Increased Flap Survival Research Articles

A Co-MOF encapsulated microneedle patch activates hypoxia induction factor-1 to pre-protect transplanted flaps from distal ischemic necrosis

Avoiding ischemic necrosis after flap transplantation remains a significant clinical challenge. Developing an effective pretreatment method to promote flap survival postoperatively is crucial. Cobalt chloride (CoCl2) can increase cell tolerance to ischemia and hypoxia condition by stimulating hypoxia-inducible factor-1 (HIF-1) expression. However, the considerable toxic effects severely limit the clinical application of CoCl2. In this study, cobalt-based metal-organic frameworks (Co-MOF) encapsulated in a microneedle patch (Co-MOF@MN) was developed to facilitate the transdermal sustained release of Co2+ for rapid, minimally invasive rapid pretreatment of flap transplantation. The MN patch was composed of a fully methanol-based two-component cross-linked polymer formula, with a pyramid structure and high mechanical strength, which satisfied the purpose of penetrating the skin stratum corneum of rat back to achieve subcutaneous vascular area administration. Benefiting from the water-triggered disintegration of Co-MOF and the transdermal delivery via the MN patch, preoperative damage and side effects were effectively mitigated. Moreover, in both the oxygen-glucose deprivation/recovery (OGD/R) cell model and the rat dorsal perforator flap model, Co-MOF@MN activated the HIF-1α pathway and its associated downstream proteins, which reduced reperfusion oxidative damage, improved blood supply in choke areas, and increased flap survival rates post-transplantation. This preprotection strategy, combining MOF nanoparticles and the MN patch, meets the clinical demands for trauma minimization and uniform administration in flap transplantation. Statement of significanceCobalt chloride (CoCl2) can stimulate the expression of hypoxia-inducible factor (HIF-1) and improve the tolerance of cells to ischemia and hypoxia conditions. However, the toxicity and narrow therapeutic window of CoCl2 severely limit its clinical application. Herein, we explored the role of Co-MOF as a biocompatible nanocage for sustained release of Co2+, showing the protective effect on vascular endothelial cells in the stress model of oxygen-glucose deprivation. To fit the clinical needs of minimal trauma in flap transplantation, a Co-MOF@MN system was developed to achieve local transdermal delivery at the choke area, significantly improving blood supply opening and flap survival rate. This strategy of two-step delivery of Co2+ realized the enhancement of biological functions while ensuring the biosafety.

Short-Term Periodic Fasting Reduces Ischemia-Induced Necrosis in Musculocutaneous Flap Tissue.

Periodic fasting (PF) as a form of dietary restriction has been shown to induce tissue-protective effects against ischemic injury in several different tissues. Accordingly, in this study we analyzed whether a short-term 24 h fast is suitable to prevent necrosis of musculocutaneous flap tissue undergoing acute persistent ischemia. C57BL/6N mice were randomly divided into a PF group (n = 8) and a control group that was given unrestricted access to standard chow (n = 8). The PF animals underwent a 24 h fast immediately before flap elevation and had unrestricted access to food for the rest of the 10 day observation period. Musculocutaneous flaps with a random pattern design were dissected on the animals' backs and mounted into dorsal skinfold chambers. On days 1, 3, 5, 7 and 10 after surgery, nutritive tissue perfusion, angiogenesis and flap necrosis were evaluated using intravital fluorescence microscopy. Thereafter, the flap tissue was excised and fixed for histological and immunohistochemical analyses. The flaps of PF-treated animals exhibited a higher functional capillary density and more newly formed microvessels, resulting in a significantly increased flap survival rate. Moreover, they contained a lower number of myeloperoxidase (MPO)-positive neutrophilic granulocytes and cleaved caspase-3-positive apoptotic cells in the transition zone between vital and necrotic flap tissue. These findings indicate that short-term PF improves tissue survival in ischemically challenged musculocutaneous flaps by maintaining nutritive blood perfusion and dampening ischemia-induced inflammation.

