Microphysiological Engineering of Self-Assembled and Perfusable Microvascular Beds for the Production of Vascularized Three-Dimensional Human Microtissues

Abstract

The vasculature is an essential component of the circulatory system that plays a vital role in the development, homeostasis, and disease of various organs in the human body. The ability to emulate the architecture and transport function of blood vessels in the integrated context of their associated organs represents an important requirement for studying a wide range of physiological processes. Traditional in vitro models of the vasculature, however, largely fail to offer such capabilities. Here we combine microfluidic three-dimensional (3D) cell culture with the principle of vasculogenic self-assembly to engineer perfusable 3D microvascular beds in vitro. Our system is created in a micropatterned hydrogel construct housed in an elastomeric microdevice that enables coculture of primary human vascular endothelial cells and fibroblasts to achieve de novo formation, anastomosis, and controlled perfusion of 3D vascular networks. An open-top chamber design adopted in this hybrid platform also makes it possible to integrate the microengineered 3D vasculature with other cell types to recapitulate organ-specific cellular heterogeneity and structural organization of vascularized human tissues. Using these capabilities, we developed stem cell-derived microphysiological models of vascularized human adipose tissue and the blood−retinal barrier. Our approach was also leveraged to construct a 3D organotypic model of vascularized human lung adenocarcinoma as a high-content drug screening platform to simulate intravascular delivery, tumor-killing effects, and vascular toxicity of a clinical chemotherapeutic agent. Furthermore, we demonstrated the potential of our platform for applications in nanomedicine by creating microengineered models of vascular inflammation to evaluate a nanoengineered drug delivery system based on active targeting liposomal nanocarriers. These results represent a significant improvement in our ability to model the complexity of native human tissues and may provide a basis for developing predictive preclinical models for biopharmaceutical applications.

Recreating Physiological Environments In Vitro: Design Rules for Microfluidic‐Based Vascularized Tissue Constructs

“…B) The application of a microfluidic model for vascularized human adipose tissue, vascularized tumors, blood‐retina barrier, and drug testing. Reproduced with permission . Copyright 2019, American Chemical Society.…”

“…Sobrino et al constructed an in vitro 3D vascularized microtumors platform to mimic the microenvironment of colorectal and breast cancer . In addition, Paek et al generated a model of the vascularized tumor spheroids of the human lung by coculturing the human lung adenocarcinoma cells and HUVECs to emulate the solid tumors in the lung . By using the same platform, they also developed vascularized human adipose tissue by combining the human adipose‐derived stem cells and primary human adipose microvascular endothelial cells to recapitulate the highly vascularized white adipose tissue (Figure B) .…”

“…In addition, Paek et al generated a model of the vascularized tumor spheroids of the human lung by coculturing the human lung adenocarcinoma cells and HUVECs to emulate the solid tumors in the lung . By using the same platform, they also developed vascularized human adipose tissue by combining the human adipose‐derived stem cells and primary human adipose microvascular endothelial cells to recapitulate the highly vascularized white adipose tissue (Figure B) . However, the system could be further improved by incorporating the supporting cells such as immune cells and stromal cells.…”

“…Through further research and development, the combined method was redesigned and developed. Paek et al adopted both the needle‐template and self‐assembly methods in constructing an open‐top microfluidic platform to develop models of vascularized human tissues . Wang et al also integrated the vasculogenesis and EC patterning strategies to generate a vasculature model representing human artery, vein, and capillary network …”

Photoacoustic imaging of cells in a three-dimensional microenvironment

“…Tumor cell intravasation and extravasation through the vascular wall to other organs is a critical step of tumor migration and metastasis [16]. 3D cell cultures have been utilized in biomimetic models of the tumor vasculature or angiogenesis for investigating the intrinsic or extrinsic modulation of the tumor vascular niche [17][18][19][20]. Preclinical studies of the normalization of tumor vasculature or drug screening for anti-angiogenesis have also been performed [21,22].…”