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器官3D打印,进了一步-突破打印细胞营养输送难题

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摘要 : 生命结构如此精巧,即使“打印”人造器官的梦想由来已久,却迟迟不能完全成真。浙大机械工程学院傅建中教授课题组日前开发出一种全新的器官打印工艺,在打印组织结构的同时打印出内部的营养输送通道,成功解决了3D打印细胞的营养维持问题。

器官3D打印,进了一步-突破打印细胞营养输送难题
在共聚焦显微镜及扫描电镜下的流道结构

器官3D打印,进了一步-突破打印细胞营养输送难题
打印出的含营养通道网络的二维及三维凝胶结构

生命结构如此精巧,即使“打印”人造器官的梦想由来已久,却迟迟不能完全成真。浙大机械工程学院傅建中教授课题组日前开发出一种全新的器官打印工艺,在打印组织结构的同时打印出内部的营养输送通道,成功解决了3D打印细胞的营养维持问题。有了营养,细胞就能“活”得更久,这使得大尺寸器官3D打印成为可能。

相关论文“Coaxial nozzle-assisted 3Dbioprinting with built-in microchannels for nutrients delivery”(营养通道同步制造的器官打印方法)5月19日在线发表在《Biomaterials》(《生物材料》)杂志上。论文第一作者为博士生高庆,通讯作者为课题组的贺永副教授。

器官打印,是用3D打印的办法,将含细胞的生物墨水进行一层层的精确可控沉积,从而构造出含细胞的三维结构,再加以后续培养,以获得想要的组织。3D打印人造器官的前景很美,如果彻底实现,那么当前器官移植的巨大缺口将得到缓解;科学家还可以直接拿人造器官来做前期的药物筛选实验。

而打印“活物”远比打印一般的三维模型困难许多。“营养输送是器官打印的三大关键难题之一。”贺永说,目前,摆在器官打印的面前的有“三座大山”:一是寻找合适的凝胶材料,把细胞包裹起来打印成型;二是组织打印“成型”后,如何对细胞输送营养,实现体外培养;三是培养过程中,如何调控培养环境使得独立的细胞个体融合成功能性组织。

“组织内遍布纤细的血管,它们是输送营养的流道。我们要在体外重构这‘血管’。”贺永介绍,这是3D打印的一个热点问题。由于凝胶材料非常软,现有思路多为先打印组织,再构造流道的“二次打印”法,效果不够理想。

贺永课题组的思路,是同时打印组织结构和营养输送流道——一次成型!在一次实验中,他们偶然发现使用同轴喷头挤中空凝胶丝时、挤出的两条凝胶丝可以融合在一起,并具有一定的强度。“由于凝胶纤维内部是中空的,那应该能利用其进行营养输送,”贺永说,受此启发,课题组用了一年的时间,尝试基于中空凝胶纤维进行器官打印。

一次成型的工艺是否可靠?贺永说,除了在工艺上方便快捷之外,一系列实验也证明了这一工艺的优越性:流道不但能稳定输送营养,能让大分子营养物质渗透到细胞中去,此外有或没有我们的流道,细胞的活性大相径庭。”

据介绍,目前的器官打印受限于营养输送问题,导致很多区域营养难以有效输送,导致后续的培养失败,因此器官尺寸无法扩大 。“我们的这一工艺将为接近真实尺寸的器官制造提供可能。”贺永说,这一方法还可以广泛应用于片上器官、凝胶基微流控芯片、细胞传感器芯片、药物筛选芯片等领域。

“当然我们只是初步解决了器官打印中的一个问题而已,实现器官制造的终极目标:器官打印还需要诸多学科的科学家持续不断的努力。”

原文链接:

Coaxial nozzle-assisted 3D bioprinting with built-in microchannels for nutrients delivery.

原文摘要:

This study offers a novel 3D bioprinting method based on hollow calcium alginate filaments by using a coaxial nozzle, in which high strength cell-laden hydrogel 3D structures with built-in microchannels can be fabricated by controlling the crosslinking time to realize fusion of adjacent hollow filaments. A 3D bioprinting system with a Z-shape platform was used to realize layer-by-layer fabrication of cell-laden hydrogel structures. Curving, straight, stretched or fractured filaments can be formed by changes to the filament extrusion speed or the platform movement speed. To print a 3D structure, we first adjusted the concentration and flow rate of the sodium alginate and calcium chloride solution in the crosslinking process to get partially crosslinked filaments. Next, a motorized XY stages with the coaxial nozzle attached was used to control adjacent hollow filament deposition in the precise location for fusion. Then the Z stage attached with a Z-shape platform moved down sequentially to print layers of structure. And the printing process always kept the top two layers fusing and the below layers solidifying. Finally, the Z stage moved down to keep the printed structure immersed in the CaCl2 solution for complete crosslinking. The mechanical properties of the resulting fused structures were investigated. High-strength structures can be formed using higher concentrations of sodium alginate solution with smaller distance between adjacent hollow filaments. In addition, cell viability of this method was investigated, and the findings show that the viability of L929 mouse fibroblasts in the hollow constructs was higher than that in alginate structures without built-in microchannels. Compared with other bioprinting methods, this study is an important technique to allow easy fabrication of lager-scale organs with built-in microchannels.

DOI:10.1016/j.biomaterials.2015.05.031

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