Advances in the fields of tissue engineering and regenerative medicine require biomaterials that instruct, rather than simply permit, a desired cellular response. A major challenge to progress in our field is the complex organization of the tissues in our bodies, which are hierarchical, vary in space and time, and can differ person-to person. Prof. Harley’s research program is developing approaches to structurally and biomolecularly pattern biomaterials to enable tissue regeneration after injury as well as to study processes linked to homeostasis and disease progression outside of the body. A major area of our work targets development of a degradable biomaterial to regenerate craniomaxillofacial bones and musculoskeletal insertions. We are using bioinspired design motifs to create composite materials that instruct desired cell activities while retaining mechanical competence required for clinical translation. I will describe (granular) hydrogel models to study niche regulation of hematopoietic stem cells and patient-derived glioblastoma specimens. These tools enable study of dynamic processes such as niche remodeling and reciprocal signaling linked to stem cell quiescence as well as the role of angiocrine signals and immune interactions on invasive spreading and drug resistance in primary brain cancer. We are adapting these approaches to develop hierarchical models of the endometrial tissue microenvironment to investigate trophoblast invasion and endometrial pathologies.