Neuregulin-1, a member of the epidermal growth factor family, mitigates STING-mediated pyroptosis and necroptosis in ischaemic flaps.

Background: Ensuring the survival of the distal end of a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention of programmed cell death is a potential strategy for inhibiting ischaemic flap necrosis. The activation of stimulator of interferon genes (STING) pathway promotes inflammation and leads to cell death. The epidermal growth factor family member neuregulin-1 (NRG1) reduces cell death by activating the protein kinase B (AKT) signalling pathway. Moreover, AKT signalling negatively regulates STING activity. We aimed to verify the efficacy of NRG1 injection in protecting against flap necrosis. Additionally, we investigated whether NRG1 effectively enhances ischemic flap survival by inhibiting pyroptosis and necroptosis through STING suppression. Methods: A random-pattern skin flap model was generated on the backs of C57BL/6 mice. The skin flap survival area was determined. The blood supply and vascular network of the flap was assessed by laser Doppler blood flow analysis. Cluster of differentiation 34 immunohistochemistry (IHC) and haematoxylin and eosin (H&E) staining of the flap sections revealed microvessels. Transcriptome sequencing analysis revealed the mechanism by which NRG1 promotes the survival of ischaemic flaps. The levels of angiogenesis, oxidative stress, necroptosis, pyroptosis and indicators associated with signalling pathways in flaps were examined by IHC, immunofluorescence and Western blotting. Packaging adeno-associated virus (AAV) was used to activate STING in flaps. Results: NRG1 promoted the survival of ischaemic flaps. An increased subcutaneous vascular network and neovascularization were found in ischaemic flaps after the application of NRG1. Transcriptomic gene ontology enrichment analysis and protein level detection indicated that necroptosis, pyroptosis and STING activity were reduced in the NRG1 group. The phosphorylation of AKT and forkhead box O3a (FOXO3a) were increased after NRG1 treatment. The increased expression of STING in flaps induced by AAV reversed the therapeutic effect of NRG1. The ability of NRG1 to phosphorylate AKT-FOXO3a, inhibit STING and promote flap survival was abolished after the application of the AKT inhibitor MK2206. Conclusions: NRG1 inhibits pyroptosis and necroptosis by activating the AKT-FOXO3a signalling pathway to suppress STING activation and promote ischaemic flap survival.

Causal effects for neurodegenerative diseases on the risk of myocardial infarction: a two-sample Mendelian randomization study.

Several studies have demonstrated a correlation between neurodegenerative diseases (NDDs) and myocardial infarction (MI), yet the precise causal relationship between these remains elusive. This study aimed to investigate the potential causal associations of genetically predicted Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple sclerosis (MS) with MI using two-sample Mendelian randomization (TSMR). Various methods, including inverse variance weighted (IVW), weighted median (WM), MR-Egger regression, weighted mode, and simple mode, were employed to estimate the effects of genetically predicted NDDs on MI. To validate the analysis, we assessed pleiotropic effects, heterogeneity, and conducted leave-one-out sensitivity analysis. We identified that genetic predisposition to NDDs was suggestively associated with higher odds of MI (OR_IVW=1.07, OR_MR-Egger=1.08, OR_WM=1.07, OR_weighted mode=1.07, OR_simple mode=1.10, all P<0.05). Furthermore, we observed significant associations of genetically predicted DLB with MI (OR_IVW=1.07, OR_MR-Egger=1.11, OR_WM=1.09, OR_weighted mode=1.09, all P<0.05). However, there was no significant causal evidence of genetically predicted PD and MS in MI. Across all MR analyses, no horizontal pleiotropy or statistical heterogeneity was observed (all P>0.05). Additionally, results from MRPRESSO and leave-one-out sensitivity analysis confirmed the robustness of the causal effect estimations for genetically predicted AD, DLB, PD, and MS on MI. This study provides further support for the causal effects of AD on MI and, for the first time, establishes robust causal evidence for the detrimental effect of DLB on the risk of MI. Our findings emphasize the importance of monitoring the cardiovascular function of the elderly experiencing neurodegenerative changes.

