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Background The risk of flap necrosis in tissue reconstruction surgery is elevated in patients with vascular disorders, such as diabetes mellitus. Chronic hyperglycemia causes endothelial cell dysfunction and increases inflammatory process, causing vascular insufficiency. Platelet-rich plasma (PRP) contains high levels of platelets, growth factors, and fibrinogens. Its regenerative properties spark interest in supporting flap survival in relation to diabetic complications.

Background The risk of flap necrosis in tissue reconstruction surgery is elevated in patients with vascular disorders, such as diabetes mellitus. Chronic hyperglycemia causes endothelial cell dysfunction and increases inflammatory process, causing vascular insufficiency. Platelet-rich plasma (PRP) contains high levels of platelets, growth factors, and fibrinogens. Its regenerative properties spark interest in supporting flap survival in relation to diabetic complications. Methods Thirty Wistar rats were divided into three groups. The first group included diabetic rats without PRP injection, which underwent flap procedure. The second group included diabetes-induced rats receiving PRP subcutaneous injection 1 day prior to flap procedure. The third group included nondiabetic rats receiving PRP injection 1 day prior to flap procedure. Flap tissue samples were taken on the seventh day to measure vascular endothelial growth factor (VEGF) levels using enzyme-linked immunosorbent assay method; angiogenesis and collagen density were measured from histopathology examination, and flap viability was analyzed using digital measurements. Results Analysis showed that flap viability, angiogenesis, and VEGF levels were significantly higher in the PRP-injected diabetic rats compared with diabetic rats that did not receive PRP. The levels of VEGF, angiogenesis, and viability of flaps in diabetic rats given PRP did not differ significantly compared with nondiabetic rats that received PRP. Conclusion Flap preconditioning through local injection of activated PRP enhances flap viability, VEGF levels and angiogenesis, in random skin flaps in diabetic rats, to the level where it does not differ significantly to nondiabetic rats that were given PRP. [ABSTRACT FROM AUTHOR]

Flaps are mainly used for wound repair. However, postoperative ischemic necrosis of the distal flap is a major problem, which needs to be addressed urgently. We evaluated whether tetrandrine, a compound found in traditional Chinese medicine, can prolong the survival rate of random skin flaps. Thirty‐six rats were randomly divided into control, low‐dose tetrandrine (25 mg/kg/day), and high‐dose tetrandrine (60 mg/kg/day) groups. On postoperative Day 7, the flap survival and average survival area were determined. After the rats were sacrificed, the levels of angiogenesis, apoptosis, and inflammation in the flap tissue were detected with immunology and molecular biology analyses. Tetrandrine increased vascular endothelial growth factor and Bcl‐2 expression, in turn promoting angiogenesis and anti‐apoptotic processes, respectively. Additionally, tetrandrine decreased the expression of Bax, which is associated with the induction of apoptosis, and also decreased inflammation in the flap tissue. Tetrandrine improved the survival rate of random flaps by promoting angiogenesis, inhibiting apoptosis, and reducing inflammation in the flap tissue through the modulation of the PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

Random skin flaps have limited clinical application as a broad surgical reconstruction treatment because of distal necrosis. The prolyl hydroxylase domain‐containing protein inhibitor roxadustat (RXD) enhances angiogenesis and reduces oxidative stress and inflammation. This study explored the function of RXD in the survival of random skin flaps. Thirty‐six male Sprague–Dawley rats were randomly divided into low‐dose RXD group (L‐RXD group, 10 mg/kg/2 day), high‐dose RXD group (H‐RXD group, 25 mg/kg/2 day), and control group (1 mL of solvent, 1:9 DMSO:corn oil). The proportion of surviving flaps was determined on day 7 after surgery. Angiogenesis was assessed by lead oxide/gelatin angiography, and microcirculation blood perfusion was evaluated by laser Doppler flow imaging. Specimens in zone II were obtained, and the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured as indicators of oxidative stress. Histopathological status was evaluated with haematoxylin and eosin staining. The levels of hypoxia‐inducible factor‐1α (HIF‐1α), vascular endothelial growth factor (VEGF), and the inflammatory factors interleukin (IL)‐1β, IL‐6, and tumour necrosis factor‐α (TNF‐α) were detected by immunohistochemistry. RXD promoted flap survival and microcirculatory blood perfusion. Angiogenesis was detected distinctly in the experimental group. SOD activity increased and the MDA level decreased in the experimental group. Immunohistochemistry indicated that the expression levels of HIF‐1α and VEGF were increased while the levels of IL‐6, IL‐1β, and TNF‐α were decreased after RXD injection. RXD promoted random flap survival by reinforcing vascular hyperplasia and decreasing inflammation and ischaemia‐reperfusion injury. [ABSTRACT FROM AUTHOR]

• Demonstrated that Maresin 1 (MaR1) significantly enhances the viability of random flaps by reducing oxidative stress and cell death. • Identified the Keap1/Nrf2 pathway as a key mechanism by which MaR1 controls reactive oxygen species-driven apoptosis and ferroptosis. • Employed a range of advanced imaging and histological techniques to quantify improvements in flap survival and tissue health. • Found that MaR1 treatment leads to increased vascular density and collagen deposition, supporting enhanced tissue repair and survival. • Highlighted potential therapeutic applications of MaR1 in tissue reconstruction and surgical repairs. Random flaps are widely used in tissue reconstruction, but the high incidence of flap necrosis after operation remains a significant challenge. Maresin 1 (MaR1), a mediator derived from docosahexaenoic acid, has been shown to have significant effects in resolving inflammation and promoting tissue regeneration. This study investigated the role of MaR1 in the survival of random flaps. Histological analysis, laser Doppler blood flow imaging, Masson trichrome staining, and survival area analysis were used to assess the viability of the flaps. Apoptosis, ferroptosis, oxidative stress, angiogenesis, and the underlying mechanisms were explored by examining the expression of specific molecules using immunofluorescence, western blotting, and other immunological and molecular biology techniques. The findings demonstrated that MaR1 could improve flap lifespan by significantly reducing oxidative stress, apoptosis, and ferroptosis, as well as by enhancing angiogenesis. The Keap1-Nrf2 pathway was upregulated by MaR1, which inhibited ROS-mediated apoptosis and ferroptosis. The protective effect of MaR1 on flap survival was abolished by ML385. Our findings indicate that MaR1 could be a novel therapeutic agent for enhancing flap treatment outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

Random skin flap is commonly used in plastic and reconstructive surgery, however, distal part of skin flap often occurs ischemia and necrosis. Limonin, with bioactivities of anti-inflammation, anti-apoptosis and anti-oxidative stress, may be effective for skin flap survival. In our study, random flap model was performed in mice to explore the role of limonin in the survival of skin flap. On postoperative day 7, the necrosis of skin flaps was observed, while visualization of blood flow below the tissue surface was detected through Laser Doppler blood flow imaging (LDBFI). Then flap tissues were acquired to assess and levels of angiogenesis, apoptosis and oxidative stress. The results showed that limonin decreased necrosis and edema of skin flaps compared with the control group, with more blood flow in the flap under LDBFI detection. Limonin treatment also increased the mean vessels density, elevated the expression levels of angiogenic proteins (matrix metallopeptidase 9, vascular endothelial growth factor, Cadherin5) and antioxidant proteins [superoxide dismutase 1 (SOD1), endothelial nitric oxide synthase, heme oxygenase], and reduced the expression of apoptotic factors (BAX, CYC, Caspase3). In summary, limonin could effectively enhance the survival of random skin flap, the potential mechanism may attribute to the induction of angiogenesis, and inhibition of apoptosis and oxidative stress.

