The brain is the most complex organ of our body. Such a complexity spans from the single-cell morphology up to the intricate connections that hundreds of thousands of neurons establish to create dense neuronal networks. All these components are involved in the genesis of the rich patterns of electrophysiological activity that characterize the brain. Over the years, researchers coming from different disciplines developed in vitro simplified experimental models to investigate in a more controllable and observable way how neuronal ensembles generate peculiar firing rhythms, code external stimulations, or respond to chemical drugs. Nowadays, such in vitro models are named brain-on-a-chip pointing out the relevance of the technological counterpart as artificial tool to interact with the brain: multi-electrode arrays are well-used devices to record and stimulate large-scale developing neuronal networks originated from dissociated cultures, brain slices, up to brain organoids. In this review, we will discuss the state of the art of the brain-on-a-chip, highlighting which structural and biological features a realistic in vitro brain should embed (and how to achieve them). In particular, we identified two topological features, namely modular and three-dimensional connectivity, and a biological one (heterogeneity) that takes into account the huge number of neuronal types existing in the brain. At the end of this travel, we will show how ‘far’ we are from the goal and how interconnected-brain-regions-on-a-chip is the most appropriate wording to indicate the current state of the art.

大脑是我们身体中最复杂的器官。这种复杂性从单细胞形态到数十万个神经元建立以创建密集神经元网络的错综复杂的连接。所有这些成分都参与了表征大脑的丰富的电生理活动模式的起源。多年来，来自不同学科的研究人员开发了体外简化实验模型，以更可控和可观察的方式研究神经元集合如何产生特殊的放电节律、编码外部刺激或对化学药物的反应。如今，这种体外模型被命名为“大脑芯片”。指出技术对应物作为与大脑交互的人工工具的相关性：多电极阵列是记录和刺激源自分离培养物、脑切片乃至脑类器官的大规模发展中的神经元网络的常用设备。在这篇综述中，我们将讨论片上大脑的最新技术，强调哪些结构和生物学特征是现实的体外大脑应该嵌入（以及如何实现它们）。特别是，我们确定了两个拓扑特征，即模块化和三维连通性，以及考虑到大脑中存在的大量神经元类型的生物学特征（异质性）。在这次旅行的最后，我们将展示我们离目标有多远，以及芯片上互连的大脑区域如何是最合适的措辞来表明当前的技术水平。