Engineering choroid plexus-on-a-chip with oscillatory flow for modeling brain metastasis

Jungeun Lim; Stephen Rhee; Hyeri Choi; Jungseub Lee; Shruthy Kuttappan; Tri Tho Yves Nguyen; Sunbeen Choi; YongTae Kim; Noo Li Jeon

doi:10.1016/j.mtbio.2023.100773

Engineering choroid plexus-on-a-chip with oscillatory flow for modeling brain metastasis

Mater Today Bio. 2023 Aug 19:22:100773. doi: 10.1016/j.mtbio.2023.100773. eCollection 2023 Oct.

Authors

Jungeun Lim^{1

2}, Stephen Rhee¹, Hyeri Choi³, Jungseub Lee¹, Shruthy Kuttappan⁴, Tri Tho Yves Nguyen¹, Sunbeen Choi¹, YongTae Kim^{2

5

6

7}, Noo Li Jeon^{1

3

4}

Affiliations

¹ School of Mechanical Engineering, Seoul National University, Seoul, 08826, South Korea.
² George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, North Ave NW, Atlanta, GA, 30332, USA.
³ Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, 08826, South Korea.
⁴ Institute of Advanced Machinery and Design, Seoul National University, Seoul, 08826, South Korea.
⁵ Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
⁶ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
⁷ Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA, 30332, USA.

Abstract

The human brain choroid plexus (ChP) is a highly organized secretory tissue with a complex vascular system and epithelial layers in the ventricles of the brain. The ChP is the body's principal source of cerebrospinal fluid (CSF); it also functions as a barrier to separate the blood from CSF, because the movement of CSF through the body is pulsatile in nature. Thus far, it has been challenging to recreate the specialized features and dynamics of the ChP in a physiologically relevant microenvironment. In this study, we recapitulated the ChP structure by developing a microfluidic chip in accordance with established design rules. Furthermore, we used image processing and analysis to mimic CSF flow dynamics within a rlcking system; we also used a hydrogel containing laminin to mimic brain extracellular matrix (ECM). Human ChP cells were cultured in the ChP-on-a-chip with in vivo-like CSF dynamic flow and an engineered ECM. The key ChP characteristics of capillaries, the epithelial layer, and secreted components were recreated in the adjusted microenvironment of our human ChP-on-a-chip. The drug screening capabilities of the device were observed through physiologically relevant drug responses from breast cancer cells that had spread in the ChP. ChP immune responses were also recapitulated in this device, as demonstrated by the motility and cytotoxic effects of macrophages, which are the most prevalent immune cells in the ChP. Our human ChP-on-a-chip will facilitate the elucidation of ChP pathophysiology and support the development of therapeutics to treat cancers that have metastasized into the ChP.

Keywords: Brain metastasis; Cerebrospinal fluid dynamics; Choroid plexus; Organ-on-a-chip; Tumor-immune microenvironment.