Random flaps are extensively utilized in plastic surgery due to their flexibility compared to traditional axial vascular system arrangements and their resemblance to injured skin in color, thickness, and texture. Despite these advantages, they are susceptible to ischemia-reperfusion injuries and subsequent necrosis post-transplantation. Bilobalide (BB), a sesquiterpene compound derived from Ginkgo biloba, exhibits notable antioxidant and anti-inflammatory properties and is commonly used to treat ischemiareperfusion injuries. However, its short half-life restricts its sustained efficacy in random flaps. In this study, we synthesized a multi-crosslinked, photosensitive methacryloyl hyaluronic acid(HAMA)/laponite(Lap)/bilobalide (BB) hydrogel. This dualcrosslinked hydrogel demonstrates superior mechanical properties and biocompatibility while providing a stable release of bilobalide. In vitro experiments showed that it significantly reduces edema, promotes angiogenesis, and enhances the survival of random flaps. Further network pharmacology analysis and recovery experiments suggested that the hydrogel's beneficial effects are mediated by the regulation of endoplasmic reticulum stress and specifically identified the regulation of the PERK/TXNIP/NLRP3 signaling pathway as crucial to its anti-inflammatory effects. Therefore, this HAMA/Lap/BB hydrogel promotes the survival of random flaps in rats by alleviating endoplasmic reticulum stress, providing a novel intervention strategy for the treatment of random flaps injuries., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ye jiangtian reports financial support was provided by Wenzhou Medical University. Ye Jiangtian reports a relationship with Wenzhou Medical University that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Skin flaps are often used for repair and reconstruction, including oral cavity and palate. However, postoperative flap necrosis limited applications. Myrtenol, a plant-derived bicyclic monoterpene, has pharmacological effects including inhibiting apoptosis and promoting autophagy. But any impact on skin flaps survival remains unclear. Thus, we established modified McFarlane flaps on 24 Sprague-Dawley rats and applied myrtenol. They were randomly divided into low-dose myrtenol (L-Myr), high-dose myrtenol (H-Myr), inhibitor and control groups. On postoperative day 7, flap survival rate was increased and Laser Doppler images showed blood circulation improvement under myrtenol treatment. Hematoxylin and eosin staining (H&E) results indicated that it increased micro vessel density (MVD) and decreased neutrophil numbers. Besides, kits detection showed that it improved anti-oxidant stress factors activities and reduced pro-oxidant stress factors contents. Moreover, immunofluorescence and Western blot results demonstrated that it upregulated the expression of pro-angiogenic factors, anti-apoptotic proteins, pro-autophagic proteins, mitogen-activated protein kinase 1/2 (MEK1/2) and extracellular signal-regulated kinases 1/2 (ERK1/2) and downregulated the expression of pro-inflammatory cytokines, pro-apoptotic proteins and anti-autophagic proteins. The specific inhibitor U0126 of MEK/ERK pathway partially reversed these effects. Overall, Myrtenol promoted angiogenesis, reduced oxidative stress, ameliorated inflammation, inhibited apoptosis and upregulated autophagy via MEK/ERK pathway to promote flap survival. [Display omitted] • Myrtenol promoted skin flap survival in rats. • Myrtenol upregulated VEGF expression, thus improving blood perfusion and alleviating ischemia/reperfusion injury. • Myrtenol increased SOD activity and decreased the content of MDA to inhibit oxidative stress. • Myrtenol suppressed inflammation by diminishing the synthesis of TNF-α and IL-6. • Myrtenol inhibited apoptosis and promoted autophagy by regulating the related proteins through MEK/ERK pathway. [ABSTRACT FROM AUTHOR]

The random flap is one of the commonly used techniques for tissue defect repair in surgery and orthopaedics, however the risk of ischaemic necrosis at the distal end of the flap limits its size and clinical application. Metformin (Met) is a first-line medication in the treatment of type 2 diabetes, with additional effects such as anti-tumor, anti-aging, and neuroprotective properties. In this study, we aimed to investigate the biological effects and potential mechanisms of Met in improving the survival of random skin flaps. Twenty-four male Sprague-Dawley rats and 12 male C57BL/6J mice underwent McFarlane flap surgery and divided into control (Ctrl) and Met groups (100 mg/kg). The survival rate of the flap were evaluated on day 7. Angiography, Laser doppler blood flow imaging, and H&E staining were used to assess blood flow supply and the levels of microvascular density. Then, reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured by test kits. Immunohistochemistry analysis was conducted to evaluate the expression of Vascular Endothelial Growth Factor A (VEGFA), Vascular endothelial cadherin (VE-cadherin) and CD31. Rats and mice in the Met group exhibited higher flap survival rate, microcirculatory flow, and higher expression levels of VEGFA and VE-cadherin compared with the Ctrl group. In addition, the level of oxidative stress was significantly lower in the met group. And then we demonstrated that the human umbilical vein endothelial cells (HUVECs) treated with Met can alleviate tert -butyl hydroperoxide (TBHP)-stimulated cellular dysfunction and oxidative stress injury. Mechanistically, Met markedly stimulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and promoted Nrf2 nuclear translocation. Silencing of Nrf2 partially abolished the antioxidant and therapeutic effects of Met. In summary, our data have confirmed that Met has a positive effect on flap survival and reduces necrosis. The mechanism of action involves the regulation of the Nrf2/HO-1 signaling pathway to combat oxidative stress and reduce damage. [Display omitted] • Metformin promotes flap survival. • Metformin reduces oxidative stress. • Metformin promotes the Nrf2/HO-1 expression. [ABSTRACT FROM AUTHOR]

Background: Asiaticoside (AS) is extracted from the traditional herbal medicine Centella asiatica, and has angiogenic, antioxidant, anti-inflammatory, and wound-healing effects. We investigated the effects of AS on skin flap survival. Methods: Dorsal McFarlane flaps were harvested from 36 rats and divided into two groups: an experimental group treated with 40 mg/kg AS administered orally once daily, and a control group administered normal saline in an identical manner. On day 2, superoxide dismutase (SOD) and malondialdehyde (MDA) levels, and production of the cytokines tumor necrosis factor-α and interleukin (IL)-6 were evaluated. On day 7, tissue slices were stained with hematoxylin and eosin. The expression of vascular endothelial growth factor (VEGF), IL-6, and IL-1β were immunohistochemically evaluated. Microcirculatory flow was measured using laser Doppler flowmetry. Flap angiography, using the lead oxide-gelatin injection technique, was performed with the aid of a soft X-ray machine. Results: The AS group exhibited greater mean flap survival area, improved microcirculatory flow, and higher expression levels of SOD and VEGF compared with the control group. However, MDA levels and the inflammatory response were significantly reduced. Conclusions: AS exhibits promise as a therapeutic option due to its effects on the viability and function of random skin flaps in rats.

