From flow to form: structuring and patterning hydrogels using microfluidic approaches

Three-dimensional (3D) cell culture can leverage the precise arrangement of materials, known as patterning, to generate physiologically relevant tissue-like structures. Hydrogels are widely used in 3D cell culture due to their ability to mimic the properties of biological extracellular matrix networks. In this tutorial review, we discuss the use of microfluidic systems to control fluid movement and placement within fabricated microchannels to pattern hydrogel precursors in 3D through the use of capillary flow. Such systems offer unique advantages in their ability to create complex biomimetic structures, organs-on-a-chip, and microphysiological systems with high spatial resolution and relatively small volumes of hydrogel material. We first discuss the fundamental principles behind capillary pinning and aspiration-mediated patterning. We then review literature describing the development and applications of three different types of microfluidic systems - closed, semi-open, and open - and describe how different patterning techniques are applied to each system. We also discuss modular microfluidic systems, in which multiple classes of microfluidic systems are combined together for complex and biomimetic modeling of biological systems. In each section, we provide synthesis and critical analysis of established and novel techniques to draw connections across diverse papers in literature. Finally, we offer our perspectives on the advantages of microfluidic systems for hydrogel patterning and the future of the field. Taken together, microfluidic flow-based patterning is an exciting tool for microphysiological systems and other 3D cell culture models that are poised to transform our understanding of basic biological mechanisms and provide new opportunities for studying diverse phenomena in physiologically relevant tissue models.