Versatile conductive hydrogel orchestrating neuro-immune microenvironment for rapid diabetic wound healing through peripheral nerve regeneration.

Diabetic wound (DW), notorious for prolonged healing processes due to the unregulated immune response, neuropathy, and persistent infection, poses a significant challenge to clinical management. Current strategies for treating DW primarily focus on alleviating the inflammatory milieu or promoting angiogenesis, while limited attention has been given to modulating the neuro-immune microenvironment. Thus, we present an electrically conductive hydrogel dressing and identify its neurogenesis influence in a nerve injury animal model initially by encouraging the proliferation and migration of Schwann cells. Further, endowed with the synergizing effect of near-infrared responsive release of curcumin and nature-inspired artificial heterogeneous melanin nanoparticles, it can harmonize the immune microenvironment by restoring the macrophage phenotype and scavenging excessive reactive oxygen species. This in-situ formed hydrogel also exhibits mild photothermal therapy antibacterial efficacy. In the infected DW model, this hydrogel effectively supports nerve regeneration and mitigates the immune microenvironment, thereby expediting the healing progress. The versatile hydrogel exhibits significant therapeutic potential for application in DW healing through fine-tuning the neuro-immune microenvironment.

Flexible and antibacterial conductive hydrogels based on silk fibroin/polyaniline/AgNPs for motion sensing and wound healing promotion under electrical stimulation.

Flexible conductive hydrogel-based electronic skin (E-skin) for simultaneous biotherapeutics and sensing applications is one of the current research directions. In this study, conductive and homogeneous silk fibroin/polyaniline/AgNP complexes (SPAg complexes) were prepared with the assistance of silk fibroin, which greatly optimized the compatibility of PANI with the hydrogel matrix. Then, SPAg was introduced into the covalently crosslinked polymer network to prepare poly(acrylamide-co-sulfobetaine methacrylate) - SPAg hydrogels (labeled as PSPAg hydrogels). The PSPAg hydrogels exhibit good biocompatibility, excellent mechanical properties, superb adhesive performance, and fantastic sensing capabilities. Being connected to a smartphone via a Bluetooth system, the SPAg hydrogel-based E-skin was employed to accurately monitor human movements including vigorous joint movements and subtle facial micro-expressions. Finally, benefiting from the synergistic effect of antimicrobial and exogenous electrical stimulation, through promoting angiogenesis and accelerating collagen production in diabetic wounds, PSPAg E-skin successfully facilitates rapid diabetic wound healing. Therefore, the multifunctional PSPAg hydrogel-based E-skin shows great promise for applications in wearable devices and bioelectronics.

Modified Chitosan-Based Coating/Packaging Composites with Enhanced Antibacterial, Antioxidant, and UV-Resistant Properties for Fresh Food Preservation.

Chitosan-based biomass packaging materials are a promising material for food preservation, but their limited solubility, antioxidant capacity, UV resistance, and mechanical properties severely restrict their application. In this study, we developed a novel chitosan-based coating/packaging composite (QCTO) using quaternary ammonium salt and tannic acid (TA)-modified chitosan (QCS-TA) and oxidized chitosan (OCS). The introduction of quaternary ammonium salt and TA effectively improves the water solubility and antibacterial, antioxidant, and UV-resistant properties of chitosan. The Schiff-base bond formed between OCS and QCS-TA, along with the TA-mediated multiple interactions, conferred the prepared composite film with good mechanical properties (69.9 MPa tensile strength) and gas barrier performance to water (14.3 g·h-1·m-2) and oxygen (3.5 g·mm·m-2·h-1). Meanwhile, the prepared QCTO composites demonstrate excellent biocompatibility and safety and are applied as coatings for strawberries and bananas as well as packaging films for mushrooms. These preservation experiments demonstrated that the prepared composites are able to effectively reduce weight loss, prevent microbial growth, maintain color, and significantly prolong the shelf life of fresh products (bananas, strawberries, and mushrooms extended shelf life by 6, 5, and 6 days, respectively). Therefore, the developed QCTO coating/packaging film shows great potential for applications in the field of food preservation and packaging.

Cation-π Interaction-Enhanced Self-Healing Injectable Hydrogels for Gastric Perforation Repair.

