Individualized design program of multiple flaps for adapting different zones to repair large irregular wounds in children.

Objective: Management of large irregular wounds in children had been confusing plastic and reconstructive surgeons. Herein, this study was aimed to propose a new treatment method based on the principle of adapting different recipient zones to overcome the intractable wounds, simplifying and programing the design process of targeted flaps for covering large irregular soft-tissue defects. Patients and methods: From January 2009 to December 2020, 31 children (9 girls and 22 boys) aged 3-16 years (mean 9.8 years) underwent multiple modular flaps with edge to edge splicing reconstruction of the lower extremities. All the wounds were large with non-adjacent defects and with or without a dead space. Several variants of flaps were harvested according to the needs and reconstruction requirements of patients. Results: A total of 71 flaps were harvested from 31 patients and all flaps donor sites received primary closure. Nine patients underwent split-thickness skin grafting, and three cases of flaps survived from vascular crisis by rebuilding the vessels and the rest accepting LD flap transplants. And five partial necrosis of the distal epidermis flaps recovered using skin grafting and dressing change. No major complication was encountered in other patients and donor sites, except one heel ulcer. During the follow-up (ranging from 16 to 38 months, mean 27.7 months), aesthetic and functional results of reconstructed limbs were satisfactory in all patients. Conclusions: The Individualized design program of multiple flaps for adapting different recipient zones is an alternative for repairing large irregular soft-tissue defects in children, beneficial for plastic and reconstructive surgeons to simplify and program the process of designing and perform multiple flaps to achieve this goal. Level of evidence: III, Retrospective.

Emodin activates autophagy to suppress oxidative stress and pyroptosis via mTOR-ULK1 signaling pathway and promotes multi-territory perforator flap survival.

BACKGROUND: Multi-territory perforator flap reconstruction has been proven effective in treating large skin and soft tissue defects in clinical settings. However, in view of that the multi-territory perforator flap is prone to partial postoperative necrosis, increasing its survival is the key to the success of reconstruction. In this study, we aimed to clarify the effect of emodin on multi-territory perforator flap survival. METHODS: Flap survival was assessed by viability area analysis, infrared laser imaging detector, HE staining, immunohistochemistry, and angiography. Western blotting, immunofluorescence assays, and real-time fluorescent quantitative PCR were performed to detect the indicators of oxidative stress, pyroptosis and autophagy. RESULTS: After emodin treatment, the multi-territory perforator flap showed a significantly increased survival rate, which was shown to be closely related to the inhibition of oxidative stress and pyroptosis and enhanced autophagy. Meanwhile, the use of autophagy inhibitor 3 MA was found to reverse the inhibitory effects of emodin on oxidative stress and pyroptosis and weaken the improving effect of emodin on flap survival, suggesting that autophagy plays a critical role in emodin-treated flaps. Interestingly, our mechanistic investigations revealed that the positive effect of emodin on multi-territory perforator flap was attributed to the mTOR-ULK1 signaling pathway activation. CONCLUSIONS: Emodin can inhibit oxidative stress and pyroptosis by activating autophagy via the mTOR-ULK1 pathway, thereby improving the multi-territory perforator flap survival.

Free vascularized bone graft from the lateral epicondylar region of the humerus for treatment of scaphoid nonunion.

