Aim:Post-cardiac arrest brain injury (PCABI) is the leading cause of death and disability after resuscitation. This study aimed to investigate the pathogenesis and novel biomarkers for monitoring the progression and early prognostication of PCABI. Methods:Mouse model of PCABI was induced by hyperkalemia-induced asystole and successful resuscitation. Young adult male C57BL/6 mice were randomized into sham-operation or asystole/resuscitation. The sham-operated mice were selected as control. Neurological examinations were performed at 24 h after resuscitation, and three groups were set: control (n = 4), severe PCABI (n = 3), and mild PCABI (n = 3). Cerebral cortexes were collected for data-independent acquisition-proteomic analyses. The pathogenesis and potential biomarkers were identified through the pairwise comparisons of three subgroups and subsequent bioinformatics analyses. Human serum proteomes profiles, extracted from a published work of the second analysis of TTM-trial, were used for joint analyses to identify the common and clinically relevant biomarkers at the same timepoint. Experimental and external validation were performed to verify the association between novel biomarkers and neural death in PCABI. Results:The proteomic analysis identified and quantified 7,745 proteins. The most prominent proteomic changes were related to response to external stimulus, stress response, regulation of biological and metabolic process, endomembrane system, and inflammatory response in the PCABI progression. 10 potential biomarkers were identified by the pairwise comparisons of three groups, and lipocalin-2 and angiotensinogen are common biomarkers with human studies at 24 h after resuscitation. Experimental validation verified that lipocalin-2 was closely associated with neurodegeneration in PCABI. Conclusions:Stress, inflammatory, and metabolic responses play important roles in the progression of PCABI. Lipocalin-2 is a novel biomarker for monitoring and early neuroprognostication at 24 h after resuscitation.

Excessive formation of neutrophil extracellular traps (NETs) significantly impedes diabetic wound healing. Although conditioned medium of mesenchymal stem cells (MSC-CM) has shown therapeutic potential due to its anti-inflammatory, antioxidant, and immunosuppressive properties, its regulatory effects on NETs remain poorly understood. Herein, this study systematically investigates the impact of MSC-CM, particularly conditioned medium of hypoxia-conditioned MSCs (HCM), on NET formation and diabetic wound repair. Transcriptomic analysis and public database mining revealed that circadian clock dysfunction drives aberrant NET formation. Notably, HCM exhibited superior efficacy over conditioned medium of normoxia-conditioned MSCs (NCM) in suppressing reactive oxygen species (ROS) production and NET formation while accelerating diabetic wound healing. Mechanistically, HCM-derived prostaglandin E2 (PGE2) upregulated brain and muscle ARNT-Like protein 1 (BMAL1), a core circadian regulator, through PGE2 receptor 2 (EP2)-EP4 signaling, thereby reducing ROS accumulation and subsequent NET formation. To achieve non-invasive, on-demand delivery of HCM bioactive components (especially PGE2), we developed a multifunctional hydrogel composed of phenylboronic acid-grafted quaternized soy protein isolate, sodium alginate and HCM (BQSA-HCM). This hydrogel system features glucose/ROS responsiveness, self-healing capability, injectability and excellent biocompatibility, enabling controlled PGE2 release. Importantly, HCM incorporation endows the hydrogel with immunomodulatory properties. In vivo experiments demonstrated that BQSA-HCM hydrogel significantly enhanced BMAL1 expression, suppressed NET formation, and promoted diabetic wound healing. This study clarifies the critical role of BMAL1 in regulating NET formation, validates the therapeutic potential of HCM in targeting NET-related diabetic wounds, and presents an innovative controlled-release hydrogel platform for advanced diabetic wound therapy.

