Cell Armor for Protection Against Environmental Stress: Advances, Challenges and Applications in Micro- and Nanoencapsulation of Mammalian Cells.

Unlike unicellular organisms and plant cells surrounded with a cell wall, naked plasma membranes of mammalian cells make them more susceptible to environmental stresses encountered during in vitro biofabrication and in vivo cell therapy applications. Recent advances in micro- and nanoencapsulation of single mammalian cells provide an effective strategy to isolate cells from their surroundings and protect them against harsh environmental conditions. Microemulsification and droplet-based microfluidics have enabled researchers to encapsulate single cells within a variety of microscale hydrogel materials with a range of biochemical and mechanical properties and functionalities including enhanced cell-matrix interactions or on-demand degradation. In addition to microcapsules, nanocoatings of various organic and inorganic substances on mammalian cells have allowed for the formation of protective shells. A wide range of synthetic and natural polymers, minerals and supramolecular metal-organic complexes have been deposited as nanolayers on the cells via electrostatic interactions, receptor-ligand binding, non-specific interactions, and in situ polymerization/crosslinking. Here, current strategies in encapsulation of single mammalian cells along with challenges and advances are reviewed. Protection of encapsulated stem cells, fibroblasts, red and white blood cells and cancer cells against harsh in vitro and in vivo conditions including anoikis, UV radiation, physical forces, proteolytic enzymes and immune clearance are discussed. STATEMENT OF SIGNIFICANCE: The mechanical fragility of the plasma membrane and susceptibility to extracellular biochemical factors due to the lack of a physical barrier like a tough cell wall or exoskeleton make mammalian cells extra sensitive to harsh environmental conditions. This sensitively, in turn, limits the ex vivo storage, handling and manipulation of mammalian cells, as well as their in vivo applications. Environmental stresses such as exposure to UV, reactive chemicals and mechanical stress during biofabrication processes like 3D bioprinting can often compromise cell viability and function. Micro- and nanoencapsulation of single mammalian cells in protective shells have emerged as promising approaches to isolate cells from their surroundings and enhance resistance against perturbations in conditions during regenerative medicine and tissue engineering applications. In this review, the current state of art of single cell encapsulation strategies and the challenges associated with these technologies are discussed in detail. This is followed by the review of the protection provided by cell armor against a range of harsh in vitro and in vivo conditions.