Puerarin enhances TFEB-mediated autophagy and attenuates ROS-induced pyroptosis after ischemic injury of random-pattern skin flaps.

BACKGROUND AND AIM: Necrosis of random-pattern flaps restricts their application in clinical practice. Puerarin has come into focus due to its promising therapeutic effects in ischemic diseases. Here, we employed Puerarin and investigated its role and potential mechanisms in flap survival. EXPERIMENTAL PROCEDURE: The effect of Puerarin on the viability of human umbilical vein endothelial cells (HUVECs) was assessed by CCK-8, EdU staining, migration, and scratch assays. Survival area measurement and laser Doppler blood flow (LDBF) were utilized to assess the viability of ischemic injury flaps. Levels of molecules related to oxidative stress, pyroptosis, autophagy, transcription factor EB (TFEB), and the AMPK-TRPML1-Calcineurin signaling pathway were detected using western blotting, immunofluorescence, dihydroethidium (DHE) staining, RT-qPCR and Elisa. KEY RESULTS: The findings demonstrated that Puerarin enhanced the survivability of ischemic flaps. Autophagy, oxidative stress, and pyroptosis were implicated in the ability of Puerarin in improving flap survival. Increased autophagic flux and augmented tolerance to oxidative stress contribute to Puerarin's suppression of pyroptosis. Additionally, Puerarin modulated the activity of TFEB through the AMPK-TRPML1-Calcineurin signaling pathway, thereby enhancing autophagic flux. CONCLUSIONS AND IMPLICATIONS: Puerarin promoted flap survival from ischemic injury through upregulation of TFEB-mediated autophagy and inhibition of oxidative stress. Our findings offered valuable support for the clinical application of Puerarin in the treatment of ischemic diseases, including random-pattern flaps.

Effect of orthostatic hypotension on long-term prognosis of elderly patients with stable coronary artery disease: a retrospective cohort study.

Background: The long-term prognosis of patients with stable coronary artery disease (CAD) combined with orthostatic hypotension (OH) has rarely been reported. This research was designed to examine whether OH increases the risk of all-cause mortality and cardiovascular death among patients with stable CAD. Methods: We retrospectively analyzed retired military personnel over 65 years of age who were hospitalized at the General Hospital of Southern Theater Command of the Chinese People's Liberation Army between March and July 2010. A total of 924 patients with stable CAD were included, among whom 263 had OH. The risk of all-cause mortality and cardiovascular death in OH and non-OH groups were analyzed with the Cox proportional hazards models, and restricted cubic spline plots were utilized for subgroup analyses. Furthermore, competing risk models were applied for sensitivity analyses. Results: The median age of the patients was 82.00 (80.00-85.00) years. Over 159 months of follow-up, the loss to follow-up rate was 2.27%, and all-cause mortality was observed in 574 (63.57%) patients, including 184 with OH. Moreover, cardiovascular death occurred in 127 patients (13.73%), with 58 cases associated with OH. Although the relationship between OH and all-cause mortality was non-significant [body mass index (BMI) < 25 group, adjusted hazard ratio (HR) = 1.10 with a 95% confidence interval (CI): 0.82-1.40; BMI ≥ 25 group, adjusted HR = 1.30, 95% CI: 0.98-1.70], it was independently related to a growing risk of cardiovascular death (adjusted HR = 1.80, 95% CI: 1.20-2.60). This finding was further validated by using a competing risk model (subdistribution HR = 1.74, 95% CI: 1.22-2.49). Moreover, age, low-density lipoprotein cholesterol, and frequency of hospital admissions were identified as risk factors of cardiovascular death among patients with OH (P < 0.05). Conclusion: Our study, based on retired military personnel with stable CAD, found that OH led to a significantly higher risk of cardiovascular death, but it was not noticeably associated with all-cause mortality on long-term prognosis.

