The prevention and treatment of pathological scars remain challenging. Corticosteroids are the mainstay drugs in clinical scar prevention and treatment as they effectively induce scar regression and improve scar pruritus and pain. Currently, intralesional injections of corticosteroids are widely used in clinical practice. These require professional medical manipulation; however, the significant accompanying injection pain, repetition of injections and adverse effects, such as skin atrophy, skin pigmentation and telangiectasia, make this treatment modality an unpleasant experience for patients. Transdermal administration is, therefore, a promising non-invasive and easy-to-use method for corticosteroid administration for scar treatment. In this review, we first summarize the mechanisms of action of corticosteroids in scar prevention and treatment; then, we discuss current developments in intralesional injections and the progress of transdermal delivery systems of corticosteroids, as well as their corresponding advantages and disadvantages.

Wound healing is a common occurrence. However, delayed healing and aberrant scarring result in pathological wound healing. Accordingly, a scarless wound healing remains a significant clinical challenge. In this study, we constructed hyaluronic acid (HA)-modified and verteporfin (VP)-loaded polylactic acid (PLA) nanogels (HA/VP-PLA) to promote scarless wound healing by accelerating wound re-epithelialization and controlling scar formation. Owing to the unique structure of HA incorporating and coating in VP-loaded PLA nanoparticles, HA/VP-PLA could be topically applied on wound to achieve targeted delivery to fibroblasts. Then, HA/VP-PLA released HA and lactic acid (LA) to stimulate the proliferation and migration of fibroblasts, as well as VP to inhibit Yes-associated protein (YAP) expression and nuclear localization to suppress fibrosis. In vitro (skin fibroblasts) and in vivo (rat and rabbit models) experiments strongly suggested that HA/VP-PLA promoted scarless wound healing by accelerating wound re-epithelialization and controlling scar formation. Therefore, our work provides a feasible strategy for scarless wound healing, and the sophisticated HA/VP-PLA exhibit a great potential for clinical applications.

Transdermal drug delivery system (TDDS) is an attractive method for drug delivery with convenient application, less first-pass effect, and fewer systemic side effects. Among all generations of TDDS, transdermal nanocarriers show the greatest clinical potential because of their non-invasive properties and high drug delivery efficiency. However, it is still difficult to design optimal transdermal nanocarriers to overcome the skin barrier, control drug release, and achieve targeting. Hence, surface modification becomes a promising strategy to optimize and functionalize the transdermal nanocarriers with enhanced penetration efficiency, controlled drug release profile, and targeting drug delivery. Therefore, this review summarizes the developed transdermal nanocarriers with their transdermal mechanism, and focuses on the surface modification strategies via their different functions.

Synergistic transdermal photodynamic therapy (PDT)/photothermal therapy (PTT) has emerged as a novel strategy for improving hypertrophic scar (HS) therapeutic outcomes. Herein, a near-infrared heptamethine cyanine dye, named IR-808, has been selected as the desirable photosensitizer owing to its PDT and PTT properties. Benefitting from the transdermal delivery ability of ethosomes (ESs), IR-808 loaded nanoethosomes (IR-808-ES) have been prepared as a novel nanophotosensitizer for the transdermal PDT/PTT of HSs. The special structure of IR-808 aggregate distribution in the ES lipid membrane enhances ROS generation and hyperthermia. The in vitro experiments indicate that the IR-808-ES enhances the PDT/PTT efficacy for inducing the HS fibroblast (HSF) apoptosis via the intrinsic mitochondrial pathway. Furthermore, the in vivo transdermal delivery studies reveal that the IR-808-ES efficiently delivers IR-808 into HSFs in the HS tissue. Systematic assessments in the rabbit ear HS models demonstrate that the enhanced PDT/PTT performance of the IR-808-ES has remarkable therapeutic effects on improving the HS appearance, promoting HSF apoptosis and remodeling collagen fibers. Therefore, the IR-808-ES integrates both the transdermal delivery ability and the aggregation-enhanced PDT/PTT effect, and these features endow the IR-808-ES with significant potential as a novel nanophotosensitizer for the transdermal phototherapy of HSs in the clinical field.