Cancer vaccines utilizing nanoparticle (NP) structures that integrate antigens and adjuvants to enhance delivery and stimulate immune responses are emerging as a promising avenue in cancer immunotherapy. However, the development of cancer vaccines has been significantly hindered by the low immunogenicity of tumor antigens. To address this challenge, substantial efforts have been made in developing innovative adjuvants to elicit effective immune responses. In this study, we develop a NP cancer vaccine assisted by a polysaccharide derivative adjuvant, designed through a computational strategy, to evoke effective antigen-specific antitumor immunity. Using TLR4 as the putative receptor, we conducted a comprehensive evaluation of a prescreening library consisting of 34 inulin derivatives through docking and molecular dynamics simulation. Consequently, a new derivative, benzoylated inulin (InBz), is selected as the most promising TLR4 agonist. The adjuvant effect of InBz is evaluated by fabricating InBz NPs encapsulating the model antigen ovalbumin (OVA). In vitro, InBz-OVA NPs effectively activate the TLR4 signaling pathways and facilitate dendritic cell maturation, thereby enhancing the antigen delivery and presentation. In vivo, InBz-OVA NPs outperform a commercial aluminum-based adjuvant, elicit robust antibody titers, induce antigen-specific cytotoxic T lymphocytes, and achieve significant tumor suppression in murine models. Besides, the adjuvant effects of other representative derivatives, namely, acetylated and chloroacetylated inulin, with moderate and low potential from the library, are also chemically synthesized and experimentally evaluated and found to be in agreement with computational predictions, confirming the credibility of the strategy. This study provides an effective platform for the pursuit of efficient polysaccharide-based vaccine adjuvants.

Cardiac arrest (CA) is one of the most common illnesses worldwide. Post-CA brain injury (PCABI) is a major cause of death and poor recovery in CA patients and the current CA treatments are not very effective. The microbiome-gut-brain axis has been found to significantly affect brain ischemia injury. Furthermore, in ischemic stroke patients, short-chain fatty acids (SCFA), especially sodium butyrate (SB), have been observed to promote neuroprotective effects by modulating inflammatory response and microglial polarization in the cortex. However, the precise mechanism of SB on CA-induced injury remains elusive. Therefore, this research study established an oxygen–glucose deprivation and reoxygenation (OGD/R) model using BV-2 microglial and HT22 cells to simulate cerebral ischemia/reperfusion injury in vitro and a potassium chloride-induced CA mouse model to mimic CA in vivo. The data revealed that SB markedly improved neurological scores and reduced neuronal death and apoptosis. Moreover, it reduced M1 microglia and neuroinflammation in CA mice. In addition, SB increased intestinal integrity and alleviated systemic inflammation. The 16S rDNA sequencing analysis indicated that SB intervention mitigated CA-induced gut microbiota dysbiosis and SCFA depletion. It was also observed that CA mice’s brain and OGD/R-exposed BV2 cells had substantially increased levels of MyD88, phosphorylated NF-κB p65, and TLR4 proteins, which were reduced after SB treatment. In summary, this study revealed that SB can protect against cerebral ischemia–reperfusion injury by controlling microglia polarization and microbiome-gut-brain axis to inhibit brain inflammation via the TLR4/MyD88/NF-κB pathway.

The burn wounds are particularly susceptible to bacterial infection, while the hydrogel wound dressings with antibacterial property are expected to promote burn wound repairing progress. In this research, carboxymethyl cellulose bearing hydrazide groups and hemostatic polyphosphate moiety (CHP) was synthesized and cross-linked with dopamine grafted oxidized pectin (OPD) to prepare hemostatic self-healing hydrogel for burn wound repairing. Polydopamine coated graphene oxide (PGO) was loaded into the hydrogel to endow it with photothermal stimulated antibacterial property and enhanced the ROS scavenging ability, which can inhibit bacterial infection and promote tissue regeneration. Moreover, the loaded tannic acid (TA) further enhanced the antioxidant and anti-inflammatory properties of the hydrogel. As a result, the photothermal property of PGO and TA greatly reduced bacterial infection and promoted cell proliferation both in vitro and in vivo. More importantly, the composite PGO/TA/Gel hydrogel exhibited satisfactory therapeutic effect in burn wound healing in mice model through reducing inflammation response, enhance the collagen deposition and promote angiogenesis based on histological analysis. These advantages make this composite hydrogel great potential applications in the field of wound dressings in biomedication.

