Before a lead compound goes through a clinical trial, preclinical studies utilize two‐dimensional (2D) in vitro models and animal models to study the pharmacodynamics and pharmacokinetics of that lead compound. However, these current preclinical studies may not accurately represent the efficacy and safety of a lead compound in humans, as there has been a high failure rate of drugs that enter clinical trials. All of these failures and the associated costs demonstrate a need for more representative models of human organ systems for screening in the preclinical phase of drug development. In this study, we review the recent advances in in vitro modeling including three‐dimensional (3D) organoids, 3D microfabrication, and 3D bioprinting for various organs including the heart, kidney, lung, gastrointestinal tract (intestine–gut–stomach), liver, placenta, adipose, retina, bone, and brain as well as multiorgan models. The availability of organ‐on‐chip models provides a wealth of opportunities to understand the pathogenesis of human diseases and provide a potentially better model to screen a drug, as these models utilize a dynamic 3D environment similar to the human body. Although there are limitations of organ‐on‐chip models, the emergence of new technologies have refined their capability for translational research as well as precision medicine.

The blood-brain barrier (BBB) is comprised of brain microvascular endothelial central nervous system (CNS) cells, which communicate with other CNS cells (astrocytes, pericytes) and behave according to the state of the CNS, by responding against pathological environments and modulating disease progression. The BBB plays a crucial role in maintaining homeostasis in the CNS by maintaining restricted transport of toxic or harmful molecules, transport of nutrients, and removal of metabolites from the brain. Neurological disorders, such as NeuroHIV, cerebral stroke, brain tumors, and other neurodegenerative diseases increase the permeability of the BBB. While on the other hand, semipermeable nature of BBB restricts the movement of bigger molecules i.e. drugs or proteins (>500 kDa) across it, leading to minimal bioavailability of drugs in the CNS. This poses the most significant shortcoming in the development of therapeutics for CNS neurodegenerative disorders. Although the complexity of the BBB (dynamic and adaptable barrier) affects approaches of CNS drug delivery and promotes disease progression, understanding the composition and functions of BBB provides a platform for novel innovative approaches towards drug delivery to CNS. The methodical and scientific interests in the physiology and pathology of the BBB led to the development and the advancement of numerous in vitro models of the BBB. This review discusses the fundamentals of BBB structure, permeation mechanisms, an overview of all the different in-vitro BBB models with their advantages and disadvantages, and rationale of selecting penetration prediction methods towards the critical role in the development of the CNS therapeutics.

No abstract

The paradigm of central nervous system (CNS) drug discovery has mostly relied on traditional approaches of rodent models or cell-based in vitro models. Owing to the issues of species differences between humans and rodents, it is difficult to correlate the robustness of data for neurodevelopmental studies. With advances in the stem-cell field, 3D CNS organoids have been developed and explored owing to their resemblance to the human brain architecture and functions. Further, CNS organoids provide a unique opportunity to mimic the human brain physiology and serve as a modeling tool to study the normal versus pathological brain or the elucidation of mechanisms of neurological disorders. Here, we discuss the recent application of a CNS organoid explored for neurodevelopment disease or a screening tool for CNS drug development.Teaser-3D cerebral organoids are a novel class of in vitro tool possessing a close resemblance to human brain architecture and function. They serve as a robust model to study early-stage neurodevelopment and CNS drug toxicity screening.

No abstract