Bioengineered Efficacy Models of Skin Disease: Advances in the Last 10 Years

Abstract

Models of skin diseases, such as psoriasis and scleroderma, must accurately recapitulate the complex microenvironment of human skin to provide an efficacious platform for investigation of skin diseases. Skin disease research has been shifting from less complex and less relevant 2D (two-dimensional) models to significantly more relevant 3D (three-dimensional) models. Three-dimensional modeling systems are better able to recapitulate the complex cell–cell and cell–matrix interactions that occur in vivo within skin. Three-dimensional human skin equivalents (HSEs) have emerged as an advantageous tool for the study of skin disease in vitro. These 3D HSEs can be highly complex, containing both epidermal and dermal compartments with integrated adnexal structures. The addition of adnexal structures to 3D HSEs has allowed researchers to gain more insight into the complex pathology of various hereditary and acquired skin diseases. One method of constructing 3D HSEs, 3D bioprinting, has emerged as a versatile and useful tool for generating highly complex HSEs. The development of commercially available 3D bioprinters has allowed researchers to create highly reproducible 3D HSEs with precise integration of multiple adnexal structures. While the field of bioengineered models for study of skin disease has made tremendous progress in the last decade, there are still significant efforts necessary to create truly biomimetic skin disease models. In future studies utilizing 3D HSEs, emphasis must be placed on integrating all adnexal structures relevant to the skin disease under investigation. Thorough investigation of the intricate pathology of skin diseases and the development of effective treatments requires use of highly efficacious models of skin diseases.

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

“…Fibroblasts are responsible for the production of ECM, providing skin with sufficient strength and good ductility [ 75 ]. Keratinocytes and fibroblasts play an important role in wound healing and pathological development of skin diseases [ 76 ]. Though the combination of epidermal keratinocyte and dermal fibroblast is better than being individually used [ 11 ], skin equivalents containing only two types of cells simply restore the structure of skin.…”

“…Animal models and two-dimensional (2D) cultured cells are not always effective at discovering human pathophysiological and toxicological responses. Numerous instances of significant differences between the disease phenotypes observed in animal models and humans have been reported [ 76 , 156 , 157 ]. Cells in 2D petri dish could not exactly mimic native cell behavior and the complexity interactions with the microenvironment in vivo [ 158 ].…”

Histological and functional characterization of 3D human skin models mimicking the inflammatory skin diseases psoriasis and atopic dermatitis

“…In general, complete HSE models consist of a dermal compartment and the epidermis with stratified, differentiated keratinocytes and a well-developed stratum corneum. They can be generated using genetically modified cells, patient-derived cells or induced pluripotent stem cells ( Stanton et al, 2022 ). In addition, HSEs are highly customizable and can vary significantly in complexity depending on the desired application of the model ( Stanton et al, 2022 ).…”

“…They can be generated using genetically modified cells, patient-derived cells or induced pluripotent stem cells ( Stanton et al, 2022 ). In addition, HSEs are highly customizable and can vary significantly in complexity depending on the desired application of the model ( Stanton et al, 2022 ). It is possible to integrate different types of immune cells such as Langerhans cells, macrophages and T cells into HSEs ( Facy et al, 2005 ; Lorthois et al, 2017 ; van den Bogaard et al, 2014 ), which allows for the study of immune cells in human skin models.…”

“…It is possible to integrate different types of immune cells such as Langerhans cells, macrophages and T cells into HSEs ( Facy et al, 2005 ; Lorthois et al, 2017 ; van den Bogaard et al, 2014 ), which allows for the study of immune cells in human skin models. Even adnexal skin structures such as hair follicles or sweat glands have been integrated in HSEs ( Stanton et al, 2022 ). Furthermore, microfluidic culture devices using bioreactor platforms called ‘skin-on-a-chip’ were developed to simulate the vascular structures and blood flow of human skin ( Ali et al, 2015 ; Niehues et al, 2018 ; van den Broek et al, 2017 ).…”