BACKGROUND: Free vascularized bone grafting (FVBG) has become one of the essential methods for treating scaphoid nonunion complicated by avascular necrosis. However, commonly used bone graft, including the medial femoral condyle bone graft and iliac crest bone graft, still present challenges such as a high rate of donor site complications and variations of vascular pedicle. In this study, we have introduced a novel bone graft-the lateral humeral condyle bone graft with the posterior branch of the radial collateral artery (PBRCA) as the vascular pedicle-as an alternative option, with the aim of overcoming some of the limitations of previously described FVBG procedures. METHODS: Nine patients who had a nonunion of the scaphoid that had been present for an average of 16.8 months (range 9-35 months) were managed with use of a free vascularized bone graft obtained from the lateral humeral epicondylar region. Avascularity of the scaphoid, as assessed on preoperative magnetic resonance imaging and intraoperative bone marrow puncture test. Postoperatively, regular X-ray and CT scans examinations were conducted to assess the progress of fracture healing. Active motion of the wrist, and grip strength recovery were measured periodically. Wrist pain was graded using the Visual Analogue Scale (VAS), while wrist joint functionality was evaluated using the Quick Disabilities of the Arm, Shoulder, and Hand (Quick-DASH) questionnaire and the Patient-Rated Wrist Evaluation (PRWE) scale. The elbow functional outcome was evaluated by the Mayo Elbow Performance Score (MEPS). RESULTS: All of nine lateral humeral epicondylar bone grafts were successfully harvested. The blood supply of the graft during surgery was excellent in six cases and good in three cases. The size of the bone grafts ranges from 1.0 cm × 0.5 cm × 0.5 cm to 2.0 cm × 1.0 cm × 0.5 cm. The average vascular pedicle length was 3.4 cm (range 2.0-6.0 cm). There were no early complications in either the donor or recipient areas after surgery. Union was successfully achieved in all nine patients, with an average time to union of 14.3 weeks (range 11-20 weeks) after surgery. The average follow-up period was 31.2 months (range 26-40 months). At the final follow-up, the average palmar flexion, dorsal extension, radial deviation, and ulnar deviation angles of the injured wrist joint were 56.1° (range 45°-70°), 56.1° (range 40°-80°), 10.6° (range 5°-20°), and 22.2° (range 15°-35°), respectively, which reached 79.0%, 82.1%, 59.4%, and 72.8% of the average activity of the contralateral normal side. The average grip strength of the injured side was 35.2 kg (range 22-51 kg), which was equivalent to 81.3% of the average grip strength of the contralateral side. The average VAS score for wrist joint pain was 1.0 point (range 0-2 points); the Quick-DASH score was 9.2 points (range 6-18 points); and the PRWE score was 13.1 points (range 9-16 points), the Mayo Elbow Performance Index was 100 points (range 100-100 points). One patient reported a feeling of friction during movement but no pain. One patient reported numbness in the donor site. One patient complained of pain when applying force to the scar in the donor area. During the follow-up period, these complications showed improvement without any treatment. CONCLUSION: The FVBG technique has been considered an effective method for treating scaphoid nonunion with avascular necrosis. Compared to traditional FVBG, the lateral humeral epicondylar bone graft exhibits a higher union rate, fewer complications, and easier accessibility, making it a favorable choice.

M2 macrophage-derived exosomes induce angiogenesis and increase skin flap survival through HIF1AN/HIF-1α/VEGFA control.

BACKGROUND: Skin flap transplantation is a routine strategy in plastic and reconstructive surgery for skin-soft tissue defects. Recent research has shown that M2 macrophages have the potential for pro-angiogenesis during tissue healing. METHODS: In our research, we extracted the exosomes from M2 macrophages(M2-exo) and applied the exosomes in the model of skin flap transplantation. The flap survival area was measured, and the choke vessels were assessed by morphological observation. Hematoxylin and eosin (H&E) staining and Immunohistochemistry were applied to assess the neovascularization. The effect of M2-exo on the function of Human umbilical vein endothelial cells (HUVECs) was also investigated. We also administrated 2-methoxyestradiol (2-ME2, an inhibitor of HIF-1α) to explore the underlying mechanism. We tested the effects of M2-Exo on the proliferation of HUVECs through CCK8 assay and EdU staining assay. RESULTS: The survival area and number of micro-vessels in the skin flaps were increased in the M2-exo group. Besides, the dilation rate of choke vessels was also enhanced in the M2-exo group. Additionally, compared with the control group, M2-exo could accelerate the proliferation, migration and tube formation of HUVECs in vitro. Furthermore, the expression of the pro-angiogenesis factors, HIF-1α and VEGFA, were overexpressed with the treatment of the M2-exo. The expression of HIF1AN protein level was decreased in the M2-exo group. Finally, treatment with HIF-1α inhibitor reverses the pro-survival effect of M2-exo on skin flaps by interfering with the HIF1AN/HIF-1α/VEGFA signaling pathway. CONCLUSION: This study showed that M2-exosomes promote skin flap survival by enhancing angiogenesis, with HIF1AN/HIF-1α/VEGFA playing a crucial role in this process.

The versatile thoracodorsal artery perforator flap for extremity reconstruction: from simple to five types of advanced applications and clinical outcomes.

