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Prospects & Overviews Cellular shellization: Surface engineering gives cells an exterior Review essays Ben Wang1)y, Peng Liu1)y and Ruikang Tang1)2)Ã Unlike eggs and diatoms, most single cells in nature do Introduction not have structured shells to provide extensive protec- tion. It is a challenge to artificially confer shell structures Progress in biological science and materials engineering has begun to blur the boundary between living and non-living on living cells to improve their inherent properties and systems. Synthetic biologists can now engineer complex, arti- functions. We discuss four different types of cellular ficial biological systems to help understand natural biological shellizations: man-made hydrogels, sol-gels, polyelectro- phenomena and use in a variety of biomedical applications [1]. lytes, and mineral shells. We also explore potential appli- Advances in directed evolution and membrane biophysics cations, such as cell storage, protection, delivery, and make the synthesis of simple living cells an imaginable therapy. We suggest that shellization could provide goal [2]. Cellular life is the basic unit of a living organism and another means to regulate and functionalize cells. defines the presence of a stable information reservoir con- Specifically, the integration of living cells and non-living nected to the external world by a well-defined boundary [3]. functional shells may be developed as a novel strategy The cell membrane separates the interior of a cell from the to create ‘‘super’’ or intelligent cells. Unlike biological outside environment and must meet specific requirements approaches, this material-based bio-interface regulation such as semi-permeability to permit communication and molecular transport across the border [4]. Using natural is inexpensive, effective, and convenient, opening up a membranes as a model, it is possible to build an artificial novel avenue for cell-based technologies and practices. shell from natural constituents or from synthetic soft or hard materials, introducing robustness to the capsule – the cell- Keywords: shell combination. Furthermore, we can also design the shell .biointerface; biomimetic mineralization; cellular shell; to alter the inherent biological qualities of the cell. functional materials; polyelectrolyte In the evolution of natural systems, living organisms have developed various mineralized structures, such as teeth, bones, shells, carapaces, and spicules. Those composite biomaterials often exhibit complex hierarchical structures and possess important functions such as mechanical DOI 10.1002/bies.200900120 1) Center for Biomaterials and Biopathways and Department of Chemistry, Abbreviations: Zhejiang University, Hangzhou, Zhejiang 310027, China ACT, adoptive cell therapy; ALP, alkaline phosphatase; bioMEMS, bio-Micro- 2) State Key Laboratory of Silicon Materials, Zhejiang University, Hangzhou, Electro-Mechanical Systems; BMSC, bone marrow mesenchymal stem cells; Zhejiang 310027, China BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; EB, embryoid bodies; *Corresponding author: ECM, extracellular matrix; EDTA, ethylenediaminetetraacetic acid; HA, Ruikang Tang hyaluronic acid; hESC, human embryonic stem cell; HMS, hydrogel matrix E-mail: [email protected] shell; IMS, induced mineral shell; LbL, Layer by layer; MELN cells, MCF-7 cells transfected with a construct expressing the luciferase gene under the control of an estrogen-regulated promoter; mESCs, murine embryonic stem cells; MRI, Magnetic Resonance Imaging; MSC, mesenchymal stem cells; PAA, poly(acrylic sodium); PDADMAC, poly(diallyldimethylammonium chloride); PE, polyelectrolyte; PES, polyelectrolyte shell; PLL, poly (L- lysine); PSS, polystyrene sulfonate; SGS, sol-gel shell; SLeX, Sialyl Lewis(x); TMOS, tetramethyl orthosilicate; VNPs, viral nanoparticles. yThese authors contributed equally to this work. 698 www.bioessays-journal.com Bioessays 32: 698–708,ß 2010 WILEY Periodicals, Inc. ....Prospects & Overviews B. Wang et al. Review essays Figure 1. Scheme of an egg and overview of cellular shellization. A: A chicken egg is a typical cell with a shell (its main inorganic composition is calcite). B: The unique structure of eggshells (the organic matrix) provides crystallization sites for the deposition of calcite layer onto the cells. C: Different approaches for cellular shellization and its potential applications: HMS, SGS, PES, and IMS. support, protection, motility, and sensing of signals [5]. different approaches that have been undertaken to Marine organisms such as mollusks [6] and arthropods [7] construct artificial shells, such as hydrogel matrix shell use biominerals as their exterior coats to protect their soft (HMS), sol-gel shell (SGS), polyelectrolyte shell (PES), and bodies from