Synthesizing Living Tissues with Microfluidics.

In native tissues, various cell types organize and spatiotemporally function and communicate with neighboring or remote cells in a highly regulated way. How can we replicate these amazing functional structures in vitro? From the view of a chemist, the heterogeneous cells and extracellular matrix (ECM) could be regarded as various chemical substrate materials for "synthetic" reactions during tissue engineering. But how can we accelerate these reactions? Microfluidics provides ideal solutions. Microfluidics could be metaphorically regarded as a miniature "biofactory", whereas the on-chip critical chemical cues such as biomolecule gradients and physical cues such as geometrical confinement, topological guidance, and mechanical stimulations, along with the external stimulations such as light, electricity, acoustics, and magnetics, could be regarded as "catalytic cues" which can accelerate the "synthetic reactions" by precisely and effectively manipulating a series of cell behaviors including cell adhesion, migration, growth, proliferation, differentiation, cell-cell interaction, and cell-matrix interaction to reduce activation energy of the "synthetic reactions". Thus, on the microfluidics platform, the "biofactory", various "synthetic" reactions take place to change the substrate materials (cells and ECM) into products (tissues) in a nonlinear way, which is a typical feature of a biological process. By precisely organizing the substrate materials and spatiotemporally controlling the activity of the products, as a "biofactory", the microfluidics system can not only "synthesize" living tissues but also recreate physiological or pathophysiological processes such as immune responses, angiogenesis, wound healing, and tumor metastasis in vitro to bring insights into the mechanisms underlying these processes taking place in vivo. In this Account, we borrow the concept of chemical "synthesis" to describe how to "synthesize" artificial tissues using microfluidics from a chemist's view. Accelerated by the built-in physiochemical cues on microfluidics and external stimulations, various tissues could be "synthesized" on a microfluidics platform. We summarize that there are "step-by-step synthesis" and "one-step synthesis" on microfluidics for creating desired tissues with unprecedented precision, accuracy, and speed. In recent years, researchers developed various microfluidic techniques including creating adhesive domains for mediating reverse and precise adhesion, chemical gradients for directing cell growth, geometrical confinements and topological cues for manipulating cell migration, and mechanics for stimulating cell differentiation. By employing and orchestrating these on-chip tissue "synthetic" conditions, "step-by-step synthesis" could be realized on chips to develop multilayered tissues such as blood vessels. "One-step synthesis" on chips could develop functional three-dimensional tissue structures such as neural networks or nephron-like structures. Based on these on-chip studies, many critical physiological and pathophysiological processes such as wound healing, tumor metastasis, and atherosclerosis could be deeply investigated, and the drugs or therapeutic approaches could also be evaluated or screened conveniently. The "synthetic tissues on microfluidics" system would pave an avenue for precise creation of artificial tissues for not only fundamental research but also biomedical applications such as tissue engineering.