Identification, characterization and engineering aspects for osteogenesis

Abstract

Calcium channels are present in osteoblasts involving in new bone formation and osteoclasts involving in bone degradation, and hence it occupies a prominent position in an extensive array of electrophysiological processes for osteogenesis. Their importance in cellular function arises from their abilities to sense membrane voltage and to conduct calcium ions (〖Ca〗^(2+)) across the cell membrane. Through this relationship, activation of calcium channels is tightly coupled to the gamut of cellular functions of osteoblast which are dependent on intracellular 〖Ca〗^(2+) for bone formation.

This research project explores what is unknown concerning the voltage-gated calcium (CaV) channels that have not yet been explored on an atomic level for osteoblasts. Structural and functional correlation of CaV channels are simulated by molecular dynamic and docking studies to understand tissue-specific function of this channel in osteoblasts that defines an exciting new target for the maintenance of 〖Ca〗^(2+)influx and cellular homeostasis in bone regeneration although this area is limited by the relative scarcity of knowledge available at present.

Because CaV channels are capable of responding to specific compound and likely to be coupled to distinct cellular 〖Ca〗^(2+) homeostasis, it is interesting to dissect the molecular nature of polyphenolic compounds (flavonoids) that may act as activator or blocker of the CaV channels in osteoblasts to further defining the relationship between CaV channels, compound signals and physiological responses in osteogenesis. As such, the molecular modelling technique of quantitative structure-activity relationship has been applied to define and develop statistical correlation between the biochemical features and the behavioral manifestations of structurally similar polyphenolic compounds in the CaV channels. The simulation results provide a reasonable basis for establishing predictive models via different types of molecular descriptors that play a significant role in identification as well as analysis of the biochemical responses of flavanoids involved in activating or inhibiting the CaV channels for osteogenic function.

On the other hand, this project aims to achieve osteogenesis using the tissue engineering strategies since the design of scaffolds are deemed to provide a decent cellular microenvironment for osteoblasts to grow in a fast pace. In particular, the physical scaffolds of synthetic polymer, that ensures theartificial construct to be mechanically stable, can act as three-dimensional extracelluar matrix to provide signals to manipulate osteoblasts’ growth. Thus, it is paramount to decorate the novel scaffolds for osteoblasts which respond to it biochemically and biophysically.

In this study, various polymer-metallic dioxides biocomposites are electrospun by using synthetic polymer (Poly-L-lactic acid) and metallic dioxides including zirconia (ZrO_2), titania (TiO_2), silica (SiO_2) and hafnia (HfO_2) to be novel hybrid scaffolds through electrospinning process. By computational methods, this study has succeeded in screening the chemical structures of polyphenolic compounds and interpreting its binding affinities in the CaV channels in order to afford the effective biomimesis of the osteoblasts in the scaffolds. Finally, the screened flavonoid has successfully been pioneered as growth factors to enhance the cell proliferation towards the surface of the hybrid scaffolds for osteogenesis.