Abstract
In the drug therapy of tumor, efficient and stable drug screening platforms are required since the drug efficacy varies individually. Here, inspired by the microstructures of hepatic lobules, in which hepatocytes obtain nutrients from both capillary vessel and the central vein, we present a novel hierarchical hydrogel system with ordered micro-nano structure for liver cancer-on-a-chip construction and drug screening. The hierarchical hydrogel system was fabricated by using pregel to fill and replicate self-assembled colloidal crystal arrays and microcolumn array template. Due to the synergistic effect of its interconnected micro-nano structures, the resultant system could not only precisely control the size of cell spheroids but also realize adequate nutrient supply of cell spheroids. We have demonstrated that by integrating the hierarchical hydrogel system into a multichannel concentration gradients microfluidic chip, a functional liver cancer-on-a-chip could be constructed for high-throughput drug screening with good repeatability and high accuracy. These results indicated that the hierarchical hydrogel system and its derived liver cancer-on-a-chip are ideal platforms for drug screening and have great application potential in the field of personalized medicine.
Highlights
Liver cancer has been one of the most common and refractory diseases over the world due to its poor prognosis and high mortality
Since the hydrogel system precisely mimics the natural extracellular matrix (ECM) environment, cells embedded in the hydrogel will produce endogenous ECM proteins and continue to aggregate to form cell spheroids [13,14,15]
A pregel containing polyethylene glycol diacrylate (PEGDA) and methacrylate gelatin (GelMA) hydrogels was completely filled into the gaps between nanoparticles and microarray
Summary
Liver cancer has been one of the most common and refractory diseases over the world due to its poor prognosis and high mortality. The efficacy of these drugs varies individually in the patients with advanced stage of liver cancer because of the tumor heterogeneity [7,8,9]. Three-dimensional (3D) cell culture based on hydrogel system has gained great interest as a promising platform for anticancer drug screening [10,11,12]. The cell spheroids obtained by simple embedding method are usually with uneven size and poor monodispersity, which might affect the repeatability and accuracy of subsequent drug screening. Due to the simple structure of these hydrogels, the cells in the core of some big spheroids are lacking of nutrition and prone to necrosis during the culture process, which would make the screening results unreliable. The development of drug screening platform with more sophisticated structures and functions is still requisite
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