Biofabrication strategies for creating microvascular complexity

Abstract

Design and fabrication of effective biomimetic vasculatures constitutes a relevant and yet unsolved challenge, lying at the heart of tissue repair and regeneration strategies. Even if cell growth is achieved in 3D tissue scaffolds or advanced implants, tissue viability inevitably requires vascularization, as diffusion can only transport nutrients and eliminate debris within a few hundred microns. This engineered vasculature may need to mimic the intricate branching geometry of native microvasculature, referred to herein as vascular complexity, to efficiently deliver blood and recreate critical interactions between the vascular and perivascular cells as well as parenchymal tissues. This review first describes the importance of vascular complexity in labs-and organs-on-chips, the biomechanical and biochemical signals needed to create and maintain a complex vasculature, and the limitations of current 2D, 2.5D, and 3D culture systems in recreating vascular complexity. We then critically review available strategies for design and biofabrication of complex vasculatures in cell culture platforms, labs-and organs-on-chips, and tissue engineering scaffolds, highlighting their advantages and disadvantages. Finally, challenges and future directions are outlined with the hope of inspiring researchers to create the reliable, efficient and sustainable tools needed for design and biofabrication of complex vasculatures.

The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors

“…An even greater challenge is to develop vascularization around (or inside) the tumor. Here, novel biofabrication strategies will play a decisive role [207]. In particular, 3D bioprinting will be also a valuable asset [208,209].…”

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

“…With the advent of new biofabrication strategies for creating 3D, biomimetic vascular networks, more in‐depth mechanistic investigations of hemodynamic forces and vascular mechanobiology have become possible. [ 48–52 ] Implementation of hydrogels has facilitated the integration of vascular networks with mesoscale, heterogeneous, tissue‐specific constructs with complex flow patterns. [ 28,35 ] Hydrogels used for recreating vascular microenvironments include natural, synthetic, and hybrid blends, which can be tuned to cover a wide range of physical (stiffness, porosity, nanotopography, diffusivity) and biochemical properties (adhesivity, degradability, paracrine signaling cues) to emulate organ‐specific ECM composition ( Table 2 ).…”

“…Over the past few decades, a multitude of strategies have been developed for fabrication of 3D in vitro microfluidic and vascular networks. [ 27,49–51,174 ] The major considerations with regard to these techniques are scalability, user‐programmability with a high degree of control, reproducibility, throughput, resolution, cost, architectural complexity and intricacy, spatial positioning of multiple cell types, cytotoxicity, material handling and processability, and control over local physical and biochemical cues for rapid vascular morphogenesis and functional integration (see Figure 1 in Bogorad et al [ 29 ] ).…”

“…To overcome some of these challenges, photolithography‐based fabrication techniques have been developed that allow precise, spatiotemporal, nano‐ to microscale tuning of local hydrogel properties that lead to directed cellular organization and user‐controlled geometric vascular assembly. [ 50,51,206 ] These approaches also facilitate the immobilization of controlled concentrations of bioactive molecules to mimic native architectures for investigation of sprouting, EC migration, and vessel formation. [ 270–272 ] These techniques can be broadly categorized into: 1) mask‐based photolithography, 2) stereolithography, and 3) laser‐based lithography.…”

“…Although majority of investigations on vascular mechanobiology have been conducted in simple and reductionist models, recent advances in fabrication technologies to generate engineered tissue constructs with vascular networks have aided the close recapitulation of native tissue and organ niches. [ 49–51 ] Particular examples of these niches and the underlying role of vascular mechanobiology driving these processes are discussed below.…”