Random skin flaps are frequently used to repair skin damage. However, the ischemic and hypoxic necrosis limits their wider application. Rivastigmine, a carbamate cholinesterase inhibitor (ChEI), has also been shown to reduce ischemia–reperfusion injury (IRI) and inflammation. This study was performed to examine the effect of rivastigmine on flap survival. Sixty male Sprague–Dawley rats with a modified McFarland flap were randomly divided into three groups: control group, 1 ml of solvent (10% DMSO + 90% corn oil); low-dose rivastigmine group (Riv-L), 1.0 mg/kg; and high-dose rivastigmine group (Riv-H), 2.0 mg/kg. All rats were treated once a day. On day 7, the skin flap survival area was measured. After staining with hematoxylin and eosin (H&E), the pathological changes and microvessel density (MVD) were examined. The expression of inflammatory factors IL-1β and IL-18, CD34, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was examined by immunohistochemical staining. The malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were examined to determine the degree of oxidative stress. Lead oxide/gelatin angiography showed neovascularization and laser Doppler blood flowmetry showed the blood filling volume. Rivastigmine significantly increased the flap survival area and improved neovascularization. CD34, VEGF, and HIF-1α expression were increased, These changes were more pronounced in the Riv-H group. Treatment with rivastigmine reduced the level of MDA, improved SOD activity, and reduced expression of IL-1β and IL-18. Our results indicate that Rivastigmine can increase angiogenesis and significantly improve flap survival. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of Shu Xue Tong treatment on random skin flap survival. Methods: Twenty-four male Sprague–Dawley (SD) rats were administered Shu Xue Tong or normal saline. On postoperative day 7, flap survival area, flap angiogenesis angiography, blood flow and vascular endothelial growth factor (VEGF), Notch1, and Delta-like ligand 4 (Dll4) expression were assessed. Results: The mean flap survival area, blood vessel regeneration, microcirculatory flow, and expression of VEGF were enhanced with Shu Xue Tong treatment relative to the control. However, in Shu Xue Tong-treated rat flap, Notch1 and Dll4 levels were significantly reduced. Conclusions: These results demonstrate the beneficial action of Shu Xue Tong on random skin flap survival and suggest that its mechanism of action involves the promotion of angiogenesis via the VEGF-Notch1/Dll4 signaling pathway.

Study Objective: We investigated the effect of bone marrow mesenchymal stem cells (BMMSCs) and chicken embryo extract (CEE), alone and in combination, on tissue viability of skin flaps, and mast cells (MCs), in an experimental random skin flap (RSF) rat model. Materials and Methods: A 30 mm × 80 mm RSF was made on the dorsum of each of the forty rats, which were then divided into four groups. One group did not receive any treatment and served as the control, the second group received BMMSCs, the third group received CEE + BMMSCs, and the fourth group received CEE. For BMMSC treatment, 6 × 109 BMMSCs were injected into twelve separate injection sites of each flap. Seven days after RSF surgery, the remaining viable part of each flap was measured and examined to determine the number of blood vessels, MCs, and degranulated MCs. Results: The CEE, CEE + BMMSC, and BMMSC groups displayed significantly higher levels of flap viability (ANOVA test: p = 0.000; LSD test for all groups: p = 0.000), and a greater number of vessels (ANOVA test: p = 0.000; LSD test: p = 0.000, 0.002, and 0.012, respectively), compared with the control group. The flap viability was poorer in the BMMSC group than in the CEE and CEE + BMMSC groups. The BMMSC group also had a greater number of degranulated and total MCs, compared with the CEE and CEE + BMMSC groups. Conclusions: We observed biostimulatory effects of BMMSCs, CEE, and CEE + BMMSCs on flap viability and vessel numbers, compared to the control group. MCs produced in response to BMMSC treatment have an inhibitory effect on the RSFs survival in an ischemic tissue model.

Objective: The purpose of our experiment was to determine whether morroniside can improve the survival of ischemic skin flaps in rats. Methodology: A total of 40 male Sprague-Dawley rats were randomly divided into two groups (control group and treatment group). Modified McFarlane flaps were performed (causally based, 9 cm × 3 cm). The percentage of survival of each flap was calculated. Flap blood flows were measured by Laser-Doppler flowmeter. Flap vasculature was assessed by angiography after Lead oxide-gelatin injection. Vascular endothelial growth factor (VEGF) was evaluated by immunochemistry. Superoxide Dismutase (SOD) level and malondiadehyde (MDA) content were determined using assay kits. Results: At the seventh postoperative day, the morroniside-treated rats showed a higher percentage of flap survival than the control rats. Flap perfusion and the level of vascular endothelial growth factor were significantly elevated in the morroniside-treated group. In the treatment group, the distal section of the flap was nearly saturated with contrast agent, while in the control group, the contrast agent perfused only half of the flap. In the treatment group, morroniside administration significantly increased SOD level and reduced MDA content. Conclusion: Morroniside can enhance ischemic flap survival.

Random skin flaps are frequently used to repair skin damage. However, the ischemic and hypoxic necrosis limits their wider application. Rivastigmine, a carbamate cholinesterase inhibitor (ChEI), has also been shown to reduce ischemia–reperfusion injury (IRI) and inflammation. This study was performed to examine the effect of rivastigmine on flap survival. Sixty male Sprague–Dawley rats with a modified McFarland flap were randomly divided into three groups: control group, 1 ml of solvent (10% DMSO + 90% corn oil); low-dose rivastigmine group (Riv-L), 1.0 mg/kg; and high-dose rivastigmine group (Riv-H), 2.0 mg/kg. All rats were treated once a day. On day 7, the skin flap survival area was measured. After staining with hematoxylin and eosin (H&E), the pathological changes and microvessel density (MVD) were examined. The expression of inflammatory factors IL-1β and IL-18, CD34, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was examined by immunohistochemical staining. The malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were examined to determine the degree of oxidative stress. Lead oxide/gelatin angiography showed neovascularization and laser Doppler blood flowmetry showed the blood filling volume. Rivastigmine significantly increased the flap survival area and improved neovascularization. CD34, VEGF, and HIF-1α expression were increased, These changes were more pronounced in the Riv-H group. Treatment with rivastigmine reduced the level of MDA, improved SOD activity, and reduced expression of IL-1β and IL-18. Our results indicate that Rivastigmine can increase angiogenesis and significantly improve flap survival.

Random-pattern skin flap is a vital technique frequently applied in reconstruction surgeries for its convenience and effectiveness in solving skin defects. However, ischemic necrosis, especially in the distal areas of the flap, still needs extra attention after surgery. Earlier evidence has suggested that paeoniflorin (PF) could stimulate angiogenesis and suppress ischemic cardiovascular disease. However, few studies have focused on the role of PF in flap survival. In this study, we have demonstrated that the human umbilical vein endothelial cells (HUVECs) treated with PF can alleviate tert-butyl hydroperoxide (TBHP)-stimulated cellular dysfunction and apoptosis. To better evaluate, HUVECs' physiology, cell tube formation, migration, and adhesion were assessed. Mechanistically, PF protects HUVECs against apoptosis via stimulating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. PF also downregulates mitochondrial ROS production to reduce excessive intracellular ROS production induced by TBHP and restore TBHP-induced mitochondrial depolarization. As a result, silencing Nrf2 partially abolishes the protective effect of PF exposure on HUVECs. In in vivo experiments, the oral administration of PF was shown to have enhanced the vascularization of regenerated tissues and promote flap survival. However, the PF-mediated protection was partially lost after co-treatment with ML385, a selective Nrf2 inhibitor, suggesting that PF is a crucial modulator regulating the Nrf2/HO-1 signaling pathway. In summary, our data have provided a new insight into PF as a potential therapy for enhancing random-pattern flap viability. [ABSTRACT FROM AUTHOR]

Random-pattern skin flap is a vital technique frequently applied in reconstruction surgeries for its convenience and effectiveness in solving skin defects. However, ischemic necrosis, especially in the distal areas of the flap, still needs extra attention after surgery. Earlier evidence has suggested that paeoniflorin (PF) could stimulate angiogenesis and suppress ischemic cardiovascular disease. However, few studies have focused on the role of PF in flap survival. In this study, we have demonstrated that the human umbilical vein endothelial cells (HUVECs) treated with PF can alleviate tert-butyl hydroperoxide (TBHP)-stimulated cellular dysfunction and apoptosis. To better evaluate, HUVECs’ physiology, cell tube formation, migration, and adhesion were assessed. Mechanistically, PF protects HUVECs against apoptosis via stimulating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. PF also downregulates mitochondrial ROS production to reduce excessive intracellular ROS production induced by TBHP and restore TBHP-induced mitochondrial depolarization. As a result, silencing Nrf2 partially abolishes the protective effect of PF exposure on HUVECs. In in vivo experiments, the oral administration of PF was shown to have enhanced the vascularization of regenerated tissues and promote flap survival. However, the PF-mediated protection was partially lost after co-treatment with ML385, a selective Nrf2 inhibitor, suggesting that PF is a crucial modulator regulating the Nrf2/HO-1 signaling pathway. In summary, our data have provided a new insight into PF as a potential therapy for enhancing random-pattern flap viability.

