通过3D神经体外系统对生理系统进行建模的能力可能会为各种疾病的新治疗方法提供可能性，同时降低对具有挑战性的动物和人体测试的需求。创建这样的环境，甚至更有影响力的是，模拟机械刺激下的人脑组织，将对研究与脑创伤相关的一系列人特有的生物过程和疾病条件非常有用。一种方法是使用体外模型的人脑器官样结构（hCOs）。hCOs重新创建了人脑的关键细胞结构特征，与传统的2D培养和器官芯片模型以及体内动物模型有所区别。在这里，我们提出了一种新的方法，使用经历创伤性脑损伤（TBI）迹象的hCOs来模拟轻度和中度TBI。我们将hCOs置于轻度（2 s[Formula: see text]）和中度（14 s[Formula: see text]）的加载条件下，检查机械转导反应，并研究下游的基因组效应和调控通路。我们发现了一些相关的信号传导通路，包括细胞死亡、代谢和生物合成通路，涉及到基因CARD9、ENO1和FOXP3。此外，我们发现随着对器官样结构施加更高的加载条件，钙信号传递的上升速度更快。通过可靠的人脑器官样模型阐明神经对机械刺激的反应，有助于更好地理解人类TBI。© 2023. Springer Nature Limited.

The ability to model physiological systems through 3D neural in-vitro systems may enable new treatments for various diseases while lowering the need for challenging animal and human testing. Creating such an environment, and even more impactful, one that mimics human brain tissue under mechanical stimulation, would be extremely useful to study a range of human-specific biological processes and conditions related to brain trauma. One approach is to use human cerebral organoids (hCOs) in-vitro models. hCOs recreate key cytoarchitectural features of the human brain, distinguishing themselves from more traditional 2D cultures and organ-on-a-chip models, as well as in-vivo animal models. Here, we propose a novel approach to emulate mild and moderate traumatic brain injury (TBI) using hCOs that undergo strain rates indicative of TBI. We subjected the hCOs to mild (2 s[Formula: see text]) and moderate (14 s[Formula: see text]) loading conditions, examined the mechanotransduction response, and investigated downstream genomic effects and regulatory pathways. The revealed pathways of note were cell death and metabolic and biosynthetic pathways implicating genes such as CARD9, ENO1, and FOXP3, respectively. Additionally, we show a steeper ascent in calcium signaling as we imposed higher loading conditions on the organoids. The elucidation of neural response to mechanical stimulation in reliable human cerebral organoid models gives insights into a better understanding of TBI in humans.© 2023. Springer Nature Limited.