# A Molecular View on Biomaterials and Dental Stem Cells Interactions: Literature Review
## 4 Dental Stem Cells and Biomaterial Interactions
### Mechanotransduction Pathways in Dental Stem Cells  
As mentioned in the previous section, the attachment of cells to biomaterial substrates is essential to establishing communication between cells and the ECM microenvironment. In this way, the activated biochemical signals can modulate specific signaling pathways to regulate cell activity in processes, such as adhesion, proliferation, and differentiation. This section will address current studies on the signaling pathways involved in the differentiation process in biomaterials with DPSCs. Biomaterials act as adhesion substrates that send mechanical signals to cells, influencing the differentiation of DT-MSCs. Stem cell differentiation during biomaterial interactions involves many signaling pathways (Figure 3). For example, [PERSON] et al. (2015) [105] examined with DPSCs a scaffold of magnetite and polycarbonate nanoparticles and the signaling pathways involved in the mechanisms of adhesion, migration, and odontogenic differentiation. Their results demonstrated that integrin (subunits \(\alpha\)1, \(\alpha\)2, \(\beta\)1, and \(\beta\)3) signaling with activation of FAK/MAPK and NF-kB by the scaffold is involved in cellular events in DPSCs [105]. Another study by [PERSON] et al. (2014) [102] evaluated the osteoinductive effect of a bioadhesive on PDLSCs for use as a dental implant. They reported that the biomaterial stimulated osteogenic differentiation of PDLSCs through activation of \(\alpha\)5/\(\beta\)1 integrin-PI3K signaling [102]. Additionally, [PERSON] et al. (2012) [106] investigated whether MAPK signaling pathways are a mediator in odontogenic differentiation of DPSCs cultured on five different biomaterials. Their results showed enhanced odontogenic differentiation and dentin-like tissue formation in natural biomaterials derived from mineralized tissue (dentin matrix and bovine bone ceramic) through the phosphorylation of ERK1/2 and p38 [106]. Another study by [PERSON] et al. in 2018 [107] employed a pharmacological perturbation approach to identify which signaling pathways were involved in the differentiation and mineralization of DPSCs cultured on a fluorapatite-modified polycaprolactone nanofiber biomaterial. The authors reported that the Hedgehog, insulin, and Wnt signaling pathways are involved in biomaterial-induced DPSCs differentiation and can activate the osteogenesis process through autophagic modulation [107]. There are currently novel biomaterial designs in the literature that have been used to investigate the signaling pathways involved during DPSCs differentiation. The design of nanoarrays as therapeutic platforms has aroused particular interest because dental stem cells can recognize nanofibrous topology and respond to biochemical signals from their environment. In this context, [PERSON] et al. (2016) [108] designed in vitro nanofiberarrays containing bioactive glass nanoparticles that release dexamethasone, a signaling molecule of odontogenesis. The authors reported that the integrin pathway (\(\alpha\)2, \(\alpha\)5, \(\beta\)1), bone morphogenetic protein, and mTOR signaling pathways are possible mechanisms involved in the stimulation of odontogenesis. Other signaling pathways have also been reported in cell differentiation events in three-dimensional nanomaterials [108]. For example, [PERSON] et al. (2018) [109] designed a biomaterial containing a tetrahedral DNA nanostructure (TDN) self-assembled by four specific single-stranded DNAs (ssDNAs) by complementary base pairing. The authors reported that TDN stimulated the osteogenic differentiation of PDLSCs by activating the Wnt/\(\beta\)-catenin pathway, while in DPSCs, TDN increased the expression of HES1, HEY1, and NOTCH1, which are crucial factors of the Notch pathway [109]. These results indicate that although the cells have the same dental origin, their biochemical response can be different for the same biomaterial, which will be interesting to study in the future to develop methodologies for the regeneration of dental and nondental tissues.