Jinti Lin,1–3 Chang Jia,3,4 Yongli Wang,5 Shanghong Jiang,3 Zhenyu Jia,6 Nan Chen,3 Shimin Sheng,3 Shihen Li,1–3 Liangfu Jiang,1–3 Huazi Xu,1–3 Kailiang Zhou,1–3 Yijie Chen3,71Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, People’s Republic of China; 2Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, People’s Republic of China; 3The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325027, People’s Republic of China; 4Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, People’s Republic of China; 5Department of Orthopaedics, Huzhou Central Hospital, Huzhou 313300, People’s Republic of China; 6School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325027, People’s Republic of China; 7Department of Obstetrics and Gynecology, The Second Affliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, People’s Republic of ChinaBackground: Random skin flap is frequently used in plastic and reconstructive surgery, but its distal part often occurs ischemia and necrosis. Pravastatin (Prava) with bioactivities of pro-angiogenesis, anti-apoptosis and anti-oxidative stress, may be beneficial for flap survival.Materials and methods: A modified McFarlane flap model was performed in Sprague-Dawley rats. The animals were divided into the Control and Prava groups and treated as follows: the Prava group was injected intraperitoneally with 2 mg/kg Prava for consecutive 7 days, and the Control group received an equal volume of vehicle daily. On day 7, the necrosis skin flaps were observed, while visualization of blood flow below the tissue surface was performed by Laser Doppler blood flow imaging (LDBFI). Then animals were euthanized, and levels of angiogenesis, apoptosis and oxidative stress were analyzed.Results: Prava decreased necrosis and edema of skin flaps compared with the Control group, with more blood flow in the flap under LDBFI. Prava treatment increased the mean vessels density, elevated the expression levels of angiogenic proteins (matrix metallopeptidase 9, vascular endothelial growth factor, Cadherin5) and antioxidant proteins (superoxide dismutase 1 (SOD1), endothelial nitric oxide synthase, heme oxygenase), and decreased the expression of apoptotic factors (BAX, CYC, Caspase3). In addition, malondialdehyde content was reduced, and glutathione level and SOD activity were increased in the skin flaps after treatment with Prava.Conclusion: Prava promotes survival of random skin flap through induction of angiogenesis, and inhibition of apoptosis and oxidative stress.Keywords: Pravastatin, random skin flap, angiogenesis, oxidative stress, apoptosis

Increasing evidence indicates that pyroptosis, a new type of programmed cell death, may participate in random flap necrosis and play an important role. ROS-induced lysosome malfunction is an important inducement of pyroptosis. Transcription factor E3 (TFE3) exerts a decisive effect in oxidative metabolism and lysosomal homeostasis. We explored the effect of pyroptosis in random flap necrosis and discussed the effect of TFE3 in modulating pyroptosis. Histological analysis via hematoxylin-eosin staining, immunohistochemistry, general evaluation of flaps, evaluation of tissue edema, and laser Doppler blood flow were employed to determine the survival of the skin flaps. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays were used to calculate the expressions of pyroptosis, oxidative stress, lysosome function, and the AMPK-MCOLN1 signaling pathway. In cell experiments, HUVEC cells were utilized to ensure the relationship between TFE3, reactive oxygen species (ROS)-induced lysosome malfunction and cell pyroptosis. Our results indicate that pyroptosis exists in the random skin flap model and oxygen and glucose deprivation/reperfusion cell model. In addition, NLRP3-mediated pyroptosis leads to necrosis of the flaps. Moreover, we also found that ischemic flaps can augment the accumulation of ROS, thereby inducing lysosomal malfunction and finally initiating pyroptosis. Meanwhile, we observed that TFE3 levels are interrelated with ROS levels, and overexpression and low expression of TFE3 levels can, respectively, inhibit and promote ROS-induced lysosomal dysfunction and pyroptosis during in vivo and in vitro experiments. In conclusion, we found the activation of TFE3 in random flaps is partially regulated by the AMPK-MCOLN1 signal pathway. Taken together, TFE3 is a key regulator of ROS-induced pyroptosis in random skin flaps, and TFE3 may be a promising therapeutic target for improving random flap survival.

Random skin flaps are frequently applied in plastic and reconstructive surgery for patients suffering from soft tissue defects caused by congenital deformities, trauma and tumor resection. However, ischemia and necrosis in distal parts of random skin flaps remains a common challenge that limits the clinical application of this procedure. Recently, chemically modified mRNA (modRNA) was found to have great therapeutic potential. Here, we explored the potential of fibroblasts engineered to express modified mRNAs encoding the stromal cell-derived factor-1α (SDF-1α) to improve vascularization and survival of therapeutic random skin flaps. Our study showed that fibroblasts pre-treated with SDF-1α modRNA have the potential to salvage ischemic skin flaps. Through a detailed analysis, we revealed that a fibroblast SDF-1α modRNA combinatorial treatment dramatically reduced tissue necrosis and significantly promoted neovascularization in random skin flaps compared to that in the control and vehicle groups. Moreover, SDF-1α modRNA transcription in fibroblasts promoted activation of the SDF-1α/CXCR4 pathway, with concomitant inactivation of the MEK/ERK, PI3K/AKT, and JAK2/STAT3 signaling pathways, indicating a possible correlation with cell proliferation and migration. Therefore, fibroblast-mediated SDF-1α modRNA expression represents a promising strategy for random skin flap regeneration.

Random skin flaps are often used in plastic surgery, but the complications of marginal flap ischemia and necrosis often limit their wider clinical application. Apigenin (Api) is a flavonoid found in various fruits and vegetables. Api has been shown to promote angiogenesis, as well as reduce oxidative stress, membrane damage, and inflammation. In this study, we assessed the effects of Api treatment on random skin flap survival. Dorsal McFarlane skin flaps were transplanted into rats, which were randomly divided into three groups: control (normal saline), low-dose Api (20 mg/kg), and high-dose Api (50 mg/kg). Seven days after the surgery, the activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) were measured. Histological analyses were performed to determine flap survival and tissue edema. H&E staining was performed to assess the histopathological changes in skin flaps, and the levels of microvascular density (MVD) were determined. Laser doppler flowmetry was used to assess microcirculation blood flow. Flap angiography was performed by injection of lead oxide/gelatin. The expression levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interlukin-1β (IL-lβ) were evaluated by immunohistochemistry. Rats in the high-dose Api group exhibited higher average flap survival area, microcirculatory flow, increased SOD activity, and higher VEGF expression levels compared with the other two groups. Furthermore, the levels of MDA and pro-inflammatory cytokines were significantly decreased in rats treated with high-dose Api. Our findings suggest the potential usefulness of Api in preventing skin flap tissue necrosis.