BACKGROUND: Application of the thoracodorsal artery perforator (TDAP) flap is known to be a popular and reliable method for extremity reconstruction. This manuscript presents our clinical outcomes in reconstructing soft tissue defects using simple and advanced TDAP flaps. METHODS: From 2013 to 2022, 53 patients with a mean age of 23 years (ranging from 2 to 72 years) underwent reconstructive surgery with different patterns of free TDAP flaps, including chimeric TDAP flaps, double skin paddle TDAP flaps, flow-through TDAP flaps, conjoined TDAP flaps, and microdissected debulking TDAP flaps. RESULTS: All TDAP flaps survived. The size of the TDAP skin paddle ranged between 5 × 3 and 25 × 10 cm2. Primary closure of the donor site was achieved in all patients in the simple application group, and one patient in the advanced application group underwent partial skin grafting. Partial flap loss occurred in one case in the simple TDAP flap group and four cases in the advanced application group. There was one case of flap bulkiness and two cases of scar hyperplasia in the simple TDAP flap group. The mean follow-up duration was 11 months (4-46 months). CONCLUSIONS: The free TDAP flap, with five types of advanced applications, makes it versatile for reconstructing different kinds of soft tissue defects of the extremities that can be used to achieve individualized defect reconstruction, minimize donor site morbidities, and an aesthetic appearance.

Variations in deep iliac circumflex artery perforator chimeric flap design for single-stage customized-reconstruction of composite bone and soft-tissue defect.

BACKGROUND: The deep iliac circumflex artery (DICA) perforator (DICAP) chimeric flap is a valuable treatment strategy for single-stage reconstruction of composite bone and soft-tissue defects in upper and lower extremities. However, its utilization rate remains low owing to anatomical variations that lead to challenges when identifying and dissecting perforators. METHODS: A comprehensive anatomical investigation was conducted on the DICA system by injecting lead oxide into 12 fresh cadavers following a standardized procedure. From January 2008 to December 2020, 30 patients with composite bone and soft-tissue defects received reconstruction surgery with DICAP chimeric flap. One of the four specified surgical techniques was used to create a modified DICAP chimeric flap for the patients based on the size, shape, and location of the defect. RESULTS: Two branching patterns of DICA, transverse and ascending branches, were observed, and the former gave off the osteomusculocutaneous perforators and terminal musculocutaneous perforators. Thirty DICAP chimeric flaps were elevated successfully. The size of the skin paddles measured from 9 × 4.5 cm to 22 × 9 cm, and the bone components ranged from 3 × 2.5 × 1.5 cm to 6 × 3.5 × 2 cm. All flaps survived successfully after the operation, and all patients achieved primary closure of the donor sites. No patient encountered the fracture of transferred iliac segments. The mean bone union time was 5.5 months (ranging from 4 to 8 months). CONCLUSION: The DICA system is a suitable source for harvesting the DICAP chimeric flap to reconstruct composite bone and soft-tissue defects. It provides a flexible design for individualized coverage of such defects with limited donor-site morbidity.

Identification of A Novel Variant of Filamin A Destroying the Attraction Between Benzene Rings and Sulfhydryl in Developmental Dysplasia of the Hip.

Developmental dysplasia of the hip (DDH), characterized by acetabular deformity that manifests from loose ligaments to complete dislocation of the hip, can cause notable pain and dysfunction and lead to hip dislocation, secondary fractures, scoliosis, and osteoarthritis of hip. Variants in FLNA may produce a spectrum of malformations in multiple organs, especially the skeleton. This study aimed to identify the genetic etiologies of DDH patients and provide genetic testing information for further diagnosis and treatment of DDH. We recruited a Chinese woman with DDH and her family members. Whole-exome sequencing was used to identify the patient's genetic etiologies. Protein models were used to analyze the pathogenic mechanism of the identified variants. A novel variant (c.3493T>G, p.C1165G) of FLNA was detected. The structural models of the mutant FLNA protein indicated that the variant would lose its sulfhydryl side chain and destroy the attraction between benzene rings and sulfhydryl. We reported a novel variant (c.3493T>G, p.C1165G) of FLNA in a Chinese woman with DDH. Our research outcome enriches the gene pool for hip dysplasia and emphasizes the pathogenicity of sulfhydryl side chain disruption in FLNA.

Exosomes derived from LPS-preconditioned bone marrow-derived MSC modulate macrophage plasticity to promote allograft survival via the NF-κB/NLRP3 signaling pathway.

