2.2.1. Nano Silica

A huge amount of investigations on biomedical applications of silica nanostructures have been carried out in the past decade [249]. The ability to synthesize uniform, porous and dispersible nanoparticles, together with the fact that particles' size and shape can be easily controlled [226], certainly favored the variety of applications of silica in tissue engineering [250]. Furthermore, as silica is biocompatible and chemically stable [251,252], it has been used also for biomedical imaging and medication administration [225], either itself or as a coating of other compounds [251].

Mesoporous silica nanoparticles (MSNPs) have been used as a drug delivery vehicle [253] and to improve mechanical properties of biological materials. It was noted their use as well as for sustained and prolonged release or administration of intracellular genes in bone tissue engineering [226]. MSNPs work as efficient biocompatible nanocarriers due to (i) high visibility, (ii) dispersibility, (iii) binding capability to a target tissue, (iv) ability to load and deliver large concentrations of cargos, and (v) triggered or controlled release of cargos [250]. The functioning of MSNPs can be tailored by modifying the silanol group present within the pore interiors and on the outer surface. These positive chemical moieties are adsorbed by negatively charged SiO– groups at neutral pH, through electrostatic interactions (Figure 12).

**Figure 12.** Schematic of a multifunctional mesoporous silica nanoparticle showing possible core/shell design, surface modifications, and multiple types of cargos. (Adapted with permission from © 2013 American Chemical Society [250]).

Anitha et al. [254] reported a composite matrix containing crystalline rod-shaped core with uniform amorphous silica sheath (Si–n HA), which showed good biocompatibility, osteogenic differentiation, vascularization, and bone regeneration potential. Silicate containing hydroxyapatite stimulates cell viability of human mesenchymal stem cells for extended proliferation [255]. Zhou et al. [256] synthesized PLGA–SBA15 composite membranes with different silica contents by electrospinning method; these membranes showed better osteogenic initiation then the pure PLGA membranes. Ding et al. [257] successfully fabricated levofloxacin (LFX)-loaded polyhydroxybutyrate/ poly(ε-caprolactone) (PHB/PCL) and PHB/PCL/sol–gel-derived silica (SGS) scaffolds, which support the growth of MG-63 osteoblasts. A microfluidic device was used to generate photo-cross-linkable gelatin microgels (GelMA), coupled with providing a protective silica hydrogel layer for applications in injectable tissue constructs [258]. Dexamethasone (DEX)-loaded aminated mesoporous silica nanoparticles (MSNs-NH2) were prepared via electrophoretic deposition (EPD) and successfully incorporated within poly(l-lactic acid)/poly(ε-caprolactone) (PLLA/PCL) matrix to fabricate composite nanofibrous scaffolds for bone tissue engineering applications [259].