Propionyl-l-carnitine mitigates ischemia-reperfusion injury in rat epigastric island flaps

BackgroundIschemia-reperfusion injury presents a substantial concern in various medical scenarios, notably in reconstructive surgery involving tissue flaps. Despite reports on the protective benefits of Propionyl-l-carnitine against ischemia-reperfusion injury, a thorough assessment of its efficacy in epigastric island flap models is currently lacking. MethodsSixteen male Sprague-Dawley rats underwent epigastric island flap surgery and were divided into two groups: a Propionyl-l-carnitine group that received intraperitoneal Propionyl-l-carnitine prior to ischemia induction and a sham group that received saline treatment. A comprehensive evaluation was performed including macroscopic, biochemical and histological assessments encompassing measurements of flap survival areas, lipid peroxidation (malondialdehyde), glutathione, myeloperoxidase, nitric oxide and peripheral neutrophil counts. ResultsThe Propionyl-l-carnitine group demonstrated significantly increased flap survival areas when compared to the sham group. Administration of Propionyl-l-carnitine led to reduced malondialdehyde levels and elevated glutathione levels indicating a reduction in oxidative stress. Furthermore, the Propionyl-l-carnitine group exhibited lower myeloperoxidase levels, higher nitric oxide levels and reduced peripheral neutrophil counts, suggesting a decrease in the inflammatory response. Histopathological analysis revealed decreased levels of inflammation, necrosis, polymorphonuclear leukocyte infiltration and edema in the Propionyl-l-carnitine group. Additionally, vascularity was enhanced in the Propionyl-l-carnitine group. ConclusionThis study provides compelling evidence that Propionyl-l-carnitine administration effectively mitigates the deleterious effects of ischemia-reperfusion injury in epigastric island flaps. This is substantiated by the improved flap survival, diminished oxidative stress and inflammation, as well as the enhanced vascularity observed. Propionyl-l-carnitine emerges as a promising therapeutic intervention to enhance tissue flap survival in reconstructive surgery, warranting further exploration through larger-scale investigations.

VEGF and Other Gene Therapies Improve Flap Survival-A Systematic Review and Meta-Analysis of Preclinical Studies.

Surgical flaps are basic tools in reconstructive surgery. Their use may be limited by ischemia and necrosis. Few therapies address or prevent them. Genetic therapy could improve flap outcomes, but primary studies in this field present conflicting results. This systematic review and meta-analysis aimed to appraise the efficacy of external gene delivery to the flap for its survival in preclinical models. This review was registered with PROSPERO (CRD42022359982). PubMed, Embase, Web of Science, and Scopus were searched to identify studies using animal models reporting flap survival outcomes following any genetic modifications. Random-effects meta-analysis was used to calculate mean differences in flap survival with accompanying 95% CI. The risk of bias was assessed using the SYRCLE tool. Subgroup and sensitivity analyses were performed to ascertain the robustness of primary analyses, and the evidence was assessed using the GRADE approach. The initial search yielded 690 articles; 51 were eventually included, 36 of which with 1576 rats were meta-analyzed. VEGF gene delivery to different flap types significantly improved flap survival area by 15.66% (95% CI 11.80-19.52). Other interventions had smaller or less precise effects: PDGF-13.44% (95% CI 3.53-23.35); VEGF + FGF-8.64% (95% CI 6.94-10.34); HGF-5.61% (95% CI 0.43-10.78); FGF 3.84% (95% CI 1.13-6.55). Despite considerable heterogeneity, moderate risk of bias, and low quality of evidence, the efficacy of VEGF gene therapy remained significant in all sensitivity analyses. Preclinical data indicate that gene therapy is effective for increasing flap survival, but further animal studies are required for successful clinical translation.

Extrinsic Vascular Pathway Preservation Improves Survival in a Rat Three-Territory Flap Model Based on the Deep Circumflex Iliac Artery.

