Generating structurally and functionally programmable hydrogels by biological membrane hybridization

Hydrogels, as 3D cross-linked hydrophilic networks that exhibit favorable flexibility, cargo loading and release abilities and structure and function designability, are desirable for diverse biomedical applications. For in vivo implementation, however, hydrogels often suffer from swelling-weakened mechanical strength, uncontrollable cargo release and complex composition, inevitably hindering further translation. Despite different reported synthetic approaches, the development of a facile yet universal method capable of fabricating hydrogels with dynamically adjustable structure and function remains difficult. Recently, inspired by biological tissues, we have developed a versatile biological membrane hybridization strategy to generate structurally and functionally programmable hydrogels. Specifically, biological membranes are used as a cross-linker to form a cross-linked network through a supramolecular-covalent cascade reaction route. This protocol demonstrates the construction of two biological membrane-hybridized hydrogels, including liposome-hybridized muscle-mimicking hydrogels with swelling-strengthening mechanical behavior and extracellular vesicle-hybridized skin-mimicking hydrogels with enhanced mechanical strength, lubricity, antibacterial activity and immunoactivity. We describe the detailed preparation procedures and characterize the structures and functions of the obtained hydrogels. We also expand the applicability of this biological membrane hybridization strategy to further tune the structure and function of the biomimetic hydrogels by incorporating a second network. This protocol provides a robust preparative platform to develop dual structure- and function-tunable hydrogels for different biomedical applications. Excluding the synthesis of reactive group-functionalized biological membranes, the fabrication of muscle-mimicking hydrogels takes ~3 d, while the construction of skin-mimicking hydrogels takes ~1 d. The implementation of the protocol requires expertise in polymer modification, hydrogel preparation, nanoscale vesicles, surface functionalization and cell culture.