OBJECTIVES: This study investigated whether exosomes from LPS pretreated bone marrow mesenchymal stem cells (LPS pre-MSCs) could prolong skin graft survival. METHODS: The exosomes were isolated from the supernatant of MSCs pretreated with LPS. LPS pre-Exo and rapamycin were injected via the tail vein into C57BL/6 mice allografted with BALB/c skin; graft survival was observed and evaluated. The accumulation and polarization of macrophages were examined by immunohistochemistry. The differentiation of macrophages in the spleen was analyzed by flow cytometry. For in vitro, an inflammatory model was established. Specifically, bone marrow-derived macrophages (BMDMs) were isolated and cultured with LPS (100 ng/ml) for 3 h, and were further treated with LPS pre-Exo for 24 h or 48 h. The molecular signaling pathway responsible for modulating inflammation was examined by Western blotting. The expressions of downstream inflammatory cytokines were determined by Elisa, and the polarization of macrophages was analyzed by flow cytometry. RESULTS: LPS pre-Exo could better ablate inflammation compared to untreated MSC-derived exosomes (BM-Exo). These loaded factors inhibited the expressions of inflammatory factors via a negative feedback mechanism. In vivo, LPS pre-Exo significantly attenuated inflammatory infiltration, thus improving the survival of allogeneic skin graft. Flow cytometric analysis of BMDMs showed that LPS pre-Exo were involved in the regulation of macrophage polarization and immune homeostasis during inflammation. Further investigation revealed that the NF-κB/NLRP3/procaspase-1/IL-1ß signaling pathway played a key role in LPS pre-Exo-mediated regulation of macrophage polarization. Inhibiting NF-κB in BMDMs could abolish the LPS-induced activation of inflammatory pathways and the polarization of M1 macrophages while increasing the proportion of M2 cells. CONCLUSION: LPS pre-Exo are able to switch the polarization of macrophages and enhance the resolution of inflammation. This type of exosomes provides an improved immunotherapeutic potential in prolonging graft survival.

Clinical application of magnetic resonance lymphangiography in the vascularized omental lymph nodes transfer with or without lymphaticovenous anastomosis for cancer-related lower extremity lymphedema.

Background: The recent increase in the number of patients with lower extremities lymphedema and the development of microsurgery techniques have led to a rise in lymphedema treatment. Vascularized omental lymph node transfer (VOLT), an emerging treatment modality for extremity lymphedema, has shown its unique advantages in reconstructing lymphatic circulation and absorbing exudated lymphatic fluid. Patients who underwent radical tumor resection with/without radiation therapy treatment often present with impairment or degeneration of the inguinal lymph nodes. For such cases, VOLT could provide adequate lymph nodes and tissue to absorb edema fluid in these areas. Therefore, we analyzed the operative outcomes of VOLT under the guidance of magnetic resonance lymphangiography (MRL) in this study, as this individualized and precise surgical procedure could benefit patients and improve their quality of life. Methods: From November 2021 to September 2022, a total of 14 patients' 19 legs with extremity lymphedema underwent a VOLT with or without lymphaticovenous anastomosis (LVA). Outcomes, including circumference reduction rates, preoperative and postoperative MRL results, and other complications, were analyzed. Results: The mean follow-up period was 8.86±1.41 months (range, 7-11 months). The mean circumference reduction rates {circumference reduction rate (%) = [1 - (postoperative affected limb - healthy limb)/(preoperative affected limb - healthy limb)] × 100%} of different planes (i.e., ankle, 10 cm above the knee, 10 cm below the knee, 10 cm above the ankle, and 20 cm above the knee) were 15.64%±40.08%, 11.79%±30.69%, 20.25%±24.94%, 7.73%±30.05%, -1.517%±16.75%. Notably, one patient had multi-drug-resistant gram-negative infections, which resulted in the loss of three flaps. The postoperative MRL showed improved lymphatic drainage and lower extremity volume in the remaining 13 cases. Conclusions: The precision evaluation of inguinal lymph nodes and lower extremities lymphatic system through MRL using VOLT can provide surgeons with a comprehensive understanding and reliable evidence for the treatment of cancer-related lower extremity lymphedema.

Hypoxic mesenchymal stem cell-derived exosomes promote the survival of skin flaps after ischaemia-reperfusion injury via mTOR/ULK1/FUNDC1 pathways.

