A tissue-engineered human psoriatic skin model: targeting inflammation and glucose metabolism dysregulation in psoriasis using microneedle patches.

Psoriasis, an inflammatory skin disease, affects nearly 43 million individuals globally, and patients are 59% more likely to have type 2 diabetes. In this study, tissue-engineered psoriatic human skin substitutes were produced using keratinocytes and fibroblasts derived from patients with plaque psoriasis, and were enriched with human T lymphocytes to amplify the inflammation. Tissue-engineered healthy human skin substitutes served as a control. The psoriatic model exhibited type 2 diabetes-like features, including diminished uptake of insulin and glucose, with glucose uptake being approximately eight times lower than in the healthy skin model. Insulin-like growth factor signalling was impaired with lower insulin-like growth factor 1 (IGF-1), and insulin-like growth factor binding protein 2 (IGFBP-2) levels, as well as elevated insulin-like growth factor binding protein 4 (IGFBP-4) levels in the cell culture supernatants. This is the first human skin model to concurrently exhibit both psoriatic inflammation and insulin resistance. Moreover, to assess therapeutic potential, phloretin-loaded microneedle patches were applied for 1 week. They reduced the levels of cytokines involved in both psoriasis and insulin resistance: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage migration inhibitory factor (MIF), and interleukin-17A (IL-17A). This anti-inflammatory activity was more pronounced than that of systemic-like methotrexate and methotrexate-loaded microneedle patches. The microneedles loaded with phloretin tended to enhance insulin uptake and reduce IGFBP-4 levels in the supernatants; however, these changes were not statistically significant. Prolonging the treatment period beyond 1 week or combining it with another compound loaded into the microneedles that improves insulin sensitivity may increase the efficacy of this approach by simultaneously addressing psoriasis and type 2 diabetes.