Engineering of functional, perfusable 3D microvascular networks on a chip

TLDR

Generating perfusable 3D microvessels in vitro is a key goal for tissue engineering and reliable blood vessel modeling, yet existing in‑vitro models fail to accurately reproduce endothelial dynamics and responses needed for functional 3D networks. The study presents a microfluidic platform that models developmental and angiogenic programs to generate perfusable 3D microvessels and tumor vasculatures via spatially controlled co‑culture of endothelial cells with stromal fibroblasts, pericytes, or cancer cells. The microfluidic platform spatially co‑cultures endothelial cells with stromal fibroblasts, pericytes or cancer cells to form an open, unobstructed microvasculature that allows nutrient delivery, chemical exchange, and flow‑induced mechanical stimuli, and responds to physiological shear stress with cytoskeletal rearrangement and increased nitric oxide synthesis. The resulting microvessels display in‑vivo‑like morphology, biochemical markers, robust barrier function, and long‑term stability, while the open microvasculature supports nutrient and chemical delivery, flow‑induced shear responses, and offers a versatile platform for vascular physiology studies and organ‑on‑a‑chip disease modeling for drug screening.

Abstract

Generating perfusable 3D microvessels in vitro is an important goal for tissue engineering, as well as for reliable modelling of blood vessel function. To date, in vitro blood vessel models have not been able to accurately reproduce the dynamics and responses of endothelial cells to grow perfusable and functional 3D vascular networks. Here we describe a microfluidic-based platform whereby we model natural cellular programs found during normal development and angiogenesis to form perfusable networks of intact 3D microvessels as well as tumor vasculatures based on the spatially controlled co-culture of endothelial cells with stromal fibroblasts, pericytes or cancer cells. The microvessels possess the characteristic morphological and biochemical markers of in vivo blood vessels, and exhibit strong barrier function and long-term stability. An open, unobstructed microvasculature allows the delivery of nutrients, chemical compounds, biomolecules and cell suspensions, as well as flow-induced mechanical stimuli into the luminal space of the endothelium, and exhibits faithful responses to physiological shear stress as demonstrated by cytoskeleton rearrangement and increased nitric oxide synthesis. This simple and versatile platform provides a wide range of applications in vascular physiology studies as well as in developing vascularized organ-on-a-chip and human disease models for pharmaceutical screening.