Castaño Irene Mencía, Raftery Rosanne M, Chen Gang, Cavanagh Brenton, Quinn Brian, Duffy Garry P, Curtin Caroline M, O'Brien Fergal J
Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, Dublin 2, Ireland.
Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, Dublin 2, Ireland; School of Pharmacy, RCSI, Dublin, Ireland.
Acta Biomater. 2023 Dec;172:480-493. doi: 10.1016/j.actbio.2023.09.049. Epub 2023 Oct 4.
Angiogenesis is critical for successful bone repair, and interestingly, miR-210 and miR-16 possess counter-active targets involved in both angiogenesis and osteogenesis: miR-210 acts as an activator by silencing EFNA3 & AcvR1b, while miR-16 inhibits both pathways by silencing VEGF & Smad5. It was thus hypothesized that dual delivery of both a miR-210 mimic and a miR-16 inhibitor from a collagen-nanohydroxyapatite scaffold system may hold significant potential for bone repair. Therefore, this systems potential to rapidly accelerate bone repair by directing enhanced angiogenic-osteogenic coupling in host cells in a rat calvarial defect model at a very early 4 week timepoint was assessed. In vitro, the treatment significantly enhanced angiogenic-osteogenic coupling of human mesenchymal stem cells, with enhanced calcium deposition after just 10 days in 2D and 14 days on scaffolds. In vivo, these dual-miRNA loaded scaffolds showed more than double bone volume and vessel recruitment increased 2.3 fold over the miRNA-free scaffolds. Overall, this study demonstrates the successful development of a dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair for the first time, and the possibility of extending this 'off-the-shelf' platform system to applications beyond bone offers immense potential to impact a myriad of other tissue engineering areas. STATEMENT OF SIGNIFICANCE: miRNAs have potential as a new class of bone healing therapeutics as they can enhance the regenerative capacity of bone-forming cells. However, angiogenic-osteogenic coupling is critical for successful bone repair. Therefore, this study harnesses the delivery of miR-210, known to be an activator of both angiogenesis and osteogenesis, and miR-16 inhibitor, as miR-16 is known to inhibit both pathways, from a collagen-nanohydroxyapatite scaffold system to rapidly enhance osteogenesis in vitro and bone repair in vivo in a rat calvarial defect model. Overall, it describes the successful development of the first dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair. This 'off-the-shelf' platform system offers immense potential to extend beyond bone applications and impact a myriad of other tissue engineering areas.
血管生成对于成功的骨修复至关重要，有趣的是，miR - 210和miR - 16具有参与血管生成和成骨过程的拮抗靶点：miR - 210通过沉默EFNA3和AcvR1b发挥激活作用，而miR - 16通过沉默VEGF和Smad5抑制这两条通路。因此，有人推测从胶原 - 纳米羟基磷灰石支架系统中双重递送miR - 210模拟物和miR - 16抑制剂可能在骨修复方面具有巨大潜力。因此，在大鼠颅骨缺损模型中，在非常早期的4周时间点，评估了该系统通过引导宿主细胞中增强的血管生成 - 成骨偶联来快速加速骨修复的潜力。在体外，该处理显著增强了人间充质干细胞的血管生成 - 成骨偶联，在二维培养中仅10天后以及在支架上培养14天后钙沉积增加。在体内，这些负载双miRNA的支架显示骨体积增加了一倍多，血管募集比无miRNA的支架增加了2.3倍。总体而言，本研究首次证明了用于增强体内骨修复的双miRNA模拟物/抑制剂支架系统的成功开发，并且将这个“现成的”平台系统扩展到骨以外的应用领域的可能性为影响众多其他组织工程领域提供了巨大潜力。重要性声明：miRNA作为一类新型的骨愈合治疗药物具有潜力，因为它们可以增强骨形成细胞的再生能力。然而，血管生成 - 成骨偶联对于成功的骨修复至关重要。因此，本研究利用从胶原 - 纳米羟基磷灰石支架系统中递送已知为血管生成和成骨激活剂的miR - 210以及已知抑制这两条通路的miR - 16抑制剂，来快速增强体外成骨和大鼠颅骨缺损模型中的体内骨修复。总体而言，它描述了首个用于增强体内骨修复的双miRNA模拟物/抑制剂支架的成功开发。这个“现成的”平台系统具有扩展到骨以外应用领域并影响众多其他组织工程领域的巨大潜力。
