Microphysiological Engineering of Self-Assembled and Perfusable Microvascular Beds for the Production of Vascularized Three-Dimensional Human Microtissues
Microphysiological Engineering of Self-Assembled and Perfusable Microvascular Beds for the Production of Vascularized Three-Dimensional Human Microtissues
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DOI：
10.1021/acsnano.9b00686
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发表时间：
2019-07-01
期刊：
影响因子：
17.1
通讯作者：
Huh, Dongeun
中科院分区：
文献类型：
--
作者：
Paek, Jungwook;Park, Sunghee E.;Huh, Dongeun
脉管系统是循环系统的重要组成部分，在人体各器官的发育、体内平衡和疾病中起着至关重要的作用。在其相关器官的综合背景下模拟血管的结构和运输功能的能力代表了研究广泛的生理过程的重要要求。然而，传统的体外血管模型在很大程度上无法提供这种能力。在这里，我们将微流体三维细胞培养与血管生成自组装原理结合起来，在体外设计可灌注的三维微血管床。我们的系统是在一个微图案水凝胶结构中创建的，该结构被安置在一个弹性微装置中，可以使原代人血管内皮细胞和成纤维细胞共同培养，以实现3D血管网络的新生形成、吻合和受控灌注。该混合平台采用的开顶腔室设计也使得将微工程3D血管系统与其他细胞类型整合在一起成为可能，以概括血管化人体组织的器官特异性细胞异质性和结构组织。利用这些能力，我们开发了干细胞衍生的血管化人类脂肪组织和血液视网膜屏障的微生理模型。我们的方法也被用来构建血管化人肺腺癌的三维器官型模型，作为一个高含量的药物筛选平台来模拟临床化疗药物的血管内递送、肿瘤杀伤效应和血管毒性。此外，我们通过创建血管炎症的微工程模型来评估基于活性靶向脂质体纳米载体的纳米工程药物输送系统，证明了我们的平台在纳米医学应用中的潜力。这些结果代表了我们在模拟天然人体组织复杂性方面的重大进步，并可能为开发用于生物制药应用的预测性临床前模型提供基础。
The vasculature is an essential component of the circulatory system that plays a vital role in the development, homeostasis, and disease of various organs in the human body. The ability to emulate the architecture and transport function of blood vessels in the integrated context of their associated organs represents an important requirement for studying a wide range of physiological processes. Traditional in vitro models of the vasculature, however, largely fail to offer such capabilities. Here we combine microfluidic three-dimensional (3D) cell culture with the principle of vasculogenic self-assembly to engineer perfusable 3D microvascular beds in vitro. Our system is created in a micropatterned hydrogel construct housed in an elastomeric microdevice that enables coculture of primary human vascular endothelial cells and fibroblasts to achieve de novo formation, anastomosis, and controlled perfusion of 3D vascular networks. An open-top chamber design adopted in this hybrid platform also makes it possible to integrate the microengineered 3D vasculature with other cell types to recapitulate organ-specific cellular heterogeneity and structural organization of vascularized human tissues. Using these capabilities, we developed stem cell-derived microphysiological models of vascularized human adipose tissue and the blood retinal barrier. Our approach was also leveraged to construct a 3D organotypic model of vascularized human lung adenocarcinoma as a high-content drug screening platform to simulate intravascular delivery, tumor-killing effects, and vascular toxicity of a clinical chemotherapeutic agent. Furthermore, we demonstrated the potential of our platform for applications in nanomedicine by creating microengineered models of vascular inflammation to evaluate a nanoengineered drug delivery system based on active targeting liposomal nanocarriers. These results represent a significant improvement in our ability to model the complexity of native human tissues and may provide a basis for developing predictive preclinical models for biopharmaceutical applications.