Hybrid biofabricated blood vessel for medical devices testing

Current <i>in vitro</i> and <i>in vivo</i> tests applied to assess the safety of medical devices retain several limitations, such as an incomplete ability to faithfully recapitulate human features, and to predict the response of human tissues together with non-trivial ethical aspects. We here challenged a new hybrid biofabrication technique that combines bioprinting and Fast Diffusion-induced Gelation strategy to generate a vessel-like structure with the attempt to spatially organize fibroblasts, smooth-muscle cells, and endothelial cells. The introduction of Fast Diffusion-induced Gelation minimizes the endothelial cell mortality during biofabrication and produce a thin endothelial layer with tunable thickness. Cell viability, Von Willebrand factor, and CD31 expression were evaluated on biofabricated tissues, showing how bioprinting and Fast Diffusion-induced Gelation can replicate human vessels architecture and complexity. We then applied biofabricated tissue to study the cytotoxicity of a carbothane catheter under static condition, and to better recapitulate the effect of blood flow, a novel bioreactor named CuBiBox (Customized Biological Box) was developed and introduced in a dynamic modality. Collectively, we propose a novel bioprinted platform for human <i>in vitro</i> biocompatibility testing, predicting the impact of medical devices and their materials on vascular systems, reducing animal experimentation and, ultimately, accelerating time to market. Our study provides an innovative convergence of 3D biofabrication technologies to realize multi-cellularized vessel-like models, as a new tool for <i>in vitro</i> biocompatibility testing of medical devices, minimizing animal experimentation.

当前用于评估医疗器械安全性的体外（in vitro）与体内（in vivo）检测方法仍存在诸多局限：其一，无法完整且精准地重现人体生理特征，难以准确预测人体组织的应答反应；其二，伴随不容忽视的伦理问题。本研究针对一种全新的混合生物制造技术开展验证，该技术将生物打印（bioprinting）与快速扩散诱导凝胶化（Fast Diffusion-induced Gelation）策略相结合，旨在实现成纤维细胞、平滑肌细胞与内皮细胞的空间排布，构建类血管结构。引入快速扩散诱导凝胶化策略后，可显著降低生物制造过程中的内皮细胞死亡率，并制备出厚度可调控的薄层内皮结构。研究人员对生物制造得到的组织进行了细胞活力、血管假性血友病因子（Von Willebrand factor）及CD31表达水平检测，结果证实生物打印联合快速扩散诱导凝胶化技术可精准复刻人体血管的结构形态与复杂性。随后，研究人员利用生物制造得到的组织在静态条件下评估了碳氨酯导管的细胞毒性；为更真实地模拟血流影响，本研究开发了一款名为CuBiBox（Customized Biological Box，定制化生物反应盒）的新型生物反应器，并以动态模式开展实验。综上，本研究提出了一种全新的生物打印体外生物相容性检测平台，可用于预测医疗器械及其材料对血管系统的影响，减少动物实验，并最终缩短产品上市周期。本研究实现了3D生物制造技术的创新性融合，构建了多细胞类血管模型，可作为医疗器械体外生物相容性检测的新型工具，进一步降低动物实验的使用需求。