Dihydrocapsaicin suppresses the STING-mediated accumulation of ROS and NLRP3 inflammasome and alleviates apoptosis after ischemia-reperfusion injury of perforator skin flap.

Avascular necrosis frequently occurs as a complication following surgery involving the distal perforator flap. Dihydrocapsaicin (DHC) can protect tissue from ischemia-reperfusion (I/R) injury, but its specific role in multizone perforator flaps remains unclear. In this study, the prospective target of DHC in the context of I/R injury was predicted using network pharmacology analysis. Flap viability was determined through survival area analysis, laser Doppler blood flow, angiograms, and histological examination. The expressions of angiogenesis, apoptosis, NLR family pyrin domain containing 3 (NLRP3) inflammasome, oxidative stress, and molecules related to cyclic guanosine monophosphate (GMP)-adenosine monophosphate synthase (cGAS)-interferon gene stimulant (STING) pathway were assessed using western blotting, immunofluorescence, TUNEL staining, and dihydroethidium (DHE) staining. Our finding revealed that DHC promoted the perforator flap survival, which involves the cGAS-STING pathway, oxidative stress, NLRP3 inflammasome, apoptosis, and angiogenesis. DHC induced oxidative stress resistance and suppressed the NLRP3 inflammasome, preventing apoptosis in vascular endothelial cells. Through regulation of STING pathway, DHC controlled oxidative stress in endothelial cells and NLRP3 levels in ischemic flaps. However, activation of the cGAS-STING pathway led to the accumulation of reactive oxygen species (ROS) and NLRP3 inflammasome, thereby diminishing the protective role of DHC. DHC enhanced the survival of multidomain perforator flaps by suppressing the cGAS-STING pathway, oxidative stress, and the formation of NLRP3 inflammasome. These findings unveil a potentially novel mechanism with clinical significance for promoting the survival of multidomain perforator flaps.

Hygrothermal stress increases malignant arrhythmias susceptibility by inhibiting the LKB1-AMPK-Cx43 pathway.

High mortality due to hygrothermal stress during heat waves is mostly linked to cardiovascular malfunction, the most serious of which are malignant arrhythmias. However, the mechanism associated with hygrothermal stress leading to malignant arrhythmias remains unclear. The energy metabolism regulated by liver kinase B1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) and the electrical signaling based on gap junction protein, connexin43 (Cx43), plays important roles in the development of cardiac arrhythmias. In order to investigate whether hygrothermal stress induces arrhythmias via the LKB1-AMPK-Cx43 pathway, Sprague-Dawley rats were exposed to high temperature and humidity for constructing the hygrothermal stress model. A final choice of 40 °C and 85% humidity was made by pre-exploration based on different gradient environmental conditions with reference to arrhythmia event-inducing stability and risk of sudden death. Then, the incidence of arrhythmic events, as well as the expression, phosphorylation at Ser368, and distribution of Cx43 in the myocardium, were examined. Meanwhile, the adenosine monophosphate-activated protein kinase activator, Acadesine, was also administered to investigate the role played by AMPK in the process. Our results showed that hygrothermal stress induced malignant arrhythmias such as ventricular tachycardia, ventricular fibrillation, and severe atrioventricular block. Besides, hygrothermal stress decreased the phosphorylation of Cx43 at Ser368, induced proarrhythmic redistribution of Cx43 from polar to lateral sides of the cardiomyocytes, and also caused LKB1 and phosphorylated-AMPK expression to be less abundant. While, pretreatment with Acadesine significantly actived the LKB1-AMPK-Cx43 pathway and thus ameliorated malignant arrhythmias, indicating that the hygrothermal stress-induced arrhythmias is associated with the redistribution of gap junctions in cardiomyocytes and the organism's energy metabolism.

