Unsatisfied cytoreductive surgery predicts worse clinical outcomes. Previous studies have found that cyclophosphamide (CTX) is a rhythmic immune modulator that can target suppressive regulatory immune cells and meanwhile enhance effector cells. Here, a therapeutic scaffold is engineered based on a fibrin hydrogel to codeliver CTX and anti‐PD‐L1 antibody (aPDL1) for the prevention of cancer recurrence postsurgery. It is demonstrated that the sequential release of CTX and aPDL1 from the fibrin hydrogel can lead to selective depletion of regulatory T cells (Treg) in the residual tumor, which would then synergize the immune checkpoint blockade therapy. The therapeutic benefit is demonstrated in an orthotopic breast tumor and an orthotopic ovarian tumor model after incomplete resection of primary tumors. In this work, the strategy provides a clinically valuable option for preventing cancer recurrence postsurgery.
Healing of full-thickness skin wounds remains a major challenge. Recently, human umbilical cord mesenchymal stem cells (hUC-MSCs) were shown to possess an extraordinary potential to promote skin repair in clinical settings. However, their low survival rate after transplantation limits their therapeutic efficiency in treating full-thickness skin wounds. Hydrogels are considered an ideal cell transplantation vector owing to their three-dimensional mesh structure, good biosafety, and biodegradation. The objective of this study was to investigate the skin wound healing effect of a fibrin hydrogel scaffold loaded with hUC-MSCs. We found that the fibrin hydrogel had a three-dimensional mesh structure and low cytotoxicity and could prolong the time of cell survival in the peri-wound area. The number of green fluorescent protein (GFP)-labeled hUC-MSCs was higher in the full-thickness skin wound of mice treated with hydrogel–hUC-MSCs than those of mice treated with cell monotherapy. In addition, the combination therapy between the hydrogel and hUC-MSCs speed up wound closure, its wound healing rate was significantly higher than those of phosphate-buffered saline (PBS) therapy, hydrogel monotherapy, and hUC-MSCs monotherapy. Furthermore, the results showed that the combination therapy between hydrogel and hUC-MSCs increased keratin 10 and keratin 14 immunofluorescence staining, and upregulated the relative gene expressions of epidermal growth factor (EGF), transforming growth factor-β1 (TGF-β1), and vascular endothelial growth factor A (VEGFA), promoting epithelial regeneration and angiogenesis. In conclusion, the fibrin hydrogel scaffold provides a relatively stable sterile environment for cell adhesion, proliferation, and migration, and prolongs cell survival at the wound site. The hydrogel–hUC-MSCs combination therapy promotes wound closure, re-epithelialization, and neovascularization. It exhibits a remarkable therapeutic effect, being more effective than the monotherapy with hUC-MSCs or hydrogel.
Background: Full-thickness skin wound healing remains a major challenge. Recently, human umbilical cord mesenchymal stem cells (hUC-MSCs) have exerted their brilliant potential to promote skin repair in clinical applications. However, low survival rate of hUC-MSCs after transplantation limits their therapeutic efficiency in treating full-thickness skin wound. The fibrin hydrogel is considered an ideal cell transplantation vectors owing to its three-dimensional mesh structure and low cytotoxicity. The objective of this study was to investigate the skin wound healing effect of fibrin hydrogel scaffold loaded with hUC-MSCs.Methods: The cytotoxicity of the fibrin hydrogel was determined via cell counting kit-8 (CCK-8) assay. A total of 36 mice aged 8 weeks were randomly divided into four groups: control group (n = 9); hydrogel-alone group (n = 9); hUC-MSC-alone group (n = 9); and hydrogel-hUC-MSC combination group (n = 9). PBS, fibrin hydrogel, hUC-MSCs or fibrin hydrogel loaded with hUC-MSCs were injected into wounds, respectively. The wound of each mice was recorded with a digital camera to calculate the wound healing rate. On days 3, 7 and 14, serial sections of the wound and surrounding tissues were prepared. Hematoxylin and eosin staining, immunofluorescent staining for green fluorescent protein, keratin 10, and keratin 14 were performed. Meanwhile, the expressions of vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and transforming growth factor-β1 (TGF-β1) were detected using RT-PCR. Results: We found that the fibrin hydrogel owned three-dimensional mesh structure and low cytotoxicity, and could prolong the cell survival time around the wound. The combination therapy of hydrogel and hUC-MSCs sped up wound closure. The combination therapy of hydrogel and hUC-MSCs upregulated the relative gene expressions of EGF, TGF-β1, VEGF, and VEGFA, which promoting epithelial regeneration and angiogenesis.Conclusions: The fibrin hydrogel scaffold provides a relatively stable sterile environment for cell adhesion, proliferation, and migration and prolongs cell survival at the wound site. The hydrogel-hUC-MSC combination therapy can promote wound closure, re-epithelialization, and neovascularization. It exhibits a remarkable therapeutic effect than hUC-MSCs or the hydrogel alone.
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