Bioinspired cell-in-shell systems in biomedical engineering and beyond: Comparative overview and prospects

With the development in tissue engineering, cell transplantation, and genetic technologies, living cells have become an important therapeutic tool in clinical medical care. For various cell-based technologies including cell therapy and cell-based sensors in addition to fundamental studies on single-cell biology, the cytoprotection of individual living cells is a prerequisite to extend cell storage life or deliver cells from one place to another, resisting various external stresses. Nature has evolved a biological defense mechanism to preserve their species under unfavorable conditions by forming a hard and protective armor. Particularly, plant seeds covered with seed coat turn into a dormant state against stressful environments, due to mechanical and water/gas constraints imposed by hard seed coat. However, when the environmental conditions become hospitable to seeds, seed coat is ruptured, initiating seed germination. This seed dormancy and germination mechanism has inspired various approaches that artificially induce cell sporulation via chemically encapsulating individual living cells within a thin but tough shell forming a 3D "cell-in-shell" structure. Herein, the recent advance of cell encapsulation strategies along with the potential advantages of the 3D "cell-in-shell" system is reviewed. Diverse coating materials including polymeric shells and hybrid shells on different types of cells ranging from microbes to mammalian cells will be discussed in terms of enhanced cytoprotective ability, control of division, chemical functionalization, and on-demand shell degradation. Finally, current and potential applications of "cell-in-shell" systems for cell-based technologies with remaining challenges will be explored.