In vitro Models of the Blood–Brain Barrier: Tools in Translational Medicine

Abstract

Medical progress has historically depended on scientific discoveries. Until recently, science was driven by technological advancements that, once translated to the clinic, fostered new treatments and interventions. More recently, technology-driven medical progress has often outpaced laboratory research. For example, intravascular devices, pacemakers for the heart and brain, spinal cord stimulators, and surgical robots are used routinely to treat a variety of diseases. The rapid expansion of science into ever more advanced molecular and genetic mechanisms of disease has often distanced laboratory-based research from day-to-day clinical realities that remain based on evidence and outcomes. A recognized reason for this hiatus is the lack of laboratory tools that recapitulate the clinical reality faced by physicians and surgeons. To overcome this, the NIH and FDA have in the recent past joined forces to support the development of a “human-on-a-chip” that will allow research scientists to perform experiments on a realistic replica when testing the effectiveness of novel experimental therapies. The development of a “human-on-a-chip” rests on the capacity to grow in vitro various organs-on-a-chip, connected with appropriate vascular supplies and nerves, and our ability to measure and perform experiments on these virtually invisible organs. One of the tissue structures to be scaled down on a chip is the human blood–brain barrier. This review gives a historical perspective on in vitro models of the BBB and summarizes the most recent 3D models that attempt to fill the gap between research modeling and patient care. We also present a summary of how these in vitro models of the BBB can be applied to study human brain diseases and their treatments. We have chosen NeuroAIDS, COVID-19, multiple sclerosis, and Alzheimer's disease as examples of in vitro model application to neurological disorders. Major insight pertaining to these illnesses as a consequence of more profound understanding of the BBB can reveal new avenues for the development of diagnostics, more efficient therapies, and definitive clarity of disease etiology and pathological progression.

Brain and Retinal Organoids for Disease Modeling: The Importance of In Vitro Blood–Brain and Retinal Barriers Studies

“…Similar to the BRB, the BBB can act as a checkpoint to the transit of many drugs, and for these reasons, in vitro vascularization of the brain and retinal organoids using ECs might contribute to fostering the identification and development of new molecular targets [ 22 ]. It is well recognized that in vitro models of BBB and BRB could be used as tools in translational medicine [ 168 , 174 ]. However, no data have been reported yet, because of many limitations of traditional brain organoid transplant.…”

“…The assessment of barriers in organs-on-chips can be difficult, but they offer the opportunity of continuous, non-invasive sensing of barrier quality, which allows better investigation of central aspects of pathophysiology, biological processes, and progress of therapies that target barrier tissues [ 204 ]. The development of more accurate and sophisticated barriers-on-a-chip with the capacity to grow in vitro connected with appropriate vascular supplies and nerves, paves the way for the development of functional and integral in vitro BRB and BBB models and offer a promising avenue by enabling future research scientists to perform experiments on a realistic replica when testing the effectiveness of novel experimental therapies [ 168 , 174 ].…”

“…Finally, in vitro BBB models may be critical to the screening and development of novel and effective therapeutics against many neurological disorders, and a valid one to three cell type models have been described [ 166 , 167 ]. Recently, a summary of how these in vitro models of the BBB can be applied to the study of human brain diseases and their treatments was extensively reported by Williams-Medina et al [ 168 ]. The latter have chosen NeuroAIDS, COVID-19, multiple sclerosis, and AD as examples of in vitro model application to neurological disorders.…”

The role of astrocytes in brain metastasis at the interface of circulating tumour cells and the blood brain barrier

“…Moreover, further studies are currently being undertaken to investigate potential differential molecular crosstalk in enhancing brain metastasis and therapeutic targets. For instance, in vitro 3D models mimicking the complex BBB microenvironment is currently being developed to closely study the crosstalk between different cell types, barrier function and drug design [70][71][72]. Lee et al [73] have recently developed a microfluidic 3D in vitro system of the BBB by adopting the CNS angiogenesis model.…”

Drug Penetration into the Central Nervous System: Pharmacokinetic Concepts and In Vitro Model Systems

“…As a consequence, a number of in vitro approaches have been introduced to complement or replace in vivo studies for early estimation of brain penetration by candidate drugs. With regard to in vitro models of the BBB, a number of excellent reviews have addressed the history, current state and future directions of the field [8][9][10][11][12][13], but there is still uncertainty concerning their actual value for the drug development process. For example, while estimates for the rate of drug transport across the BBB derived from in vitro models have long been used to identify promising candidates for development of CNS-targeted therapeutics, the rate of BBB penetration per se is now recognized as a poor predictor for the effectiveness of drugs that are dosed continuously [14,15].…”