High-precision fabrication enables on-chip modeling with organ-level structural and mechanical complexity
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Organ-on-chip models are a rapidly evolving and promising tool for studying human physiology and disease and developing therapeutics. However, due to the lack of fabrication processes of pertinent precision to deliver well-defined architectural and mechanical elements, organ-on-chip models have been limited in recapitulating structural and biomechanical features of many tissues, which has impeded the modeling power and clinical relevance of these tools. The elusive in vitro replication of the pumping function and mechanical loading of the human heart, an outstanding instance of a structurally and mechanically complex physiological system, exemplifies the need for stronger fabrication processes. In this work, we investigated the potential of two-photon direct laser writing (TPDLW), an emerging high-precision fabrication technique, in enabling the generation of structurally and biomechanically complex organ-on-chip models. We first identify the functional principles, advantages and limitations of TPDLW, and review existing applications of TPDLW for in vitro studies. Inspired by the fabrication versatility of TPDLW, we then engineer a microfluidic cardiac pump powered by human stem-cell-derived cardiomyocytes (hiPSC-CM), aiming to replicate the ventricular pumping function on a chip by constructing miniaturized analogues of the functional elements of the human heart. We specifically fabricate a microscale metamaterial scaffold with fine-tuned mechanical properties to support the formation and cyclic contraction of an unprecedentedly miniaturized induced pluripotent stem cell derived ventricular chamber. Furthermore, we fabricate microfluidic valves with extreme sensitivity to rectify the flow generated by the ventricular chamber. The integrated microfluidic system recapitulates ventricular fluidic function and exhibits for the first time in vitro all phases of the ventricular hemodynamic loading pattern. Finally, we demonstrate a technique of increasing the fabrication output of TPDLW that could enable its broader adoption. Together, our results highlight the potential of high-precision fabrication in expanding the accessible spectrum of organ-on-a-chip models towards structurally and biomechanically sophisticated tissue architectures. This dissertation is accompanied by a set of supplementary videos depicting the results of our experimental efforts. Movie 1 shows a cardiac tissue beating on an inverted hexagon scaffold. Movie 2 shows a compressive test on helical scaffold that is later embedded in a cardiac tissue. Movie 3 show a beating cardiac chamber on helical scaffold that can generate measurable flow. Movie 4 shows a functional suspension valve that is later embedded in the device with the cardiac chamber. Movie 5 shows the function of a suspension valve that rectifies oscillating flow. Movie 6 shows that the same suspension valve can rectify flow of increasing frequency. Movie 7 shows that the combined chamber and valves exhibit directional flow. Finally, movie 8 shows that the addition of afterload in the combined system leads to the emergence of isovolumetric phases.