Background: Asiaticoside (AS) is extracted from the traditional herbal medicine Centella asiatica, and has angiogenic, antioxidant, anti-inflammatory, and wound-healing effects. We investigated the effects of AS on skin flap survival. Methods: Dorsal McFarlane flaps were harvested from 36 rats and divided into two groups: an experimental group treated with 40 mg/kg AS administered orally once daily, and a control group administered normal saline in an identical manner. On day 2, superoxide dismutase (SOD) and malondialdehyde (MDA) levels, and production of the cytokines tumor necrosis factor-α and interleukin (IL)-6 were evaluated. On day 7, tissue slices were stained with hematoxylin and eosin. The expression of vascular endothelial growth factor (VEGF), IL-6, and IL-1β were immunohistochemically evaluated. Microcirculatory flow was measured using laser Doppler flowmetry. Flap angiography, using the lead oxide-gelatin injection technique, was performed with the aid of a soft X-ray machine. Results: The AS group exhibited greater mean flap survival area, improved microcirculatory flow, and higher expression levels of SOD and VEGF compared with the control group. However, MDA levels and the inflammatory response were significantly reduced. Conclusions: AS exhibits promise as a therapeutic option due to its effects on the viability and function of random skin flaps in rats. [ABSTRACT FROM AUTHOR]

Hongqiang Wu,1–3,* Jian Ding,1–3,* Lei Wang,3 Jinti Lin,1–3 Shihen Li,1–3 Guangheng Xiang,1–3 Liangfu Jiang,1–3 Huazi Xu,1–3 Weiyang Gao,1–3 Kailiang Zhou1–3 1Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China; 3The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325027, China *These authors contributed equally to this work Background: Random skin flaps are commonly applied during plastic surgery, but distal flap necrosis limits their clinical applications. Valproic acid (VPA), a histone deacetylase inhibitor and a traditional antiepileptic agent, may promote flap survival.Materials and methods: Sprague–Dawley rats were randomly divided into VPA-treated and control groups. All rats received VPA or saline by intraperitoneal injections once daily for 7 days after the modified McFarlane flap model was established. On postoperative day 7, flap survival, laser Doppler blood flow, and water content were examined for flap viability, hematoxylin and eosin staining (H&E), immunohistochemistry (IHC), and Western blot analysis, and the status of angiogenesis, apoptosis, and oxidative stress were detected in the ischemic flaps.Results: VPA increased the survival area, blood flow, and number of microvessels in skin flaps on postoperative day 7 and reduced edema. VPA promoted angiogenesis by enhancing vascular endothelial growth factor (VEGF) mRNA transcription and upregulating VEGF and cadherin 5 expression, inhibited apoptosis via reduction of caspase 3 cleavage, and relieved oxidative stress by increasing superoxide dismutase (SOD) and glutathione (GSH) levels and reducing the malondialdehyde (MDA) level.Conclusion: VPA promoted random skin flap survival by enhancing angiogenesis and inhibiting oxidative stress and apoptosis. Keywords: valproic acid, random skin flap, angiogenesis, oxidative stress, apoptosis

Renjin Lin,1,2,* Jinti Lin,1,2,* Shihen Li,1,2 Jian Ding,1,2 Hongqiang Wu,1,2 Guangheng Xiang,1,2 Shi Li,1,2 Yijia Huang,2 Dingsheng Lin,1,2 Weiyang Gao,1,2 Jianzhong Kong,1,2 Huazi Xu,1,2 Kailiang Zhou1,2 1Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325027, China *These authors contributed equally to this work Background: Random skin flaps are routinely placed during plastic and reconstructive surgery, but the distal areas often develop ischemia and necrosis. Baicalein, a major flavonoid extracted from the traditional Chinese herbal medicine huangqin, Scutellaria baicalensis Georgi, may improve flap viability. Materials and methods: Rats were randomly divided into baicalein and control groups and they underwent placement of modified McFarlane flaps after intraperitoneal administration of baicalein or vehicle. Flap survival and water content were measured 7 days later, as were angiogenesis, apoptosis, and oxidative stress in ischemic flaps. Results: Baicalein promoted flap survival, reduced edema, increased mean vessel density, and enhanced vascular endothelial growth factor production at both the translational and transcriptional levels. Baicalein reduced caspase 3 cleavage, increased superoxidase dismutase and glutathione levels, and decreased the malondialdehyde level. Conclusion: Baicalein promoted flap viability by stimulating angiogenesis and inhibiting apoptosis and oxidation. Keywords: baicalein, random skin flap, angiogenesis, apoptosis, oxidation

Study Objective: We investigated the effect of bone marrow mesenchymal stem cells (BMMSCs) and chicken embryo extract (CEE), alone and in combination, on tissue viability of skin flaps, and mast cells (MCs), in an experimental random skin flap (RSF) rat model. Materials and Methods: A 30 mm × 80 mm RSF was made on the dorsum of each of the forty rats, which were then divided into four groups. One group did not receive any treatment and served as the control, the second group received BMMSCs, the third group received CEE + BMMSCs, and the fourth group received CEE. For BMMSC treatment, 6 × 109 BMMSCs were injected into twelve separate injection sites of each flap. Seven days after RSF surgery, the remaining viable part of each flap was measured and examined to determine the number of blood vessels, MCs, and degranulated MCs. Results: The CEE, CEE + BMMSC, and BMMSC groups displayed significantly higher levels of flap viability (ANOVA test: p = 0.000; LSD test for all groups: p = 0.000), and a greater number of vessels (ANOVA test: p = 0.000; LSD test: p = 0.000, 0.002, and 0.012, respectively), compared with the control group. The flap viability was poorer in the BMMSC group than in the CEE and CEE + BMMSC groups. The BMMSC group also had a greater number of degranulated and total MCs, compared with the CEE and CEE + BMMSC groups. Conclusions: We observed biostimulatory effects of BMMSCs, CEE, and CEE + BMMSCs on flap viability and vessel numbers, compared to the control group. MCs produced in response to BMMSC treatment have an inhibitory effect on the RSFs survival in an ischemic tissue model. [ABSTRACT FROM AUTHOR]

Objective: The purpose of our experiment was to determine whether morroniside can improve the survival of ischemic skin flaps in rats. Methodology: A total of 40 male Sprague-Dawley rats were randomly divided into two groups (control group and treatment group). Modified McFarlane flaps were performed (causally based, 9 cm × 3 cm). The percentage of survival of each flap was calculated. Flap blood flows were measured by Laser-Doppler flowmeter. Flap vasculature was assessed by angiography after Lead oxide-gelatin injection. Vascular endothelial growth factor (VEGF) was evaluated by immunochemistry. Superoxide Dismutase (SOD) level and malondiadehyde (MDA) content were determined using assay kits. Results: At the seventh postoperative day, the morroniside-treated rats showed a higher percentage of flap survival than the control rats. Flap perfusion and the level of vascular endothelial growth factor were significantly elevated in the morroniside-treated group. In the treatment group, the distal section of the flap was nearly saturated with contrast agent, while in the control group, the contrast agent perfused only half of the flap. In the treatment group, morroniside administration significantly increased SOD level and reduced MDA content. Conclusion: Morroniside can enhance ischemic flap survival. [ABSTRACT FROM AUTHOR]

One of the most severe complications in aesthetic and reconstructive surgeries is the partial or total necrosis of a skin flap. In our experimental study, we demonstrated the use of adipose‐derived stem cells in the increase of skin flap survival rates. Stem cells were isolated from the fat of Wistar rats and genetically modified to permanently produce a green fluorescent protein (GFP). Two random‐pattern skin flaps (2 cm × 8 cm) were elevated on the dorsal area of the spine, and after being separated from the surgical wounds with a thin silicone sheet, they were placed back onto their original location. Then, the autologous GFP‐producing cells were injected intradermally into the dorsal area of the rats. At the seventh day, after the implantation of the stem cells, a clinical and immunohistochemical control was performed. The fluorescence microscopy revealed green vascular formations, suggesting that autologous GFP stromal cells were converted into endothelial cells through neovascularization. In the control skin flaps, where no stromal cells were used, no fluorescence was observed. The statistical analysis showed significantly lower necrosis rates in the right‐sided flaps (i.e., the flaps where adipose‐derived stromal cells were injected) compared with the left‐sided ones. Findings from our study demonstrate that adipose‐derived stem cells play an important role in the improvement of skin flap survival. Neovascularization is an effective way of achieving it. [ABSTRACT FROM AUTHOR]

