Nature-inspired microfluidics network for organ-on-a-chip application

Abstract

The miniaturized fluid distribution network to transport nutrients and metabolic byproducts plays a significant role in the development of engineered tissues and organ­on-a-chip systems for tissue regeneration, drug screening and other clinical applications. However, most of the existing microfluidic networks are designed with relatively simple architectural organizations or uniform vascular pathways, which fail to provide physiologically relevant levels of mechanical cues. Thus, considerable attention has been directed towards engineering microfluidic system inspired by the natural complex vascular networks, through which animals and plants efficiently distribute and collect fluids and cells. As a nature-optimized microfluidic system, leaf venation networks have been proven to obey Murray's law, the physiological law describing the hierarchical structures of blood vessels in human cardiovascular system. Thus, this thesis aims to propose fabrication strategies to develop a leaf-venation-inspired (LVI) microfluidic network for engineering perfusable tissue constructs and organ-on-a-chip systems. In the first study, three different approaches were developed to fabricate the LVI microfluidics system with multiscale channels ranging from 1 mm to 30 µm. While two of these approaches directly utilized the skeleton of leaf venation as the replicating mold or photomask for microfabrication, the third one involved acquiring photos of leaf venation to fabricate computer aided design (CAD) for microfabrication. This extra process enabled free editing of the biomimetic channels, which offered many opportunities to create unique niches such as chambers and specialized channels for tissue engineering applications. In the second study, the fluid dynamics of LVI microfluidics network were studied to investigate the architecture-induced merits of leaf venation network. It was demonstrated that the fluid was transported in half-and-half mode symmetrically along the main vein in PDMS leaf chips and addition of chambers into the vascular network had no significant effect on flow velocity distribution within the system. Also, the fluids were able to transport throughout the whole LVI chips of hydrogel matrices without external pump-driven force, resulting in the design of a pump-free platform for tissue culture. In the third study, the architecture-induced merits of leaf venation network were utilized in three biological applications. Firstly, it was found that the LVI channels could function as convection pathways to perfuse culture medium for the long-term culture and endothelialization of the populated tissues in a pump-free bioreactor setup. Secondly, the dimension of microwells was optimized based on the statistics of veins and areoles to engineer microwell-integrated LVI microfluidic chips for culturing high-throughput cell samples. Thirdly, a biomimetic vascular system integrated with chamber-specific vascularized organs was developed, which allows for conducting comparative and metastasis studies in a single chip. Thus, our work demonstrates the potential to engineer a biomimetic microfluidic network inspired by leaf venation into various biomaterials. The architectures-induced merits were illustrated and utilized for engineering perfusable tissue constructs and organ-on-a-chip system for high-throughput cell culture and integrated multiorgan culture.