*3.4. Growth Factors*

Growth factors are biomacromolecules responsible for inducing cellular growth, proliferation, and di fferentiation; they also play important roles in wound healing, bone formation, and vascularization. The most known growth factor is somatotropin, the human growth factor, which is widely employed to promote impaired growth in healthy individuals. The main drawback of this therapy is the need to accomplish a continuous—intramuscular or subcutaneous—dosage in order to achieve a sustained effect. Because of this, it is a treatment with very low adherence and, therefore, it needs improvement. Among the new strategies developed, the most promising are those that permit reaching long-lasting formulations with noninvasive administration routes [95,96]. With regard to the remaining growth factors, mostly cytokines and steroid hormones, it is typical to have compounds with very little aqueous solubility. As a result, they also require form delivery agents to perform their action properly. This need could be a niche for non-biogenic carriers, especially those of high loading capacity such as silica-based platforms.

Regarding the examples available in the literature, ten years ago, Zhang et al. already reported the potential of MSNs as carriers for growth factors [79]. In this contribution, a water-in-oil microemulsion strategy was employed to create ad hoc MSNs for the 18-kDa basic fibroblast growth factor (bFGF) protein. The resulting system was able to release the protein for over 20 days, and it could be satisfactorily taken up by HUVEC cells. Moreover, the cytotoxicity assay showed low toxicity even when administered at high concentrations (50 μg/mL). Despite this promising result, the remaining examples with therapeutic growth factors are limited to two contributions by Gan et al., who employed two complementary approaches for the delivery of the bone morphogenetic protein 2 (BMP-2). In their first contribution, they prepared chitosan-coated MSNs to deposit proteins onto the particles' surfaces [80], while, in their second work, SBA-15 microparticles with iron oxide nanocaps were employed to load the protein within the 6.2-nm mesopores [81]. In the first example, the authors included dexamethasone, a corticoid, into the mesopores to increment bone growth due to co-delivery of two osteogenic species. Unfortunately, although a significant osteogenesis was achieved, it was completely uncontrolled, and significant ectopic bone formation occurred. To prevent this, the authors changed the model to deliver only the growth factor. To do so, they employed large-pore silica microparticles to carry the BMP-2 and Fe3O4 nanocaps to prevent a premature release. The resulting pH-driven carrier was able to deliver the protein while exhibiting excellent biocompatibility, but only in vitro, where the huge size of the chosen silica particles did not a ffect the gues<sup>t</sup> survival.
