Microfluidic models of the human circulatory system: versatile platforms for exploring mechanobiology and disease modeling

Abstract

The human circulatory system is a marvelous fluidic system, which is very sensitive to biophysical and biochemical cues. The current animal and cell culture models do not recapitulate the functional properties of the human circulatory system, limiting our ability to fully understand the complex biological processes underlying the dysfunction of this multifaceted system. In this review, we discuss the unique ability of microfluidic systems to recapitulate the biophysical, biochemical, and functional properties of the human circulatory system. We also describe the remarkable capacity of microfluidic technologies for exploring the complex mechanobiology of the cardiovascular system, mechanistic studying of cardiovascular diseases, and screening cardiovascular drugs with the additional benefit of reducing the need for animal models. We also discuss opportunities for further advancement in this exciting field.

Keywords: Cardiovascular diseases; Human circulatory system; Mechanobiology; Microfluidics; Organ-on-a-chip.

Fig. 1

a Schematic of the human circulatory system, consisting of the heart at the center and a complex network of vessels which interact with other organs. b Animal models are extensively used for studying the human circulatory system. c The complexity, cost, and inherent differences between the human and animal models have led to the evolution of cell models, ranging from simple 2D models (Petri dish, flasks) to more complex 3D models (hydrogel, spheroids, organoids) and more physiologically relevant microfluidic models

Fig. 2

Methods for fabricating microfluidic vessel structures: a Microfluidic vessel structures with rectangular, semi-circular, and circular cross sections which can be fabricated using, b lithography, 3D printing, and bioprinting techniques

Fig. 3

Methods for coating the surface of microfluidic vessel structures: a single layer involving vascular endothelial cells directly coated onto the surface, b double layer involving collagen coated onto the surface to serve as an extracellular matrix for vascular endothelial cells, and c triple layer involving smooth muscle cells, collagen, and endothelial cells coated onto the surface

Fig. 4

Microfluidic structures with movable elements: a simultaneous mechanical and shear stress stimulation of cells using a multilayered microfluidic system (Ribas et al. 2017), b harmonically deflecting cantilever beams to mimic cardiac muscles (Agarwal et al. 2013), and c leaflet-like barriers to mimic the complex flow dynamics of heart valves (Hu et al. 2020)

Fig. 5

Microfluidic vessel structures allowing for modeling various cardiovascular diseases or pathological flows: a atherosclerosis (Zhang et al. 2020), b vessel stenosis (Westein et al. 2013), c valve leaflet stenosis (Baratchi et al. 2020), d reversed flow (Tovar-Lopez et al. 2019), e vessel injury (Muthard and Diamond 2013), and f tumor angiogenesis (Sobrino et al. 2016)

Fig. 6

Microfluidic vessel structures allowing for studying a renal reabsorption in kidney proximal tubules (Lin et al. 2019), b permeability of the blood-brain barrier (Booth and Kim 2012), and c oxygenation of blood across the alveoli (Grigoryan et al. 2019)