Extended flaps are commonly applied for large defects. However, a postoperative flap necrosis incidence of 11% to 44% remains a major complication. Previous clinical studies have shown that maintaining the extrinsic vascular pathway (EVP) can increase the survival area of extended flaps. The authors hypothesized that preserving the EVP would improve flap survival by reducing blood resistance within the vascular territory. Twenty-four adult male Sprague-Dawley rats were used. Tissue samples were obtained from eight untreated rats as a baseline control. Three-territory flaps were elevated in the remaining 16 rats. The EVP was preserved or ligated. Flap perfusion was assessed immediately using indocyanine green angiography. Rats were euthanized on day 7. The flap survival area was measured using Adobe Photoshop. Hematoxylin and eosin staining, CD31 immunostaining, and Western blot analysis of vascular endothelial growth factor protein expression were used to quantitatively assess vasodilation and angiogenesis in choke zones. Indocyanine green angiography revealed that blood could flow through the preserved EVP and perfuse the third vascular territory of the flap. EVP preservation significantly increased flap survival area (86.3%, 19.3% difference; P < 0.001), promoted vasodilation (5.0/choke zone, 3.0/choke zone difference; P = 0.013) and angiogenesis (29.3/mm 2 , 14.3/mm 2 difference; P = 0.002), and increased vascular endothelial growth factor expression (0.6, 0.2 difference; P = 0.067) in the second choke zone. EVP preservation improves flap survival in this rat three-territory flap model. Further investigation in large-animal models is required for clinical translation. Although further validation in large animal models and prospective clinical trials are necessary to verify the efficacy of the authors' hypothesis, their findings suggest that the EVP preservation procedure could provide an alternative for surgeons to create an extended flap in defect reconstruction.

Effects of Catalpol from Rehmannia glutinosa Extract on Skin Flaps.

Flaps are commonly used for repairing tissues and wounds in surgery. However, various factors can cause postoperative necrosis in these flaps. Catalpol is a bioactive component in extracts from Rehmannia glutinosa , which has pharmacologic characteristics that may improve flap survival. The experiments were performed in 36 male Sprague-Dawley rats divided into three groups: control, low-dose catalpol, and high-dose catalpol. The flap survival rate, neutrophil density, microvessel density, superoxide dismutase, and malondialdehyde levels were measured; histopathologic analysis was performed 7 days after surgery. Blood flow was measured by laser Doppler flowmetry and lead oxide-gelatin angiography. The levels of vascular endothelial growth factor, toll-like receptor 4, nuclear factor-kappa B, tumor necrosis factor-α, interleukin (IL)-6, nod-like receptor 3, cysteinyl aspartate specific proteinase-1 (caspase-1), IL-1β, and IL-18 were determined by immunohistochemistry. Catalpol treatment increased flap survival, reduced neutrophil recruitment and release, decreased malondialdehyde levels, and increased superoxide dismutase levels; thus, it effectively reduced oxidative stress, up-regulated the expression of vascular endothelial growth factor, and increased microvessel density. Laser Doppler flowmetry and lead oxide-gelatin angiography showed that catalpol treatment improved angiogenesis. Immunohistochemical analyses showed that catalpol inhibited the production of inflammatory factors, such as tumor necrosis factor-α and IL-6, by down-regulating toll-like receptor 4 and nuclear factor-κB. Furthermore, catalpol reduced cell pyroptosis by inhibiting the production of nod-like receptor 3 inflammasomes, thereby down-regulating the release of IL-1β and IL-18. Catalpol can improve the rate of flap survival. The research verified that the Rehmannia extract catalpol, through angiogenesis, inflammatory response, ischemia-reperfusion injury, and pyroptosis-related pathways, effectively improved the flap survival rate, which will provide new ideas for clinical medication.

Exosomes derived from human dental pulp stem cells increase flap survival with ischemia-reperfusion injuries.

