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Skin in vitro models offer much promise for research, testing drugs, cosmetics, and medical devices, reducing animal testing and extensive clinical trials. There are several in vitro approaches to mimicking human skin behavior, ranging from simple cell monolayer to complex organotypic and bioengineered 3-dimensional models. Some have been approved for preclinical studies in cosmetics, pharmaceuticals, and chemicals. However, development of physiologically reliable in vitro human skin models remains in its infancy. This review reports on advances in in vitro complex skin models to study skin homeostasis, aging, and skin disease.

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Tissue barrier permeability plays a crucial role in determining the selective transport of substances across epithelial tissues, including drugs, cosmetic substances, and chemicals. The ability of these substances to cross through tissue barriers affects their absorption into the bloodstream and ultimately their effectiveness. Therefore, the determination of their permeability on these type of tissue barriers represents a useful tool for pharmaceutical and cosmetic industries as well as for toxicological studies.In this regard, microfluidic devices and organ-on-chip technologies are becoming more important to generate reliable data. We have designed and performed an alternative new stratified epithelia-on-chip model that allows to correlate the Stokes radius and the diffusion of molecules and/or nanoformulations through the in vitro generated barrier and establish a system suitable for the analysis of diffusion through stratified epithelium. Thus, extrapolating from experimental data we can predict the Stokes radius for unknown fluorescent labelled particles within a molecular size range, such as gold nanoparticles.

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The skin is the body's largest organ, continuously exposed to and affected by natural and anthropogenic nanomaterials (materials with external and internal dimensions in the nanoscale range). This broad spectrum of insults gives rise to irreversible health effects (from skin corrosion to cancer). Organ-on-chip systems can recapitulate skin physiology with high fidelity and potentially revolutionize the safety assessment of nanomaterials. Here, we review current advances in skin-on-chip models and their potential to elucidate biological mechanisms. Further, strategies are discussed to recapitulate skin physiology on-chip, improving control over nanomaterials exposure and transport across cells. Finally, we highlight future opportunities and challenges from design and fabrication to acceptance by regulatory bodies and industry.

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The high variability in subcutaneous bioavailability of protein therapeutics is poorly understood, contributing to critical delays in patient access to new therapies. Preclinical animal and in vitro models fail to provide a physiologically relevant testbed to parse potential contributors to human bioavailability, therefore new strategies are necessary. Here, we present a microphysiological model of the human hypodermal vasculature at the injection site to study the interactions of administered protein therapeutics within the microenvironment that influence subcutaneous bioavailability. Our model combines human dermal endothelial cells, fibroblasts, and adipocytes, self-assembled into three-dimensional, perfusable microvessels that express relevant extracellular matrix. We demonstrate the utility of the model for measurement of biophysical parameters within the hypodermal microenvironment that putatively impact protein kinetics and distribution at the injection site. We propose that microphysiological models of the subcutaneous space have applications in preclinical development of protein therapeutics intended for subcutaneous administration with optimal bioavailability.

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Bacterial skin infections cause a variety of common skin diseases that require drugs that are safer than antibiotics and have fewer side effects. However, for evaluating skin disease drugs, human skin tissue in vitro constructed traditionally on Transwell has inefficient screening ability because of its fragile barrier function. With mechanical forces and dynamic flow, the organ-on-a-chip system became an innovative, automatic, and modular way to construct pathological models and analyze effective pharmaceutical ingredients in vitro. In this research, we integrated skin extracellular matrix and skin cells into a microfluidic chip to construct a biomimetic "interface-controlled-skin-on-chip" system (IC-SoC), which constructed a stable air-liquid interface (ALI) and necessary mechanical signals for the development of human skin equivalents. The results demonstrated that in the microfluidic system with a flowing microenvironment and ALI, the skin tissue formed in vitro could differentiate into more mature tissue morphological structures and improve barrier function. Then, following exposing the skin surface on the IC-SoC to the stimulation of Propionibacterium acnes (P.acnes) and SLS (sodium lauryl sulfate), the barrier function decreased, as well as inflammatory factors such as IL-1α, IL-8, and PEG2 increased in the medium channel of the IC-SoC. After this pathological skin model was treated with dexamethasone and polyphyllin H, the results showed that polyphyllin H had a significant repair effect on the skin barrier and a significant inhibition effect on the release of inflammation-related cytokines, and the effects were more prominent than dexamethasone. This automated microfluidic system delivers an efficient tissue model for toxicological applications and drug evaluation for bacterial-infected damaged skin instead of animals.

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Preclinical research remains hampered by an inadequate representation of human tissue environments which results in inaccurate predictions of a drug candidate's effects and target's suitability. While human 2D and 3D cell cultures and organoids have been extensively improved to mimic the precise structure and function of human tissues, major challenges persist since only few of these models adequately represent the complexity of human tissues. The development of skin-on-chip technology has allowed the transition from static 3D cultures to dynamic 3D cultures resembling human physiology. The integration of vasculature, immune system, or the resident microbiome in the next generation of SoC, with continuous detection of changes in metabolism, would potentially overcome the current limitations, providing reliable and robust results and mimicking the complex human skin. This review aims to provide an overview of the biological skin constituents and mechanical requirements that should be incorporated in a human skin-on-chip, permitting pharmacological, toxicological, and cosmetic tests closer to reality.

