Hyaluronic acid-based models of the brain microenvironment: Challenges and advances

While hyaluronic acid (HA) extracellular matrix (ECM) models continue to provide valuable insights into brain physiology and disease, much room for improvement remains in terms of capturing the cellular and structural complexity of the brain microenvironment. Here we review next-generation HA models that are aimed at better capturing brain microenvironmental complexity. We discuss functionalization and crosslinking strategies designed to improve HA stability and biocompatibility. We also cover efforts to incorporate ECM proteins and stromal elements into HA hydrogels, including astrocytes, endothelial cells, and macrophages. We conclude with a brief discussion of nascent advancements and applications of these models, ranging from the reconstruction of multicellular stromal structures to the development of high-throughput screening platforms. This new suite of matrix technologies and the resulting applications should contribute greatly to mechanistic and therapeutic discovery in brain physiology and disease.