Harnessing circadian rhythmicity at the blood-cerebrospinal fluid barrier with a perfusable biomimetic hydrogel-integrated chip

The brain and spinal cord are surrounded by cerebrospinal fluid (CSF), a clear fluid essential for brain health and development. CSF deliveres various components like electrolytes, hormones, and neurotransmitters to the brain that support neural function and can indicate disease states. CSF composition changes throughout the day due to circadian rhythms. While CSF components can arise from multiple sources like secretions and waste from the brain or through tightly regulated brain barriers, CSF is largely produced by the choroid plexus, which regulates the exchange between blood and CSF, maintaining a stable environment for the brain. 

The choroid plexus has its own circadian clock that influences its functions based on the time of day. Understanding how these rhythms affect the choroid plexus is vital for brain health, yet the impact of the surrounding microenvironment on choroid plexus rhythms is not well understood. Research on the choroid plexus blood-CSF barrier has been complicated by the involvement of multiple tissues, making it difficult to develop targeted therapies. Further, the choroid plexus is a key brain barrier that can be targeted to deliver therapies to the brain when it is better understood. Therefore, there is an urgent need to develop more realistic models of choroid plexus-specific barrier.

To address this, we propose a new collaborative approach that combines three innovative strategies: (1) synchronized circadian regulation of choroid plexus cells, (2) custom-engineered extracellular matrix hydrogels, and (3) perfusable vascularized choroid plexus-on-a-chip models. This approach aims to identify the specific properties of the choroid plexus barrier and its secretion processes, ultimately enhancing our understanding of CSF composition and improving therapeutic strategies for brain health.