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. 2023 Nov:168:117319.
doi: 10.1016/j.trac.2023.117319.

Sensorization of microfluidic brain-on-a-chip devices: Towards a new generation of integrated drug screening systems

Attilio Marino  1 , Matteo Battaglini  1 , Marie Celine Lefevre  1 , Maria Cristina Ceccarelli  1   2 , Kamil Ziaja  1   2   3 , Gianni Ciofani  1
Affiliations

Sensorization of microfluidic brain-on-a-chip devices: Towards a new generation of integrated drug screening systems

Attilio Marino et al. Trends Analyt Chem. 2023 Nov.

Abstract

Brain-on-a-chip (BoC) devices show typical characteristics of brain complexity, including the presence of different cell types, separation in different compartments, tissue-like three-dimensionality, and inclusion of the extracellular matrix components. Moreover, the incorporation of a vascular system mimicking the blood-brain barrier (BBB) makes BoC particularly attractive, since they can be exploited to test the brain delivery of different drugs and nanoformulations. In this review, we introduce the main innovations in BoC and BBB-on-a-chip models, especially focusing sensorization: electrical, electrochemical, and optical biosensors permit the real-time monitoring of different biological phenomena and markers, such as the release of growth factors, the expression of specific receptors/biomarkers, the activation of immune cells, cell viability, cell-cell interactions, and BBB crossing of drugs and nanoparticles. The recent improvements in signal amplification, miniaturization, and multiplication of the sensors are discussed in an effort to highlight their benefits versus limitations and delineate future challenges in this field.

Keywords: Blood-brain barrier; Brain organoids; Brain-on-a-chip; Digital immunosensors; Electrical sensors; Electrochemical sensors; Genetically-encoded sensors; Optical sensors; Vascularized brain models.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gianni Ciofani reports financial support was provided by Fondazione Istituto Italiano di Tecnologia. N/A.

Figures

Fig. 1
Fig. 1
The growing number of research articles, reviews, and patents on a) brain organoid and b) microfluidic dynamic BBB models from 2015 to 2023 (data up to May 31st, 2023).
Fig. 2
Fig. 2
Biomimetic microfluidic BoC mimicking the NVU-tumor interactions in a collagen-based extracellular matrix. Schematic representations of a) the in vivo NVU, b) the in vitro fluidic NVU model with human brain endothelial cells, human brain pericytes, and human astrocytes (BBB chip), and c) the cross-section of the microfluidic system. d) Imaging of the cells developing the blood vessel (left) and of the cells in the extracellular matrix (ECM). e) BBB chip incorporating a 3D GBM (tumor chip): f) schematic representation, g) imaging, and h) analysis of the tumor-induced angiogenesis. i) Imaging and l) analysis of the NVU dilation induced by the presence of the tumor. Adapted with permission from Ref. [31].
Fig. 3
Fig. 3. Representative sensors designed for integration into BoC models.
a) Schematic of digital immunosensors integrated into BBB-on-a-chip model for the sequential detection of cytokines. Reprinted with permission from. Ref. [69]. b) Schematic representation of an integrated optical Mach-Zender interferometer for the detection of target spike protein S1 subunit crossing the BBB after coronavirus infection. Reprinted with permission from Ref. [70]. c) Schematic illustration of 3D high-density microelectrode array integrated into a 3D neural network in vitro model. Reprinted with permission from Ref. [71]. d) Schematic of the sensing mechanisms of the ref-OECT-based E-AB sensor for the detection of TGF-B1. Reprinted with permission from Ref. [52].
Fig. 4
Fig. 4. Schematic representation of different sensors integrated into a biomimetic BoC.
See this image and copyright information in PMC

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