Skin-on-a-Chip Technology: Microengineering Physiologically Relevant In Vitro Skin Models

Abstract

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.

Advancements in microfluidics for skin cosmetic screening

“…98 The ideal future skin-on-a-chip platform should integrate physical sensors for monitoring relevant cell culture parameters ( e.g. pH, temperature), electrochemical sensors for measuring soluble protein biomarkers, and trans-epithelial resistance (TEER) sensors 99 for measuring the skin barrier function to help monitor in real time the processes occurring during skin equivalence formation or drug administration.…”

Organ‐on‐a‐chip technologies for biomedical research and drug development: A focus on the vasculature

“…The main OOC models for specific organs in this system aim to replicate the skin 104,105 ; while mammary glands, for example, are often only studied in the context of branching morphogenesis 106 or breast cancer 107 . Replicating skin is of high relevance for skin‐targeted delivery systems (topical, dermal, and transdermal approaches) 108 . Hence, most skin models focus on the efficient study of skin–drug interactions and toxicology, where the transport properties and the intrinsic heterogeneity of the skin are key for the validation of drugs and cosmetic compounds 109–111 …”

“…107 Replicating skin is of high relevance for skin-targeted delivery systems (topical, dermal, and transdermal approaches). 108 Hence, most skin models focus on the efficient study of skin-drug interactions and toxicology, where the transport properties and the intrinsic heterogeneity of the skin are key for the validation of drugs and cosmetic compounds. [109][110][111] 2.9 | Circulatory system…”

Advances in 3D skin bioprinting for wound healing and disease modeling

“…In addition to the strategies reviewed above, other emerging technologies, for instance, four-dimensional (4D) bioprinting [ 126–128 ], bioprinted skin-on-a-chip [ 129–131 ], and microfluidics-assisted extrusion bioprinting [ 9 , 132–134 ], are being or to be applied for skin tissue engineering and wound healing researches as well. Derived from 3D bioprinting, 4D bioprinting may have the potential to recreate the spatiotemporal changes in tissue geometry and transformations in the spatial distribution of cells and ECM [ 128 ].…”

“…Various engineered skin models have been developed to meet the urgent need [ 132 , 163 ]. Some skin-on-a-chip models combine the basic components with perfusion pumps or even with other organ-on-a-chip models or organoids to examine multi-cell and multi-organ interactions especially in more complicated cases [ 129 , 134 ]. Although most of them remain to be further validated in terms of both the fabrication process and the efficacy in toxicity and allergenicity testing, they offer the possibility of measuring the impact of subjects on skin main compartments with high throughput and efficiency.…”