Batroxobin is a medicinal preparation extracted from the venom of the Fer-de-Lance snake, and is used to lower blood viscosity, promote blood fibrinogen decomposition, and inhibit thrombosis. This research is to investigate whether batroxobin can improve the survival of random skin flaps in a rat model. Dorsal McFarlane flaps were harvested from 36 rats divided into two groups. Experimental group: Batroxobin was administered via the tail vein once daily. Control group: The same amount of normal saline was injected instead. On day 2, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured. On day 7, tissue slices were stained with haematoxylin and eosin. Expression of vascular endothelial growth factor (VEGF) was immunohistochemically evaluated. Microcirculatory flow was measured by laser Doppler flowmetry. Flap angiography, using the lead oxide-gelatin injection technique, was performed with the aid of a soft X-ray machine. The batroxobin group exhibited a greater mean flap survival area, a better microcirculatory flow, and higher-level expression of SOD and VEGF compared with the control group. However, the MDA level was significantly reduced. Batroxobin effectively improved the survival of random skin flaps. • Batroxobin injection tail vein administered significantly improve the survival of random skin flaps in rats. • Batroxobin can resist oxidation. SOD activity of the experimental group is increased, however, the MDA level is lowered. • Batroxobin injection may have a dose-dependent and angiogenesis promotion effect, and the VEGF expression is increased. • Batroxobin injection significantly inhibits the inflammatory response and ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

[Display omitted] • The new effects of leonurine on random skin flap survival were found. • Leonurine improved the survival of random skin flaps by promoting angiogenesis and reducing oxidative stress. • The eNOS was found to play a critical role in Leo's action on the flaps. In reconstructive and plastic surgery, random skin flaps are commonly utilized to treat skin abnormalities produced by a variety of factors. Flap delay procedure is commonly used to reduce flap necrosis. Due to the limitations of various conditions, the traditional surgical improvement can't effectively alleviate the skin flap necrosis. And leonurine (Leo) has antioxidant and anti-inflammatory effects. In this study, we researched the mechanism underlying the influences of varied Leo concentrations on the survival rate of random skin flaps. Our results showed that after Leo treatment, tissue edema and necrosis of the flap were significantly reduced, while angiogenesis and flap perfusion were significantly increased. Through immunohistochemistry and Western blot, we proved that Leo treatment can upregulate the level of angiogenesis, while Leo treatment significantly reduced the expression levels of oxidative stress, apoptosis and inflammation. As a result, it can significantly improve the overall viability of the random skin flaps through the increase of angiogenesis, restriction of inflammation, attenuation of oxidative stress, and reduction of apoptosis. And this protective function was inhibited by LY294002 (a broad-spectrum inhibitor of PI3K) and L-NAME (NG- nitro-L-arginine methyl ester, a non-selective NOS inhibitor). All in all, Leo is an effective drug that can activate the eNOS via the PI3K/Akt pathway. By encouraging angiogenesis, preventing inflammation, minimizing oxidative stress, and lowering apoptosis, Leo can raise the survival rate of random skin flaps. The recommended concentration of Leo in this study was 30 mg/kg. [ABSTRACT FROM AUTHOR]

• Nesfatin-1 can inhibit the expression of the inflammatory signaling pathway HMGB1-TLR4-NF-κB. • For the first time, this study reveals the role of Nesfatin-1 in promoting the survival of random skin flap in rats. • The HMGB1-TLR4-NF-κB pathway provide a new avenue for pharmacotherapy research related to random skin flap transplantation. Random skin flaps are often placed by plastic surgeons to treat limb deformities and dysfunction. Nesfatin-1 (NES) is a peptide that exerts angiogenic, anti-inflammatory, and anti-oxidant effects. We assessed the impact of NES on flap survival and the underlying mechanism. We modified the McFarlane random skin flap rat model. Thirty-six male Sprague-Dawley rats were randomly divided into a control group (corn oil solution with DMSO), low-dose group (NES-L at 10 µg/kg/day), and high-dose group (NES-H at 20 µg/kg/day). On day 7 after surgery, average flap survival areas were calculated. Laser Doppler blood flow monitoring and lead oxide/gelatin angiography were used to evaluate blood perfusion and neovascularization, respectively. Flap histopathological status was evaluated by hematoxylin and eosin (H&E) staining. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Immunohistochemical techniques were used to evaluate the expression of angiogenetic and inflammatory factors. In the experimental groups, the mean skin flap survival areas and blood perfusion increased considerably. The SOD activities in the experimental groups increased and the MDA contents decreased. Immunohistochemically, VEGF expression was upregulated in the experimental groups and the expression levels of inflammatory factors decreased markedly. NES inhibited ischemic skin flap necrosis, promoted angiogenesis, and reduced ischemia-reperfusion injury and inflammation. Inhibition of the inflammatory HMGB1-TLR4-NF-κB signal pathway, which reduced flap inflammation and oxidative stress, may explain the enhanced flap survival. [ABSTRACT FROM AUTHOR]

Objective(s): The aim of this study is to determine the effects of progesterone treatment on the survival of random skin flaps. Materials and Methods: McFarlane flaps were established and 40 male rats were randomly assigned to the progesterone-treated as the test group or normal saline-treated as the control group. Progesterone or normal saline (10 mg/kg) was administered intraperitoneally once daily. On postoperative day 2, malondialdehyde (MDA) and superoxide dismutase (SOD) were detected using test kits. Flap survival rates were evaluated with transparent graph paper under direct visualization, the levels of inflammation were examined by haematoxylin and eosin (H&E) staining, and the expression of vascular endothelial growth factor (VEGF) was immunohistochemically evaluated on day 7. Results: Compared to that in the control group, the mean survival area was significantly larger in the progesterone group. SOD activity was increased significantly, but the MDA levels in the test group were decreased. H&E-stained slices revealed that inflammation was inhibited in the test group. VEGF expression markedly increased in the progesterone group. Conclusion: This study showed that progesterone administered intraperitoneally significantly improved random skin flap survival in rats.

Random-pattern skin flap transplantation is frequently applied in plastic and reconstructive surgery. However, the distal part of the flap often suffers necrosis due to ischemia. In this study, the effects of salvianolic acid B (Sal B) on flap survival were evaluated, and the underlying mechanisms were investigated. Sal B improved the survival area, reduced tissue edema, and increased the number of microvessels in skin flaps after 7 days, whereas an autophagy inhibitor (3-methyladenine) reversed the Sal B-induced increase in flap viability. In addition, Sal B stimulated angiogenesis, inhibited apoptosis, reduced oxidative stress, and upregulated autophagy in areas of ischemia. Moreover, the effects of Sal B on angiogenesis, apoptosis, and oxidative stress were reversed by autophagy inhibition. Overall, our findings suggest that Sal B has pro-angiogenesis, anti-apoptosis, and anti-oxidative stress effects by stimulating autophagy, which enhances the survival of random-pattern skin flaps.