Impacts of small-molecule STAT3 inhibitor SC-43 on toxicity, global proteomics and metabolomics of HepG2 cells.

OBJECTIVE: In this study, we aimed to investigate the cytotoxicity and potential mechanisms of SC-43 by analyzing the global proteomics and metabolomics of HepG2 cells exposed to SC-43. METHODS: The effect of SC-43 on cell viability was evaluated through CCK-8 assay. Proteomics and metabolomics studies were performed on HepG2 cells exposed to SC-43, and the functions of differentially expressed proteins and metabolites were categorized. Drug affinity responsive target stability (DARTS) was utilized to identify the potential binding proteins of SC-43 in HepG2 cells. Finally, based on the KEGG pathway database, the co-regulatory mechanism of SC-43 on HepG2 cells was elucidated by conducting a joint pathway analysis on the differentially expressed proteins and metabolites using the MetaboAnalyst 5.0 platform. RESULTS: Liver cell viability is significantly impaired by continuous exposure to high concentrations of SC-43. Forty-eight dysregulated proteins (27 upregulated, 21 downregulated) were identified by proteomics analysis, and 184 dysregulated metabolites (65 upregulated, 119 downregulated) were determined by metabolomics in HepG2 cells exposed to SC-43 exposure compared with the control. A joint pathway analysis of proteomics and metabolomics data using the MetaboAnalyst 5.0 platform supported the close correlation between SC-43 toxicity toward HepG2 and the disturbances in pyrimidine metabolism, ferroptosis, mismatch repair, and ABC transporters. Specifically, SC-43 significantly affected the expression of several proteins and metabolites correlated with the above-mentioned functional pathways, such as uridine 5'-monophosphate, uridine, 3'-CMP, glutathione, γ-Glutamylcysteine, TF, MSH2, RPA1, RFC3, TAP1, and glycerol. The differential proteins suggested by the joint analysis were further selected for ELISA validation. The data showed that the RPA1 and TAP1 protein levels significantly increased in HepG2 cells exposed to SC-43 compared to the control group. The results of ELISA and joint analysis were basically in agreement. Notably, DARTS and biochemical analysis indicated that SART3 might be a potential target for SC-43 toxicity in HepG2 cells. CONCLUSION: In summary, prolonged exposure of liver cells to high concentrations of SC-43 can result in significant damage. Based on a multi-omics analysis, we identified proteins and metabolites associated with SC-43-induced hepatocellular injury and clarified the underlying mechanism, providing new insights into the toxic mechanism of SC-43.

A snake cathelicidin enhances transcription factor EB-mediated autophagy and alleviates ROS-induced pyroptosis after ischaemia-reperfusion injury of island skin flaps.

BACKGROUND AND PURPOSE: Ischaemia-reperfusion (I/R) injury is a major contributor to skin flap necrosis, which presents a challenge in achieving satisfactory therapeutic outcomes. Previous studies showed that cathelicidin-BF (BF-30) protects tissues from I/R injury. In this investigation, BF-30 was synthesized and its role and mechanism in promoting survival of I/R-injured skin flaps explored. EXPERIMENTAL APPROACH: Survival rate analysis and laser Doppler blood flow analysis were used to evaluate I/R-injured flap viability. Western blotting, immunofluorescence, TdT-mediated dUTP nick end labelling (TUNEL) and dihydroethidium were utilized to examine the levels of apoptosis, pyroptosis, oxidative stress, transcription factor EB (TFEB)-mediated autophagy and molecules related to the adenosine 5'-monophosphate-activated protein kinase (AMPK)-transient receptor potential mucolipin 1 (TRPML1)-calcineurin signalling pathway. KEY RESULTS: The outcomes revealed that BF-30 enhanced I/R-injured island skin flap viability. Autophagy, oxidative stress, pyroptosis and apoptosis were related to the BF-30 capability to enhance I/R-injured flap survival. Improved autophagy flux and tolerance to oxidative stress promoted the inhibition of apoptosis and pyroptosis in vascular endothelial cells. Activation of TFEB increased autophagy and inhibited endothelial cell oxidative stress in I/R-injured flaps. A reduction in TFEB level led to a loss of the protective effect of BF-30, by reducing autophagy flux and increasing the accumulation of reactive oxygen species (ROS) in endothelial cells. Additionally, BF-30 modulated TFEB activity via the AMPK-TRPML1-calcineurin signalling pathway. CONCLUSION AND IMPLICATIONS: BF-30 promotes I/R-injured skin flap survival by TFEB-mediated up-regulation of autophagy and inhibition of oxidative stress, which may have possible clinical applications.