Aim: To investigate the effect of hDPSC-Exos in flap I/R injury, a condition in which tissue damage increases after blood flow is restored to the flap after ischemia. Materials & methods: HUVECs were used to investigate the influences and mechanisms of hDPSC-Exos on cell proliferation and migration. A rat model was established to verify the role of hDPSC-Exos in flap I/R injuries in vivo. Results: hDPSC-Exos promoted the proliferation, migration and tube formation of HUVECs in a dose-dependent way by activating PI3K/AKT signaling pathway, and improved the survival and microvessel density of the flap and suppressed epithelial cell apoptosis. Conclusion: hDPSC-Exos can enhance flap repair after I/R injury. This process may be mediated by the activation of PI3K/AKT signaling pathway.

Postoperative free flap monitoring in reconstructive surgery-man or machine?

Free tissue transfer is widely used for the reconstruction of complex tissue defects. The survival of free flaps depends on the patency and integrity of the microvascular anastomosis. Accordingly, the early detection of vascular comprise and prompt intervention are indispensable to increase flap survival rates. Such monitoring strategies are commonly integrated into the perioperative algorithm, with clinical examination still being considered the gold standard for routine free flap monitoring. Despite its widespread acceptance as state of the art, the clinical examination also has its pitfalls, such as the limited applicability in buried flaps and the risk of poor interrater agreement due to inconsistent flap (failure) appearances. To compensate for these shortcomings, a plethora of alternative monitoring tools have been proposed in recent years, each of them with inherent strengths and limitations. Given the ongoing demographic change, the number of older patients requiring free flap reconstruction, e.g., after cancer resection, is rising. Yet, age-related morphologic changes may complicate the free flap evaluation in elderly patients and delay the prompt detection of clinical signs of flap compromise. In this review, we provide an overview of currently available and employed methods for free flap monitoring, with a special focus on elderly patients and how senescence may impact standard free flap monitoring strategies.

Fibroblast Growth Factor 9 Inhibited Apoptosis in Random Flap via the ERK1/2-Nrf2 Pathway to Improve Tissue Survival.

The application of random pattern skin flaps is limited in plastic surgery reconstruction due to necrosis. Fibroblast growth factor 9 (FGF9) was reported to exert a protective effect against myocardial damage and cerebral ischemia injury, but the impact of FGF9 in random flap survival is still unclear. In this study, we used a mouse model of random flaps to verify that FGF9 can directly increase flap survival area and blood flow intensity by promoting angiogenesis. In total, 84 male C57BL/6 mice weighing between 22 and 25 g were randomly divided into three groups (n = 28 each group). After skin flap operation, one group served as a control, a treatment group received FGF9, and a treatment group received FGF9+U0126. All flap samples were incised on postoperative day 7. Our results showed that flap survival was significantly increased in the FGF9 group compared with that in the control group. This protective function was restrained by U0126. The results of histopathology, laser Doppler, and fluorescent staining all showed significant increases in capillary count, collagen deposition, and angiogenesis. FGF9 also significantly increased the expression of antioxidant stress proteins SOD1, eNOS, HO-1, vascular marker proteins CD31, VE cadherin, and pericyte marker protein PDGFRβ. Western blot showed that the phosphorylation degree of ERK1/2 increased after FGF9 treatment, and the expression of Nrf2, a downstream factor, was u-regulated. Western blot and immunofluorescence results of apoptosis-related proteins cleaved caspase-3, BAX, and Bcl2 showed that FGF9 inhibited apoptosis. ERK inhibitor U01926 reduced the beneficial effects of FGF9 on skin flap survival, including promoting angiogenesis, and showing antiapoptosis and antioxidative stress activities. Exogenous FGF9 stimulates angiogenesis of random flap and survival of tissue. the impact of FGF9 is closely linked to the prevention of oxidative stress mediated by ERK1/2-Nrf2. In the function of FGF9 in promoting effective angiogenesis, there may be a close interaction in the FGF9-FGFR-PDGFR-ERK-VE cadherin pathway. In particular, PDGFR and VE cadherin may interact.