Inadequate tissue blood supply as may be found in a wound or a poorly vascularised graft, can result in tissue ischemia and necrosis. As revascularization is a slow process relative to the proliferation of bacteria and the onset of tissue necrosis, extensive tissue damage and loss can occur before healing is underway. Necrosis can develop rapidly, and treatment options are limited such that loss of tissue following necrosis onset is considered unavoidable and irreversible. Oxygen delivery from biomaterials exploiting aqueous decomposition of peroxy-compounds has shown some potential in overcoming the supply limitations by creating oxygen concentration gradients higher than can be attained physiologically or by air saturated solutions. We sought to test whether subdermal oxygen delivery from a material composite that was buffered and contained a catalyst, to reduce hydrogen peroxide release, could ameliorate necrosis in a 9 × 2 cm flap in a rat model that reliably underwent 40 % necrosis if untreated. Blood flow in this flap reduced from near normal to essentially zero, along its 9 cm length and subdermal perforator vessel anastomosis was physically prevented by placement of a polymer sheet. In the middle, low blood flow region of the flap, treatment significantly reduced necrosis based on measurements from photographs and histological micrographs. No change was observed in blood vessel density but significant differences in HIF1-α, inducible nitric oxide synthase and liver arginase were observed with oxygen delivery., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jake Barralet reports financial support was provided by Natural Sciences and Engineering Research Council of Canada., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Random-pattern skin flap transplantation is frequently applied in plastic and reconstructive surgery. However, the distal part of the flap often suffers necrosis due to ischemia. In this study, the effects of salvianolic acid B (Sal B) on flap survival were evaluated, and the underlying mechanisms were investigated. Sal B improved the survival area, reduced tissue edema, and increased the number of microvessels in skin flaps after 7 days, whereas an autophagy inhibitor (3-methyladenine) reversed the Sal B-induced increase in flap viability. In addition, Sal B stimulated angiogenesis, inhibited apoptosis, reduced oxidative stress, and upregulated autophagy in areas of ischemia. Moreover, the effects of Sal B on angiogenesis, apoptosis, and oxidative stress were reversed by autophagy inhibition. Overall, our findings suggest that Sal B has pro-angiogenesis, anti-apoptosis, and anti-oxidative stress effects by stimulating autophagy, which enhances the survival of random-pattern skin flaps. [ABSTRACT FROM AUTHOR]

Necrosis in distal areas of random skin flaps remains a challenging issue. Curculigoside A (CA), one of the main bioactive phenolic compounds, has been reported to induce angiogenesis in vitro by increasing proliferation, tube formation, and migration. In addition, CA was shown to increase vascular endothelial growth factor (VEGF) expression. In this study, we investigated the potential use of CA as a novel candidate to enhance the viability of the ischemic skin flap. A modified McFarlane flap was used as a surgical model in Sprague-Dawley rats. Three groups of rats were treated as follows: the control group received 0.9% saline orally, while rats in the two treatment groups were administered 10 mg/kg or 20 mg/kg CA orally for 7 days, respectively. On day7, the mice were killed, and tissue samples were collected for hematoxylin and eosin staining and immunohistochemical examination, while laser Doppler imaging and oxide-gelatin angiography were performed to assess angiogenesis. Kits for the analysis of superoxide dismutase (SOD) and malondialdehyde (MDA) were used to verify the oxidative stress level. Treating animals with CA significantly increased the surviving portion of the flaps. VEGF and SOD expression and microvessel development were markedly increased, and the MDA level was reduced, in the CA treatment groups. Histological studies demonstrated that CA promoted angiogenesis and attenuated inflammatory cell numbers. These findings indicated that CA increases random skin flap survival. [ABSTRACT FROM AUTHOR]

Background Tirofiban is a glycoprotein IIb/IIIa receptor antagonist that is widely used clinically. In the present study, we investigated whether tirofiban promotes flap survival in rat random skin flap model. Methods "McFarlane flaps" models were developed in 60 male rats. The rats were divided into a tirofiban-treated group (n=30) and a saline-treated group (n=30). The flap surviving rate was calculated 7 days after surgery. Tissue samples were collected and subjected to histopathological evaluation. Lead oxide-gelatin angiography and immunohistochemical staining analysis were taken to evaluate angiogenesis. Analysis of oxidative stress was performed by measuring the activity of superoxide dismutase (SOD) and malondialdehyde (MDA). Results Compared with controls, the tirofiban-treated groups exhibited significantly larger mean areas of flap survival, significantly increased SOD activity, and vascular endothelial growth factor (VEGF) expression, and significantly reduced MDA level. Hematoxylin and eosin staining revealed that naringin promoted angiogenesis and inhibited inflammation. Conclusion These findings demonstrate that tirofiban increases flap survival of random skin flaps in rats. [ABSTRACT FROM AUTHOR]

• Saxagliptin promotes random skin flap survival in rats. • Effect of saxagliptin on prevention of flap necrosis partly regulated by antiinflammation, promotion of angiogenesis and reduction of oxidative stress. • Saxagliptin inhibits inflammation via inhibiting NLRP3/caspase-1/GSDMD mediated pyroptosis. Flap necrosis is a common issue encountered in clinical flap transplantation surgery. Here, we assessed the effects of saxagliptin, a dipeptidyl peptidase-4 inhibitor, on flap survival and explored the underlying mechanisms. A dorsal McFarlane flap model was established in 36 rats, which were randomly divided into a high-dose saxagliptin (HS) group (saxagliptin, 30 mg/kg/day, n = 12), low-dose saxagliptin (LS) group (saxagliptin, 10 mg/kg/day, n = 12), and control group (n = 12). On day 7, flap survival was examined by eye in six rats from each group, along with determination of blood perfusion by laser Doppler flowmetry and angiogenesis by angiography. The remaining rats were sacrificed for harvesting of flap tissue. The status of the flap tissue was examined histopathologically by staining with hematoxylin and eosin (H&E). Oxidative stress was evaluated by determination of superoxide dismutase (SOD) activity and malonaldehyde (MDA) content. Gasdermin D (GSDMD), vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), NOD-like receptor pyrin domain containing 3 (NLRP3), interleukin (IL)-6, IL-18, Toll-like receptor 4 (TLR4), IL-1β, caspase-1, and nuclear factor-κB (NF-κB) expression were detected by immunohistochemical analysis. The experimental group exhibited a larger area of flap survival, with more blood perfusion and neovascularization and better histopathological status than the control group. The degree of oxidative stress and the levels of NF-κB, TLR4, proinflammatory cytokines, and pyroptosis-associated protein were decreased in the experimental group, while the VEGF level was increased in a saxagliptin dose-dependent manner. Saxagliptin promotes random skin flap survival. [ABSTRACT FROM AUTHOR]

Purpose Skin flap necrosis due to inadequate blood supply has remained a common postoperative problem in constructive surgery. As low-dose irradiation (LDI) has been shown to promote the wound-healing process, this study aims to investigate whether LDI could increase neovascularization and skin flap survival in rats. Methods McFarlane flaps were created in 21 male rats, which were divided into one control and two treatment groups (Ta and Tb). The treatment groups received a whole body single dose of 100 cGy gamma ray irradiation before (Tb) and after (Ta) flap surgery. The flap survival area was evaluated after seven days. The skin samples were collected for histological analysis and determining the vascular endothelial growth factor (VEGF) using the immunohistochemical method. Serum malondialdehyde (MDA) was examined with the kit. Results The mean areas of flap survival were 56.7 ± 3.24, 61.7 ± 2.6, and 66.5 ± 3.82 in the control, Tb, and Ta groups, respectively. There were significant differences between the Tb and Ta groups in comparison with the control group (P < 0.05 and P < 0.01, respectively). Compared with the control group (8.0 ± 0.73), the mean numbers of the blood vessels in the Ta group (22 ± 1.24) and the Tb group (14 ± 1.29) were significantly higher (P < 0.001 and P < 0.01). Moreover, the mean numbers of the VEGF-positive cells in the Ta group (4.5 ± 1.04) were significantly higher (P < 0.05) than the control group (2.5 ± 0.83). However, no significant differences in the MDA levels were observed among the groups. Conclusion The findings of this study suggest that LDI has the potential to promote neovascularization to improve flap survival. [ABSTRACT FROM AUTHOR]