Tetrahydropalmatine: Orchestrating survival - Regulating autophagy and apoptosis via the PI3K/AKT/mTOR pathway in perforator flaps.

BACKGROUND: Introduced in clinical practice in 1989, perforator flaps are vital for tissue defect repair, but they are challenged by distal necrosis. Tetrahydropalmatine (THP) from celandine is renowned for its anti-inflammatory and analgesic effects. This study investigates THP's use in perforator flaps. METHODS: Thirty rats were divided into a control group and four THP concentration groups, while seventy-eight rats were categorized as control, THP, THP combined with rapamycin (RAP), and RAP alone. We created 11 cm by 2.5 cm multi-regional perforator flaps on rat backs, assessing survival blood flow and extracting skin flap tissue for autophagy, oxidative stress, apoptosis, and angiogenesis markers. RESULTS: The THP group exhibited significantly reduced distal necrosis, increased blood flow density, and survival area on the seventh day compared to controls. Immunohistochemistry and Western blot results demonstrated improved anti-oxidative stress and angiogenesis markers, along with decreased autophagy and apoptosis indicators. Combining THP with RAP diminished flap survival compared to THP alone. This was supported by protein expression changes in the PI3K-AKT-mTOR pathway. CONCLUSION: THP enhances flap survival by modulating autophagy, reducing tissue edema, promoting angiogenesis, and mitigating apoptosis and oxidative stress. THP offers a potential strategy for enhancing multi-regional perforator flap survival through the PI3K/AKT/mTOR pathway. These findings highlight THP's promise in combatting perforator flap necrosis, uncovering a novel mechanism for its impact on flap survival.

A Strong and Double-sided Self-Adhesive Hydrogel Sensor.

Flexible self-adhesive hydrogel sensors are attracting considerable concerns in recent years. However, creating a self-adhesive hydrogel sensor with excellent mechanical properties remains to be challenging. Herein, a double-sided self-adhesive hydrogel capable of strain sensor with high strength is demonstrated by penetration strategy. The middle poly(acrylic acid)-polyacrylamide/Fe3+ (PAA-PAM/Fe3+ ) tough layer endows the double-sided self-adhesive hydrogel with high mechanical properties, while the bilateral poly[2-(methacryloyloxy) ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide-polyacrylamide (PSBMA-PAM) adhesive layers are used to ensure excellent adhesiveness on diverse substrates. The tough layer of the double-sided self-adhesive hydrogel sensor shows a strong interface bonding force against the adhesive layer. The double-sided self-adhesive hydrogel sensor enables excellent adhesiveness on diverse substrates. More importantly, it can accurately detect different strains and human motions as a self-adhesive hydrogel strain sensor. This work manifests a new route of structural design to develop a self-adhesive hydrogel sensor with excellent mechanical properties that is suitable for a wide range of applications.

Correlations of Inflammatory Cytokines in the Intestinal Mucosa, Serum Inflammation, Oxidative Stresses and Immune Changes with Vitamin Deficiency in Ulcerative Colitis Patients.