BACKGROUND Cardiac arrest (CA) and successful cardiopulmonary resuscitation (CPR) cause post-CA brain injury (PCABI) and extracerebral multiple organ dysfunction (EMOD), leading to low survival and disability in resuscitated patients. The pathogenesis of PCABI is still poorly understood, and no therapeutic-related factors have been identified to improve survival and neurological outcomes to date. Bumetanide is a promising pharmaceutical intervention for some neurological disorders that have some common pathophysiology with PCABI, and it also exhibit systemic protective effects on vital organs under pathological conditions. This study aims to investigate the protective effects of bumetanide on PCABI and EMOD after CA/CPR, and uncover the pathogenesis and biomarkers of PCABI at protein level.METHODS We generated a hyperkalemia-induced asystole CA/CPR mouse model with bumetanide/vehicle treatment after resuscitation. Survival, neurological outcome, functional outcome, key pathophysiological process underlying PCABI, and injury level of EMOD were evaluated. Proteomics analysis of cerebral cortex was performed for investigating mechanisms of PCABI.RESULTS Bumetanide significantly improved outcomes after CA/CPR and reduced the main pathophysiological processes of PCABI, including seizures, neurodegeneration, neuroinflammation, decreased cerebral blood flow, blood-brain barrier disruption, and oxidative stress. CA/CPR-induced injury in heart, lung, liver, kidney, spleen, adrenal gland, spinal cord, pennis, and urinary bladder were also alleviated by bumetanide. Proteomic study and experimental verification identified LCN2/NGAL is a potential biomarker for early neuroprognostication and has association with PCABI severity.CONCLUSIONS Systemic administration of bumetanide improved outcomes and prevented multiple organ dysfunction after CA/CPR. LCN2/NGAL is a novel biomarker for early neuroprognostication at 24 hours after CA/CPR.Clinical Perspective 1. What Is New? 2. What Are the Clinical Implications? ### Competing Interest StatementThe authors have declared no competing interest.* BBB : blood-brain barrier BUM : bumetanide CA : cardiac arrest CBF : cerebral blood flow CNS : central nervous system COG : cluster ortholog groups CPR : cardiopulmonary resuscitation CVC : central venous catheterization DEPs : differentially expressed proteins DHE : dihydroethidium DIA : data-independent acquisition EMOD : extracerebral multiple organ dysfunction FJB : Fluoro-Jade B GFAP : glial fibrillary acidic protein GO : gene ontology HE : hematoxylin-eosin HIBI : hypoxic ischemic brain injury Iba1 : ionized calcium-binding adaptor molecule 1 LCN2 : lipocalin-2 LSCI : laser speckle contrast imaging MODS : multiple organ dysfunction syndrome NGAL : neutrophil gelatinase-associated lipocalin NKCC1 : sodium-potassium-chloride cotransporter 1 PAS : periodic acid-Schiff PCABI : post-cardiac arrest brain injury PCAMD : post-cardiac arrest myocardial dysfunction PCAS : post-cardiac arrest syndrome PPI : protein-protein interaction PPP : persistent precipitating pathology ROS : reactive oxygen species ROSC : return of spontaneous circulation SDF : sidestream dark field SEM : standard error of the mean SIRR : systemic ischemia/reperfusion response Veh : vehicle

Effective wound care remains a significant challenge due to the need for infection prevention, inflammation reduction, and minimal tissue damage during dressing changes. To tackle these issues, we have developed a multifunctional hydrogel (CHI/CPBA/RU), composed of chitosan (CHI) modified with 4-carboxyphenylboronic acid (CPBA) and the natural flavonoid, rutin (RU). This design endows the hydrogel with body temperatureresponsive adhesion and low temperature-triggered detachment, thus enabling painless removal during dressing changes. The CHI/CPBA/RU hydrogels exhibit excellent biocompatibility, maintaining over 97 % viability of L929 cells. They also demonstrate potent intracellular free radical scavenging activity, with scavenging ratios ranging from 53 % to 70 %. Additionally, these hydrogels show anti-inflammatory effects by inhibiting proinflammatory cytokines (TNF-alpha, IL-6, and iNOS) and increasing anti-inflammatory markers (Arg1 and CD206) in RAW 264.7 macrophages. Notably, they possess robust antimicrobial properties, inhibiting over 99.9 % of the growth of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus growth. In vivo testing on a murine full-thickness skin defect model shows that the hydrogel significantly accelerates wound healing by reducing inflammation, increasing collagen deposition, and promoting angiogenesis, achieving 98 % healing by day 10 compared to 78 % in the control group. These attributes make the polysaccharide-based hydrogel a promising material for advanced wound care.