The Effect of Nitroglycerin Treatment Initiation Time on Survival in Partial Flap Necrosis: An Experimental Study.

Background: Nitroglycerin is suggested to improve flap survival based on promising results; however, there are no data on the effectiveness of treatment initiation time. This study aimed to compare the effect of various nitroglycerin treatment initiation times on partial flap survival. Materials and Methods: The study included 50 Sprague-Dawley rats. Modified McFarlane flaps were elevated on the dorsum of each rat. Group A received placebo treatment. Groups B, C, D, and E received topical nitroglycerin 2% starting 1 day before surgery, on the day of surgery, postoperative d 2, and postoperative d 4, respectively. After 7 days, the flap survival rates were calculated. Afterward, the severity and extent of inflammation and ischemia, and the severity of edema were evaluated histologically. Results: The flap survival rate was highest in group B, followed by groups C, D, E, and A. The difference between groups B and C was not significant, whereas the difference between group B and groups A, D, and E was. In addition, the difference between groups A, D, and E was not significant. Histological analysis showed that inflammation was less severe in groups B and C than in groups A, D, and E. Ischemia was the most severe in groups A and D and was the least severe in group C. Conclusion: Topical nitroglycerin treatment increases flap survival when initiated before or on the day of surgery, but has no benefit when initiated on postsurgery d 2 or 4. Preoperative initiation of nitroglycerin treatment positively affects flap survival.

Tissue-Protective Mechanisms of Bioactive Phytochemicals in Flap Surgery.

Despite careful preoperative planning, surgical flaps are prone to ischemic tissue damage and ischemia–reperfusion injury. The resulting wound breakdown and flap necrosis increase both treatment costs and patient morbidity. Hence, there is a need for strategies to promote flap survival and prevent ischemia-induced tissue damage. Phytochemicals, defined as non-essential, bioactive, and plant-derived molecules, are attractive candidates for perioperative treatment as they have little to no side effects and are well tolerated by most patients. Furthermore, they have been shown to exert beneficial combinations of pro-angiogenic, anti-inflammatory, anti-oxidant, and anti-apoptotic effects. This review provides an overview of bioactive phytochemicals that have been used to increase flap survival in preclinical animal models and discusses the underlying molecular and cellular mechanisms.

Systematic Review of Patient Safety and Quality Improvement Initiatives in Breast Reconstruction.

Improving patient care and safety requires high-quality evidence. The objective of this study was to systematically review the existing evidence for patient safety (PS) and quality improvement initiatives in breast reconstruction. A systematic review of the published plastic surgery literature was undertaken using a computerized search and following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Publication descriptors, methodological details, and results were extracted. Articles were assessed for methodological quality and clinical heterogeneity. Descriptive statistics were completed, and a meta-analysis was considered. Forty-six studies were included. Most studies were retrospective (52.2%) and from the third level of evidence (60.9%). Overall, the scientific quality was moderate, with randomized controlled trials generally being higher quality. Studies investigating approaches to reduce seroma (28.3% of included articles) suggested a potential benefit of quilting sutures. Studies focusing on infection (26.1%) demonstrated potential benefits to prophylactic antibiotics and drain use under 21 days. Enhanced recovery after surgery protocols (10.9%) overall did not compromise PS and was beneficial in reducing opioid use and length of stay. Interventions to increase flap survival (10.9%) demonstrated a potential benefit of nitroglycerin on mastectomy skin flaps. Overall, studies were of moderate quality and investigated several worthwhile interventions. More validated, standardized outcome measures are required, and studies focusing on interventions to reduce thromboembolic events and bleeding risk could further improve PS.

