Cell-Instructive Biomaterials with Native-Like Biochemical Complexity

Biochemical signals in native tissue microenvironments instruct cell behavior during many biological processes ranging from developmental morphogenesis and tissue regeneration to tumor metastasis and disease progression. The detection and characterization of these signals using spatial and highly resolved quantitative methods have revealed their existence as matricellular proteins in the matrisome, some of which are bound to the extracellular matrix while others are freely diffusing. Including these biochemical signals in engineered biomaterials can impart enhanced functionality and native-like complexity, ultimately benefiting efforts to understand, model, and treat various diseases. In this review, we discuss advances in characterizing, mimicking, and harnessing biochemical signals in developing advanced engineered biomaterials. An overview of the diverse forms in which these biochemical signals exist and their effects on intracellular signal transduction is also provided. Finally, we highlight the application of biochemically complex biomaterials in the three broadly defined areas of tissue regeneration, immunoengineering, and organoid morphogenesis.