Cardiac arrest and successful resuscitation cause whole-body ischemia and reperfusion, leading to brain injury and extracerebral multiple organ dysfunction. Brain injury is the leading cause of death and long-term disability in resuscitated survivors, and was conceptualized and treated as an isolated injury, which has neglected the brain-visceral organ crosstalk. Extracerebral organ dysfunction is common and is significantly associated with mortality and poor neurological prognosis after resuscitation. However, detailed description of the characteristics of post-resuscitation multiple organ dysfunction is lacking, and the bidirectional interactions between brain and visceral organs need to be elucidated to explore new treatment for neuroprotection. This review aims to describe current concepts of post-cardiac arrest brain injury and specific characteristics of post-resuscitation dysfunction in cardiovascular, respiratory, renal, hepatic, adrenal, gastrointestinal, and neurohumoral systems. Additionally, we discuss the crosstalk between brain and extracerebral organs, especially focusing on how visceral organ dysfunction and other factors affect brain injury progression. We think that clarifying these interactions is of profound significance on how we treat patients for neural/systemic protection to improve outcome.

OBJECTIVE:To investigate and compare the regulatory effects of umbilical cord mesenchymal stem cells (MSC) and their conditioned medium (MSC-CM) on gut microbiota of septic mice.METHODS:Twenty-eight six-to-eight-week-old female C57BL/6J mice were randomly divided into sham operation group (Sham group), sepsis model group (CLP group), sepsis+MSC treatment group (CLP+MSC group) and sepsis+MSC-CM treatment group (CLP+MSC-CM group), with seven mice in each group. The septic mouse model was established by cecal ligation and puncture (CLP). In Sham group, CLP were not performed, and other operations were the same as CLP group. Mice in the CLP+MSC group and CLP+MSC-CM group received 0.2 mL 1×106 MSC or 0.2 mL concentrated MSC-CM via intraperitoneal injection 6 hours after CLP, respectively. Sham group and CLP group were given 0.2 mL sterile phosphate buffer saline (PBS) via intraperitoneal injection. Histopathological changes were evaluated by hematoxylin-eosin (HE) staining and colon length. Levels of inflammatory factors in serum were detected by enzyme-linked immunosorbent assay (ELISA). Phenotype of peritoneal macrophages was analyzed by flow cytometry, and the gut microbiota was analyzed via 16S rRNA sequencing.RESULTS:Compared with Sham group, significant inflammatory injury in lung and colon was observed, and shorter colon was detected in CLP group (cm: 6.00±0.26 vs. 7.11±0.09), the level of inflammatory cytokine interleukin-1β (IL-1β) in serum was significantly increased (ng/L: 432.70±17.68 vs. 353.70±17.01), the proportion of F4/80+ peritoneal macrophages was increased [(68.25±3.41)% vs. (50.84±4.98)%], while the ratio of F4/80+CD206+ anti-inflammatory peritoneal macrophages was decreased [(45.25±6.75)% vs. (66.66±3.36)%]. The α diversity sobs index of gut microbiota was downregulated significantly (118.50±23.25 vs. 255.70±6.87), the structure of species composition was altered, and the relative abundance of functional gut microbiota related to transcription, secondary metabolites biosynthesis, transport and catabolism, carbohydrate transport and metabolism, and signal transduction were decreased significantly in CLP group (all P < 0.05). Compared with CLP group, upon MSC or MSC-CM treatment, the pathological injury in lung and colon was alleviated to varying extent, the length of colon was increased (cm: 6.53±0.27, 6.87±0.18 vs. 6.00±0.26), the level of IL-1β in serum was downregulated (ng/L: 382.10±16.93, 343.20±23.61 vs. 432.70±17.68), the ratio of F4/80+ peritoneal macrophages was decreased [(47.65±3.93)%, (48.68±2.51)% vs. (68.25±3.41)%], the ratio of F4/80+CD206+ anti-inflammatory peritoneal macrophages was increased [(52.73±5.02)%, (66.38±4.73)% vs. (45.25±6.75)%], and the α diversity sobs index of gut microbiota was increased (182.50±16.35, 214.00±31.18 vs. 118.50±23.25), and the effects of MSC-CM were more significant (all P < 0.05). At the same time, species composition of gut microbiota was rebuilt, and a tendency of increase in relative abundance of functional gut microbiota was observed upon MSC and MSC-CM treatment.CONCLUSIONS:Both MSC and MSC-CM could alleviate inflammatory injury in tissues, and showed regulatory effects on gut microbiota in septic mouse model, moreover, MSC-CM exhibited superior advantages over MSC.

