Diversity of human skin three-dimensional organotypic cultures

Abstract

Recently, significant strides have been made in the development of high-fidelity skin organoids, encompassing techniques such as 3D bioprinting, skin-on-a-chip systems, and models derived from pluripotent stem cells (PSCs), replicating appendage structures and diverse skin cell types. Despite the emergence of these state-of-the-art skin engineering models, human organotypic cultures (OTCs), initially proposed in the 1970s, continue to reign as the predominant in vitro cultured three-dimensional skin model in the field of tissue engineering. This enduring prevalence is owed to their cost-effectiveness, straight forward setup, time efficiency, and faithful representation of native human skin. In this review, we systematically delineate recent advances in skin OTC models, aiming to inform future efforts to enhance in vitro skin model fidelity and reproducibility.

Figure 1

Different 3D in vitro skin models and their popularity in research. (a) An overview of different 3D in vitro skin models. Graphics generated, in part, using Biorender. (b) The 10-year trend (2013–2023) of research interest in 3D in vitro skin models. Various models were investigated within the PubMed database through independent search queries: “(skin) AND ((equivalent) OR (organotypic) OR (organotypic equivalent))”, ”(skin-on-chip) OR (skin-on-a-chip) OR ((skin) AND (microfluidic devices))”, “(skin organoid) AND ((PSC) OR (pluripotent stem cells) OR (iPSC) OR (induced pluripotent stem cells) OR (embryonic stem cells))”, “(skin) AND ((bioprinting) OR (3D printing))”, and “(skin) AND (spheroid)”. OTCs, organotypic cultures; PSC, pluripotent stem cells; iPSC, induced pluripotent stem cells.

Figure 2

An overview of in vitro skin OTC models. The upper part illustrates the relationship between human skin and in vitro OTC model. The biophysiological structure of native human skin comprises three distinct layers: epidermis, dermis, and hypodermis, as depicted by a human skin biopsy. Different layers of the skin correspond to various types of OTC models. The HEE model exists in two formats: epidermis-only and pseudo-full-thickness, which includes an acellular dermal component; the HSE model consists of both epidermis and dermis, representing a full-thickness bilayer structure; the aHSE can incorporate additional cell types beyond KCs and Fibs, combine with 3D printing technology, or integrate mechanical features. It may have a bi- or tri-layered structure. “+/−” denotes inclusion or exclusion of the specified additive; “+” signifies inclusion of at least one of the displayed additives. The lower part displays the figure legend. OTC, organotypic culture; HEE, human epidermal equivalent model; HSE, human skin equivalent model; aHSE, advanced human skin equivalent model; NCs, neuronal cells; ECs, endothelial cells; MSs, melanoma spheroids; LCs, lymphatic cells; DCs, dendritic cells. Partial credit for figure generation is attributed to Biorender.