Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea.
Biomater Sci. 2019 Nov 19;7(12):5221-5231. doi: 10.1039/c9bm01103j.
Promoting angiogenesis is a key strategy for stimulating the repair of damaged tissues, including bone. Among other proangiogenic factors, ions have recently been considered a potent element that can be incorporated into biomaterials and then released at therapeutic doses. Silicate-based biomaterials have been reported to induce neovascularization through vascular endothelial growth factor signaling pathway, potentiating acceleration of bone regeneration. Here, we designed a silicate-shelled hydrogel fiber scaffold with a hard/soft layered structure to investigate the possibility of silicate coating on biopolymer for enhancing biological properties. An alginate hydrogel was injected to form a fiber scaffold with shape-tunability that was then coated with a thin silicate layer with various sol-gel compositions. The silicate/alginate scaffold could release calcium and silicate ions, and in particular, silicate ion release was highly sustainable for over one week at therapeutically relevant levels. The ionic release was highly effective in stimulating the mRNA expression of angiogenic markers (VEGF, KDR, eNOS, bFGF, and HIF1-α) in endothelial cells (HUVECs). Moreover, the in vitro tubular networking of cells was significantly enhanced (1.5 times). In vivo implantation in subcutaneous tissue revealed more pronounced blood vessel formation around the silicate-shelled scaffolds than around silicate-free scaffolds. The presence of a silicate shell was also shown to accelerate acellular mineral (hydroxyapatite) formation. The cellular osteogenesis potential of the silicate/alginate scaffold was further proven by the enhanced expression of osteogenic genes (Col1a1, ALP and OCN). When implanted in a rat calvarium defect, the silicate-shelled scaffold demonstrated significantly improved bone formation (2-3 times higher in bone volume and density) with a concurrent sign of proangiogenesis. This work highlights that the surface-layering of silicate composition is an effective approach for improving the bone regeneration capacity of polymeric hydrogel scaffolds by stimulating ion-induced angiogenesis and providing bone bioactivity to the surface.
促进血管生成是刺激受损组织（包括骨骼）修复的关键策略。在其他促血管生成因子中，离子最近被认为是一种有效的元素，可以被整合到生物材料中，并以治疗剂量释放。硅酸盐基生物材料已被报道通过血管内皮生长因子信号通路诱导新生血管形成，从而加速骨再生。在这里，我们设计了一种具有硬/软分层结构的硅酸盐壳层水凝胶纤维支架，以研究在生物聚合物上进行硅酸盐涂层以增强生物性能的可能性。将海藻酸钠水凝胶注入以形成具有形状可调性的纤维支架，然后用各种溶胶-凝胶组成的薄硅酸盐层进行涂层。硅酸盐/海藻酸钠支架可以释放钙和硅酸盐离子，特别是硅酸盐离子释放可持续一周以上，达到治疗相关水平。离子释放非常有效地刺激内皮细胞（HUVEC）中血管生成标志物（VEGF、KDR、eNOS、bFGF 和 HIF1-α）的 mRNA 表达。此外，细胞的管状网络明显增强（1.5 倍）。在皮下组织中的体内植入表明，硅酸盐壳层支架周围的血管形成比无硅酸盐支架周围更为明显。硅酸盐壳的存在也被证明可以加速无细胞矿物质（羟基磷灰石）的形成。硅酸盐/海藻酸钠支架的细胞成骨潜力进一步通过增强成骨基因（Col1a1、ALP 和 OCN）的表达得到证明。当植入大鼠颅骨缺损时，硅酸盐壳层支架表现出明显改善的骨形成（骨体积和密度增加 2-3 倍），同时伴有促血管生成的迹象。这项工作强调了通过刺激离子诱导的血管生成和为表面提供骨生物活性，对聚合物水凝胶支架的硅酸盐组成进行表面层积是提高其骨再生能力的有效方法。