The potential effect of intradermal Botulinum Toxin Type-A (BTA) injection to increase extended random skin flap survival

Background: Extended random skin flap failure often occurs due to insufficient vascularization. Several attempts have been tried to increase the viability of the flap, but none of these attempts have achieved maximal success. Previous research has shown that Botulinum toxin type A (BTA) increases the viability of cutaneous flaps by inhibiting muscle contraction along with increasing vasodilation and angiogenesis. This study examines the effect of intradermal BTA injection on extended random skin flaps viability.Methods: In thirty-six Wistar rats, a rectangular random cutaneous flap (6 cm × 1.5 cm) was made on each dorsal rat area and then elevated the flap. The treatment group was intradermally injected evenly with BTA 8 IU and saline solution for the control group. Each rat flap viability was observed after five days. Primary outcome measures are survival flap area using Visitrak, microscopic assessment of the number and diameter of capillaries and Vascular Endothelial Growth Factor (VEGF) expression was analyzed using immunohistochemistry semi-quantitative scoring system. Data were analyzed using SPSS version 21 for Windows.Results: The treatment group has better results in all observed parameters than the control group. However, Only the VEGF expression of proximal edge showed a statistically significant increase in the group treated with BTA injection (p=0.004).Conclusion: This study showed that the BTA treatment has a positive effect on random skin flap survival and the reduction of distal necrosis in rats, so it has been proven that BTA has the potential to increase flap survival rates in small animal models. Further studies are needed to determine whether BTA treatment can produce similar findings in humans.

Standardization of the Rat Dorsal Random Pattern (McFarlane) Flap Model and Evaluation of the Pharmacological Agents Aiming to Salvage Partial Flap Necrosis: A Systematic Review and a Meta-analysis.

Partial flap necrosis is a common complication after surgery. McFarlane flap model has been used for assessment of various agents' effects on random flap survival. The aim of this study was to review the methodology of studies using this flap model and reveal the most successful agents. PubMed, Scopus, and Web of Science databases were screened for words "McFarlane flap," "flap survival," and ("flap" and "rat") by using time limits between 1965 and 2019. A total of 71 original articles were reviewed. Dimensions and base (cranial/caudal) of the flap, treatment protocol, follow-up period, and survival rates were extracted. Modified survival rates were calculated. Coefficients of variation of cranial/caudally based control group flaps and most commonly used flap models were calculated to assess interstudy variability. A total of 165 different treatment regimens were studied. One-hundred twelve regimens (67.9%) were found to increase flap survival. Most common flap dimensions were 9 cm × 3 cm, followed by 10 cm × 3 cm, 8 cm × 2 cm and 6 cm × 2 cm. Studies using caudally based flaps showed less interstudy variability, but survival rates were similar. Pentoxifylline, sildenafil, chlorpromazine, phenoxybenzamine, and phentolamine were reported to be successful in multiple studies. There are numerous agents found to be effective for treatment of partial flap necrosis, but further clinical research is needed. To overcome standardization problems, use of commonly used flap dimensions with a caudal base and interpretation of results after 7 days of follow-up seems appropriate.

Evaluation of leech therapy in flap venous congestion

Background: One of the common problems in flap surgery is venous congestion. The literature contains a plethora of alternative procedures to surgical revision for dealing with this issue. The leech therapy is one of these procedures. In the present study, leech therapy was used for the treatment of twenty cases with venous congested flaps. The technique, results and complications will be presented and discussed. Aim of the study: The aim of this study is to spotlight on the efficacy of leech therapy in salvage of venous congested flaps. Patients and Methods: A prospective clinical study was carried out on 20 patients with post-operative venous congested fascio-cutaneous flaps. These patients were treated by leech therapy at Al-Zahraa University Hospital and Al-Mataria Teaching Hospital during the period between May 2020 and April 2021. Results: The percentage of congested areas in the flaps before leech therapy was ranged between 10% and 100%. The final outcomes of these congested flaps after leech therapy were dramatic regarding improvement in venous congestion and subsequently flap survival. The flap survival rate was ranged between 60% and 100% with a mean of 88.25%. Conclusion: The use of leech therapy has proved its efficacy in significantly relieving flap venous congestion and subsequently increases flap survival rate. Leech therapy should be started as early as possible after other means of venous outflow establishment are exhausted. Guidelines should be strictly fulfilled to avoid biohazards of leech therapy.

