Cortical spheroid on perfusable microvascular network in a microfluidic device

PLoS ONE, vol. 18, pp. e0288025

Abstract

Human induced pluripotent stem cell (hiPSC)-derived brain spheroids can recapitulate the complex cytoarchitecture of the brain, as well as the genetic/epigenetic footprint of human brain development. However, hiPSC-derived 3D models such as spheroid and organoids does not have a perfusable microvascular network, which plays a vital role in maintaining homeostasis in vivo. With the critical balance of positive and negative angiogenic modulators, 3D microvascular network can be achieved by angiogenesis. This paper reports on a microfluidic-based three-dimensional, cortical spheroid grafted on the vascular-network. Vascular network was formed by inducing angiogenic sprouting using concentration gradient-driven angiogenic factors in the microfluidic device. We investigate critical factors for angiogenic vascular network formation with spheroid placement, including 1) a PKCα activator, phorbol-12-myristate-13-acetate (PMA); 2) orientation of endothelial cells under perfusion and permeability of vascular network; 3) effect of extracellular matrix (ECM) types and their densities on angiogenesis; and 4) integration with cortical spheroid on vascular network. This paper demonstrates proof of concept for the potential utility of a membrane-free in vitro cortical spheroid tissue construct with perfusable microvascular network that can be scaled up to a high throughput platform. It can provide a cost-effective alternative platform to animal testing by modeling brain diseases and disorders, and screening drugs.

Authors 6

1. Teal A. Russell

   North Carolina Agricultural and Technical State University

   Affiliation as printed

   Fostering Innovation Through Biosystems for Enhanced Scientific Technologies (FIT BEST) Laboratory, Department of Chemical, Biological, and Bio Engineering, College of Engineering, North Carolina A&T State University, Greensboro, NC, United States of America

2. Qassim Dirar

   North Carolina Agricultural and Technical State University

   Affiliation as printed

   Fostering Innovation Through Biosystems for Enhanced Scientific Technologies (FIT BEST) Laboratory, Department of Chemical, Biological, and Bio Engineering, College of Engineering, North Carolina A&T State University, Greensboro, NC, United States of America

3. Yan Li

   Florida State University · Florida A&M University - Florida State University College of Engineering · Florida Agricultural and Mechanical University

   Affiliation as printed

   Chemical & Biomedical Engineering, College of Engineering, Florida A&M University-Florida State University, Tallahassee, FL, United States of America

4. Chiwan Chiang Aachen

   Mimetas (Netherlands)

   Affiliation as printed

   MIMETAS, BV, DH Oegstgeest, The Netherlands

5. Daniel T. Laskowitz

   Duke Medical Center

   Affiliation as printed

   Department of Neurology, Duke University Medical Center, Durham, NC, United States of America

6. Yeoheung Yun corresponding

   North Carolina Agricultural and Technical State University

   Affiliation as printed

   Fostering Innovation Through Biosystems for Enhanced Scientific Technologies (FIT BEST) Laboratory, Department of Chemical, Biological, and Bio Engineering, College of Engineering, North Carolina A&T State University, Greensboro, NC, United States of America