Wound healing is a critical challenge in diabetic patients, mainly due to long-term dysglycemia and its related pathological complications. Subcutaneous insulin injection represents a typical clinical solution, while the low controllability of insulin administration commonly leads to a result far from the optimal therapeutic effect. In this work, we developed a glucose-responsive insulin-releasing hydrogel for microneedle dressing fabrication and then investigated its effects on diabetic wound healing. The hydrogel system was composed of biocompatible gelatin methacrylate (GelMa), glucose-responsive monomer 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AFPBA) and gluconic insulin (G-insulin), and the Gel-AFPBA-ins hydrogel-based microneedle dressing was developed by replicating PDMS molds. The resultant hydrogel microneedle dressing exhibited adequate mechanical properties, high biocompatibility, glucose-responsive insulin release behavior upon exposure to different glucose solutions, and potent adhesion to the skin compared to hydrogels without microstructures. The microneedle dressing could accelerate the diabetic wound healing process with decreased inflammatory reaction, enhanced collagen deposition on the regenerated tissue sites, and improved blood glucose control in animals. Therefore, the glucose-responsive insulin-releasing hydrogel microneedle dressing is effective in diabetic wound management and has potential for treatment of other chronic skin injuries.

The secretome from hypoxia-preconditioned mesenchymal stem cells (MSCs) has been shown to promote resolution of inflammation and alleviate acute lung injury (ALI) through its immunomodulatory function. However, the effects of consecutive hypoxic culture on immunomodulatory function of the MSCs secretome are largely unclarified. Here, we intend to investigate the effects of consecutive hypoxia on therapeutic efficacy of conditioned medium derived from MSCs (MSCs-CM) in alleviating ALI. Human umbilical cord-derived MSCs (UC-MSCs) were consecutively cultured in 21% O2 (Nor-MSCs) or in 1% O2 (Hypo-MSCs) from passage 0. Their conditioned medium (Nor-CM and Hypo-CM respectively) was collected and administered into ALI models. Our findings confirmed that Hypo-MSCs exhibited increased proliferation ability and decreased cell senescence compared with Nor-MSCs. Consecutive hypoxia promoted UC-MSCs to secrete immunomodulatory cytokines, such as insulin-like growth factor 1(IGF1), IL10, TNFα-stimulated gene 6(TSG6), TGFβ, and prostaglandin E2 (PGE2). Both Nor-CM and Hypo-CM could effectively limit lung inflammation, promote efferocytosis and modulate anti-inflammatory polarization of lung macrophages in ALI models. Moreover, the effects of Hypo-CM were more potent than Nor-CM. Taken together, our findings indicate that consecutive hypoxic cultures could not only promote both proliferation and quality of UC-MSCs, but also enhance the therapeutic efficacy of their secretome in mitigating lung inflammation by promoting efferocytosis and anti-inflammatory polarization of macrophages.

