The increased demand for physiologically relevant in vitro human skin models for testing pharmaceutical drugs has led to significant advancements in skin engineering. One of the most promising approaches is the use of in vitro microfluidic systems to generate advanced skin models, commonly known as skin-on-a-chip (SoC) devices. These devices allow the simulation of key mechanical, functional and structural features of the human skin, better mimicking the native microenvironment. Importantly, contrary to conventional cell culture techniques, SoC devices can perfuse the skin tissue, either by the inclusion of perfusable lumens or by the use of microfluidic channels acting as engineered vasculature. Moreover, integrating sensors on the SoC device allows real-time, non-destructive monitoring of skin function and the effect of topically and systemically applied drugs. In this Review, the major challenges and key prerequisites for the creation of physiologically relevant SoC devices for drug testing are considered. Technical (e.g., SoC fabrication and sensor integration) and biological (e.g., cell sourcing and scaffold materials) aspects are discussed. Recent advancements in SoC devices are here presented, and their main achievements and drawbacks are compared and discussed. Finally, this review highlights the current challenges that need to be overcome for the clinical translation of SoC devices.

Biological barriers are essential for the maintenance of organ homeostasis and their dysfunction is responsible for many prevalent diseases. Advanced in vitro models of biological barriers have been developed through the combination of 3D cell culture techniques and organ-on-chip (OoC) technology. However, real-time monitoring of tissue function inside the OoC devices has been challenging, with most approaches relying on off-chip analysis and imaging techniques. In this study, we designed and fabricated a low-cost barrier-on-chip (BoC) device with integrated electrodes for the development and real-time monitoring of biological barriers. The integrated electrodes were used to measure transepithelial electrical resistance (TEER) during tissue culture, thereby quantitatively evaluating tissue barrier function. A finite element analysis was performed to study the sensitivity of the integrated electrodes and to compare them with conventional systems. As proof-of-concept, a full-thickness human skin model (FTSm) was grown on the developed BoC, and TEER was measured on-chip during the culture. After 14 days of culture, the barrier tissue was challenged with a benchmark irritant and its impact was evaluated on-chip through TEER measurements. The developed BoC with an integrated sensing capability represents a promising tool for real-time assessment of barrier function in the context of drug testing and disease modelling.

Poly(hydroxyalkanoates) (PHAs) with differing material properties, namely, the homopolymer poly(3-hydroxybutyrate), P(3HB), the copolymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate), P(3HB-co-3HV), with a 3HV content of 25 wt.% and a medium chain length PHA, and mcl-PHA, mainly composed of 3-hydroxydecanoate, were studied as scaffolding material for cell culture. P(3HB) and P(3HB-co-3HV) were individually spun into fibers, as well as blends of the mcl-PHA with each of the scl-PHAs. An overall biopolymer concentration of 4 wt.% was used to prepare the electrospinning solutions, using chloroform as the solvent. A stable electrospinning process and good quality fibers were obtained for a solution flow rate of 0.5 mL h⁻¹, a needle tip collector distance of 20 cm and a voltage of 12 kV for P(3HB) and P(3HB-co-3HV) solutions, while for the mcl-PHA the distance was increased to 25 cm and the voltage to 15 kV. The scaffolds’ hydrophilicity was significantly increased under exposure to oxygen plasma as a surface treatment. Complete wetting was obtained for the oxygen plasma treated scaffolds and the water uptake degree increased in all treated scaffolds. The biopolymers crystallinity was not affected by the electrospinning process, while their treatment with oxygen plasma decreased their crystalline fraction. Human dermal fibroblasts were able to adhere and proliferate within the electrospun PHA-based scaffolds. The P(3HB-co-3HV): mcl-PHA oxygen plasma treated scaffold highlighted the most promising results with a cell adhesion rate of 40 ± 8%, compared to 14 ± 4% for the commercial oxygen plasma treated polystyrene scaffold Alvetex^TM. Scaffolds based on P(3HB-co-3HV): mcl-PHA blends produced by electrospinning and submitted to oxygen plasma exposure are therefore promising biomaterials for the development of scaffolds for tissue engineering.

Current commercially available in vitro skin models do not fully reproduce the structure and function of the native human skin, mainly due to their use of animal-derived collagen and their lack of a dynamic flow system. In this study, a full-thickness skin-on-a-chip (SoC) system that reproduces key aspects of the in vivo cellular microenvironment is presented. This approach combines the production of a fibroblast-derived matrix (FDM) with the use of an inert porous scaffold for the long-term, stable cultivation of a human skin model. The culture of a dermal compartment under fluid flow results in the increased synthesis and deposition of major FDM proteins, collagen I, and fibronectin, compared to tissues cultured under static conditions. The developed SoC includes a fully differentiated epidermal compartment with increased thickness and barrier function compared to the controls. Contrary to other SoC platforms that include a collagen-based matrix, the described model presents superior stability and physiological relevance. Finally, the skin barrier function was quantitatively evaluated via in situ transepithelial electrical resistance (TEER) measurements and in situ permeation tests. The SoC model presents a significantly higher TEER and lower permeability to FITC-dextran. In the future, this innovative low-cost platform could provide a new in vitro tissue system compatible with long-term studies to study skin diseases and evaluate the safety and efficacy of novel drugs and technologies.