Preparation of Micro/Nano-Structure Copper-Substituted Hydroxyapatite Scaffolds with Improved Angiogenesis Capacity for Bone Regeneration

Abstract

The surface microstructures of calcium phosphate ceramics play an essential role in determining bone regeneration. However, it is difficult to produce micro/nano-structures on the surface of the porous hydroxyapatite (HA) scaffolds. In this study, we successfully developed and fabricated various micro/nano-structured surfaces on the HA scaffolds in copper ion (Cu2+)-containing solutions under hydrothermal conditions. The micro/nano-structures on the surface of the HA scaffolds were controlled by modulating the Cu2+ concentrations during the hydrothermal process. With an increase in the Cu2+ concentration, the surface morphology of the HA scaffolds changed significantly from sphere-like to flower-like, before becoming nano-structures. These findings indicated that the Cu2+ concentration affects the morphologies of calcium phosphate coatings that grow on the HA scaffolds. In vitro endothelial cell (EC) cultures showed that the cell proliferation was significantly enhanced when cultured on the flower-like morphology compared with other morphologies. Furthermore, an in vivo test in New Zealand rabbits demonstrated that the HA scaffold with the flower-like surface resulted in more angiogenesis compared with the control scaffold. This copper-assisted hydrothermal deposition process provides a simple and controllable route for engineering a micro/nano-structured surface on the HA scaffolds, which has benefits in terms of angiogenesis and bone regeneration.

Comprehensive In Vitro Testing of Calcium Phosphate-Based Bioceramics with Orthopedic and Dentistry Applications

“…Osteoregeneration and biomechanical properties are improved by tailoring of pore sizes [220] or even adjusting the shape and distribution of HA crystals [221]. Furthermore, Cu-doping was shown to be a modifier of the micro/nano-structured surface on the HA scaffolds, with a positive impact on angiogenesis [222].…”

Optical coherence tomography angiography for noninvasive evaluation of angiogenesis in a limb ischemia mouse model

“…However, a direct role of copper in facilitating angiogenesis was shown two decades ago 24 . CuSO 4 has been demonstrated to promote angiogenesis in vivo 25,26 . A study conducted by Chandan K showed the first evidence that cooper-inducible VEGF expression is sensitive to copper and that the angiogenic potential of copper can be used to accelerate ischemia improvements 27 .…”

Insights into the angiogenic effects of nanomaterials: mechanisms involved and potential applications

“…It can upregulate the expression of VEGF and promote the proliferation of endothelial cells. The flower-like micro-/ nanostructured hydroxyapatite scaffolds were fabricated in solutions containing copper ions under hydrothermal conditions, which are beneficial to the proliferation of endothelial cells in vitro and for stimulating angiogenesis in vivo [34]. However, research on this aspect is limited;…”

“…Bone engineering Nano-HA (1) In vitro study (2) In vivo glucocorticoid-induced bone defect model [28] In vitro study [29,33,154,155] In vivo ectopic osteogenesis study [18] In vivo calvarial defect model [20,99] Micro/Nano-structured surfaces of Cu x -HA (1) In vitro study (2) In vivo subcutaneously implant study [34] TCP nanolayers In vitro study [21] Nanofibrin In vitro study [24] GO In vivo calvarial defect study [22,26] In vivo ectopic osteogenesis study [27] PCL nanofibrous biomembranes In vivo maxillary bone lesion model [16] Mesoporous bioactive glass nanoparticles (1) In vitro study (2) In vivo ectopic osteogenesis study [30] Copper doped in electrospun bioactive glass nanofibers…”