorganic actuators, provide "life" to materials, thus adding an extra dimension to the printing technique and coining the term 4D (bio)printing. Examples of healthy cardiovascular, musculoskeletal and neural tissue models that specifically require the incorporation of dynamic features and pathological models are included.