Liver–Skin Microphysiological System for Evaluating Topical Drug Delivery-Induced Liver Injury

Drug-induced liver injury is the main cause of acute liver failure and has become a major health problem. Nowadays, topical and transdermal drug delivery has appeared as a popular approach to deliver drugs, and its risk of inducing hepatotoxicity requires careful evaluation before approval for application to humans. To date, hepatotoxicity resulting from topical administration has rarely been studied due to the lack of effective research models. Here, a highly biomimetic liver-skin microphysiological system (LS-MPS) was developed, providing a dynamic and physiologically similar microenvironment to mimic in vivo liver, skin, and cyclic flow between them. The three-dimensional (3D) liver microtissue and 3D skin microtissue were successfully established on the LS-MPS. The skin microtissue showed high cell viability and physiologically similar dermal and epidermal layers. More importantly, the barrier and permeability functions of skin were maintained for long-term culture. The 3D liver microtissue showed high cell viability, biomimetic cell arrangement, and active metabolic function. In addition, the LS-MPS was applied to evaluate the topical delivery of drug-induced liver injury, demonstrating its potential in drug safety testing. Thus, this study provides a promising platform to assess complex drug toxicity, which contributes to the development of new drugs.