The application of lab-on-a-chip technologies in in vitro cell culturing swiftly resulted in improved models of human organs compared to static culture insert-based ones. These chip devices provide controlled cell culture environments to mimic physiological functions and properties. Models of the blood-brain barrier (BBB) especially profited from this advanced technological approach. The BBB represents the tightest endothelial barrier within the vasculature with high electric resistance and low passive permeability, providing a controlled interface between the circulation and the brain. The multi-cell type dynamic BBB-on-chip models are in demand in several fields as alternatives to expensive animal studies or static culture inserts methods. Their combination with integrated biosensors provides real-time and noninvasive monitoring of the integrity of the BBB and of the presence and concentration of agents contributing to the physiological and metabolic functions and pathologies. In this review, we describe built-in sensors to characterize BBB models via quasi-direct current and electrical impedance measurements, as well as the different types of biosensors for the detection of metabolites, drugs, or toxic agents. We also give an outlook on the future of the field, with potential combinations of existing methods and possible improvements of current techniques.

The dysfunction of the blood–brain barrier (BBB) is well described in several diseases, and is considered a pathological factor in many neurological disorders. This review summarizes the most important groups of natural compounds, including alkaloids, flavonoids, anthocyanidines, carotenoids, lipids, and vitamins that were investigated for their potential protective effects on brain endothelium. The brain penetration of these compounds and their interaction with BBB efflux transporters and solute carriers are discussed. The cerebrovascular endothelium is considered a therapeutic target for natural compounds in diseases. In preclinical studies modeling systemic and central nervous system diseases, nutraceuticals exerted beneficial effects on the BBB. In vivo, they decreased BBB permeability, brain edema, astrocyte swelling, and morphological changes in the vessel structure and basal lamina. At the level of brain endothelial cells, nutraceuticals increased cell survival and decreased apoptosis. From the general endothelial functions, decreased angiogenesis and increased levels of vasodilating agents were demonstrated. From the BBB functions, elevated barrier integrity by tightened intercellular junctions, and increased expression and activity of BBB transporters, such as efflux pumps, solute carriers, and metabolic enzymes, were shown. Nutraceuticals enhanced the antioxidative defense and exerted anti-inflammatory effects at the BBB. The most important signaling changes mediating the increased cell survival and BBB stability were the activation of the WNT, PI3K-AKT, and NRF2 pathways, and inhibition of the MAPK, JNK, ERK, and NF-κB pathways. Nutraceuticals represent a valuable source of new potentially therapeutic molecules to treat brain diseases by protecting the BBB.

Nanoparticles (NPs) are the focus of research efforts that aim to develop successful drug delivery systems for the brain. Polypeptide nanocarriers are versatile platforms and combine high functionality with good biocompatibility and biodegradability. The key to the efficient brain delivery of NPs is the specific targeting of cerebral endothelial cells that form the blood–brain barrier (BBB). We have previously discovered that the combination of two different ligands of BBB nutrient transporters, alanine and glutathione, increases the permeability of vesicular NPs across the BBB. Our aim here was to investigate whether the combination of these molecules can also promote the efficient transfer of 3-armed poly(l-glutamic acid) NPs across a human endothelial cell and brain pericyte BBB co-culture model. Alanine and glutathione dual-targeted polypeptide NPs showed good cytocompatibility and elevated cellular uptake in a time-dependent and active manner. Targeted NPs had a higher permeability across the BBB model and could subsequently enter midbrain-like organoids derived from healthy and Parkinson’s disease patient-specific stem cells. These results indicate that poly(l-glutamic acid) NPs can be used as nanocarriers for nervous system application and that the right combination of molecules that target cerebral endothelial cells, in this case alanine and glutathione, can facilitate drug delivery to the brain.

Here, we report a rapid and accurate optical method for detecting cells from liquid samples in a label-free manner. The working principle of the method is based on the interference of parts of a conical laser beam, coming from a single-mode optical fiber directly, and reflected from a flat glass surface. The glass is functionalized by antibodies against the cells to be detected from the liquid sample. Cells bound to that surface modify the reflected beam, and hence, change the resulting interference pattern, too. By registering and interpreting the variation in the image, the presence of cells from the sample can be detected. As for a demonstration, cell suspensions from a U937 cell line were used in glass chambers functionalized by antibodies (TMG6-5 (mIgG1)) to which the cells specifically bind. The limit of detection (LOD) of the method was also estimated. This proof-of-concept setup offers a cost-effective and easy-to-use way of rapid and specific detection of any type of cells (including pathogens) from suspensions (e.g., body fluids). The possible portability of the device predicts its applicability as a rapid test in clinical diagnostics.