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The healing of deep skin wounds is a complex phenomenon evolving according with a fine spatiotemporal regulation of different biological events (hemostasis, inflammation, proliferation, remodeling). Due to the spontaneous evolution of damaged human dermis toward a fibrotic scar, the treatment of deep wounds still represents a clinical concern. Bioengineered full-thickness skin models may play a crucial role in this direction by providing a deep understanding of the process that leads to the formation of fibrotic scars. This will allow (i) to identify new drugs and targets/biomarkers, (ii) to test new therapeutic approaches, and (iii) to develop more accurate in silico models, with the final aim to guide the closure process toward a scar-free closure and, in a more general sense, (iv) to understand the mechanisms involved in the intrinsic and extrinsic aging of the skin. In this work, the complex dynamic of events underlaying the closure of deep skin wound is presented and the engineered models that aim at replicating such complex phenomenon are reviewed. Despite the complexity of the cellular and extracellular events occurring during the skin wound healing the gold standard assay used to replicate such a process is still represented by planar in vitro models that have been largely used to identify the key factors regulating the involved cellular processes. However, the lack of the main constituents of the extracellular matrix (ECM) makes these over-simplistic 2D models unable to predict the complexity of the closure process. Three-dimensional bioengineered models, which aim at recreating the closure dynamics of the human dermis by using exogenous biomaterials, have been developed to fill such a gap. Although interesting mechanistic effects have been figured out, the effect of the inflammatory response on the ECM remodelling is not replicated yet. We discuss how more faithful wound healing models can be obtained by creating immunocompetent 3D dermis models featuring an endogenous ECM.

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Organ-on-chip (OoC) technology is full of engineering and biological challenges, but it has the potential to revolutionize the Next-Generation Risk Assessment of novel ingredients for consumer products and chemicals. A successful incorporation of OoC technology into the Next-Generation Risk Assessment toolbox depends on the robustness of the microfluidic devices and the organ tissue models used. Recent advances in standardized device manufacturing, organ tissue cultivation and growth protocols offer the ability to bridge the gaps towards the implementation of organ-on-chip technology. Next-Generation Risk Assessment is an exposure-led and hypothesis-driven tiered approach to risk assessment using detailed human exposure information and the application of appropriate new (non-animal) toxicological testing approaches. Organ-on-chip presents a promising in vitro approach by combining human cell culturing with dynamic microfluidics to improve physiological emulation. Here, we critically review commercial organ-on-chip devices, as well as recent tissue culture model studies of the skin, intestinal barrier and liver as the main metabolic organ to be used on-chip for Next-Generation Risk Assessment. Finally, microfluidically linked tissue combinations such as skin-liver and intestine-liver in organ-on-chip devices are reviewed as they form a relevant aspect for advancing toxicokinetic and toxicodynamic studies. We point to recent achievements and challenges to overcome, to advance non-animal, human-relevant safety studies.

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Malignant melanoma still remains a cancer with very poor survival rates, although it is at the forefront of personalized medicine. Most patients show partial responses and disease progressed due to adaptative resistance mechanisms, preventing long-lasting clinical benefits to the current treatments. The response to therapies can be shaped by not only taking into account cancer cell heterogeneity and plasticity, but also by its structural context as well as the cellular component of the tumor microenvironment (TME). Here, we review the recent development in the field of immunotherapy and target-based therapy and how, in the era of tumor micro-tissue engineering, ex-vivo assays could help to enhance our melanoma biology knowledge in its complexity, translating it in the development of successful therapeutic strategies, as well as in the prediction of therapeutic benefits.

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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.

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The skin is the largest and most exposed organ in the human body. Not only it is involved in numerous biological processes essential for life but also it represents a significant endpoint for the application of pharmaceuticals. The area of in vitro skin tissue engineering has been progressing extensively in recent years. Advanced in vitro human skin models strongly impact the discovery of new drugs thanks to the enhanced screening efficiency and reliability. Nowadays, animal models are largely employed at the preclinical stage of new pharmaceutical compounds development for both risk assessment evaluation and pharmacokinetic studies. On the other hand, animal models often insufficiently foresee the human reaction due to the variations in skin immunity and physiology. Skin-on-chips devices offer innovative and state-of-the-art platforms essential to overcome these limitations. In the present review, we focus on the contribution of skin-on-chip platforms in fundamental research and applied medical research. In addition, we also highlighted the technical and practical difficulties that must be overcome to enhance skin-on-chip platforms, e.g. embedding electrical measurements, for improved modeling of human diseases as well as of new drug discovery and development.

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The importance of skin to survival, and the devastating physical and psychological consequences of scarring following reparative healing of extensive or difficult to heal human wounds, cannot be disputed. We discuss the significant challenges faced by patients and healthcare providers alike in treating these wounds. New state of the art technologies have provided remarkable insights into the role of skin stem and progenitor cells and their niches in maintaining skin homeostasis and in reparative wound healing. Based on this knowledge, we examine different approaches to repair extensive burn injury and chronic wounds, including full and split thickness skin grafts, temporising matrices and scaffolds, and composite cultured skin products. Notable developments include next generation skin substitutes to replace split thickness skin autografts and next generation gene editing coupled with cell therapies to treat genodermatoses. Further refinements are predicted with the advent of bioprinting technologies, and newly defined biomaterials and autologous cell sources that can be engineered to more accurately replicate human skin architecture, function and cosmesis. These advances will undoubtedly improve quality of life for patients with extensive burns and difficult to heal wounds.

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