Surgical operations are the preferred treatment for gastric perforation (GP) but incur postoperative complications such as gastrointestinal adhesions and bacterial infections, leading to inefficient wound healing and serious complications that may even threaten the life of the patient. Developing hydrogel dressings capable of adapting to the gastric environment (acid) and decreasing visceral adhesions and bacterial infections after GP treatment is crucial. In this article, we developed an injectable, self-healing hydrogel using cation-π interactions between protonated amines and aromatic rings under acidic conditions and explored it for GP repair. The hydrogels demonstrate exceptional self-healing capabilities under acidic conditions and can be effectively tailored for the gastric environment. In addition, the hydrogel demonstrated significant efficacy in preventing gastrointestinal adhesion, reducing inflammation, promoting angiogenesis, and effectively facilitating wound healing in a rat GP model. This novel hydrogel demonstrates adaptability to the gastric environment, rendering it highly promising for potential applications in gastric trauma healing.

Developing NIR xanthene-chalcone fluorophores with large Stokes shifts for fluorescence imaging.

A series of novel near-infrared (NIR) xanthene-chalcone fluorophores were constructed through a modular synthesis with the electron-donating xanthene moiety and the electron-withdrawing chalcone moiety. These fluorophores are convenient for fluorescence imaging in living cells, benefiting from their NIR emissions (650-710 nm), large Stokes shifts (>100 nm), moderate quantum yields and low cytotoxicity. The substituted hydroxyl group of the xanthene-chalcone fluorophore HCA-E facilitates the development of multifunctional fluorescent probes. As an example, a highly sensitive and selective probe N-HCA-E for glutathione (GSH) detection was developed based on the fluorophore HCA-E. A 4-nitrobenzenesulfonyl (4-Ns) group was introduced to cage the hydroxyl group of HCA-E, which was used as a selective recognition site for the thiol of GSH and an effective fluorescence quencher. Probe N-HCA-E revealed NIR "turn-on" fluorescence (709 nm) for endogenous and exogenous GSH detection in lysosomes with a large Stokes shift (129 nm) and high anti-interference ability.

A hyaluronic acid hydrogel as a mild photothermal antibacterial, antioxidant, and nitric oxide release platform for diabetic wound healing.

Hyaluronic acid (HA)-based biopolymer hydrogels are promising therapeutic dressings for various wounds but still underperform in treating diabetic wounds. These wounds are extremely difficult to heal and undergo a prolonged and severe inflammatory process due to bacterial infection, overexpression of reactive oxygen species (ROS), and insufficient synthesis of NO. In this study, a dynamic crosslinked hyaluronic acid (HA) hydrogel dressing (Gel-HAB) loaded with allomelanin (AMNP)-N, N'-dis-sec-butyl-N, N'-dinitroso-1, 4-phenylenediamine (BNN6) nanoparticles (AMNP-BNN6) was developed for healing diabetic wounds. The dynamic acylhydrazone bond formed between hydrazide-modified HA (HA-ADH) and oxidized HA (OHA) makes the hydrogel injectable, self-healing, and biocompatible. The hydrogel, loaded with AMNP-BNN6 nanoparticles, exhibits promising ROS scavenging ability and on-demand release of nitric oxide (NO) under near-infrared (NIR) laser irradiation to achieve mild photothermal antibacterial therapy (PTAT) (∼ 48 °C). Notably, the Gel-HAB hydrogel effectively reduced the oxidative stress level, controlled infections, accelerated vascular regeneration, and promoted angiogenesis, thereby achieving rapid healing of diabetic wounds. The injectable self-healing nanocomposite hydrogel could serve as a mild photothermal-enhanced antibacterial, antioxidant, and nitric oxide release platform for the treatment of diabetic wounds.

Gold-Catalyzed Oxidation Reactions of Thioalkynes with Quinoline N-Oxides: A DFT Study.

Mechanistic investigation of the gold-catalyzed oxidative reactions of thioalkynes with quinoline N-oxides was performed using density functional theory (DFT) calculations. For the oxidative rearrangement of thioalkynes with quinoline N-oxide to yield the same products, the Cß-oxidation of thioalkynes was predicted to be competitive with Cα-oxidation, with the Cß-oxidative process slightly more favorable. However, for the oxidative alkenylation of propargyl aryl thioethers with quinoline N-oxides, the Cß-oxidation of thioether by quinoline N-oxide generated the product 3-hydroxy-1-alkylidene phenylthiopropan-2-one. Moreover, the ring opening of the four-membered sulfonium intermediate was achieved by the nucleophilic attack of quinoline N-oxide rather than a water molecule.

Multi-MSIProcessor: Data Visualizing and Analysis Software for Spatial Metabolomics Research.