Flap necrosis, the most prevalent postoperative complication of reconstructive surgery, is significantly associated with ischaemia-reperfusion injury. Recent research indicates that exosomes derived from bone marrow mesenchymal stem cells (BMSCs) hold potential therapeutic applications in several diseases. Traditionally, BMSCs are cultured under normoxic conditions, a setting that diverges from their physiological hypoxic environment in vivo. Consequently, we propose a method involving the hypoxic preconditioning of BMSCs, aimed at exploring the function and the specific mechanisms of their exosomes in ischaemia-reperfusion skin flaps. This study constructed a 3 × 6 cm2 caudal superficial epigastric skin flap model and subjected it to ischaemic conditions for 6 h. Our findings reveal that exosomes from hypoxia-pretreated BMSCs significantly promoted flap survival, decrease MCP-1, IL-1ß, and IL-6 levels in ischaemia-reperfusion injured flap, and reduce oxidative stress injury and apoptosis. Moreover, results indicated that Hypo-Exo provides protection to vascular endothelial cells from ischaemia-reperfusion injury both in vivo and in vitro. Through high-throughput sequencing and bioinformatics analysis, we further compared the differential miRNA expression profiles between Hypo-Exo and normoxic exosomes. Results display the enrichment of several pathways, including autophagy and mTOR. We have also elucidated a mechanism wherein Hypo-Exo promotes the survival of ischaemia-reperfusion injured flaps. This mechanism involves carrying large amounts of miR-421-3p, which target and regulate mTOR, thereby upregulating the expression of phosphorylated ULK1 and FUNDC1, and subsequently further activating autophagy. In summary, hypoxic preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of BMSC-derived exosomes in the treatment of flap ischaemia-reperfusion injury.

Knowledge mapping and emerging trends of ferroptosis in ischemia reperfusion injury research: A bibliometric analysis (2013-2022).

Objective: Ischemia/reperfusion (I/R) injury is an inevitable dilemma when previously ischemic multiple organs and tissues are returned to a state of blood flow, with confirming a critical role of ferroptosis in molecular, pathway mechanisms, subcellular structure. Discovering the potential relationship may provide useful approaches for the clinical treatment and prognosis of the pathophysiological status of IRI. Therefore, a comprehensive visualization and scientometric analysis were conducted to systematically summarize and discuss the "ferroptosis in ischemia reperfusion injury" research to demonstrate directions for scholars in this field. Methods: We retrieved all publications focusing on I/R injury and ferroptosis from the Web of Science Core Collection (WoSCC), published from 2013 to October 2022. Next, scientometric analysis of different items was performed using various bibliometrics softwares to explore the annual trends, countries/regions, institutions, journals, authors and their multi-dimensional relationship pointing to current hotspots and future advancement in this field. Results: We included a total of 421 English articles in set timespan. The number of publications increased steadily annually. China produced the highest number of publications, followed by the United States. Most publications were from Central South University, followed by Sichuan University and Wuhan University. The most authoritative academic journal was Oxidative Medicine and Cellular Longevity. Cell occupied the first rank of co-cited journal list. Andreas Linkermann and Scott J Dixon may have the highest influence in this intersected field with the highest number of citations and co-cited references respectively. The essential biological reactions such as oxidative stress response, lipid peroxidation metabolism, anti-inflammmatory and pro-inflammatory procedure, and related molecular pathways were knowledge base and current hotspots. Molecules pathways exploration, effective inhibition of I/R injury and promising strategy of improving allografts may become future trends and focuses. Conclusions: Research on ferroptosis in I/R injury had aroused great interest recently. This first bibliometric study comprehensively analyzed the research landscape of ferroptosis and I/R injury, and also provided a reliable reference for related scholars to facilitate further advancement in this field.

Down-Regulation of HSP by Pd-Cu Nanozymes for NIR Light Triggered Mild-Temperature Photothermal Therapy Against Wound Bacterial Infection: In vitro and in vivo Assessments.

Purpose: We aimed to develop an oxidative-stress-activated palladium-copper nanozyme to reduce bacterial's heat sensitivity by down-regulating heat shock proteins to overcome the shortcomings of conventional photothermal antimicrobial therapy and achieve mild photothermal bactericidal efficacy. Methods: We first synthesized palladium-copper nanozymes (PC-NPs) by hydration and used transmission electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy to demonstrate their successful preparation. Their photothermal therapy (PTT) and chemo-dynamic therapy (CDT) activities were then determined by a series of photothermal performance tests and peroxidase-like performance tests, and the destruction of heat shock proteins by reactive oxygen species (ROS) was verified at the protein level by Western Blotting tests, providing a basis for the effective bacteria-killing by the mild-temperature photothermal treatment subsequently applied. We also validated this promising programmed and controlled antimicrobial treatment with palladium-copper nanozymes by in vivo/in vitro antimicrobial assays. A hemolysis assay, MTT cytotoxicity test and histopathological analysis were also performed to assess the in vivo safety of PC-NPs. Results: In the micro-acidic environment of bacterial infection, PC-NPs showed peroxidase-like activity that broke down the H2O2 at the wound into hydroxyl radicals and down-regulated bacterial heat shock proteins. The application of PC-NPs increased bacteria's sensitivity to subsequent photothermal treatment, enabling the elimination of bacteria via mild photothermal treatment. Conclusion: The programmed synergistic catalytic enhancement of CDT and mild photothermal therapy achieves the most efficient killing of bacteria and their biofilms, which brings future thinking in the relationship between heat shock proteins and oxidative stress damage in bacteria.

