# Sol-Gel Silica Nanoparticles in Medicine: A Natural Choice. Design, Synthesis and Products
## 3 Silica NP Design
### NPs Synthesis Methodologies
#### 3.3.1 Colloidal Route  
In colloidal routes, sol-gel SiO\({}_{2}\) NPs are formed in an aqueous medium through the supersaturation, polymerization and (eventual) precipitation of silica polymorphs. In the geological world silica NPs of \(\sim\)1 nm (basically orthosilicic acid, a weakly acidic molecule with pK\({}_{\text{a}}\)\(\sim\)9.8) undergo rapid growth to 2-4 nm, at pH 2-3 (as pH\({}_{\text{PZC}}\)\(\sim\)2.2; \(\zeta\)\(\sim\)0 mV at pH \(\sim\)2-3, facilitating NPs growth). As silica solubility increases well above pH 7 particles grow up to 4-6 \(\upmu\)m by coalescence and Ostwald ripening (pH \(>>\) pH\({}_{\text{PZC}}\), and \(\zeta<-\)30 mV). At pH \(>\) 9 (the ionized form of monomeric silicic acid Si(OH)\({}_{3}\)O\({}^{-}\) predominates) silica NPs cement to form a bulk gel, originating opal-like structures [38; 39]. Ostwald ripening of silica particles originates from surface instability of silicon dioxide and is driven by differences in chemical potential between particles of different size and shape. The local radius of curvature and ratio of surface area to volume accounts for the particle's surface energy, which is greater in the case of small particles or those with rough surfaces. Under kinetically favorable conditions these high surface energy particles dissolve preferentially, with the material being deposited onto particles with the largest radius. Silica dissolution proceeds via cleavage of siloxane bonds on the NPs' surface (which is faster in amorphous structures), resulting in the release of soluble silicic acid (Figure 5). Commercial precipitated silica, formed from sodium silicate solution and sulfuric acid, has the largest share of global market of silica particles (in classical industries), a position that is expected to grow in the next decade [2; 3; 4]. In the biological world plants, diatoms and sponges are capable of accumulating, storing and processing Si to create biogenic silica (at mild ambient conditions and under-saturated aqueous solutions of silicic acid). Several factors affected the process of natural silica condensation, namely concentration of silicic acid, temperature, pH, and the concentration of co-precipitating/nucleating agents (external small molecules and polymers) [93]. Plants started by taking up Si in the form of Si(OH)\({}_{4}\)] or Si(OH)\({}_{3}\)O\({}^{-}\) (present in soils at concentrations as low as few mg kg\({}^{-1}\)). When the silicic acid concentration is in excess of 100-200 mg kg\({}^{-1}\), polycondensation reactions occur at final location, forming silica polymers equal or higher in size than the critical nuclei size. The viable _nuclei_ grow to form spherical NPs, as the absence of crystallographic patterns promotes isotropic spherical growth. Figure 5: Sol-gel silica NPs growth through Ostwald ripening: (**a**) initial and (**b**) final stages. The final SiO\({}_{2}\) NPs are amorphous at the 1-nm length scale [94], built up from SiO\({}_{4}\) tetrahedron with variable Si-O-Si angles and Si-O bond distances. However, a great variety of medium/long range order patterns may be found in nature (branched chains, structural motifs or even hierarchical patterned structures) resulting in different density, hardness, solubility, viscosity and composition values [54; 55; 93]. As the silica NPs reach 1-3 nm in size, they interact with plant cell walls (due to the negatively charged silica NPs surfaces, at neutral pH). As to diatoms, there are more than 105 species with unique frustule architectures (Figure 6). The micro- and nano-sized diatoms can be also produced by cultivation, and here purification and chemical modification protocols are well established to generate pure active biohybrid materials [95]. Furthermore, the production of diatoms is environmentally friendly (compared to synthetic silica-based NPs), due to absence of toxic waste products and low energy consumption.