Four-Dimensional Printing Technology at the Frontier of Advanced Modeling and Applications in Brain Tissue Engineering

The complex process behind the brain topology, which has been extensively studied for the last ten years, is still unclear. Therefore, neural tissue engineering studies are needed to better understand cortical folds. With the development of 4-dimensional (4D) bioprinters using cell-loaded smart materials, a promising path has been opened in the mimicry of the neural tissue. In our study, we review the usage areas of 4D printers, which have been developing in recent years, in modelling brain tissue. As a result of development of smart materials printed with 3-dimensional (3D) printers caused emerging of 4D printers, rapidly. Smart materials can change their properties based on physical, chemical and biological stimuli, and this change can be a reversible process. Cell-loaded printed smart materials should have little effect on cell viability of both the incoming stimulus and the physical change. It is also important that the material used is non-toxic and the solvent is suitable for cell viability. On the other hand, hydrogels are frequently studied to mimic the complex neural network of neural tissue. Agents that affect the crosslinking or degree of crosslinking of hydrogels can be easily controlled and changed. In addition, studies with neural stem cells have shown that hydrogels have a supportive effect on the proliferation and maturation of neural stem cells. Since the folding time, strength and location of smart materials cannot be known precisely, it can be an advantage of 4D bioprinters as it can be controlled and studied whether the results of the stress on the cells in this region will affect other cells. It is an ideal methodology to study the effect of cortical folding on neural stem cells, especially thanks to the ease of experimental manipulations provided by 4D bioprinters. It is expected that 4D bioprinters will be adopted and rapid developments will occur in the multidisciplinary field of tissue engineering of brain tissue in the near coming years.