The application of infrared thermography technology in flap: A perspective from bibliometric and visual analysis.

The application of infrared thermography technology (IRT) in flap has become a major focus of research, as it provides a non-invasive, real-time, and quantitative approach for monitoring flap perfusion. In this regard, we conducted a comprehensive visualization and scientometric analysis to systematically summarize and discuss the current state of research in this field. We systematically reviewed publications on the application of IRT in flap procedures from 1999 to 2022, using the Web of Science Core Collection (WoSCC). Through scientometric analysis, we examined annual trends, affiliations, countries, journals, authors, and their relationships, providing insights into current hotspots and future developments in this area. We analysed 522 English studies and found a steady increase in annual publications. The United States and Germany had the highest publication rates, with Beth Israel Deaconess Medical Center and Shanghai Jiaotong University being leading institutions. Notably, Lee BT and Alex Keller emerged as influential authors in this field. Compared to existing techniques, infrared-based technology offers significant advantages for non-invasive monitoring of flap perfusion, including simplicity of operation and objective results. Future trends should focus on interdisciplinary collaborations to develop new infrared devices and achieve intelligent image processing, enabling broader application in various clinical scenarios. This bibliometric study summarizes the progress and landscape of research on 'the Application of infrared thermography technology in flap' over the past two decades, providing valuable insights and serving as a reliable reference to drive further advancements and spark researchers' interest in this field.

Itaconic acid induces angiogenesis and suppresses apoptosis via Nrf2/autophagy to prolong the survival of multi-territory perforator flaps.

Background: Perforator flaps are widely used in hand microsurgery to reconstruct and repair soft tissue injuries. However, ischemia and subsequent ischemia-reperfusion injury may cause distal necrosis of the flap. Itaconic acid (IA) is a modulator of macrophage function, which exerts anti-inflammatory effects in macrophage activation. Methods: The necrotic area of the flap was detected by measuring the flap temperature with an infrared thermometer. Flap cell apoptosis was detected by TUNEL staining and Western blot analysis of the apoptosis-associated proteins Bcl-2 and Bax. HE staining was used to detect angiogenesis of the skin flaps. CD31 was detected to identify positive vascular expression, and the survival of choke vessels in different areas of the skin flap was assessed by arteriography. In addition, Western blot was performed to quantify the expressions of VEGF, Nrf2, LC3II, SQSTM1, and CTSD. Results: Itaconic acid raises VEGF protein levels in skin flaps and the number of CD31-positive vessels. The skin flaps in the IA treatment group exhibited higher neovascularization and less necrosis than those in the control group. The results of TUNEL staining and Western blot revealed that Itaconic acid attenuated apoptosis in the ischemic area of flap. The combination of itaconic acid and Nrf2 inhibitor ML385 reversed this beneficial effect. The results revealed that itaconic acid attenuated apoptosis, enhanced angiogenesis, and enhanced autophagy. Conclusion: In summary, our findings indicate that itaconic acid might be an effective treatment to reduce flap necrosis. Additionally, this study identified a novel mechanism for the effects of itaconic acid on flap survival.

Development and usability of a Mobile Interactive Application (VCPW) for Vascular Crisis Prewarning after Skin Flap Transplantation.

