Hydrogel-tissue chemistry (HTC) steps toward tissue functionalization. The main steps for transformation of the tissue, as shown for (a) the diagrammed cell prior to the HTC process, include (b) hydrogel-monomer infusion followed by cross-linking to native macromolecules and then gelation, (c) stringent delipidation with detergent without the risk of extensive biomolecule loss or structural disruption, (d) optical clearing, refractive index matching, high-resolution volumetric imaging (through delipidized tissue), and read-out of biomolecules tethered to the tissue-hydrogel coordinate system, shown in green.