Mass spectrometry imaging (MSI) has emerged as a revolutionary analytical strategy in biomedical research for molecular visualization. By linking the characterization of functional metabolites with tissue architecture, it is now possible to reveal unknown biological functions of tissues. However, due to the complexity and high dimensionality of MSI data, mining bioinformatics-related peaks from batch MSI data sets and achieving complete spatially resolved metabolomics analysis remain a great challenge. Here, we propose novel MSI data processing software, Multi-MSIProcessor (MMP), which integrates the data read-in, MSI visualization, processed data preservation, and biomarker discovery functions. The MMP focuses on the AFADESI-MSI data platform but also supports mzXML and imzmL data input formats for compatibility with data generated by other MSI platforms such as MALDI/SIMS-MSI. MMP enables deep mining of batch MSI data and has flexible adaptability with the source code opened that welcomes new functions and personalized analysis strategies. Using multiple clinical biosamples with complex heterogeneity, we demonstrated that MMP can rapidly establish complete MSI analysis workflows, assess batch sample data quality, screen and annotate differential MS peaks, and obtain abnormal metabolic pathways. MMP provides a novel platform for spatial metabolomics analysis of multiple samples that could meet the diverse analysis requirements of scholars.

The application and progress of tissue engineering and biomaterial scaffolds for total auricular reconstruction in microtia.

Microtia is a congenital deformity of the ear with an incidence of about 0.8-4.2 per 10,000 births. Total auricular reconstruction is the preferred treatment of microtia at present, and one of the core technologies is the preparation of cartilage scaffolds. Autologous costal cartilage is recognized as the best material source for constructing scaffold platforms. However, costal cartilage harvest can lead to donor-site injuries such as pneumothorax, postoperative pain, chest wall scar and deformity. Therefore, with the need of alternative to autologous cartilage, in vitro and in vivo studies of biomaterial scaffolds and cartilage tissue engineering have gradually become novel research hot points in auricular reconstruction research. Tissue-engineered cartilage possesses obvious advantages including non-rejection, minimally invasive or non-invasive, the potential of large-scale production to ensure sufficient donors and controllable morphology. Exploration and advancements of tissue-engineered cartilaginous framework are also emerging in aspects including three-dimensional biomaterial scaffolds, acquisition of seed cells and chondrocytes, 3D printing techniques, inducing factors for chondrogenesis and so on, which has greatly promoted the research process of biomaterial substitute. This review discussed the development, current application and research progress of cartilage tissue engineering in auricular reconstruction, particularly the usage and creation of biomaterial scaffolds. The development and selection of various types of seed cells and inducing factors to stimulate chondrogenic differentiation in auricular cartilage were also highlighted. There are still confronted challenges before the clinical application becomes widely available for patients, and its long-term effect remains to be evaluated. We hope to provide guidance for future research directions of biomaterials as an alternative to autologous cartilage in ear reconstruction, and finally benefit the transformation and clinical application of cartilage tissue engineering and biomaterials in microtia treatment.

Applications of 3D printing in aging.

Aging is inevitable, and how to age healthily is a key concern. Additive manufacturing offers many solutions to this problem. In this paper, we first briefly introduce various 3D printing technologies commonly used in the biomedical field, particularly in aging research and aging care. Next, we closely examine aging-related health conditions of nervous system, musculoskeletal system, cardiovascular system, and digestive system with a focus on the application of 3D printing in these fields, including the creation of in vitro models and implants, production of drugs and drug delivery systems, and fabrication of rehabilitation and assistive medical devices. Finally, the opportunities, challenges, and prospects of 3D printing in the field of aging are discussed.

Botulinum Toxins for the Treatment of Raynaud Phenomenon: A Systematic Review With Meta-analysis.

OBJECTIVE: Botulinum toxin (Btx) therapy has emerged as a potential treatment for patients with Raynaud phenomenon (RP) in recent years. This study aimed to investigate the efficacy and safety of Btx treatment for RP. METHODS: Databases of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from their inception up to August 2022. Studies that reported Btx use for the treatment of RP were included. A meta-analysis was conducted for the Shortened version of the Disabilities of the Arm, Shoulder, and Hand (Quick DASH) score and visual analog scale pain score using a random-effects model. RESULTS: Thirteen full-text studies were included. The pooled standard mean changes for the visual analog scale pain score and QuickDASH score were -3.82 (95% confidence interval, -6.62 to -1.02) and 0.83 (95% confidence interval, -1.47 to -0.19), respectively. The 2 most common complications were injection site pain and intrinsic hand weakness. CONCLUSIONS: The effect of Btx treatment on RP is promising based on current evidence. Nevertheless, more studies and randomized clinical trials with larger sample sizes are needed to confirm the current results.

