Angiogenesis is of great importance to bone regeneration, but it remains a significant challenge to induce sufficient angiogenesis and osteogenesis within bone grafts for large bone defect healing. The aim of this study is to investigate the effects of hydroxyapatite (HA) scaffold via a novel graded pore distribution approach on vascularization and osteoinduction. Two types of graded porous scaffolds were fabricated by sugar templates-leaching techniques: (1) one with large pores of 1100–1250 μm in the center and small pores of 500–650 μm at the periphery (HALS); (2) the other with small pores of 500–650 μm in the center and large pores of 1100–1250 μm at the periphery (HASL). In vivo data showed different pore size distribution had a remarkable impact on blood vessel formation during bone formation, which led to distinct localization of new bone within the defects. After one month of implantation, the diameters of the blood vessels infiltrated on the periphery of HASL were substantially larger than those in the center though the host blood vessels were successful in infiltrating throughout the whole scaffold. In contrast, vascularization within HALS appeared to be poor with very few blood vessels formed in the center, indicating heterogeneous vascularization in the scaffolds. After 3 months of implantation, we found that HASL induced more homogeneous bone formation in the whole bone graft but new bone was only found at the periphery of HALS. This study suggests that the pores size distribution in graded scaffolds cannot only affected early stage vascularization, but also influence late stage bone formation and remodeling. The architecture of larger pores at the periphery of graded scaffold may be capable of enhancing angiogenesis and osteogenesis during large size bone defect healing.

血管生成对骨再生非常重要，但是在骨移植物中诱导足够的血管生成和成骨作用以进行大的骨缺损愈合，仍然是一项重大挑战。这项研究的目的是通过新颖的分级孔分布方法研究羟基磷灰石（HA）支架对血管形成和骨诱导的影响。通过糖模板浸出技术制造了两种类型的梯度多孔支架：（1）一种在中心具有1100–1250μm的大孔，而在外围（HALS）具有500-650μm的小孔；（2）另一个在中心有500–650μm的小孔，而在外围有1100–1250μm的大孔（HASL）。体内数据显示，不同的孔径分布对骨骼形成过程中的血管形成有显着影响，这导致了新骨在缺损内的独特定位。植入一个月后，尽管宿主血管成功渗入整个支架，但在HASL周围浸润的血管直径明显大于在中心的直径。相反，HALS内的血管化似乎很差，中心很少形成血管，表明支架中的异质血管化。植入3个月后，我们发现HASL在整个植骨中诱导了更均匀的骨形成，但新骨仅在HALS的周围发现。这项研究表明，分级支架中的孔尺寸分布不仅会影响早期血管生成，而且还会影响晚期骨骼形成和重塑。