Emerging Three-Dimensional Integrated Systems for Biomimetic Neural In Vitro Cultures

3D in vitro neural cultures have gained interest in recent years as promising biomimetic micro-environments which can regulate cell response to neural guidance cues. Several bioengineered technologies have been developed in combination with biomaterials to produce 3D models, such as scaffold-based neural constructs, neurospheres, cerebral organoids, and brain-on-chip devices. While the strategic selection of bioengineering approaches and associated biomaterials has opened a multitude of opportunities in building increasingly advanced neural tissues, technical limitations remain a challenge in modeling the complexity of in vivo cell–cell and cell–microenvironment interactions. In this context, potential synergies between different model systems can provide solutions for long-standing in vitro challenges in neural tissue engineering. Here, the authors provide a critical and comprehensive overview of biomimetic in vitro brain modeling strategies, and explore how 3D integrated brain systems can be implemented in multidisciplinary neural tissue engineering, regenerative and personalized medicine, disease modeling, and drug discovery applications.