# Mini-Review: Potential of Diatom-Derived Silica for Biomedical Applications
## 2 Silicon Capture from the Environment, Transport and Storage, Frustule Formation  
In contrast with nitrogen and phosphorus metabolisms, silicon uptake in diatoms is linked with aerobic respiration rather than being strictly related to photosynthesis [27]. Silicon is mainly found in aquatic environments as Si(OH)4, and is usually transformed into solid SiO2 or other siliceous composites in the presence of organic substances, through condensation reactions [28]. It can enter cells by diffusion across their membranes; nevertheless, at very low concentrations of silicic acid in the surrounding environment, the cells activate silicon transporters that facilitate the uptake [29]. The genes coding for silicic acid transporters (SITs) were isolated and characterized from the marine diatom _Cylindrothea fusiformis_ several years ago [30; 31] and, recently, in the freshwater species _Synedra ulna_ subsp. _danica_[32]. The SITs specifically transport silicic and germanic acids through the lipid bilayer [33]. Studies performed on _C. fusiformis_ revealed that ten transmembrane segments allow the passage of silicic acid through the lipid bilayer membrane, and chemical recognition is likely based on amino acids (Figure 1). The extent of frustule silicification depends on the rate of silicon uptake that is driven, in turn, by both the availability of the substrate and the expression levels of the SIT genes [30]. Five distinct clades have been identified for SIT genes in diatoms. The presence of genes from distinct clades within the same diatom species is likely to reflect different responses to changes in silicon availability and environmental conditions [34]. Intracellular pools of silicic acid can reach concentrations well beyond the saturation limit (2 mM), and this is likely due to complexation by organic compounds that prevents polymerization. The extent of the internal pools is both species-specific [35] and dependent upon environmental conditions [36]. When silicon deposition and uptake are imbalanced and internal pool tends to increase, a concentration gradient determines the efflux of the \"unbound\" silicon fraction outside the cell membrane [37]. The diatom cell wall has a Petri dish-like structure, with an upper part, known as epithea, overlapping the smaller lower part, named hypothea (Figure 2). Both epithea and hypothea consist, in turn, of valves and siliceous girdle bands, which confer an ordered structure to the frustule. Diatom frustule is a composite made of biogenic silica, carbohydrates and glycoproteins [31]. Figure 1: Silicic acid transporters (STIs) in _Cylindotheca fusiformis_. STIs contain 10 transmembrane segments (white cylinders), which allow the passage of silicic acid through the lipid bilayer membrane; an intracellular amino-terminal segment (INS); and an intracellular carboxy segment (ICS) connected to a coiled-coil motif (CC), which may play a role in the interactions with other proteins. Pluses (+) and minuses (-) indicate the position of positively and negatively charged amino acids, respectively. A major role in silicon uptake is likely played by cysteine residues (C) because of their sulfhydryl blocking agents. Figure redrawn from [31]. Frustule formation occurs through the polymerization of siliciic acid in specific compartments, namely, the silica deposition vesicles (SDV), associated to the membrane silicalemma [39; 40]. Silicelemma contributes to silicification through both the regulation and recognition of membrane-associated compounds, as well as the formation of a suitable microenvironment for polymerization. SDVs in diatoms are formed inside the plasma membrane during cell division [41]. During valve formation, the SDVs rapidly expand and their movement is driven by the cytoskeleton [42]. The following several frustule-associated proteins are involved in the formation of the diatom cell wall: frustulins, pleuralins, cingulins, silicidins and silaffins. Aside from proteins, long-chain polyamines, which are constituents of diatom biosilica, are likely involved in silica biogenesis [43].