Anterolateral thigh free flaps with T-shaped pedicles and multiple venous anastomosis for extremity reconstruction.

The anterolateral thigh free flap is one of the most preferred options for reconstructing soft tissues of the extremities and vascular anastomosis is one of the most important factors for flaps survival. T-anastomosis and double venous anastomosis have been widely used for increasing flap survival. This report shows both application of T-shape pedicle and multiple venous anastomosis to each 43 cases for extremity reconstruction that have not been described so far in the literature and it showed the necessity of multiple anastomosis. The locations of the lesions were 8 upper extremities (4 hands, 3 forearms, and 1 upper arm) and 35 lower extremities (5 forefeet, 6 dorsal feet, 4 plantar feet, 11 ankles, and 9 lower legs). We applied T-shaped arterial pedicle to limited anatomical area that had 2 or more major arterial communication sites to overcome the obstruction by reverse flow from communication vessels when 1 of the 2 anastomosis was obstructed. We classified multiple venous anastomosis according to flow direction and the vascular connections between the superficial and deep veins. In result, 37 cases survived completely but 2 flaps developed severe necrosis (>50%) because of infection and hematoma and 4 flaps developed partial necrosis due to wound infection. In conclusion, T-shaped pedicle and multiple venous anastomosis is a method to improve free flap survival and useful in cases where sacrificing a dominant vessel is inevitable or those in which only 1 vessel remains.

Botulinum Toxin A and B Improve Perfusion, Increase Flap Survival, Cause Vasodilation, and Prevent Thrombosis: A Systematic Review and Meta-analysis of Controlled Animal Studies.

A systematic review and meta-analysis of case-control animal model studies will help clarify the vascular effects of botulinum toxin (BTX). Preferred Reporting Items of Systematic reviews and Meta-Analyses guidelines were used to identify all animal case-control studies published before September 13, 2020, evaluating the vascular effects of BTX. Primary parameters included the following: perfusion, flap survival, arterial and venous dilation, and arterial and venous thrombosis. Thirty-six studies with 1032 animals met the systematic review inclusion criteria. Twenty-nine studies had quantifiable data for statistical analysis. Statistically significant increases in perfusion with BTX over saline were detected within 1 day and sustained up to 8 weeks. The following represent weighted mean data from the meta-analysis. The administration of BTX has a 26% increase in both random pattern and pedicled flap survival area over controls. Botulinum toxin causes vasodilation. Botulinum toxin increases vessel diameter in arteries by 40% and in veins by 46% compared with saline controls. The administration of BTX reduces thrombosis by 85% in arteries and by 79% in veins compared with saline controls. Vascular effects were consistent across both BTX-A and BTX-B serotypes, multiple animal species, and various doses. No clear relationships between vascular effects and BTX pretreatment time were identified. Perivascular BTX administration intraoperatively or as a chemical delay pretreatment several days before surgery in multiple animal species and models shows multiple changes to the vascular system. Extrapolation of lessons learned from this systematic review and meta-analysis of animal models could expand research and clinical use of BTX in human vascular disease and surgery.

