The favorable microstructure and bioactivity of tissue-engineered
bone scaffolds are closely associated with the regenerative efficacy
of bone defects. For the treatment of large bone defects, however,
most of them fail to meet requirements such as adequate mechanical
strength, highly porous structure, and excellent angiogenic and osteogenic
activities. Herein, inspired by the characteristics of a “flowerbed”,
we construct a short nanofiber aggregates-enriched dual-factor delivery
scaffold via 3D printing and electrospinning techniques
for guiding vascularized bone regeneration. By the assembly of short
nanofibers containing dimethyloxalylglycine (DMOG)-loaded mesoporous
silica nanoparticles with a 3D printed strontium-contained hydroxyapatite/polycaprolactone
(SrHA@PCL) scaffold, an adjustable porous structure can be easily
realized by changing the density of nanofibers, while strong compressive
strength will be acquired due to the framework role of SrHA@PCL. Owing
to the different degradation performance between electrospun nanofibers
and 3D printed microfilaments, a sequential release behavior of DMOG
and Sr ions is achieved. Both in vivo and in vitro results demonstrate that the dual-factor delivery
scaffold has excellent biocompatibility, significantly promotes angiogenesis
and osteogenesis by stimulating endothelial cells and osteoblasts,
and effectively accelerates tissue ingrowth and vascularized bone
regeneration through activating the hypoxia inducible factor-1α
pathway and immunoregulatory effect. Overall, this study has provided
a promising strategy for constructing a bone microenvironment-matched
biomimetic scaffold for bone regeneration.