Bioengineered MSC-derived exosomes in skin wound repair and regeneration.

Refractory skin defects such as pressure ulcers, diabetic ulcers, and vascular ulcers represent a challenge for clinicians and researchers in many aspects. The treatment strategies for wound healing have high cost and limited efficacy. To ease the financial and psychological burden on patients, a more effective therapeutic approach is needed to address the chronic wound. MSC-derived exosomes (MSC-exosomes), the main bioactive extracellular vesicles of the paracrine effect of MSCs, have been proposed as a new potential cell-free approach for wound healing and skin regeneration. The benefits of MSC-exosomes include their ability to promote angiogenesis and cell proliferation, increase collagen production, regulate inflammation, and finally improve tissue regenerative capacity. However, poor targeting and easy removability of MSC-exosomes from the wound are major obstacles to their use in clinical therapy. Thus, the concept of bioengineering technology has been introduced to modify exosomes, enabling higher concentrations and construction of particles of greater stability with specific therapeutic capability. The use of biomaterials to load MSC-exosomes may be a promising strategy to concentrate dose, create the desired therapeutic efficacy, and maintain a sustained release effect. The beneficial role of MSC-exosomes in wound healing is been widely accepted; however, the potential of bioengineering-modified MSC-exosomes remains unclear. In this review, we attempt to summarize the therapeutic applications of modified MSC-exosomes in wound healing and skin regeneration. The challenges and prospects of bioengineered MSC-exosomes are also discussed.

Mechanistic Investigation into the Regio-Controllable Hydroallylations of Alkynes with Allylborons under Pd-Based Synergetic Catalyses.

Density functional theory calculations were employed to investigate the Pd-catalyzed regio-selective hydroallylations of alkynes with allylborons: cooperation of Cu(OAc)2 and dppe resulting in 1,4-dienes while combination of AdCO2H and PCy3 leading to 1,5-dienes. A unified rationalization mechanism called "Lewis-acid-base-interaction promoted deprotonation/3,3-rearrangement" was proposed. Compared with the commonly reported metathesis pathway to only afford the metal-allyl intermediate, in the newly established mechanism, an additional Brønsted acid (as an initiator of the Pd0 oxidative addition) is generated by the interaction of the allylboron (Lewis acid) B atom with the nBuOH (Lewis base) O atom, and subsequent 3,3-rearrangement ensures the thermodynamic feasibility of the reaction. In addition, it was found that excess Cu(OAc)2 plays two potential roles in the oxidative addition/alkyne insertion: (i) the participation of one AcO- of Cu(OAc)2 ensures a large orbital overlap between the migrating H and Pd atoms, facilitating the formal AcO-H cleavage and (ii) the extra (OAc)2Cu···O(carboxyl) σ-coordination indirectly contributes to the (Me)C≡C(Ph) insertion into the Pd-H bond. Further analysis showed that the origin of the regioselectivity is closely related to the employed phosphorus ligand. These revealed results, which have been overlooked in the previous documents, would aid the development of new related catalytic reactions.

Mechanistic Insights Into the Rhodium-Catalyzed C-H Alkenylation/Directing Group Migration and [3+2] Annulation: A DFT Study.

The mechanism of the rhodium-catalyzed C-H alkenylation/directing group migration and [3+2] annulation of N-aminocarbonylindoles with 1,3-diynes has been investigated with DFT calculations. On the basis of mechanistic studies, we mainly focus on the regioselectivity of 1,3-diyne inserting into the Rh-C bond and the N-aminocarbonyl directing group migration involved in the reactions. Our theoretical study uncovers that the directing group migration undergoes a stepwise ß-N elimination and isocyanate reinsertion process. As studied in this work, this finding is also applicable to other relevant reactions. Additionally, the role of Na+ versus Cs+ involved in the [3+2] cyclization reaction is also probed.

Effectiveness of Chengqi-series decoctions in treating severe acute pancreatitis: A Systematic review and meta-analysis.