external stresses or aggression. A cocoon is induced mineral shell (IMS). Applications of cellular shelliza- another example of an exterior coat that fulfills multiple roles tion – cell storage, protection, delivery, and therapy – are then including protection against physical stress, toxic substances discussed (Fig. 1C). Finally, conclusions and perspectives are and natural enemies, and even mediation of messages con- offered as to where these fascinating avenues of research trolling the life cycle. Besides these examples, a number of might lead. unicellular organisms have biogenic coverings as well. Chicken eggs are perhaps the most familiar example (Fig. 1A). Eggshells provide mechanical support for the Hydrogel matrix shell (HMS) embryo and are also extremely important for maintaining the egg’s viability. It is well-known that an egg with an intact The extracellular matrix (ECM) is the portion of animal tissue shell can be stored for several weeks in ambient conditions; that provides the essential microenvironment for cells. Due to however, the egg will decay quickly if the shell is broken. The its diverse nature and composition, the ECM can serve many shell forms a shield to prevent the enclosed cells from con- functions, such as support and anchorage for cells, segregat- tamination. Eggshells also maintain the balance of oxygen, ing tissues from one another, and regulating intercellular carbon dioxide, water, and nutrients required for proper cell communication [11]. Synthetic and natural hydrogels have development [8]. In addition, shells provide the embryo with become popular as three-dimensional in vitro cell culture the minerals needed for the generation of organs high in platforms that mimic ECM. Networks of hydrophilic polymers calcium, such as the skeleton, muscles, and brain [9]. that can retain large quantities of water, hydrogels can be Diatoms, another example of a unicellular organism with a synthesized by multiple methods. Hydrogels are biocompat- mineral coat, have unique cell walls made of silica (hydrated ible, supportive of cell maintenance and growth, since they silicon dioxide) called frustules. The ornately patterned facilitate the exchange of gases and nutrients in a way similar silicified shell has evolved as a biological protection for to the environment in vivo [12]. Hydrogel encapsulation may diatoms [10]. provide cells with structural support, chemical stability or a However, most cells cannot make their own shells. measure of protection from immune attack. Both synthetic Many attempts have been made to fabricate artificial shells and naturally derived hydrogels have been explored for encap- directly onto cells or to confer to cells an ability to form sulation of a variety of cell types [13]. The use of hydrogels to their own shells. This paper gives an overview of the encapsulate stem cell populations indicates the ability of this Bioessays 32: 698–708,ß 2010 WILEY Periodicals, Inc. 699 B. Wang et al. Prospects & Overviews .... technique to manipulate cell fate. For example, murine embry- The silicate matrix is usually formed by hydrolysis of an onic stem cells (mESC) were encapsulated into 1.6% w/v alkoxide precursor followed by condensation to yield a poly- alginate microbeads. Differentiation was inhibited at the mor- meric oxo-bridged SiO2 network. In the process, molecules of ula-like stage, with no cystic embryoid bodies (EB) formed the corresponding alcohol are liberated. The ability to form within the beads. Using the same strategy to coat human hybrid silica glasses under aqueous conditions and room embryonic stem cells (hESC), stem cell colonies could be temperature (at which proteins and cells are active) opened maintained for up to 260 days in an undifferentiated state. up the possibility of extending sol-gel processing to the encap- Upon release from the alginate microbeads, hESC were able to sulation of cells. However, while sol-gel conditions are mild resume differentiation, as shown by the formation of into enough for organic molecules, they are still too harsh for living cystic EB containing beating cardiomyocytes. Retention of cell organisms to retain viability. For example, alcohol and pluripotency by encapsulation occurred even under differen- acidic pH lead to the denaturation of most proteins. tiation promoting conditions [14]. Recently, a newly developed Therefore, the sol-gel process had to be adapted to bioencap- integrated bioprocess utilized alginate hydrogel encapsulation sulation, which is currently achieved in two steps. The first Review essays of mESC to form 3D mineralized constructs without the need step is the hydrolysis of tetramethyl orthosilicate (TMOS) in for passaging or handling of the cells [15]. Chan et al. also the presence of an acid to hydrolyze

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