Multiscale Porous Carbonate Apatite Honeycomb Granules Derived from a Metastable Calcium Carbonate Precursor for Enhanced Bone Formation

Abstract

Global population aging has increased the clinical demand for maintaining and restoring skeletal function. The bone regenerative capacity of synthetic bone substitutes is strongly influenced by pore architecture. Although well-controlled large-pore structures have been widely reported, the precise regulation of pore structures at the submicron and nanoscale remains challenging. In this study, we developed a strategy to control the multiscale pore characteristics of a material by exploiting the differences in the properties of vaterite and calcite, which are metastable and stable calcium carbonate precursors, respectively. To isolate the effect of submicron and nanoporous structures, carbonate apatite (CA) honeycomb (HC) granules with identical chemical compositions and channel architectures but different submicron and nanoporous structures were fabricated. HC green bodies composed of vaterite or calcite powders were produced by extrusion molding, followed by debinding and phosphate treatment to convert them into CA through a dissolution–precipitation reaction. Both the vaterite-derived (V-CA-HC) and calcite-derived (C-CA-HC) HC granules consisted of AB-type CA containing approximately 9% carbonate and exhibited the same HC channel size (110 μm) and wall thickness (120 μm). However, the submicron and nanoporous structures of the two types of HC granules differed significantly. The V-CA-HC granules exhibited bimodal pore structures with modal diameters of 14 and 336 nm, whereas the C CA HC granules exhibited a unimodal distribution centered at 41 nm. In a rabbit femoral condyle critical-size defect model, V-CA-HC granules induced significantly greater new bone formation than C-CA-HC granules at both 4 and 12 weeks post-implantation. These results demonstrate that submicron and nanoporous structures independently regulate bone formation when the macroporous structure is kept constant, and that submicron and nanoporous structures provide a versatile strategy for designing multiscale porous bone substitutes.