The Co‐Incorporation of Zn/Cu or Zn/Co Ions Improves the Bone Regeneration Potential of PEOT/PBT–βTCP Composite 3D‐Printed Scaffolds

Treatment of critical‐sized bone defects remains challenging despite bone's regenerative capacity. Herein, a combination of a biodegradable polymer possessing bone‐bonding properties with bioactive β‐tricalcium phosphate (βTCP) particles coated with osteogenic (Zinc) and angiogenic (copper or cobalt) ions has been proposed. βTCP was coated with zinc and copper (Zn/Cu) or zinc and cobalt (Zn/Co) using 15 mM (low) or 45 mM (high) metallic ion solutions. Composites were obtained by a combination of the βTCP with poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer in a 50:50 ratio. Composites were additively manufactured into 3D porous scaffolds and their osteogenic and angiogenic properties evaluated using a direct culture with human mesenchymal stromal cells (hMSCs) as well as an indirect coculture with human umbilical vein endothelial cells (HUVECs). We hypothesized that the combination of Zn/Cu or Zn/Co in the form of a coating of the βTCP particles would stimulate both osteogenic and angiogenic properties of PEOT/PBT‐βTCP scaffolds. In addition, we investigated whether the resulting biomaterials influenced the paracrine function of hMSCs. Zn/Cu or Zn/Co were successfully co‐incorporated into the ceramic without changing its chemistry. Scaffolds containing low concentrations of Zn/Co increased the expression of RUNX2, OCN, and OPN, while scaffolds with low concentrations of Zn/Cu enhanced the expression of ALPL. On the protein level, high Zn/Co concentrations elevated ALP and collagen production. Angiogenic properties improved with increased VEGFA expression by hMSCs and branching of tubules formed by HUVECs, particularly with low concentrations of Zn/Co. Scaffolds with high ion concentrations also increased cytokine and chemokine secretion, suggesting enhanced paracrine effects.