The blood–brain barrier (BBB) is a fundamental component of the central nervous system. Its functional and structural integrity is vital in maintaining the homeostasis of the brain microenvironment. On the other hand, the BBB is also a major hindering obstacle for the delivery of effective therapies to treat disorders of the Central Nervous System (CNS). Over time, various model systems have been established to simulate the complexities of the BBB. The development of realistic in vitro BBB models that accurately mimic the physiological characteristics of the brain microcapillaries in situ is of fundamental importance not only in CNS drug discovery but also in translational research. Successful modeling of the Neurovascular Unit (NVU) would provide an invaluable tool that would aid in dissecting out the pathological factors, mechanisms of action, and corresponding targets prodromal to the onset of CNS disorders. The field of BBB in vitro modeling has seen many fundamental changes in the last few years with the introduction of novel tools and methods to improve existing models and enable new ones. The development of CNS organoids, organ-on-chip, spheroids, 3D printed microfluidics, and other innovative technologies have the potential to advance the field of BBB and NVU modeling. Therefore, in this review, summarize the advances and progress in the design and application of functional in vitro BBB platforms with a focus on rapidly advancing technologies.

Gelatin methacrylate (GelMA) has been gaining popularity in recent years as a photo-crosslinkable biomaterial widely used in a variety of bioprinting and tissue engineering applications. Several studies have established the effects of process-based and material-based parameters on the physical–mechanical properties and microstructure of GelMA hydrogels. However, the effect of encapsulated cells on the physical–mechanical properties and microstructure of GelMA hydrogels has not been fully understood. In this study, 3T3 fibroblasts were encapsulated at different cell densities within the GelMA hydrogels and incubated over 96 h. The effects of encapsulated cells were investigated in terms of mechanical properties (tensile modulus and strength), physical properties (swelling and degradation), and microstructure (pore size). Cell viability was also evaluated to confirm that most cells were alive during the incubation. It was found that with an increase in cell density, the mechanical properties decreased, while the degradation and the pore size increased.

Microfluidics-based organ-on-a-chip technology allows for developing a new class of in-vitro blood-brain barrier (BBB) models that recapitulate many hemodynamic and architectural features of the brain microvasculature not attainable with conventional two-dimensional platforms. Herein, we describe and validate a novel microfluidic BBB model that closely mimics the one in situ. Induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) were juxtaposed with primary human pericytes and astrocytes in a co-culture to enable BBB-specific characteristics, such as low paracellular permeability, efflux activity, and osmotic responses. The permeability coefficients of [¹³C₁₂] sucrose and [¹³C₆] mannitol were assessed using a highly sensitive LC-MS/MS procedure. The resulting BBB displayed continuous tight-junction patterns, low permeability to mannitol and sucrose, and quasi-physiological responses to hyperosmolar opening and p-glycoprotein inhibitor treatment, as demonstrated by decreased BBB integrity and increased permeability of rhodamine 123, respectively. Astrocytes and pericytes on the abluminal side of the vascular channel provided the environmental cues necessary to form a tight barrier and extend the model’s long-term viability for time-course studies. In conclusion, our novel multi-culture microfluidic platform showcased the ability to replicate a quasi-physiological brain microvascular, thus enabling the development of a highly predictive and translationally relevant BBB model.

As the number of confirmed cases and deaths occurring from Coronavirus disease 2019 (COVID-19) surges worldwide, health experts are striving hard to fully comprehend the extent of damage caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 primarily manifests itself in the form of severe respiratory distress, it is also known to cause systemic damage to almost all major organs and organ systems within the body. In this review, we discuss the molecular mechanisms leading to multi-organ failure seen in COVID-19 patients. We also examine the potential of stem cell therapy in treating COVID-19 multi-organ failure cases.