Distal necrosis of random skin flap is always clinical problematic in plastic surgery. The development of 3D functional vascular networks is fundamental for the survival of a local random skin flap. Herein, an effective technique on constructing 3D fibrous scaffolds for accelerated vascularization is demonstrated using a photocrosslinkable natural hydrogel based on gelatin methacryloyl (GelMA) by electrospinning. It is found that the ultraviolet (UV) photocrosslinkable gelatin electrospun hydrogel fibrous membranes exhibit soft adjustable mechanical properties and controllable degradation properties. Furthermore, it is observed that the optimized hydrogel scaffolds can support endothelial cells and dermal fibroblasts adhesion, proliferation, and migration into the scaffolds, which facilitates vascularization. Importantly, a rapid formation of tubes is observed after 3 d seeding of endothelial cells. After GelMA fibrous scaffold implantation below the skin flap in a rat model, it is found that the flap survival rate is higher than the control group, and there is more microvascular formation, which is potentially beneficial for the flap tissue vascularization. These data suggest that GelMA hydrogels can be used for biomedical applications that require the formation of microvascular networks, including the development of complex engineered tissues. [ABSTRACT FROM AUTHOR]

Background: Random pattern flap is a common reconstructive surgery procedure but its necrosis is a challenging problem. A lot of pharmacological agents and surgical procedures have been examined for the prevention of this complication to maximize the length to width ratio of these surgical flaps. Therefore, we designed an experimental study to evaluate the effects of aspirin, clopidogrel bisulfate (Plavix) and their combination on random skin flap survival in rats.Methods: Forty male rats were randomly assigned to four equal groups. Surgery was done under general anesthesia. A random, rectangular 3×11 cm dorsal skin flap was designed, elevated and sutured back into its primary site. In group one, 100 mg/kg Aspirin and in group two, 25 mg/kg Plavix were administered orally for 7 days postoperatively. Aspirin and Plavix were co-administered in the third group for the same period of time while the control group received no medication. After 7 days, the total surface of flaps, the viable and also the necrotic parts were measured by Image J software. Mean standard deviation and analysis of variance were calculated to compare the results.Results: The mean area of flap survival was 62.49% in the control, 64.04% in Aspirin, 65.09% in Plavix and 64.06% in combination groups. No statistically significant differences were found between treatment groups and control rats.Conclusion: In this study, we found no significant differences between Aspirin, Plavix or their combination on the survival of random skin flaps.

Background Bezafibrate is widely used in clinics for its comparable angiogenic effect. Our research is to investigate the effect of bezafibrate on random skin flap survival. Materials and Methods The "McFarlane flap" rat models were established in 30 male Sprague-Dawley rats which were divided into two groups. The treatment group was given bezafibrate (400 mg/kg/day; gavage administration), and the control group received the vehicle. The flap surviving area was measured after 7 days, and the tissue samples were taken for histological analysis and edema measurement. Vascular endothelial growth factor (VEGF) was determined using immunohistochemical methods. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were examined with kits. Results Seven days after the operation, the surviving area in the treatment group was larger than in the control group (p < 0.01). The expression of VEGF was increased in the treatment group compared with that in the control group. And the activity of SOD was lower in the treatment group compared with those in the control group (p < 0.01). However, tissue edema, inflammatory cell infiltration, and MDA level were markedly lower in the treatment group than those in the control group (p < 0.01). Conclusion Bezafibrate improves the survival of random skin flaps effectively. [ABSTRACT FROM AUTHOR]

Random skin flap is commonly used in plastic and reconstructive surgery, however, distal part of skin flap often occurs ischemia and necrosis. Limonin, with bioactivities of anti-inflammation, anti-apoptosis and anti-oxidative stress, may be effective for skin flap survival. In our study, random flap model was performed in mice to explore the role of limonin in the survival of skin flap. On postoperative day 7, the necrosis of skin flaps was observed, while visualization of blood flow below the tissue surface was detected through Laser Doppler blood flow imaging (LDBFI). Then flap tissues were acquired to assess and levels of angiogenesis, apoptosis and oxidative stress. The results showed that limonin decreased necrosis and edema of skin flaps compared with the control group, with more blood flow in the flap under LDBFI detection. Limonin treatment also increased the mean vessels density, elevated the expression levels of angiogenic proteins (matrix metallopeptidase 9, vascular endothelial growth factor, Cadherin5) and antioxidant proteins [superoxide dismutase 1 (SOD1), endothelial nitric oxide synthase, heme oxygenase], and reduced the expression of apoptotic factors (BAX, CYC, Caspase3). In summary, limonin could effectively enhance the survival of random skin flap, the potential mechanism may attribute to the induction of angiogenesis, and inhibition of apoptosis and oxidative stress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Zhang, Huang, Gan, Zhou, Hu, Ding, Jin and Li.)

Background Huangqi (Radix astragali) is a traditional Chinese drug, designed to "buqi," which means invigorating vital energy, widely used in clinical settings. We investigated the effect of Huangqi injection on the survival of random skin flaps. Methods McFarlane flaps were established in 60 rats divided into two groups. Postoperative celiac injections were given to both groups for 7 days. Huangqi was injected into the test group, and saline was injected into controls. On day 7, tissues were stained with hematoxylin and eosin, immunohistochemically evaluated, and the expression levels of xanthine oxidase determined. Result The mean area of flap survival in the test group was significantly higher compared with the controls. Expression of vascular endothelial growth factor and superoxide dismutase, and microvessel development, were markedly increased in the test group, and the malondialdehyde level was reduced. Conclusion Huangqi injection promotes random skin flap survival. [ABSTRACT FROM AUTHOR]

Background Random skin flaps can be used throughout the hands and fingers. Thymosin β4 can increase blood flow and reduce ischemia--reperfusion injury; the study was undertaken to investigate the effect of thymosin β4 on the survival of random skin flaps. Methods A total of 45 male Sprague-Dawley rats were used and subjected to a random-pattern skin flaps operation. Rats were randomly divided into three groups: a control group (group A: intraperitoneal injection of saline, 5 mg/kg/d) and two treatment groups (group B: intraperitoneal injection of thymosin β4, a single 5 mg/kg dose per day) and (group C: intraperitoneal injection of thymosin β4, 5 mg/kg dose twice per day). The flap surviving area was measured after 7 days, and tissue samples were stained with hematoxylin and eosin. Vascular endothelial growth factor (VEGF) expression was determined using immunohistochemical methods. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were examined with kits. Results Thymosin β4 significantly reduced the necrotic area in the treatment groups after 7 days compared with the control group, and the rats receiving thymosin β4 5mg/kg twice per day had the highest survival rate. VEGF expression and SOD activity markedly increased in the treatment groups compared with the control group, whereas MDA levels were lower in the treatment groups than in the control group. Conclusion Thymosin β4may have a dose-dependent effect to promote the survival of random skin flaps. [ABSTRACT FROM AUTHOR]

Background Therapeutic delivery of angiogenic growth factors is a promising approach for treating ischemia observed in skin flaps and chronic wounds. Several studies have demonstrated that vascular endothelial growth factor (VEGF) helps mitigate skin flap necrosis by facilitating angiogenesis. The present study aimed to demonstrate an electrically-mediated nonviral gene delivery approach using a non-invasive multi-electrode array (MEA) for effective treatment of ischemic skin flaps. Methods We used a standard random dorsal skin flap model in rats. The study aimed to determine the optimal treatment sites on the skin flap, optimal plasmid dose and timing of the treatment for preventing distal flap necrosis. Results We determined that two treatment sites on the ischemic flap with a plasmid dose of 50-100 µg per treatment site proved adequate to prevent > 95% flap necrosis, and that this was significantly better than the no treatment or injection only group. A 2-day window was critical to deliver the VEGF to achieve flap survival and prevent necrosis. Histological examination demonstrated minimal electrotransfer associated tissue damage. Conclusions Our results demonstrate that MEA can be used as a non-invasive physical gene delivery method for plasmid VEGF, resulting in a significant reduction of necrosis in ischemic wounds. We propose that this method could be translated into a potential therapeutic approach to deliver growth factors to prevent ischemia in cases of chronic wounds, burns and skin flap necrosis. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]