Hydrogels with adhesive properties have the potential for rapid haemostasis and wound healing in uncontrolled non-pressurized surface bleeding. Herein, a typical hydrogen bond-crosslinked hydrogel with the above functions was constructed by directly mixing solutions of humic acid (HA) and polyvinylpyrrolidone (PVP), in which the HA worked as a crosslinking agent to form hydrogen bonds with the PVP. By altering the concentration of HA, a cluster of stable and uniform hydrogels were prepared within 10 s. The dynamic and reversible nature of the hydrogen bonds gave the HA/PVP complex (HPC) hydrogels injectability and good flexibility, as well as a self-healing ability. Moreover, the numerous functional groups in the hydrogels enhanced the cohesion strength and interaction on the interface between the hydrogel and the substrate, endowing them with good adhesion properties. The unique chemical composition and cross-linking mechanism gave the HPC hydrogel good biocompatibility. Taking advantage of all these features, the HPC hydrogels obtained in this work were broadly applied as haemostatic agents and showed a good therapeutic effect. This work might lead to an improvement in the development of multifunctional non-covalent hydrogels for application to biomaterials.

Electrical stimulation (ES) can promote peripheral nerve repair. Nevertheless, the basis of ES generally requires conductive tissue engineering scaffolds. In this work, a neural tissue engineering scaffold is prepared from a series of conductive composites. The conductive composites, hydroxyethyl cellulose (HEC)/soy protein isolate (SPI)/polyaniline (PANI) films (HSPFs), were prepared by natural volatilization of HEC/SPI solution and then in-situ polymerization of aniline. Subsequently, the HSPFs films were confirmed by ATR-FTIR, water contact angle and SEM characterization. The conductivity of HSPFs reached 0.45 S/m superlatively and cell contact test showed that HSPFs had good cytocompatibility with PC12 cells. Most important of all, the neurite lengths and BDNF protein expression of PC12 cells on HSPFs can be promoted by ES. These results indicated that the ES may have potential application in nerve tissue engineering field through the conductive HSPFs films.

Hemostatic materials are increasingly important in civilian and military clinics. In this work, a hydrogel was fabricated from hydroxypropyl chitosan (HPCS) and soy protein isolate (SPI) through the crosslinking of epichlorohydrin. Effects of SPI content on the structure, and physical and biological properties of the prepared hydrogels were characterized using Fourier-transform infrared spectroscopy, X-ray diffractometry, scanning electron microscopy, water uptake testing, mechanical properties testing, MTT assay, hemolysis ratio testing, and routine blood coagulation test. The results indicated that the hydrogels showed high water uptake ability and compressive strength. The in vitro biocompatibility evaluation revealed that the hydrogel contains 30% SPI content (HCSH-30), could promote blood coagulation and cell proliferation. Furthermore, the hemostatic model of liver in New Zealand rabbit was applied to assess the hemostatic efficacy of the hydrogels. The results demonstrated that HCSH-30 stopped bleeding in 75 +/- 1.63 s and improved hemostasis as compared with medical gauze. Thus, the HPCS/SPI hydrogel is expected to be a potential candidate for effective hemorrhage control. Impact statement Stoppage of bleeding is of paramount clinical significance in prophylactic, surgical, and emergency scenarios. This work describes a hydroxypropyl chitosan (HPCS)/soy protein isolate hydrogel, which could promote blood coagulation and cell proliferation, as well as stop bleeding in 75 +/- 1.63 s on the liver of New Zealand rabbits. Thus, we provide a new candidate for hemostatic material and broaden the application of HPCS-based materials.

目的:统计武汉某高校教职工体检人群的血尿酸(UA)水平在不同性别、年龄组的分布情况,分析高尿酸血症的患病率及其影响因素.方法:收集2019年参加教职工体检的7225名体检对象的基本资料(剔除数据不完整资料),分析不同性别、年龄人群HUA的患病情况以及相关影响因素[空腹血糖(Glu)、舒张压、收缩压、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、总胆固醇(TC)、肌酐(Cr)、BMI].结果:体检人群中男性UA水平为(387.93±84.98)μmol/L,各年龄组之间无统计学差异(P=0.798);女性UA水平为(297.57±73.75)μmol/L,各年龄组之间有统计学差异(P<0.05);人群总体HUA的患病率为25.54％,其中男性高尿酸血症的总体患病率显著高于女性(P<0.05);无论男女,血尿酸值与BMI、TG、Cr、TC以及收缩压、舒张压之间呈显著正相关,与HDL之间呈显著负相关.结论:武汉该高校体检人群HUA的患病率较高,且男性高于女性;Cr、TG、超重以及肥胖均为高尿酸血症的独立危险因素,HDL为独立保护因素.

