Abstract

In vitro blood-brain barrier (BBB) models represent an efficient platform to conduct high-throughput quantitative investigations on BBB crossing ability of different drugs. Such models provide a closed system where different fundamental variables can be efficaciously tuned and monitored, and issues related to scarce accessibility of animal brains and ethics can be addressed. In this work, we propose the fabrication of cellulose acetate (CA) porous bio-scaffolds by exploiting both vapor-induced phase separation (VIPS) and electrospinning methods. Parameters of fabrication have been tuned in order to obtain porous and transparent scaffolds suitable for optical/confocal microscopy, where endothelial cell monolayers are allowed to growth thus obtaining biomimetic BBB in vitro models. Concerning VIPS-based approach, CA membranes fabricated using 25% H2O + 75% EtOH as non-solvent showed submicrometer-scale porosity and an optical transmittance comparable to that one of commercially available poly(ethylene terephthalate) membranes. CA membranes fabricated via VIPS have been exploited for obtaining multicellular BBB models through the double seeding of endothelial cells and astrocytes on the two surfaces of the membrane. Electrospun CA substrates, instead, were characterized by micrometer-sized pores, and were unsuitable for double seeding approach and long term studies. However, the potential exploitation of the electrospun CA substrates for modeling blood-brain-tumor barrier and studying cell invasiveness has been speculated. The features of the obtained models have been critically compared and discussed for future applications.

Highlights

  • The blood-brain barrier (BBB) is a highly specialized functional structure of the fully differentiated neurovascular system that allows selective regulation of movement of ions, molecules, and cells between the blood and the brain (Zlokovic, 2008)

  • We propose the fabrication of porous bioscaffolds of cellulose acetate (CA) suitable for optical/confocal microscopy, cell culture, and development of endothelial cell monolayers for the set-up and characterization of biomimetic BBB in vitro models

  • Regardless of the nonsolvent used, the membranes produced from 15.0% wt CA solutions were remarkably opaque; those produced from 7.5% wt CA solutions were inhomogeneous and several cases of membrane wrinkling/cracking were observed; those derived from 10.0% wt CA solutions instead showed improved light transparency and mechanical stability (Supplementary Figure 1)

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Summary

Introduction

The blood-brain barrier (BBB) is a highly specialized functional structure of the fully differentiated neurovascular system that allows selective regulation of movement of ions, molecules, and cells between the blood and the brain (Zlokovic, 2008). BBB unique selective properties protect brain parenchyma from toxic substances/pathogens, control the immunologic status of the brain, prevent the passage of large molecules and of circulating blood cells that can damage neuronal tissue, maintain. The dynamics of BBB in physio-pathological conditions, the different biochemical mechanisms involved in BBB crossing, and the delivery of drugs to the brain through BBB are objects of intensive research in biomedicine and nanomedicine for the development of new therapies for brain cancer and neurodegenerative diseases (Dong, 2018)

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