Review article
Organ-on-a-chip systems for vascular biology

https://doi.org/10.1016/j.yjmcc.2021.06.002Get rights and content

Highlights

  • Modeling vasculature requires heterogeneous structure and cell population.

  • Flow is a key driver for vascular formation and organ-on-a-chip models.

  • Patterning perfusable microvascular networks is an important achievement.

  • Fit for purpose OOC systems are needed to study vascular biology.

Abstract

Organ-on-a-chip (OOC) platforms involve the miniaturization of cell culture systems and enable a variety of novel experimental approaches. These range from modeling the independent effects of biophysical forces on cells to screening novel drugs in multi-organ microphysiological systems, all within microscale devices. As in living systems, the incorporation of vascular structure is a key feature common to almost all organ-on-a-chip systems. In this review we highlight recent advances in organ-on-a-chip technologies with a focus on the vasculature. We first present the developmental process of the blood vessels through which vascular cells assemble into networks and remodel to form complex vascular beds under flow. We then review self-assembled vascular models and flow systems for the study of vascular development and biology as well as pre-patterned vascular models for the generation of perfusable microvessels for modeling vascular and tissue function. We finally conclude with a perspective on developing future OOC approaches for studying different aspects of vascular biology. We highlight the fit for purpose selection of OOC models towards either simple but powerful testbeds for therapeutic development, or complex vasculature to accurately replicate human physiology for specific disease modeling and tissue regeneration.

Introduction

Vasculature is the universal tissue infrastructure, known for providing nutrients, taking away waste, maintaining homeostasis, and shaping tissue and organ structure. In the developing embryo, a group of vascular progenitors, known as angioblasts, emerge to differentiate and assemble into a primitive vascular network [[1], [2], [3]]. As development proceeds, this primitive network remodels, presumably triggered by changes in hemodynamic forces [4,5], surrounding cell types, and microenvironment, including chemical factors and architectural features of surrounding extracellular matrix, to establish a hierarchical vascular tree with tissue-specific functionality important for the function of each organ [6,7]. The process of de novo vascular formation is known as vasculogenesis, whereas remodeling and vascular growth from pre-existing vasculature, either by sprouting or intussusception [8], has been defined as angiogenesis. Modern evidence has shown that blood vessels also provide instructive regulatory signals to surrounding non-vascular target cells [7,9]. Building vascular models and vascularized tissues has been a major thrust in biomedical research in recent decades for understanding vascular biology, regenerating tissue, modeling diseases, and testing preclinical drugs.

Among various biomedical efforts, organ-on-a-chip (OOC) technologies have gained significant research attention in recent years, with the more specific target of designing and engineering miniaturized functional units of human tissues and organs [[10], [11], [12], [13]]. These miniaturized devices promise to better replicate native biological functions ex vivo and enable high-throughput techniques essential to disease modeling and drug testing. Central to this approach is the use of perfusable micro- and milli-fluidic platforms in which fluid flow both sustains the metabolic needs of OOC devices and replicates the distinct vascular compartment found in living organisms. In this review we explore recent advances in OOC technologies with a focus on this vascular component and technologies for replicating vascular structure and function in vivo. We will briefly review vascular structure and function, highlighting OOC systems that have advanced our understanding of fundamental aspects of vascular biology. We then explore OOC systems that utilize an engineered vasculature to explore tissue level functions in organ-specific models. We conclude with prospective remarks on choosing OOC systems of varying complexity and including proper cell populations to target suitable vascular biology questions.

Section snippets

Vasculature: heterogenous structure, cell populations and blood flow

Blood vessels are organized in a hierarchical branching network in three-dimensional (3D) space and characterized by diameters ranging from arteries and veins (1 mm to 1 cm for large vessels, and 100 μm to 1 mm for small vessels), to arterioles and venules (20–100 μm) and capillaries (5–20 μm). The curvature of vessels ranges from 10−3 to 102 mm−1 with the largest vessel curvature found in the microvasculature of complex vascular beds like the brain [14]. Variation in size and curvature

Forming EC networks

The initial process of vasculogenesis (also called tubulogenesis) has been modeled with direct cell-in-gel culture systems, by embedding endothelial cells in cell-remodelable 3D matrices like collagen, fibrin, or Matrigel [41,42]. Once encased in these extracellular matrix (ECM) hydrogels, ECs can create lumens via either intracellular or extracellular mechanisms and form connective vascular tubes [41]. Vacuoles develop in ECs and then fuse with those in neighboring cells to form an

Flow systems – vascular development and biology

Blood flow is a key driver for the proper vascular growth and remodeling. The study of the hemodynamic response of vessels has been focused in two areas: endothelial cell sensing of flow and network expansion via angiogenesis. Different model systems have been developed in these two distinct areas.

Patterning perfusable microvascular networks – vascular and tissue functions

Beyond the fundamental study of vascular biology itself, introducing vasculature into OOC systems is critical for the development of functional tissue and the study of biologic processes including vascular-parenchymal and blood-vessel interactions [93]. Perfusion through the vasculature is necessary for the nutritional support of parenchymal tissue, with tissues generally needing to be located within a few hundred microns of a vascular lumen [94]. In addition to transport and

Vascularized cardiac and organ-specific tissues

As the most metabolically active organ in the body, the heart requires significant vascular density to support efficient nutrient delivery [121]. Hence, proper vascularization has been a key requirement towards engineering thick and functional cardiac constructs. Prior efforts to vascularize cardiac grafts have often relied on the self-assembly of ECs to form connected tubes within cardiac constructs using primary ECs (e.g. HUVECs) or ECs differentiated from pluripotent stem cells [108,122].

Future directions – choosing biomechanical, biochemical, and cellular complexity

OOC devices have been applied to a wide range of research questions, spanning basic endothelial biology to disease modeling and drug discovery. Essential to these approaches is the extent to which different vascular features and compartments are modeled and the tailoring of device designs to the research question at hand. In the slow progression from simple to complex models, simplified systems targeting only some biophysical or biochemical cues have provided great insight into core aspects of

Acknowledgements

We are thankful for support from the National Institute of Health R01 HL141570, UH2/UH3 DK107343, 1R01AI148802 and R01 AI141602 (to YZ), F32 HL143949 (to SR), support from the United Therapeutics Jenesis Innovative Research Award (to SR), support from the National Science Foundation Graduate Student Research Fellowship DGE 1762114 (to CH), and support from Institute of Stem Cell and Regenerative Medicine at the University of Washington (to YJS).

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