Macro- and micro-structural features direct bone regeneration in patterned biphasic calcium phosphate scaffolds

The increasing demand for bone repair solutions for the treatment of large and load-bearing bone defects calls for the development of efficacious bone scaffolds. The design of such scaffolds involves a range of length scales from the centimeter down to the micron-scale. Biphasic calcium phosphate (BCP) scaffolds with both macropores and micropores (MP) show enhanced bone healing compared to those with macropores and no micropores (NMP), but the role of micropores is unclear. In this work, we assess the influence of scaffold macro- (> 300 μm) and microporosity (< 50 μm) on bone regeneration in BCP scaffolds implanted in pig mandibles. We evaluate capillarity induced by micropores as a mechanism that affects bone growth in vivo. We also assess the influence on bone volume, bone distribution and trabecular thickness of scaffold macro- and microporosity, as well as the ability of scaffold structure to direct bone growth in scaffolds combining domains with different architectures at the millimeter scale. Our results show that microporosity enhances bone regeneration through microporeinduced capillarity by improving the homogeneity of bone distribution in BCP scaffolds, suggesting that the explicit design and use of capillarity in bone scaffolds may lead to more effective treatments of large and complex bone defects. We also show that microporosity enhances bone volume fraction and bone distribution, regardless of macropore size. Microporosity increases trabecular thickness throughout the scaffold, while macropore size affects it only at the scaffold periphery. Finally, our results suggest that combining different architectures into one scaffold at the millimeter scale conserves the properties of each domain. Hence, bone growth and morphology can be tailored by controlling scaffold architecture from the millimeter down to the micron level. This holds promise for the customization of scaffold designs for more effective treatment of large and load-bearing bone defects.