Background: In microsurgical tissue transfer, skin flap transplantation is frequently used to heal the surface of a wound. Effective microcirculation surveillance of the skin flap is crucial. However, with traditional monitoring methods-that is, clinical observation-vascular crisis can still occur, thereby impairing postoperative recovery. A smartphone application is required to assist health care professionals in the standardized collection of flap perfusion parameters for flap management. Methods: The Vascular Crisis Prewarning Application was created using a design science research methodology that prioritizes users and problems. The system usability scale was used to assess the application's usability among medical practitioners. The application was used at the clinic from December 2020 to September 2022. The unplanned return to the operating room, time to diagnose vascular crisis, and flap survival rate were compared with and without the application. Results: The application consisted of 5 modules: patient addition and basic information entry, flap labeling, flap observation, crisis warning, and case archiving. The average rating for the application's usability among medical practitioners was 97.95 score (SD 2.36). With the application, the time to detect vascular crisis reduced from 26.71 to 16.26 h (P < 0.001), the unplanned return to the operation room increased from 8.18% to 10.24% (P = 0.587), and the flap survival rate went from 94.55% to 99.21% (P = 0.083). Conclusions: An easy-to-use flap perfusion monitoring and prewarning application for medical practitioners was produced using a user-centered development method. The application provided a more standardized and accurate platform for data collection in flap management and reduced the time to detect vascular crisis. Larger cohort studies are required in the future to better assess the full potential of the application.

Substance P promote macrophage M2 polarization to attenuate secondary lymphedema by regulating NF-kB/NLRP3 signaling pathway.

Secondary lymphedema often occurs after filariasis, trauma, lymph node dissection and radiation therapy, which is manifested by infiltration of inflammatory cells and fibrosis formation in pathologically. Substance P is a widely used neuropeptide in the field of tissue repair, while the regenerative potential of the substance P has not been proven in the secondary lymphedema. In this study, animal model of secondary lymphedema was constructed by excising the skin and subcutaneous lymphatic network in the tail of mice, and the degree of swelling in the tail of mice was evaluated after 6 weeks under the treatment with substance P. Immunofluorescence staining was also performed to assess immune cell infiltration, subcutaneous fibrosis and lymphangiogenesis. The results revealed that substance P significantly alleviated post-surgical lymphedema in mice. Furthermore, we found that substance P promoted macrophages M2 polarization, a process associated with downregulation of the NF-kB/NLRP3 pathway. After application of disodium clodronate (macrophage scavenger, CLO), the positive effect of substance P in lymphedema is significantly inhibited. In vitro experiments, we further demonstrated the polarizing effect of substance P on bone marrow-derived macrophages (BMDMs), while substance P inhibited the activation of the NF-kB/NLRP3 pathway in BMDMs after the treatment of lipopolysaccharide (LPS). In addition, polarized macrophages were demonstrated to promote the proliferation, tube-forming and migratory functions of human lymphatic endothelial cells (hLEC). In conclusion, our study provides preliminary evidence that substance P alleviates secondary lymphedema by promoting macrophage M2 polarization, and this therapeutic effect may be associated with downregulation of the NF-kB/NLRP3 pathway.

Metformin induces M2 polarization via AMPK/PGC-1α/PPAR-γ pathway to improve peripheral nerve regeneration.

OBJECTIVES: Investigating the effect of metformin on peripheral nerve regeneration and the molecular mechanism. METHODS: In this study, a rat model of sciatic nerve injury and an inflammatory bone marrow-derived macrophage (BMDM) cell model were established. We assessed the sensory and motor function of the hind limbs four weeks after sciatic nerve injury, immunofluorescence was used to detect axonal regeneration and myelin formation, as well as local macrophage subtypes. We investigated the polarizing effect of metformin on inflammatory macrophages, and western blotting was applied to detect the molecular mechanisms behind it. RESULTS: Metformin treatment accelerated functional recovery, axon regeneration and remyelination, and promoted M2 macrophage polarization. In vivo, metformin transformed pro-inflammatory macrophages into pro-regeneration M2 macrophages. Protein expression levels of phosphorylated AMP-activated protein kinase (p-AMPK), proliferator-activated receptor-γ co-activator 1α (PGC-1α), and peroxisome proliferator-activated receptor-γ (PPAR-γ) increased upon metformin treatment. Moreover, inhibition of AMPK abolished the effects of metformin treatment on M2 polarization. CONCLUSION: Metformin promoted M2 macrophage polarization by activating the AMPK/PGC-1α/PPAR-γ signaling axis, thereby promoting peripheral nerve regeneration.

A human pan-cancer system analysis of heat shock protein family A member 5.