BACKGROUND: Evidence suggests that Dachengqi and its modified decoctions are effective for treating abdominal pain, multiple organ dysfunction syndrome (MODS) and inflammation in various disease conditions. We performed a meta-analysis to ascertain the effectiveness of a series of chengqi decoctions in patients with severe acute pancreatitis (SAP). METHODS: We searched Pubmed, Embase, Cochrane library, Web of Science, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature, Wanfang database and China Science and Technology Journal Database before August 2022 to identify eligible randomized controlled trials (RCTs). Mortality and MODS were chosen as primary outcomes. Secondary outcomes included time until relief of abdominal pain, APACHE II score, complications, effectiveness, IL-6 and TNF-α levels. The risk ratio (RR) and standardized mean difference (SMD) with a 95% confidence interval (CI) were selected as effect measures. The quality of evidence was independently assessed by two reviewers using Grading of Recommendations Assessment Development and Evaluation (GRADE) system. RESULTS: Twenty-three RCTs (n = 1865) were finally included. The results showed that, compared with routine therapies, chengqi-series decoctions (CQSDs) treatment groups were associated with lower mortality rate (RR: 0.41, 95%CI: 0.32 to 0.53, p = 0.992) and incidence of MODS (RR: 0.48, 95%CI: 0.36 to 0.63, p = 0.885). They also reduced remission time of abdominal pain (SMD: -1.66, 95%CI: -1.98 to -1.35, p = 0.000), complications (RR: 0.52, 95%CI: 0.39 to 0.68, p = 0.716), APACHE II score (SMD: -1.04, 95%CI:-1.55 to -0.54, p = 0.003), IL-6 (SMD: -1.5, 95%CI: -2.16 to -0.85, p = 0.000), TNF-α (SMD: -1.18, 95%CI: -1.71 to -0.65, p = 0.000), and improved curative effectiveness (RR:1.22, 95%CI: 1.14 to 1.31, p = 0.757). The certainty of the evidence for these outcomes was low to moderate. CONCLUSION: CQSDs seem to be effective therapy for SAP patients with notable reductions in mortality, MODS and abdominal pain, with low quality evidence. Large-scale, multi-center RCTs that are more meticulous are advised in order to produce superior evidence.

Mussel-inspired adhesive zwitterionic composite hydrogel with antioxidant and antibacterial properties for wound healing.

The skin can be easily injured and attacked by external pathogens, leading to wound infection and wound healing delay. Traditional dressings adhere to wounds only and can cause secondary damage to the new epithelium and bleeding. Herein, a highly adhesive zwitterionic composite hydrogel wound dressing (PDA/PSBMA/NFC/Zn2+ [PSNZn]) with outstanding antibacterial properties, good biocompatibility and excellent rheological properties was prepared by introducing zinc ion-loaded polydopamine (PDA)-coated nanofibrillated cellulose into a covalently-crosslinked sulfobetaine methacrylate (SBMA) network. In vitro and in vivo experiments showed the broad-spectrum and lasting antibacterial activity of the PSNZn composite hydrogel against Escherichia coli and Staphylococcus aureus. In summary, the PSNZn composite hydrogel is an excellent wound dressing candidate with efficient antibacterial properties, high adhesion, excellent biocompatibility and good rheological properties.

Computational Study Revealing the Mechanistic Origin of Distinct Performances of P(O)-H/OH Compounds in Palladium-Catalyzed Hydrophosphorylation of Terminal Alkynes: Switchable Mechanisms and Potential Side Reactions.

Pd-catalyzed hydrophosphorylation of alkynes with P(O)-H compounds provided atom-economical and oxidant-free access to alkenylphosphoryl compounds. Nevertheless, the applicable P(O)-H substrates were limited to those without a hydroxyl group except H2P(O)OH. It is also puzzling that Ph2P(O)OH could co-catalyze the reaction to improve Markovnikov selectivity. Herein, a computational study was conducted to elucidate the mechanistic origin of the phenomena described above. It was found that switchable mechanisms influenced by the acidity of substrates and co-catalysts operate in hydrophosphorylation. In addition, potential side reactions caused by the protonation of PdII-alkenyl intermediates with P(O)-OH species were revealed. The regeneration of an active Pd(0) catalyst from the resulting Pd(II) complexes is remarkably slower than the hydrophosphonylation, while the downstream reactions, if possible, would lead to phosphorus 2-pyrone. Further analysis indicated that the side reactions could be suppressed by utilizing bulky substrates or ligands or by decreasing the concentration of P(O)-OH species. The presented switchable mechanisms and side reactions shed light on the co-transformations of P(O)-H and P-OH compounds in the Pd-catalyzed hydrophosphorylation of alkynes, clarify the origin of the distinct performances of P(O)-H/OH compounds, and provide theoretical clues for expanding the applicable substrate scope of hydrophosphorylation and synthesizing cyclic alkenylphosphoryl compounds.