Cardiac Arrest (CA) is one of the leading causes of mortality worldwide. The present study aimed to establish a simple and stable rat model of CA induced by transesophageal cardiac pacing for the investigation of cerebral resuscitation. A total of 26 healthy adult male Sprague-Dawley rats were randomly allocated into two groups: Sham-operated (n = 6) and experimental (n = 20) groups. High-frequency cardiac pacing (50 Hz, 2 ms and 30 V) was maintained for 3 min to induce CA. Providing CA was not achieved, an additional 2 min of pacing was performed 30 min later. After 4 min following the onset of CA, Cardiopulmonary Resuscitation (CPR) was initiated. CA was successfully induced in all 20 rats by this setting of high-frequency cardiac pacing. Among them, CA was induced in six rats after 2 min of pacing; the remaining 14 rats underwent CA after 3 min of pacing. When electrical stimulation was terminated the rate of Pulseless Electrical Activity (PEA) was 85

Peripheral nerve regeneration requires stepwise and well-organized establishment of microenvironment. Since local delivery of VEGF-A in peripheral nerve repair is expected to promote angiogenesis in the microenvironment and Schwann cells (SCs) play critical role in nerve repair, combination of VEGF and Schwann cells may lead to efficient peripheral nerve regeneration. VEGF-A overexpressing Schwann cells were established and loaded into the inner wall of hydroxyethyl cellulose/soy protein isolate/polyaniline sponge (HSPS) conduits. When HSPS is mechanically distorted, it still has high durability of strain strength, thus, can accommodate unexpected strain of nerve tissues in motion. A 10 mm nerve defect rat model was used to test the repair performance of the HSPS-SC (VEGF) conduits, meanwhile the HSPS, HSPS-SC, HSPS-VEGF conduits and autografts were worked as controls. The immunofluorescent co-staining of GFP/VEGF-A, Ki67 and MBP showed that the VEGF-A overexpressing Schwann cells could promote the proliferation, migration and differentiation of Schwann cells as the VEGF-A was secreted from the VEGF-A overexpressing Schwann cells. The nerve repair performance of the multifunctional and flexible conduits was examined though rat behavioristics, electrophysiology, nerve innervation to gastrocnemius muscle (GM), toluidine blue (TB) staining, transmission electron microscopy (TEM) and NF200/S100 double staining in the regenerated nerve. The results displayed that the effects on the repair of peripheral nerves in HSPS-SC (VEGF) group was the best among the conduits groups and closed to autografts. HSPS-SC (VEGF) group exhibited notably increased CD31+ endothelial cells and activation of VEGFR2/ERK signaling pathway in the regenerated nerve tissues, which probably contributed to the improved nerve regeneration. Altogether, the comprehensive strategy including VEGF overexpressing Schwann cells-mediated and HSPS conduit-guided peripheral nerve repair provides a new avenue for nerve tissue engineering.

Almost all cells in the human body are subjected to mechanical stresses. These forces can vary from a few Pascals (shear stress) to some mega Pascals (on hip cartilage). It is now well known that mechanical forces have a decisive effect on cellular physiology. In 1880, W. Roux introduced the concept of functional adaptation; which can be defined as a quantitative autoregulation controlled by stimuli like mechanical forces. These stresses influence functionality and cellular metabolism and can lead to appropriate tissue remodelling by triggering a cascade of reactions (mechanotransduction), being the signal for the adaptation of cells and tissues. However, although the main biological effects of mechanical forces are well documented, the relation between mechanical forces and physiological phenomena is largely unknown. In this paper, some effects of mechanical stresses on different cells (mesenchymal stem cells, bone cells, chondrocyte, endothelial cells, vascular or muscular cells, etc.) are summarized.