Exploring brain function with a human-derived Brain-on-Chip model
G眉lden Ak莽ay defended her PhD thesis at the Department of Mechanical Engineering on November 19th.
The human brain, with its astonishing complexity, orchestrates every thought, emotion, and action that defines us. Yet, over a third of the global population suffers from neurological disorders, underscoring the urgent need to better understand this vital organ. While traditional studies have often overlooked the role of mechanical forces in brain function, the PhD research of G眉lden Ak莽ay highlights their profound influence. Using a groundbreaking Brain-on-Chip (BoC) platform integrated with human-induced pluripotent stem cell (hiPSC) technology, this work replicates the brain鈥檚 dynamic and static mechanical environment. By mimicking cellular heterogeneity and regional stiffness variations within a single chip and applying controlled physiological forces, the findings reveal how mechanical stimuli shape brain function. This innovative model bridges the gap between neurophysiology and brain mechanics, paving the way for personalized medicine and new strategies to study and treat neurological diseases.
To fully understand how the brain works, we need to explore the mechanics that shape its responses. These forces, whether dynamic (due to movements resulting from blood flow and cerebrospinal fluid exchange) or static (due to subtle differences in cell types and tissue stiffness), play a crucial role in how the brain works, from the formation of new neurons to how synapses function. The mechanics of the brain, a field often overlooked in traditional neurophysiological studies, is governed by mechanotransduction processes. However, studying these processes in human brain tissue is challenging because of the complexity of the organ and the limited access to living human brain tissue. In this thesis of , a Brain-on-Chip (BoC) model, which is a platform that replicates the human brain from a mechanical point of view, has been integrated with human-induced pluripotent stem cell (hiPSC) technology.
Static and dynamic mechanical stimuli
The BoC platform is designed with three distinct layers; reservoir, membrane and channel layer. The reservoir layer is based on soft-lithography exploiting stereolithography 3D-printed molds, while the channel layer containing the microfluidic channels for membrane deformation, it is fabricated by femtoprinting directly into a glass substrate. After assembly of these devices, they are used to deploy hiPSC-derived neuronal cell cultures. Capillary flow-controlled and stacked hydrogels as well as a pneumatic pressure-driven actuation with a deformable polydimethylsiloxane (PDMS) membrane are utilized to provide both static and dynamic mechanical stimuli to the BoC cultures in a single chip, explored in this thesis.
Filling the gap
These BoCs specifically enable the exploration of patient-specific conditions, providing insight into how individual disease characteristics manifest and progress. Such an approach offers personalized medicine in the future applications of technology by studying the mechanism of action in neuropathologies related to genetic deviations in mechanotransduction pathways. This research contributes to filling the gap between brain mechanics and neurophysiology by the development of BoC technology that allows us to mechanically stimulate a neural cell culture in microenvironments that more faithfully mimic the in vivo situation.
Broader applications in the future
With the right developmental strategy, this work can transform from a proof-of-concept into a scalable model that opens the door to broader applications in the future. The ability to scale these models is vital for turning our findings into practical solutions for clinical research and personalized healthcare.
Title of PhD thesis: . Supervisors: Dr. Regina Luttge, and Prof. Jaap den Toonder.