Cholecalciferol as Bioactive Plasticizer of High Molecular Weight Poly(D,L-Lactic Acid) Scaffolds for Bone Regeneration

Synthetic thermoplastic polymers are a widespread choice as material candidates for scaffolds for tissue engineering (TE), thanks to their ease of processing and tunable properties with respect to biological polymers. These features made them largely employed in melt-extrusion-based additive manufacturing, with particular application in hard-TE. In this field, high molecular weight (M_w) polymers ensuring entanglement network strength are often favorable candidates as scaffold materials because of their enhanced mechanical properties compared with lower M_w grades. However, this is accompanied by high viscosities once processed in molten conditions, which requires driving forces not always accessible technically or compatible with often chemically nonstabilized biomedical grades. When possible, this is circumvented by increasing the operating temperature, which often results in polymer chain scission and consequent degradation of properties. In addition, synthetic polymers are mostly considered bioinert compared with biological materials, and additional processing steps are often required to make them favorable for tissue regeneration. In this study, we report the plasticization of a common thermoplastic polymer with cholecalciferol, the metabolically inactive form of vitamin D3 (VD3). Plasticization of the polymer allowed us to reduce its melt viscosity, and therefore the energy requirements (mechanical [torque] and heat [temperature]) for extrusion, limiting ultimately polymer degradation. In addition, we evaluated the effect of cholecalciferol, which is more easily available than its active counterpart, on the osteogenic differentiation of human mesenchymal stromal cells (hMSCs). Results indicated that cholecalciferol supported osteogenic differentiation more than the osteogenic culture medium, suggesting that hMSCs possess the enzymatic toolbox for VD3 metabolism. Impact statement Limitations in mechanical and biological performances of scaffolds manufactured through melt deposition may result from material thermal degradation during processing and inherent bioinertness of synthetic polymers. Current approaches involve the incorporation of chemical additives to reduce the extent of thermal degradation, which are often nonbiocompatible or may lead to uncontrolled modifications to the polymer structure. Lack of polymer bioactivity is tackled by postfunctionalization methods that often involve extra processes extending scaffold production time. Therefore, new methods to improve scaffolds performances should consider preserving the integrity of the molecular structure and improving biological responsiveness of the material while keeping the process as straightforward as possible.