Biosensors Integration in Blood–Brain Barrier-on-a-Chip: Emerging Platform for Monitoring Neurodegenerative Diseases

Abstract

Over the most recent decades, the development of new biological platforms to study disease progression and drug efficacy has been of great interest due to the high increase in the rate of neurodegenerative diseases (NDDs). Therefore, blood–brain barrier (BBB) as an organ-on-a-chip (OoC) platform to mimic brain-barrier performance could offer a deeper understanding of NDDs as well as a very valuable tool for drug permeability testing for new treatments. A very attractive improvement of BBB-oC technology is the integration of detection systems to provide continuous monitoring of biomarkers in real time and a fully automated analysis of drug permeably, rendering more efficient platforms for commercialization. In this Perspective, an overview of the main BBB-oC configurations is introduced and a critical vision of the BBB-oC platforms integrating electronic read out systems is detailed, indicating the strengths and weaknesses of current devices, proposing the great potential for biosensors integration in BBB-oC. In this direction, we name potential biomarkers to monitor the evolution of NDDs related to the BBB and/or drug cytotoxicity using biosensor technology in BBB-oC.

Integrated biosensors for monitoring microphysiological systems

“…These sensors are highly suitable for monitoring cellular ions release, particularly in BBB and adenocarcinoma cancer MPSs. 62,63 Due to its high surface-to-volume ratio, nanowire arrays-based microelectrodes can sensitively detect nitric oxide in a vascular lumen MPS with high temporal and spatial resolution. 64 Field-effect transistors (FET) also endow significant impact on real-time monitoring of biomarkers in MPS platforms.…”

BBB-on-a-chip with Integrated micro-TEER for permeability evaluation of multi-functionalized gold nanorods against Alzheimer’s disease

“…TEER is a quantitative method for assessing the endothelial barrier permeability. Gold electrodes were designed considering multiple factors that could affect the correct TEER read-out [28]. Consequently, our electrode has a diameter and separation distance of 150 µm (Figure 1B) based on our endothelial zone (width of 100 µm) to reach a uniform current density on the barrier.…”

“…Several previous works placed electrodes far away from the endothelial barrier causing higher resistance contribution from other elements such as the cell medium solution or the commercial membranes. Additionally, factors as the ratio between the electrode and endothelial barrier size is crucial to generate a homogeneous current density through the BBB to achieve a proper measurement [26][27][28].…”

Better In Vitro Tools for Exploring Chlamydia trachomatis Pathogenesis

“…OOAC recreates the complex and dynamic operations occurring in human tissues for real time monitoring of the cell and tissue response to an infection [ 50 ]. In particular, miniaturized cell-culture micro-environments with microchannels and chambers mimic the human cell pathophysiological environment, allowing the high throughput screening with the integration of automation and smart analysis systems [ 51 , 52 ]. OOAC can incorporate multiple cell layers, mimicking the complex cell interactions that occur in in vivo human tissues, and multiple organs can also be connected [ 53 ].…”

“…OOAC can incorporate multiple cell layers, mimicking the complex cell interactions that occur in in vivo human tissues, and multiple organs can also be connected [ 53 ]. Moreover, several actuators and sensors can be integrated for various analysis, potentially providing more precise and relevant clinical data [ 50 , 51 ]. Lastly, they can incorporate various biomaterials for the fabrication of cells’ microenvironment (polydimethylsiloxane, polymethylmethacrylate, polystyrene, etc.)…”