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.

In the pursuit of achieving a more realistic in vitro simulation of human biological tissues, microfluidics has emerged as a promising technology. Organ-on-a-chip (OoC) devices, a product of this technology, contain miniature tissues within microfluidic chips, aiming to closely mimic the in vivo environment. However, a notable drawback is the presence of inert material between compartments, hindering complete contact between biological tissues. Current membranes, often made of PDMS or plastic materials, prevent full interaction between cell types and nutrients. Furthermore, their non-physiological mechanical properties and composition may induce unexpected cell responses. Therefore, it is essential to minimize the contact area between cells and the inert materials while simultaneously maximizing the direct contact between cells and matrices in different compartments. The main objective of this work is to minimize inert materials within the microfluidic chip while preserving proper cellular distribution. Two microfluidic devices were designed, each with a specific focus on maximizing direct cell–matrix or cell–cell interactions. The first chip, designed to increase direct cell–cell interactions, incorporates a nylon mesh with regular pores of 150 microns. The second chip minimizes interference from inert materials, thereby aiming to increase direct cell–matrix contact. It features an inert membrane with optimized macropores of 1 mm of diameter for collagen hydrogel deposition. Biological validation of both devices has been conducted through the implementation of cell migration and cell-to-cell interaction assays, as well as the development of epithelia, from isolated cells or spheroids. This endeavor contributes to the advancement of microfluidic technology, aimed at enhancing the precision and biological relevance of in vitro simulations in pursuit of more biomimetic models.