Biofabrication strategies for creating microvascular complexity

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.