3D human skin models to understand bacterial infection

Complications from bacterial infections are the leading cause of death in patients who survive the first few days after a traumatic injury. These infections can also result in limb amputations, which makes the rapid diagnosis and treatment of wound infection and trauma of utmost importance.1 2 Skin infection studies are often limited by financial and ethical constraints, and monolayer cell culture (or 2D) models are usually applied. However, this type of cell culture does not reflect the in vivo environment for cells, limiting expression of genes and proteins due to the low multicellular interaction. Therefore, it is interesting to replace 2D for 3D culture models to more realistically simulate skin infection, in addition to offering other advantages such as the maintenance of tissue structure and cell types present in the host environment.2

3D skin equivalents are developed as a platform for dermatological research, as their epidermal barrier can reflect the morphological and molecular characteristics of the average human epidermis. Knowledge about human innate immunity has evolved drastically in line with the idea that the skin harbors a vast diversity of microbes called microbiota. Changes in the composition of this microbiota can intensify and influence inflammatory skin diseases.3

Figure 1: Schematic description of 3D skin models. 3

The growing number of studies on 3D skin models may contribute to reducing the number of animals used as models in dermatological and dermocosmetic research.3 Organotypic 3D skin models are usually composed of primary or immortalized human keratinocytes, which can also be seeded with fibroblasts. Popov et al. (2014) developed a 3D organotypic human skin tissue model to examine Staphylococcus aureus skin colonization and infection processes. S. aureus infections can manifest in a wide variety of clinical conditions, but the vast majority are skin infections. Using this type of skin model, it is possible to assess how immunization against S. aureus might have an impact on bacterial population behavior on the epidermis and the protection against invasive infections. 4

Figure 2: 3D organotypic human epidermal tissues recapitulate the stratified structure of the epidermis.4

With the same focus on designing 3D skin constructs, a study conducted at the Jena University Hospital in Germany developed a 3D model of skin to assess the bioactivity and biocompatibility of antiseptics at application-relevant concentrations. The skin model is composed of fibroblasts embedded in collagen as the dermis, and an epidermis constructed from keratinocytes. Infected skin models were treated for 24 hours with the antiseptics polyhexanide, octenidine dihydrochloride, chlorhexidine gluconate, and povidone-iodine, which protected the structure from infection by S. aureus. The results of this study show that the proposed model is a promising tool to assess the effectiveness of new antimicrobial strategies. 5


1. Havlikova, J., May, R. C., Styles, I. B. & Cooper, H. J. Direct identification of bacterial and human proteins from infected wounds in living 3D skin models. Sci. Rep. (2020).

2. Maboni, G. et al. A Novel 3D Skin Explant Model to Study Anaerobic Bacterial Infection. Front. Cell. Infect. Microbiol. 7, 404 (2017).

3. Rademacher, F., Simanski, M., Gläser, R. & Harder, J. Skin microbiota and human 3D skin models. Exp. Dermatol. 27, 489–494 (2018).

4. Popov, L., Kovalski, J., Grandi, G., Bagnoli, F. & Amieva, M. R. Three-Dimensional Human Skin Models to Understand Staphylococcus aureus Skin Colonization and Infection. Front. Immunol. 5, 41 (2014).

5. Reddersen, K., Wiegand, C., Elsner, P. & Hipler, U.-C. Three-dimensional human skin model infected with Staphylococcus aureus as a tool for evaluation of bioactivity and biocompatibility of antiseptics. Int. J. Antimicrob. Agents 54, 283–291 (2019).

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