Triculture Model of In Vitro BBB and its Application to Study BBB‐Associated Chemosensitivity and Drug Delivery in Glioblastoma

Abstract

Physiologically, brain tumors interact with surrounding vascular and glial cells, and change their responses to survive in brain tissue‐specific microenvironments. A major difficulty in brain tumor treatment is caused by the organism's high resistance to pharmaceutical drugs and poor blood–brain barrier (BBB) penetration. Therefore, mimicking the physiological environment of brain tumors on in vitro platforms can aid in predicting the cellular response to drugs. Here, an engineered 3D human glioblastoma in vitro platform that is integrated with a tricultured BBB is presented. First, the barrier function of the constructed BBB model and its reversibility are characterized, after administrating BBB‐opening agents through the microvasculature. The brain tumor cells that are cocultured in the BBB show a more aggressive growth pattern and high drug resistance, as well as secreting high concentrations of inflammatory cytokines. Finally, the delivery of BBB‐nonpenetrating drugs are promoted by chemically opening the BBB. The results of this study indicate that the platform can potentially study the physiology of the BBB, and monitor drug responses based on the interaction of the brain tumor and BBB.

Blood-brain barrier-on-a-chip for brain disease modeling and drug testing

“…2B ). These platforms can further recapitulate the in vivo BBB microenvironment with an ECM ( 40 ). Harnessing the inherent ability of vasculogenesis and angiogenesis, ECs can be self-organized to form vasculature ( Fig.…”

Advances in Hydrogel-Based Microfluidic Blood–Brain-Barrier Models in Oncology Research

“…Scientific communities have invested a lot of effort in the development of in vitro BBB models to avoid the difficulties faced in the clinical translation of results obtained from animal models. In this regard, several 2-dimensional (2D) in vitro models have been established with mono/co/tri culturing of human derived cells (ECs/PCs/ACs) in order to imitate the transportation pattern of different molecules across BBB endothelium [ 74 , 75 , 76 , 77 ]. These methods feature progressive refinement aids to promote the differentiation of human pluripotent stem cells (hPSCs) into brain microvascular ECs and display the identified attributes (the uptake of lipophilic molecules, high TEER, and transporters activities).…”

Modeling the blood-brain barrier for treatment of central nervous system (CNS) diseases

“… Microfluidic devices used for BBB modeling: (i) example of a two channel microfluidic device and components of tissue models, (ii) 3D culture on chip with various validation methods. Reproduced from Seo et al, 119 (iii) microfluidic model using a combination of PDMS, glass, and fibrin gel with a mixture of three cell types. Reproduced from Campisi et al, 66 (iv) microfluidic chip using a pump for dynamic flow of media and built-in TEER analysis.…”

“…Reproduced from Shin et al, 90 (ii, iii) BBB models utilizing tumor spheroids within the tissue chip. Reproduced from Seo et al 119 and Fan et al 140 …”

“…To predict the cellular response to pharmaceuticals, a 3D in vitro glioblastoma model was created. 119 This BBB chip utilized three layers, the top layer acted as a lid and the bottom included a sliding glass. The middle layer was fabricated from PDMS and included three parallel microchannels where a mixture of human brain vascular pericytes (HBVP), human astrocytes (HA), and collagen were injected into the microchannels ( Figure 5.ii ).…”