Design of Cytostretch Skin A human cell based stretchable, flexible and mass-producible skin tissue model for drug development

Abstract

In the near future, human cell based Organ-on-Chip models are likely to replace animal experimentation during the development of new drugs. Not only is animal testing associated with ethical issues, but human cell based models can also give a more accurate representation of the human physiology, resulting in more reliable results of drug screening experiments. Furthermore, high-throughput drug screening is made possible by real-time readout of cell activity, using electrodes or other forms of cellular readout. Additionally, the high costs of drug development will be reduced, especially if the new devices will be suitable for mass production. To be able to accurately model the human physiology, the device must be fabricated using biocompatible materials, often polymers with special requirements like flexibility and stretchability. These materials are in general not standardized in microfabrication cleanroom environments, limiting the current designs suitability for mass production. In this thesis an Organ-on-Chip device was designed, fabricated and validated for use in advanced skin tissue modeling. Without compromising for the requirements imposed by the physiology of skin tissue, the device is designed to be suitable for mass production. A prior model for cardiotoxicity screening, Cytostretch was used as a starting point for the skin model device. The new features added to the design were fabricated by adding certain steps to the manufacturing process, compatible with the current process flow. This modular approach makes the Cytostretch technology flexible and suitable to rapidly adapt the device design for modeling different tissues in the future. In this research, methods were explored for (i) the fabrication of large membranes, (ii) the fabrication of holes with a diameter of 5 to 8 micrometer, and (iii) the deposition of layers on polydimethylsiloxane (PDMS). As a result, large perforated membranes of PDMS were fabricated and a new etching technique for PDMS was developed in order to create the small feature size of maximally 8 micrometer in the membrane. Also, a novel method to prevent thermally induced stress in layers deposited on PDMS is presented. After fabrication of the device, it has been validated to be suitable for skin tissue engineering by culturing human dermal tissue on the device.