Trans-Cinnamaldehyde Increases Random Pattern Flap Survival Through Activation of the Nitric Oxide Pathway

BackgroundThe application of random pattern skin flaps is limited in plastic surgery reconstruction due to necrosis. Trans-cinnamaldehyde has antibacterial, anticancer, and antioxidant properties. In this study, we aimed to investigate the effect of trans-cinnamaldehyde on skin flap survival and its possible mechanism regarding nitric oxide.Materials and MethodsOne hundred forty male Sprague-Dawley rats were randomly divided into seven groups (n = 20 each group). After the dorsal flap was raised, different doses of trans-cinnamaldehyde (10, 20, and 30 mg/kg) were immediately given by oral gavage in the three different groups. To assess the possible involvement of the nitric oxide system, NG-nitro-L-arginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) was used in this study. All flap samples were incised on postoperative day 7.ResultsOur results showed that flap survival was increased significantly in the 20 mg/kg (P < 0.001) trans-cinnamaldehyde (TC) group compared to the control group or 30 mg/kg TC group. This protective function was restrained by coadministration of L-NAME with 20 mg/kg TC. The results of histopathology, laser Doppler, arteriography mediated with oxide–gelatine, and fluorescent staining all showed a significant increase in capillary count, collagen deposition, angiogenesis, and flap perfusion. Immunohistochemistry results revealed a significant increase in the expression of CD34, eNOS, and VEGF.ConclusionTrans-cinnamaldehyde increased flap survival through the nitric oxide synthase pathway and contributed to angiogenesis. A concentration of 20 mg/kg trans-cinnamaldehyde was recommended in this study.

Butylphthalide Inhibits Autophagy and Promotes Multiterritory Perforator Flap Survival.

Multiterritory perforator flap is an important plastic surgery technique, yet its efficacy can be limited by partial necrosis at the choke Ⅱ zone. Butylphthalide (NBP) has been used for many diseases but has not been studied in the multiterritory perforator flap. With the effect of NBP, we observed increasing in capillary density, inhibition of autophagy and oxidative stress, and a reduction in apoptosis of cells, all consistent with increased flap survival. However, the protective effect of NBP on multiterritory perforator flap was lost following administration of the autophagy agonist rapamycin (Rap). Through the above results, we assumed that NBP promotes flap survival by inhibiting autophagy. Thus, this study has found a new pharmacological effect of NBP on the multiterritory perforator by inhibiting autophagy to prevent distal postoperative necrosis and exert effects on angiogenesis, oxidative stress, and apoptosis within the flap.

Ivermectin Increases Random-Pattern Skin Flap Survival in Rats: The Novel Role of GABAergic System

Ivermectin (IVM) was first used as an antiparasitic agent; however, the role of this drug evolved into a broad spectrum. Many mechanisms have been proposed, including interaction with the GABAergic system. Considering the presence of GABA receptor in the skin tissue and its role in ischemia-reperfusion I/R injury, we aimed to evaluate the effect of IVM through GABA receptors on random-pattern skin flap survival. Sixty Wistar male rats were used. Multiple doses of IVM (0.01, 0.05, 0.2, and 0.5mg/kg) were injected intraperitoneally before the surgery. Baclofen (selective GABAB agonist) and bicuculline (selective GABAA antagonist) were administered in combination with IVM to assess the role of the GABAergic system. Histopathological evaluations, immunohistochemical staining, quantitative assessment of IL-1β and TNFα, and the expression of GABAA α1 subunit and GABAB R1 receptors were evaluated in the skin tissue. IVM 0.05mg/kg could significantly increase flap survival compared with the control group (P<0.001). Subeffective dose of baclofen (0.1mg/kg) had synergistic effect with the subeffective dose of IVM (0.01mg/kg) (P<0.001), whereas bicuculline 1mg/kg reversed the effect of IVM (0.05mg/kg) (P<0.001). IVM 0.05mg/kg could also decrease the IL-1β and TNFα levels and increase the expression of GABAA α1 subunit and GABAB R1 receptors in the flap tissue compared with the control group. IVM could improve skin flap survival, probably mediated by the GABAergic pathway. Both GABAA and GABAB receptors are involved in this process. This finding may repurpose the use of old drug, "Ivermectin."