Current overview of induced pluripotent stem cell-based blood-brain barrier-on-a-chip

BACKGROUND

Induced pluripotent stem cells (iPSCs) show great ability to differentiate into any tissue, making them attractive candidates for pathophysiological investigations. The rise of organ-on-a-chip technology in the past century has introduced a novel way to make in vitro cell cultures that more closely resemble their in vivo environments, both structural and functionally. The literature still lacks consensus on the best conditions to mimic the blood-brain barrier (BBB) for drug screening and other personalized therapies. The development of models based on BBB-on-a-chip using iPSCs is promising and is a potential alternative to the use of animals in research.

AIM

To analyze the literature for BBB models on-a-chip involving iPSCs, describe the microdevices, the BBB in vitro construction, and applications.

METHODS

We searched for original articles indexed in PubMed and Scopus that used iPSCs to mimic the BBB and its microenvironment in microfluidic devices. Thirty articles were identified, wherein only 14 articles were finally selected according to the inclusion and exclusion criteria. Data compiled from the selected articles were organized into four topics: (1) Microfluidic devices design and fabrication; (2) characteristics of the iPSCs used in the BBB model and their differentiation conditions; (3) BBB-on-a-chip reconstruction process; and (4) applications of BBB microfluidic three-dimensional models using iPSCs.

RESULTS

This study showed that BBB models with iPSCs in microdevices are quite novel in scientific research. Important technological advances in this area regarding the use of commercial BBB-on-a-chip were identified in the most recent articles by different research groups. Conventional polydimethylsiloxane was the most used material to fabricate in-house chips (57%), whereas few studies (14.3%) adopted polymethylmethacrylate. Half the models were constructed using a porous membrane made of diverse materials to separate the channels. iPSC sources were divergent among the studies, but the main line used was IMR90-C4 from human fetal lung fibroblast (41.2%). The cells were differentiated through diverse and complex processes either to endothelial or neural cells, wherein only one study promoted differentiation inside the chip. The construction process of the BBB-on-a-chip involved previous coating mostly with fibronectin/collagen IV (39.3%), followed by cell seeding in single cultures (36%) or co-cultures (64%) under controlled conditions, aimed at developing an in vitro BBB that mimics the human BBB for future applications.

CONCLUSION

This review evidenced technological advances in the construction of BBB models using iPSCs. Nonetheless, a definitive BBB-on-a-chip has not yet been achieved, hindering the applicability of the models.

Key Words: Induced pluripotent stem cells, Cell differentiation, Blood-brain barrier, Neurovascular unit, Organ-on-a-chip, Microfluidic device

Core Tip: This systematic review provided a current perspective on the applicability of induced pluripotent stem cells within blood-brain barrier (BBB)-on-a-chip with high technology advances in commercial chips and promotion of an efficient human neurovascular unit, able to screen for drugs, mimic brain dysfunctions, such as stroke and Huntington’s disease, and suitable for future personalized therapeutic approaches. However, the composition and construction of the BBB models lack consensus in the literature.

• Citation: Alves ADH, Nucci MP, Ennes do Valle NM, Missina JM, Mamani JB, Rego GNA, Dias OFM, Garrigós MM, de Oliveira FA, Gamarra LF. Current overview of induced pluripotent stem cell-based blood-brain barrier-on-a-chip. World J Stem Cells 2023; 15(6): 632-653
• URL: https://www.wjgnet.com/1948-0210/full/v15/i6/632.htm
• DOI: https://dx.doi.org/10.4252/wjsc.v15.i6.632