Heat shock protein family A member 5 (HSPA5) plays a pivotal role in the endoplasmic reticulum (ER) stress response and unfolded protein response (UPR), both of which are crucial for protein folding, assembly, and quality control within cells. In response to ER stress, HSPA5 becomes overexpressed to preserve cellular homeostasis. A previous study revealed a robust association between HSPA5 expression and various cancers. However, the prognostic function of HSPA5 and its involvement in tumor formation remain largely unknown. In this study, we integrated HSPA5 expression data from databases such as the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) to conduct a comprehensive pan-cancer analysis of HSPA5. Our findings revealed that HSPA5 is overexpressed in various tumor types and is significantly associated with poor prognosis. Additionally, HSPA5 expression is significantly correlated with immune checkpoints, stromal infiltration, and consequent alterations in the immune landscape. Verification was conducted on samples from patients with various tumor types, including breast and liver cancers. Additionally, we also performed verification in vitro. In conclusion, HSPA5 may offer a potential target for cancer treatment.

Efficacy comparison of vascularized iliac crest bone flap and Ilizarov bone transport in the treatment of traumatic bone defects of the tibia combined with large soft tissue defects.

BACKGROUND: Traumatic tibial defect complicated with soft tissue defect is a difficult problem in clinic. Vascularized iliac crest bone flap (VIBF) and Ilizarov bone transport are effective methods to treat tibial defects with limited defect length, which most need to be explored accordingly. METHODS: In this study, a total of 68 patients with traumatic tibial defect (ranging from 4 to 10 cm) and large soft tissue defect were collected retrospectively. The soft tissue defects were repaired by latissimus dorsal musculocutaneous flap (LD), anterolateral thigh flap (ALTF) or both. Thirty-three cases were treated with vascularized iliac crest bone flap transplantation and 35 cases were treated with Ilizarov bone transport. Intraoperative and postoperative follow-up data (including operation time, blood loss, bone union time, external fixation time, external fixation index, complication rate, reoperation rate, and functional evaluation) were recorded, and comparative analysis was performed. RESULTS: The median follow-up time was 32 months. Compared with Ilizarov group, the VIBF group exhibited statistically faster bone union time (6.3 ± 1.0 vs. 18.2 ± 3.0 months). Moreover, the VIBF group showed shorter EFT (7.3 ± 1.0 vs. 19.2 ± 3.0 months) and a better EFI (34.8 ± 9.2 vs. 84.2 ± 23.7 days/cm). The excellent and good rate of lower limb appearance evaluation in VIBP group was significantly better than that in Ilizarov group. The complication rate and reoperation rate were significantly higher in Ilizarov group. CONCLUSION: In summary, compared with Ilizarov bone transport, VIBP has the advantages of faster healing, shorter external fixation time, lower complication and reoperation rate, and better appearance within the limited defect length. Ilizarov bone transport is still preferred when the defect length exceeds the maximum repair length of the iliac flap. The daily handling required by bone transport process is painful. LEVEL OF EVIDENCE: III, Case-control study.

Individualized design of thoracodorsal artery perforator chimeric flap for customized reconstruction of complex three-dimensional defects in the extremities.

BACKGROUND: It was always challenging to accurately and effectively reconstruct the complicated defects with three-dimensional tissue deficits in the extremities. Muscle-chimeric perforator flap is an excellent choice for repairing those complicated wound. However, problems like donor-site morbidity and time-consuming intramuscular dissection still exist. This purpose of this study was to present a novel design of the thoracodorsal artery perforator (TDAP) chimeric flap for the customized reconstruction of complex three-dimensional tissue defects in the extremities. METHODS: From January 2012 to June 2020, 17 patients with complex three-dimensional deficits in the extremities were retrospectively analyzed. All patients in this series underwent extremity reconstruction using latissimus dorsi (LD)-chimeric TDAP flap. Three different types of LD-chimeric TDAP flaps were performed. RESULTS: A total of seventeen TDAP chimeric flaps were successfully harvested for the reconstruction of those complex three-dimensional defects in extremities. Among them, Design Type A flaps were used in 6 cases, Design Type B flaps were performed in 7 cases, and Design Type C flaps were used in the remaining 4 cases. The sizes of the skin paddles ranged from 6 cm × 3 cm to 24 cm × 11 cm. Meanwhile, the sizes of the muscle segments ranged from 3 cm × 4 cm to 33 cm × 4 cm. All the flaps survived. Nevertheless, one case required re-exploration owing to venous congestion. Moreover, the primary closure of the donor site was successfully achieved in all patients, and the mean follow-up time was 15.8 months. Most of the cases displayed satisfactory contour. CONCLUSION: The LD-chimeric TDAP flap is available for the reconstruction of complicated defects with three-dimensional tissue deficits in the extremities. It provided a flexible design for customized coverage of complex soft tissue defects with limited donor site morbidity.