Ulcerative colitis (UC) is a chronic inflammatory disease. Studies in China and foreign countries have shown that vitamins have anti-inflammation and immunoregulation functions in patients with UC, but the specific mechanism is not yet clear. In this study, the levels of inflammatory cytokines in the intestinal mucosa, serum inflammatory indexes, oxidative stress indexes and immune-related indexes were detected, and their correlations with vitamin deficiency and clinical significance were discussed. Enzyme-linked immunosorbent assay (ELISA) was adopted to detect the serum level of 25-hydroxyvitamin D3, immunohistochemistry was applied to examine the expression of inflammatory cytokines in the intestinal mucosa, serum inflammatory indexes, oxidative stress indexes and immune-related indexes were measured, and their correlations were analyzed. Inflammatory and oxidative stress indexes in the UC group were notably higher than in the control group. The Vitamin deficiency group had more inflammatory cytokines than the normal vitamin group. Oxidative stress indexes such as superoxide dismutase (SOD) and malondialdehyde (MDA) in the vitamin deficiency group were significantly different from those in the normal vitamin group, but no difference was found in myeloperoxidase (MPO). Immune-related indexes, complement 3 (C3) and interferon-gamma (IFN-γ), in the normal vitamin group were higher than those in the vitamin deficiency group. Besides, interleukin-4 (IL-4) (r=-0.37, p=0.04) and IL-1ß (r=-0.31, p=0.04) had significant correlations with vitamins. Vitamins in patients with UC have significant correlations with inflammatory responses in vivo, which can be used to predict inflammatory responses in vivo and have strong clinical significance. Vitamins are also related to oxidative stresses to some extent but have little effect on immune-related indexes.

Limiting dilution assay to quantify the self-renewal potential of cancer stem cells in hepatocellular carcinoma.

Cancer stem cells (CSCs) are a heterogeneous subpopulation of self-renewing cancer cells that sustain tumorigenesis in various types of human malignancies. Due to the diverse phenotypes of CSCs in distinct pathological conditions, it remains challenging to define CSCs by specific cell surface markers. Thus, it is essential to develop experimental protocols to quantify the self-renewal and tumorigenic potential of CSC for therapeutic purposes. To address these technical difficulties, we introduce the limiting dilution assay (LDA), a well-recognized experimental approach that accurately measures the self-renewal capacity and tumorigenicity of CSCs. Using hepatocellular carcinoma (HCC) cells as a model, we describe detailed experimental procedures for CSC culture in three-dimensional soft fibrin gel. Moreover, we provide an updated protocol for assessing CSC self-renewal in vitro and tumorigenicity in vivo in NOD/SCID IL-2Rγ-/- (NSG) mice by LDA. Taken together, these protocols are readily applicable to laboratories with basic cell culture equipment and access to experimental animal facilities, providing a valuable toolbox to dissect mechanisms underlying HCC tumorigenesis and identify CSC-targeting drugs via high-throughput screening.

Cobalt protoporphyrin promotes human keratinocyte migration under hyperglycemic conditions.

