Copyright
©The Author(s) 2026. Published by Baishideng Publishing Group Inc. All rights reserved.
Fractional carbon dioxide laser-induced photothermal activation of mesenchymal stem cell-derived exosomes accelerates diabetic wound healing by enhancing angiogenesis
Jin-Yuan Chen, Zhe Ji, Kang Guo, Hao-Nan Wang, Chen-Chen Zhu, Tao Li, Xiang-Bin Zhao, Yu-Ting Wang, Qiang Li, Pei-Sheng Jin, Xue-Yang Li
Jin-Yuan Chen, Zhe Ji, Yu-Ting Wang, Qiang Li, Pei-Sheng Jin, Xue-Yang Li, Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
Jin-Yuan Chen, Zhe Ji, Hao-Nan Wang, Chen-Chen Zhu, The First Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
Kang Guo, Department of Burn and Plastic Surgery, Shangqiu First People’s Hospital, Shangqiu 476000, Henan Province, China
Tao Li, Department of Medical Cosmetology, Caoxian People’s Hospital, Heze 274400, Shandong Province, China
Xiang-Bin Zhao, Department of Burn and Plastic Surgery, Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
Co-first authors: Jin-Yuan Chen and Zhe Ji.
Co-corresponding authors: Pei-Sheng Jin and Xue-Yang Li.
Author contributions: Chen JY and Ji Z drafted the manuscript, they contributed equally to this article, they are the co-first authors of this manuscript; Chen JY, Ji Z, Guo K, Wang HN, Zhu CC, and Wang YT performed the experiments; Chen JY, Li Q, Jin PS, and Li XY designed the research; Chen JY, Ji Z, Li T, Zhao XB, and Li XY analyzed the data; Jin PS and Li XY critically revised the manuscript, they contributed equally to this article, they are the co-corresponding authors of this manuscript; and all authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 82172224; Xuzhou Health Commission Science and Technology Project, No. XWKYHT20220136; and Xuzhou Health Commission Youth Project, No. XWKYHT20220145.
Institutional review board statement: This study was approved by the Medical Ethics Committee of Affiliated Hospital of Xuzhou Medical University, approval No. XYFY2018-KL027.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Xuzhou Medical University, No. 202302T009.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data and the code that support the findings of this study are available at reasonable request from the corresponding authors.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Xue-Yang Li, Associate Professor, Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Huai-hai West Road, Xuzhou 221006, Jiangsu Province, China.
lmlxy240923@163.com
Received: August 11, 2025
Revised: September 29, 2025
Accepted: November 13, 2025
Published online: January 15, 2026
Processing time: 156 Days and 20.2 Hours
BACKGROUND
Exosomes (Exos) derived from mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option for diabetic wound healing owing to their strong pro-angiogenic potential. Nevertheless, their relatively low bioactivity remains a major barrier to successful clinical application. Fractional CO2 laser therapy offers a precise and controllable form of photothermal stimulation that may potentiate exosome activity without the need for additional exogenous agents, possibly promoting more effective diabetic wound repair.
AIM
To investigate the mechanisms through which low-energy fractional Exos derived from CO2 laser-preconditioned adipose-derived MSCs (Ad-MSCs) (CO2 laser-Exos) promote the healing of diabetic wounds.
METHODS
Ad-MSCs were subjected to a single exposure of fractional CO2 laser at energy densities of 30 mJ/cm2, 40 mJ/cm2, or 50 mJ/cm2. Infrared thermography was employed to monitor temperature fluctuations in the culture medium. To determine the optimal energy level, western blotting was performed to assess heat shock protein 90 expression, while apoptosis was analyzed by flow cytometry. Exos were subsequently isolated through ultracentrifugation, and sphingosine-1-phosphate (S1P) concentrations within the Exos were measured using enzyme-linked immunosorbent assay. The therapeutic efficacy and underlying mechanisms of CO2 laser-Exos were further investigated through a series of in vitro and in vivo experiments.
RESULTS
Following a single exposure to fractional CO2 laser, the culture medium temperature increased rapidly and then gradually declined. Among the tested groups, Ad-MSCs treated with 40 mJ/cm2 demonstrated the highest heat shock protein 90 expression and exhibited reduced apoptosis. in vitro, CO2 laser-Exos markedly promoted the proliferation, migration, and tube formation of human umbilical vein endothelial cells, while their S1P content was higher than that of unconditioned Exos. Under high-glucose conditions, human umbilical vein endothelial cells showed increased expression of S1P receptor 1 (S1PR1). Silencing S1PR1 significantly impaired the pro-angiogenic activity of CO2 laser-Exos and suppressed the expression of phosphorylated protein kinase B, hypoxia-inducible factor 1 alpha, and vascular endothelial growth factor-A. In vivo, compared with Exos, CO2 laser-Exos substantially accelerated diabetic wound healing by promoting neovascularization within the wound bed.
CONCLUSION
Low-energy fractional CO2 laser irradiation augments the biological activity of MSC-derived Exos through photothermal stimulation. These Exos, in turn, enhance endothelial cell functions by activating the S1PR1/protein kinase B/hypoxia-inducible factor 1 alpha signaling pathway, ultimately accelerating the repair of diabetic wounds.
Core Tip: In this study, adipose-derived mesenchymal stem cells were preconditioned with low-energy fractional carbon dioxide laser irradiation, utilizing a controlled photothermal effect to enhance the bioactivity of their secreted exosomes. These exosomes exhibited elevated levels of sphingosine-1-phosphate and significantly promoted endothelial cell proliferation, migration, and tube formation through activation of the sphingosine-1-phosphate receptor 1 protein kinase B/hypoxia-inducible factor 1 alpha signaling pathway, ultimately accelerating diabetic wound healing in vivo.
