Hydrogels and microfluidics: toward more physiologically relevant organ-on-a-chip models

Hydrogel-integrated organ-on-a-chip (OoC) models have emerged as a promising platform for recapitulating the complexity of native human tissues. This review highlights the role of hydrogels as tissue-specific extracellular matrix (ECM) mimics, focusing on the physicochemical properties that regulate cellular behaviour and tissue function in three-dimensional (3D) systems. We also explore the contribution of microfluidic systems in further enhancing physiological relevance by integrating multiple microenvironmental cues, including dynamic biochemical gradients, biophysical stimuli, tissue architecture, temporal regulation, 3D cellular arrangements, and ECM incorporation. Following a discussion of different hydrogel-microfluidic integration strategies, along with their associated engineering challenges and design considerations, we examine how the synergistic integration of hydrogels with microfluidics enables the development of advanced OoC models that more faithfully reproduce native tissue organisation and physiology. These advances make hydrogel-integrated OoC models well suited to a broad range of applications, including studying fundamental biology, disease modelling, drug development, personalised medicine, and multi-organ system, helping bridge the gap between in vivo animal studies, traditional in vitro studies, and human physiology.