BACKGROUND: Complete healing of diabetic wounds continues to be a clinically unmet need. Although robust therapies such as stem cell therapy and growth factor treatment are clinically applied, these treatments are costly for most diabetic wound patients. Therefore, a cheaper alternative is needed. Cobalt protoporphyrin (CoPP) has recently been demonstrated to promote tissue regeneration. In this study, the therapeutic benefits of CoPP in diabetic wound healing were examined. METHODS: An in vitro wound healing model that mimics re-epithelialization was established to examine the effect of CoPP on the migratory capability of human keratinocytes (HaCaT) in either normal glucose (NG) or high glucose (HG) media, as well as in the presence of either H2O2 or lipopolysaccharide (LPS). At the end of the migration assays, cells were collected and subjected to Western blotting analysis and immunostaining. RESULTS: HaCaT were found to migrate significantly more slowly in the HG media compared to the NG media. CoPP treatment was found to enhance cell migration in HG media, but was found to decrease cell migration and proliferation when HaCaT were cultured in NG media. CoPP treatment induced high levels of expression of Nrf-2/HO-1 and FoxO1 in HaCaT cultured in either glucose concentration, although the FoxO1 expression was found to be significantly higher in HaCaT that underwent the migration assay in NG media compared to those in HG media. The higher level of FoxO1 expression seen in CoPP-treated HaCaT cultured in NG media resulted in upregulation of CCL20 and downregulation of TGFß1. In contrast, HaCaT migrated in HG media were found to have high levels of expression of TGFß1, and low levels of expression of CCL20. Interestingly, in the presence of H2O2, CoPP-pretreated HaCaT cultured in either NG or HG media had similar expression level of Nrf-2/HO-1 and FoxO1 to each other. Moreover, the anti-apoptotic effect of CoPP pretreatment was noticed in HaCaT cultured in either glucose concentration. Additionally, CoPP pretreatment was shown to promote tight junction formation in HaCaT suffering from LPS-induced damage. CONCLUSIONS: CoPP enhances cell migratory capacity under hyperglycemic conditions, and protects cells from oxidative and LPS-induced cellular damage in HG media containing either H2O2 or LPS.

Diallyl Trisulfide Enhances the Survival of Multiterritory Perforator Skin Flaps.

The multiterritory perforator flap is one of the widest flap patterns used to repair tissue defects. However, flap necrosis of the distal part is still a challenging issue for plastic surgeons. Diallyl trisulfide (DATS) is an efficient ingredient extracted from garlic, exerting many important effects on different diseases. Our experiment aims to reveal whether DATS has a beneficial effect on the survival of perforator flaps and to explore its mechanism of action. The results showed that DATS enhanced angiogenesis and autophagy and reduced cell apoptosis and oxidative stress, thereby improving the survival rate of skin flaps. After co-administration with autophagy inhibitor 3-methyladenine (3MA), perforator flap survival was further improved. Mechanistically, we showed that PI3K/Akt and AMPK-HIF-1α signaling pathways in flap were activated under DATS treatment. All in all, DATS promoted the survival of multiterritory perforator flaps via the synergistic regulation of PI3K/Akt and AMPK-HIF-1α signaling pathways, and inhibition of DATS-induced autophagy further improves flap survival.

Design, development and clinical validation of computer-aided surgical simulation system for streamlined orthognathic surgical planning.

PURPOSE: There are many proven problems associated with traditional surgical planning methods for orthognathic surgery. To address these problems, we developed a computer-aided surgical simulation (CASS) system, the AnatomicAligner, to plan orthognathic surgery following our streamlined clinical protocol. METHODS: The system includes six modules: image segmentation and three-dimensional (3D) reconstruction, registration and reorientation of models to neutral head posture, 3D cephalometric analysis, virtual osteotomy, surgical simulation, and surgical splint generation. The accuracy of the system was validated in a stepwise fashion: first to evaluate the accuracy of AnatomicAligner using 30 sets of patient data, then to evaluate the fitting of splints generated by AnatomicAligner using 10 sets of patient data. The industrial gold standard system, Mimics, was used as the reference. RESULT: When comparing the results of segmentation, virtual osteotomy and transformation achieved with AnatomicAligner to the ones achieved with Mimics, the absolute deviation between the two systems was clinically insignificant. The average surface deviation between the two models after 3D model reconstruction in AnatomicAligner and Mimics was 0.3 mm with a standard deviation (SD) of 0.03 mm. All the average surface deviations between the two models after virtual osteotomy and transformations were smaller than 0.01 mm with a SD of 0.01 mm. In addition, the fitting of splints generated by AnatomicAligner was at least as good as the ones generated by Mimics. CONCLUSION: We successfully developed a CASS system, the AnatomicAligner, for planning orthognathic surgery following the streamlined planning protocol. The system has been proven accurate. AnatomicAligner will soon be available freely to the boarder clinical and research communities.