Nascent extracellular matrix: the missing piece in hydrogel design

Almost every cell in vivo is surrounded by the extracellular matrix (ECM), which contributes to cell and tissue fate. Biomaterials, especially engineered hydrogels, have emerged as platforms to recreate the biochemical and mechanical properties of ECM. Yet most approaches still assume that cells directly respond to the engineered hydrogel, although there is increasing evidence that numerous cell types rapidly deposit newly synthesized (nascent) ECM (nECM). Studies have now shown that this nECM accumulates at the cell-hydrogel interface, where it also contributes to a cell's fate. In this perspective, we first highlight key studies describing the nECM as a regulator of cell fate. Next, we provide guidelines based on physicochemical principles for studying nECM through spatiotemporal mapping, mechanical/structural measurements, biochemical characterization, and functional assays. Finally, building upon existing hydrogel engineering tools, we propose chemical- and protein-engineering approaches to specifically engineer the nECM to more precisely control cell-matrix interactions.