Ligand-Controlled Regiodivergent Cyanoboration of Internal Allenes by Copper Catalysis.

The first copper-catalyzed regiodivergent cyanoboration of internal allenes with B2 pin2 (bis(pinacolato)diboron) and NCTS (N-cyano-N-phenyl-p-toluenesulfonamide) derivatives is reported. The ß,γ- and α,ß-cyanoborylated products were synthesized with high regio- and stereo-selectivity. Computational studies revealed that nucleophilic addition of allylcopper or related intermediates on cyanation reagent is the regio- and stereo-determining step, while transmetalation with B2 pin2 is the rate-determining step. The nucleophilic addition step proceeds via inner-sphere mechanism in the CuI /P(o-tol)3 and CuI /Xantphos (P(o-tol)3 =tris(o-methylphenyl)phosphine, Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) catalytic systems and via outer-sphere mechanism in the CuII /Xantphos catalytic system, respectively.

Machine learning-based prediction of in-hospital mortality for post cardiovascular surgery patients admitting to intensive care unit: a retrospective observational cohort study based on a large multi-center critical care database.

BACKGROUND AND OBJECTIVES: The acute physiology and chronic health evaluation-IV model (APACHE-IV), and the sequential organ failure assessment (SOFA) score are two traditional severity assessment systems that can be applied to cardiac surgery patients admitted to intensive care units (ICUs). However, the performance of machine learning approaches in post cardiovascular surgery (PCS) patients admitted to the ICU remains unknown. METHODS: The clinical data of adult subjects were collected from the eICU database. Seven models were constructed based on the training set (70% random sample) for predicting hospital mortality, including two traditional models based on APACHE-IV and SOFA scores and five machine learning models. We measured the models' performance in the remaining 30% of the sample by computing AUC-ROC values, prospective prediction results, and decision curves and compared the models with net reclassification improvement. RESULTS: This study included 5860 PCS patients. The AUC-ROC value of the Xgboost model significantly outperformed the APACHE-IV and SOFA scores (0.12 [0.06-0.17] p < 0.01, 0.18 [0.1-0.26] p < 0.01 respectively). The use of ML models would also gain more clinical net benefits than traditional models based on decision curve analysis. There was a significant improvement in integrated discrimination when comparing the backward stepwise linear regression model with the APACHE-IV model (0.11 [0.05, 0.16], p < 0.01) and SOFA model (0.12 [0.06, 0.17], p < 0.01). CONCLUSIONS: In conclusion, the predictive ability of ML models was better than that of traditional models. The present study suggested that developing advanced prognosis prediction tools could support clinical decision-making in the ICU for PCS patients.

Comparative effects of different types of cardioplegia in cardiac surgery: A network meta-analysis.

Objective: To compare the outcomes of four types of cardioplegia during cardiac surgery: del Nido (DN), blood cardioplegia (BC), histidine-tryptophan-ketoglutarate (HTK) and St. Thomas. Methods: Randomized controlled trials (RCTs) and observational cohort studies from 2005 to 2021 were identified in PubMed, Embase, and Cochrane databases. Data were extracted for the primary endpoint of perioperative mortality as well as the following secondary endpoints: atrial fibrillation, renal failure, stroke, use of an intra-aortic balloon pump, re-exploration, intensive care unit stay and hospital stay. A network meta-analysis comparing all four types of cardioplegia was performed, as well as direct meta-analysis comparing pairs of cardioplegia types. Results: Data were extracted from 18 RCTs and 49 observational cohort studies involving 18,191 adult patients (55 studies) and 1,634 children (12 studies). Among adult patients, risk of mortality was significantly higher for HTK (1.89, 95% CI 1.10, 3.52) and BC (RR 1.73, 95% CI 1.22, 2.79) than for DN. Risk of atrial fibrillation was significantly higher for BC (RR 1.41, 95% CI 1.09, 1.86) and DN (RR 1.51, 95% CI 1.15, 2.03) than for HTK. Among pediatric patients, no significant differences in endpoints were observed among the four types of cardioplegia. Conclusions: This network meta-analysis suggests that among adult patients undergoing cardiac surgery, DN may be associated with lower perioperative mortality than HTK or BC, while risk of atrial fibrillation may be lower with HTK than with BC or DN.