Keloid is a fibrotic dermal disease characterized by an abnormal increase in fibroblast proliferation and invasion. These pathological behaviours may be related to the heterogeneity of keloid fibroblasts (KFs); however, because of a lack of effective biomarkers for KFs it is difficult to study the underlying mechanism. Our previous studies revealed that the expansion of CD26⁺ KFs was responsible for increased keloid proliferation and invasion capabilities; the intrinsic relationship and mechanism between CD26 and keloid is therefore worthy of further investigation. The aim of this study was to explore molecular mechanisms in the process of CD26 upregulated KFs proliferation and invasion abilities, and provide more evidence for CD26 as an effective biomarker of keloid and a new clinical therapeutic target. Flow cytometry was performed to isolate CD26⁺/CD26⁻ fibroblasts from KFs and normal fibroblasts. To generate stably silenced KFs for CD26 and insulin-like growth factor-1 receptor (IGF-1R), lentiviral particles encoding shRNA targeting CD26 and IGF-1R were used for transfection. Cell proliferations were analysed by cell counting kit-8 assay and 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay. Scratching assay and transwell assay were used to assess cell migration and invasion abilities. To further quantify the regulatory role of CD26 expression in the relevant signalling pathway, RT-qPCR, western blot, ELISA, PI3K activity assay and immunofluorescence were used. Aberrant expression of CD26 in KFs was proven to be associated with increased proliferation and invasion of KFs. Furthermore, the role of the IGF-1/IGF-1 receptor axis was also studied in CD26 and was found to upregulate KF proliferation and invasion. The PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway was shown to affect CD26-regulated KF proliferation and invasion by increasing phosphorylation levels of S6 kinase and 4E-binding protein. CD26 can be the effective biomarker for KFs, and its expression is closely related to proliferation and invasion in keloids through the IGF-1-induced PI3K/AKT/mTOR pathway. This work provides a novel perspective on the pathological mechanisms affecting KFs and therapeutic strategies against keloids.

Background: Diabetic wounds remain a challenging clinical problem, which requires further treatment development. Published data showed that dermis-derived stem/progenitor cells (DSPCs) display superior wound healing in vitro. The beneficial effects of DSPCs are mediated through paracrine secretion, which can be obtained from conditioned medium (CM). Hyaluronic acid (HA) is especially suitable for skin regeneration and delivering bioactive molecules in CM. This study investigated the effect of human foreskin-derived dermal stem/progenitor cell (hFDSPC)-CM combined with HA on a diabetic mouse model and relevant mechanism in vitro.Methods: hFDSPCs and human adipose-derived stem cells (hADSCs) were identified, and the respective CM was prepared. PBS, HA, hFDSPC-CM combined with HA, or hADSC-CM combined with HA was topically applied to mice. HE, CD31, CD68, CD86, and CD206 staining was performed to evaluate gross wound condition, angiogenesis, and inflammation, respectively. Masson and Picrosirius red staining was performed to evaluate collagen deposition and maturation. The effects of hFDSPC-CM and hADSC-CM on human keratinocyte cells (HaCaT) and fibroblasts were evaluated in vitro using CCK-8 and EdU assays to determine cell viability and proliferation, respectively. The scratch assay was performed to evaluate cell migration. Tube formation assay was performed on human umbilical vein endothelial cells (HUVECs) to confirm angiogenesis. Extracellular matrix (ECM) metabolic balance-related genes and proteins, such as collagen I (COL 1), collagen III (COL 3), fibronectin (FN), α-SMA, matrix metalloproteinases 1 (MMP-1), matrix metalloproteinases 3 (MMP-3), and transforming growth factor-beta 1 (TGF-β1), were analysed.Results: hFDSPC-CM combined with HA showed superior wound closure rate over hADSC-CM. Histologically, the hFDSPC-CM combined with HA group showed significantly improved re-epithelialisation, angiogenesis, anti-inflammation, collagen regeneration, and maturation compared to hADSC-CM combined with HA group. In vitro assays revealed that hFDSPC-CM displayed significant advantages on cell proliferation, migration, and ECM regeneration through a TGF-β/Smad signalling pathway compared with hADSC-CM.Conclusions: hFDSPC-CM combined with HA was superior for treating diabetic wounds. The underlying mechanism may promote proliferation and migration of epidermal cells with fibroblasts, thus leading to ECM deposition and remodelling. Reduced inflammation may be due to the above-mentioned mechanism.