Monolithic integration of silicon and polymer microstructures for Organ-on-Chip applications

Drug development is a complex, time-consuming (10 - 15 years) and expensive process. For a new medicine to reach the market, the net expenses covered by the pharmaceutical industry have been estimated to be around $2.6 billion. Nevertheless, the risk of finding adverse effects or toxicity cases once the drug is already on the market is still high. Thus, pharmaceutical companies have been keenly looking forward to means to eliminate this at an early stage of the development process. Recently, Organs-on-Chips (OOCs) emerged as a potential alternative to traditional drug screening. These devices, promise, in the middle-term, to enhance the in vitro screening and, in the long term, to reduce and eventually eliminate animal models in safety and efficacy essays. Nevertheless, the fabrication methods for most of these devices are hardly adaptable to scalable fabrication processes for in vitro screening application, as they rely strongly on manual techniques. This thesis demonstrates the successful development of diverse microstructures for Organ-on-Chip applications by using scalable IC and MEMS-based fabrication techniques. Chapter 3 demonstrates the development of microfabricated porous PDMS membranes for barrier modelling. A simple and reproducible method to fabricate and transfer porous PDMS membranes with a high control on pore size, porosity, thickness, is shown. Very thin (thickness <10 ¹m) porous membranes with small features sizes down to 2 ¹mand porosity up to 65% can thus be fabricated and successfully transferred with high reproducibility. The presented results on cell transmigration, topology and barrier formation demonstrated the biocompatibility of the porous PDMS membranes. Chapter 4 shows further efforts towards the realization of manufacturable OOCs. A monolithically microfabricated OOC device, an alternative to the available devices capable to address many more applications, was demonstrated. Preliminary biological experiments indicate its biocompatibility as cells (HUVEC, Cardyomyocites) are successfully cultured and maintained viable in the microchannels and the silicon cavity. Finally, Chapter 5 demonstrates other possibilities allowed by the use of IC and MEMS techniques. The integration of microstructures that enable transduction mechanisms to monitor the cell microenvironment, is shown. Specifically, strain gauges for stress sensing as an alternative to monitor in situ strain in microfabricated OOCs, are presented. Relative resistance changes of approximately 0.008% and 1.2% for titanium and polymeric strain gauges have been observed, respectively. The technological advances shown in this thesis form a significant contribution towards manufacturable fabrication of Organs-on-Chips and the standardization of OOCs as routinely used tools for drug development.