A review of organ-on-chip fabrication methods: From early developments to overcoming inert barriers

Organ-on-chip (OOC) systems represent a significant advance in the effort to replicate human physiology in vitro, providing versatile models that extend beyond the limitations of static culture and animal experimentation. The fabrication methods and materials underlying these platforms play a decisive role in determining their structural accuracy, biological relevance, and potential for large-scale adoption. This review surveys the historical progression of OOC manufacturing, beginning with established microfabrication techniques such as photolithography, soft lithography, hot embossing, microinjection molding, and xurography and extending to recent innovations in additive manufacturing. Particular attention is given to emerging barrier-free strategies, including laminar flow patterning, hydrogel photopatterning, phaseguide design, and surface treatment patterning that permit direct tissue-tissue communication. These methods aim to enhance biomimicry by reducing artificial interfaces, thereby improving the simulation of intercellular gradients, multicellular crosstalk, and pathophysiological dynamics. Alongside their benefits, the review discusses the practical challenges these approaches introduce in terms of reproducibility, throughput, and scalability. By integrating advances in materials science, fabrication techniques, and microphysiological design, this review highlights the potential of next-generation OOC devices to provide predictive, translationally relevant platforms that narrow the divide between preclinical experimentation and clinical application.