PDF(Pubmed)
Abstract：
Vascular cell overgrowth and lumen size reduction in pulmonary vein stenosis (PVS) can result in elevated PV pressure, pulmonary hypertension, cardiac failure, and death. Administration of chemotherapies such as rapamycin have shown promise by inhibiting the vascular cell proliferation; yet clinical success is limited due to complications such as restenosis and off-target effects. The lack of in vitro models to recapitulate the complex pathophysiology of PVS has hindered the identification of disease mechanisms and therapies. This study integrated 3D bioprinting, functional nanoparticles, and perfusion bioreactors to develop a novel in vitro model of PVS. Bioprinted bifurcated PV constructs are seeded with endothelial cells (ECs) and perfused, demonstrating the formation of a uniform and viable endothelium. Computational modeling identified the bifurcation point at high risk of EC overgrowth. Application of an external magnetic field enabled targeting of the rapamycin-loaded superparamagnetic iron oxide nanoparticles at the bifurcation site, leading to a significant reduction in EC proliferation with no adverse side effects. These results establish a 3D bioprinted in vitro model to study PV homeostasis and diseases, offering the potential for increased throughput, tunability, and patient specificity, to test new or more effective therapies for PVS and other vascular diseases.
摘要：
肺静脉狭窄（PVS）的血管细胞过度生长和管腔大小减小可导致肺静脉压升高，肺动脉高压,心力衰竭,和死亡。化疗如雷帕霉素的给药已显示出通过抑制血管细胞增殖的前景;然而,由于并发症如再狭窄和脱靶效应,临床成功受到限制。缺乏体外模型来概括PVS的复杂病理生理学阻碍了疾病机制和疗法的鉴定。这项研究整合了3D生物打印，功能性纳米粒子，和灌注生物反应器来开发一种新型的PVS体外模型。生物打印的分叉PV构建体接种内皮细胞（EC）并灌注，证明了均匀和有活力的内皮的形成。计算模型确定了EC过度生长高风险的分叉点。外部磁场的应用使得能够在分叉位点靶向装载雷帕霉素的超顺磁性氧化铁纳米颗粒。导致EC增殖显著减少，没有不良副作用。这些结果建立了3D生物打印的体外模型来研究PV稳态和疾病，提供增加吞吐量的潜力，可调谐性，和患者特异性，测试新的或更有效的治疗PVS和其他血管疾病。
