Additive Manufacturing Strategies for Organ-on-a-Chip Applications

Abstract

Organ-on-a-chip (OOC) systems, which are cellularized microfluidic devices that emulate in vivo tissue- and organ-level physiology, hold significant potential for biomedical applications ranging from disease modeling to drug discovery. However, replicating the intricate three-dimensional architectures and microfluidic behavior of native tissues at relevant scales has posed substantial manufacturing challenges in biomedical device development. Recent advancements in microscale additive manufacturing—two-photon polymerization (2PP), specifically—offer a promising solution to these fabrication limitations. This dissertation presents a range of additive manufacturing strategies tailored for diverse organ-on-a-chip (OOC) applications. First, we explored in situ direct laser writing (isDLW) to enable the fabrication of microstructures directly within, and fluidically sealed to, microfluidic devices. Building upon this, we investigated a novel Polydimethylsiloxane (PDMS)-based photomaterial compatible with is DLW, facilitating the fabrication of PDMS-on-glass microfluidic systems—an important advancement given the widespread use of PDMS in biological research. To address the inherent limitations of is DLW, we then developed a hybrid ex situ direct laser writing (esDLW) technique, in which microstructures are fabricated directly atop and fluidically integrated with vat photopolymerization (VPP)-printed substrates. This hybrid approach overcame the height constraints of isDLW, enabling more sophisticated architectures and the ability to replicate complex biophysiological structures. Using this method, we fabricated microvessel platforms for OOC applications, specifically integrating two-photon DLW with liquid-crystal display (LCD) 3D printing to construct PDMS microvessels directly atop custom microfluidic chips. Finally, we advanced the esDLW strategy to enable precise and rapid 3D micropatterning of cells through vacuum-assisted loading, demonstrating its potential for high-resolution, biologically relevant applications. This work demonstrates a proof of concept for new classes of 3D microphysiological systems applying additive manufacturing techniques to address the limitations of conventional fabrication methods. By enabling precise architectural control and facilitating integration with established biological protocols, the study offers a promising pathway for next-generation OOC systems and other biomedical applications requiring physiologically relevant models.