Random-pattern skin flaps (RPSFs) receive blood mainly from small subcutaneous vessels rather than a defined axial vessel, leaving them vulnerable to ischemia and hypoxia after surgery. Current clinical assessments often depend on flap color, swelling, texture, vascular perfusion, or biopsy, which may be subjective, delayed, or invasive. Skin barrier function offers another window into tissue status because transepidermal water loss (TEWL) and stratum corneum hydration (SCH) reflect barrier integrity and moisture balance. Due to these challenges, further research is needed to develop objective, non-invasive, and mechanism-based methods for predicting skin flap necrosis before visible damage occurs.
In a study published (DOI: 10.1093/burnst/tkag016) on 27 February 2026 in Burns & Trauma, researchers from Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, and North Sichuan Medical College reported that skin barrier monitoring could predict RPSF necrosis and reveal the immune mechanism behind this early deterioration.
The team combined mouse RPSF models, clinical samples, prospective validation, gene ontology (GO) analysis, immunohistochemistry (IHC), immunofluorescence (IF), western blotting (WB), and cell experiments. In mice, visible necrosis appeared only after several days, but relative transepidermal water loss (RT), relative stratum corneum hydration (RS), and relative humidity (RH) changed earlier, suggesting that barrier failure precedes overt tissue death. Mechanistic experiments showed that ferroptosis, an iron-dependent form of regulated cell death, damaged keratinocytes and intensified M1 macrophage polarization. At the same time, Tregs appeared to act as a protective counterweight. Ubiquitin-specific protease 4 (USP4) stabilized tumor necrosis factor alpha-induced protein 2 (TNFAIP2) through deubiquitination, promoting C-C motif chemokine ligand 2 (CCL2)/C-C chemokine receptor 2 (CCR2)-mediated Treg recruitment. This “M1 macrophages–Tregs axis” helped restrain ferroptosis and inflammation. In clinical analysis, RT greater than 3.5 and RS lower than −2.5 showed strong predictive value for later necrosis.
The authors said the study changes how flap prognosis can be viewed after surgery. Rather than waiting for color changes, swelling, or clear necrosis, clinicians may be able to read the skin barrier as an earlier biological warning. They said the work also explains why that warning appears: ischemic stress activates ferroptosis and inflammatory macrophages, while the USP4–TNFAIP2 pathway helps recruit Tregs to limit damage. This makes barrier monitoring both a practical bedside signal and a window into the immune biology of flap survival.
The findings could support earlier and more precise postoperative decision-making, especially within the first three days after RPSF surgery, when intervention may still reduce tissue loss. A portable skin barrier monitoring approach may help clinicians identify vulnerable flaps, guide timely treatment, and reduce reliance on invasive or subjective assessment. The study also highlights the USP4–TNFAIP2–CCL2/CCR2 pathway as a possible target for future therapies aimed at strengthening protective immune feedback and limiting ferroptosis-driven barrier damage. Larger multicenter studies, including other flap types and patients with comorbidities, will be important before broader clinical adoption.
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References
DOI
10.1093/burnst/tkag016
Original Source URL
https://doi.org/10.1093/burnst/tkag016
Funding information
This research was supported by Shanghai Clinical Research Center of Plastic and Reconstructive Surgery supported by Science and Technology Commission of Shanghai Municipality (Grant No. 22MC1940300), the National Natural Science Foundation of China (NSFC) International (Regional) Cooperation and Exchange Program (Grant No. 82361138568), the Disruptive Technology Innovation Special Project of the Science and Technology Commission of Shanghai Municipality (25DIPA00100), the Basic Public Welfare Research Project of Zhejiang Province (LGF22H110002), the Project of Wenzhou Science and Technology Bureau(Y20240823) and the Project of Wenzhou Science and Technology Bureau (Y2023399).
About Burns & Trauma
Burns & Trauma is an open access, peer-reviewed journal publishing the latest developments in basic, clinical, and translational research related to burns and traumatic injuries, with a special focus on various aspects of biomaterials, tissue engineering, stem cells, critical care, immunobiology, skin transplantation, prevention, and regeneration of burns and trauma injury.