Polyethylene glycol (PEG) hydrogels are tunable cell culture platforms that recapitulate tissue geometry, water content, and bulk modulus. Despite these benefits, PEG hydrogels elicit an acute immune response, limiting their use in regenerative medicine, and they critically underrepresent the cell-instructive proteins found in the extracellular matrix (ECM). Here, I developed a new class of tissue-specific PEG-based materials and provided biocompatible strategies to improve the user handling and cell viability post-encapsulation when using these hydrogels. I also demonstrated that decreasing the protein fouling to PEG does not decrease the foreign body response to implanted hydrogels, a common misconception in the field. While PEG hydrogels can easily be tuned to mimic tissue mechanics, most PEG platforms contain between 1-3 biofunctional peptide moieties, chosen to maximize cell phenotype, rather than represent features of specific tissues. This directly contrasts the complex protein signature of real tissues and neglects many properties that contribute to the function of the organ via directing cell migration, stem cell fate, and organoid development. Here, I took a tissue-centric approach to create three-dimensional cell culture microenvironments using a simple base set of materials. I characterized the mechanics and proteomics of real bone marrow and used this data to customize the design of a hydrogel made with only PEG and synthetic peptides. Bioinformatics on human tissue histology identified 20 different cell-instructive peptides that represent the protein signature of bone marrow and can be incorporated into a hydrogel matched to the compressive modulus of marrow. Compared to a non-tissue specific hydrogel, the marrow-customized hydrogel provides a better niche for bone marrow-derived mesenchymal stem cell differentiation and proliferation in response to soluble cues. I also highlighted how tissue-inspired hydrogels can improve in vitro studies of cell-cell and cell-matrix interactions. PEG is a versatile material that can be used for both cell encapsulation and tissue regeneration applications. The tunability of the material provides simple incorporation of tissue-like features and an avenue to explore how material-properties interface with cells and tissue. Ultimately, this work can be applied to any tissue or organ, creating a new class of designer biomaterials that can be used to elucidate ECM-driven disease mechanisms that currently lack appropriate in vitro models.