Key Takeaways & Executive Findings
- •• Fibroblast exosome-loaded PF-127 hydrogel significantly enhances proliferation, migration, and tube formation of human umbilical vein endothelial cells under high glucose conditions. • The hydrogel inhibits ferroptosis in endothelial cells, as evidenced by reduced lipid peroxidation and improved mitochondrial morphology. • In a diabetic rat model, the hydrogel accelerates wound closure and improves healing quality, with increased CD31-positive angiogenesis. • The therapeutic mechanism involves suppression of ferroptosis and restoration of endothelial cell function, offering a novel strategy for diabetic wound treatment.
Abstract
BACKGROUND: Exosomes, as an important mediator of intercellular communication, have been widely used in tissue repair and regeneration. Exosome-loaded hydrogels can significantly improve the stability and bioavailability of exosomes, thereby enhancing therapeutic efficacy. OBJECTIVE: To investigate the effects of fibroblast-exosome-loaded hydrogels on endothelial cell function recovery and wound repair in diabetic rats. METHODS: Exosomes isolated from human skin fibroblasts were added to PF-127 hydrogels to prepare fibroblast-exosome-loaded PF-127 hydrogels. (1) Cellular experiment: A suspension of third-generation human umbilical vein endothelial cells was divided into four groups: control group (5 mmol/L glucose), high glucose group (50 mmol/L glucose), high glucose + hydrogel group (50 mmol/L glucose + PF-127 hydrogel), and high glucose + exosome-loaded hydrogel group (50 mmol/L glucose + exosome-loaded PF-127 hydrogel). Cell proliferation was detected by EdU staining, migration ability by scratch and Transwell assays, tube formation ability by tube formation assay, and ferroptosis by Western blot and transmission electron microscopy. (2) Animal experiment: Twenty-four SD rats were randomly divided into four groups: control group (n=6) received a full-thickness skin defect wound of 1 cm diameter on the back without treatment; diabetic group (n=6) received the same wound after establishing type 1 diabetes model without treatment; diabetic + hydrogel group (n=6) and diabetic + exosome-loaded hydrogel group (n=6) received the wound and were injected with PF-127 hydrogel or exosome-loaded PF-127 hydrogel, respectively, twice a week for 3 weeks. Wound healing was observed during treatment. After treatment, samples were collected for hematoxylin-eosin staining and CD31 immunohistochemical staining. RESULTS AND CONCLUSION: (1) Cellular experiment: High glucose treatment inhibited proliferation, migration, and tube formation of human umbilical vein endothelial cells and induced ferroptosis; exosome-loaded PF-127 hydrogel significantly improved these functions and inhibited ferroptosis under high glucose conditions. (2) Animal experiment: The wound closure rate in the diabetic + exosome-loaded hydrogel group was faster than that in the diabetic and diabetic + hydrogel groups. Hematoxylin-eosin staining showed poor wound healing quality in the diabetic and diabetic + hydrogel groups, while the diabetic + exosome-loaded hydrogel group had better healing quality but not as good as the control group. CD31 immunohistochemical staining showed less angiogenesis in the diabetic and diabetic + hydrogel groups compared with the control and diabetic + exosome-loaded hydrogel groups. (3) These results indicate that fibroblast-exosome-loaded PF-127 hydrogel accelerates diabetic wound healing by inhibiting ferroptosis and promoting endothelial cell function recovery.
1. Introduction
Diabetes is a global chronic metabolic disease with an increasing incidence. Diabetic wound healing impairment is a common complication that severely affects patients' quality of life. Ferroptosis is an iron-dependent form of regulated cell death characterized by mitochondrial damage and lipid peroxidation accumulation. Recent studies have implicated various regulated cell death pathways in wound repair, with ferroptosis playing a significant role in diabetic wound healing disorders; however, research on the mechanisms of ferroptosis in diabetic wound repair remains limited.
Fibroblast exosomes, as important mediators of intercellular communication, have gained attention in tissue repair and regeneration. Evidence suggests that fibroblasts accumulate at diabetic skin wounds and contribute to wound closure, though the underlying mechanisms require further elucidation. Hydrogels are emerging materials with promising applications in tissue engineering and regenerative medicine. For example, chitosan hydrogels have been shown to reduce postoperative inflammation and promote pancreatic wound healing in a rat model of pancreatic fistula. Studies have demonstrated that exosome-combined hydrogel therapy significantly shortens the healing course in cartilage injury and fracture models. Therefore, the role and mechanism of fibroblast exosomes combined with hydrogels in treating diabetic wounds warrant further exploration.
This study investigates the effects of fibroblast-exosome-loaded PF-127 hydrogel on inhibiting ferroptosis, promoting endothelial cell function recovery, and accelerating diabetic wound repair, aiming to provide a new therapeutic strategy for diabetic wounds.
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ZHANG Jing, HE Liping, WEN Yu, FU Hang (2026). Hydrogel loaded with fibroblast exosomes promotes endothelial cell function recovery and diabetic wound healing. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21454
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Frequently Asked Questions
What is the role of ferroptosis in diabetic wound healing?
Ferroptosis is an iron-dependent cell death mechanism that contributes to impaired diabetic wound healing by damaging endothelial cells and reducing angiogenesis. The study shows that inhibiting ferroptosis can promote endothelial cell function and accelerate wound closure.
How does the fibroblast exosome-loaded PF-127 hydrogel work?
The hydrogel delivers fibroblast-derived exosomes to the wound site, which suppress ferroptosis in endothelial cells, enhance their proliferation, migration, and tube formation, thereby promoting angiogenesis and tissue repair.
What are the advantages of using PF-127 hydrogel for exosome delivery?
PF-127 is a thermosensitive hydrogel that is liquid at low temperatures and gels at body temperature, providing a sustained release of exosomes, improving their stability and bioavailability, and offering a supportive 3D environment for cell growth.
What were the main findings of the animal study?
In diabetic rats, the hydrogel significantly accelerated wound closure, improved healing quality, and increased CD31-positive blood vessel formation compared to controls, indicating enhanced angiogenesis.
What is the clinical significance of this research?
This study provides a novel therapeutic approach for diabetic wounds by combining exosome therapy with a biocompatible hydrogel, potentially improving outcomes for patients with impaired wound healing.
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