3D Printed Human Small Intestine Models for Drug Delivery Testing and Disease Modelling

There is a strongly increasing interest in biomimetic in vitro tissue models and organs-on-a-chip systems to recapitulate key functionalities of specific organs. Along this path in vitro models of the small intestine have attracted a lot of attention among the scientists in the field of oral drug delivery to examine the toxicity and efficacy of new drugs or model various diseases.

Intestine models offer a cheaper and more ethical alternative for the conventional animal studies. A number of sophisticated 3D models and gut-on-a-chip systems have been recently developed—thanks to the advanced microfabrication techniques—which provide more accurate information than conventional static two-dimensional cell cultures.

However, most of the 3D scaffolds are fabricated through laborious multi-step processes, and state-of-the-art gut-on-a-chip systems fail to mimic the native tissue’s complex crypt-villus surface topology, which maximizes the surface area for selective absorption of compounds such as orally administrated drugs into the bloodstream.

In the present doctoral thesis, biomimetic human intestine models were fabricated using fully-automated high-resolution multi-material stereolithographic 3D printing. Three different in vitro models were designed and fabricated with various complexity and biological relevance. These platforms are mainly made of polyethylene glycol diacrylate (PEGDA), which depending on molecular weight, exhibits extensively different physiochemical properties.

The hydrogel compartment, made of the medium molecular weight PEGDA monomers, serves as a diffusion-open and mechanically stable cell culture support. The compartment surface encompasses an array of micropillar structures to mimic the intestinal surface topology, and the structured surface is lined by human intestinal epithelial cells.

In the microfluidic platforms capillary channels are incorporated to supply oxygen and nutrients for the intestinal cells by perfusion of culture medium. The solid diffusion-close compartments, on the other hand, limit the diffusion toward the hydrogel part and therefore, enable acquisition of quantitative data describing the model barrier properties.

Finally, the models are coupled with the advanced microscopes to visualize and characterize the established intestinal barrier. These platforms provide powerful alternative in vitro models to advance our understanding of intestinal physiology and its role in drug uptake and personalized medicine.