Abstract
Wound infection is a major clinical challenge that can significantly delay the healing process, can create pain, and requires prolonged hospital stays. Pre-clinical research to evaluate new drugs normally involves animals. However, ethical concerns, cost, and the challenges associated with interspecies variation remain major obstacles. Tissue engineering enables the development of in vitro human skin models for drug testing. However, existing engineered skin models are representative of healthy human skin and its normal functions. This paper presents a functional infected epidermis model that consists of a multilayer epidermis structure formed at an air-liquid interface on a hydrogel matrix and a three-dimensionally (3D) printed vascular-like network. The function of the engineered epidermis is evaluated by the expression of the terminal differentiation marker, filaggrin, and the barrier function of the epidermis model using the electrical resistance and permeability across the epidermal layer. The results showed that the multilayer structure enhances the electrical resistance by 40% and decreased the drug permeation by 16.9% in the epidermis model compared to the monolayer cell culture on gelatin. We infect the model with Escherichia coli to study the inflammatory response of keratinocytes by measuring the expression level of pro-inflammatory cytokines (interleukin 1 beta and tumor necrosis factor alpha). After 24 h of exposure to Escherichia coli, the level of IL-1β and TNF-α in control samples were 125 ± 78 and 920 ± 187 pg/mL respectively, while in infected samples, they were 1429 ± 101 and 2155.5 ± 279 pg/mL respectively. However, in ciprofloxacin-treated samples the levels of IL-1β and TNF-α without significant difference with respect to the control reached to 246 ± 87 and 1141.5 ± 97 pg/mL respectively. The robust fabrication procedure and functionality of this model suggest that the model has great potential for modeling wound infections and drug testing.
Highlights
Skin is the largest human organ, and serves as a physiological and immunologic barrier to protect the body from ultraviolet (UV) light, pathogens, environmental pollutants, and micro-organisms
We developed a simplified functional skin model, resembling a skin barrier function to use in studying wound infection, pro-inflammatory response, and drug testing
The results show that the epidermis model provides a higher electrical resistance with 3.5 ± 0.3 kΩ compared to the bare gelatin hydrogel with 2.0 ± 0.4 kΩ electrical resistance and 2D cell culture on gelatin with 2.5 ± 0.4 kΩ (Figure 5D)
Summary
Skin is the largest human organ, and serves as a physiological and immunologic barrier to protect the body from ultraviolet (UV) light, pathogens, environmental pollutants, and micro-organisms. Recent advances in tissue engineering and advanced manufacturing techniques have enabled researchers to create biomimetic tissues in a high-throughput fashion [17,18] These models start from multilayered sheets of keratinocytes [4] and evolve to reconstructed, full-thickness human skin models using cell inserts [19,20], microfluidics [3,14], and 3D printing [21,22]. We developed a simplified functional skin model, resembling a skin barrier function to use in studying wound infection, pro-inflammatory response, and drug testing. E. coli was used to study the pro-inflammatory response of keratinocytes to infection and drug testing
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