Building a microphysiological skin model from induced pluripotent stem cells

Abstract

The discovery of induced pluripotent stem cells (iPSCs) in 2006 was a major breakthrough for regenerative medicine. The establishment of patient-specific iPSCs has created the opportunity to model diseases in culture systems, with the potential to rapidly advance the drug discovery field. Current methods of drug discovery are inefficient, with a high proportion of drug candidates failing during clinical trials due to low efficacy and/or high toxicity. Many drugs fail toxicity testing during clinical trials, since the cells on which they have been tested do not adequately model three-dimensional tissues or their interaction with other organs in the body. There is a need to develop microphysiological systems that reliably represent both an intact tissue and also the interaction of a particular tissue with other systems throughout the body. As the port of entry for many drugs is via topical delivery, the skin is the first line of exposure, and also one of the first organs to demonstrate a reaction after systemic drug delivery. In this review, we discuss our strategy to develop a microphysiological system using iPSCs that recapitulates human skin for analyzing the interactions of drugs with the skin.

Figure 1

Schematic diagram of generating induced pluripotent stem cells to create three-dimensional skin equivalents for drug testing. Human somatic cells such as skin fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs), from which various cell types (including fibroblasts and keratinocytes) can be differentiated. Subsequently, the iPSC-derived cells can be combined with collagen to reconstitute three-dimensional (3D) skin constructs for drug testing.

Figure 2

Schematic diagram of microfluidic channels fabricated with sacrificial alginate. A sacrificial alginate construct will be fabricated using a polydimethylsiloxane mold and embedded in a collagen gel. Subsequent removal of alginate will leave behind a void that can serve as channels.

Figure 3

Schematic diagram of a multiorgan system. Different organs can be integrated as indicated. In this system, only a single pump will be needed to recirculate a common medium through different organs. Eight organs are shown in this system, but the configuration can be modified to accommodate different number of human organs.