3D printed VEGF-CPO biomaterial scaffold to promote subcutaneous vascularization and survival of transplanted islets for the treatment of diabetes.

Diabetes is a complex metabolic disease and islet transplantation is a promising approach for the treatment of diabetes. Unfortunately, the transplanted islets at the subcutaneous site are also affected by various adverse factors such as poor vascularization and hypoxia. In this study, we utilize biocompatible copolymers l-lactide and D,l-lactide to manufacture a biomaterial scaffold with a mesh-like structure via 3D printing technology, providing a material foundation for encapsulating pancreatic islet cells. The scaffold maintains the sustained release of vascular endothelial growth factor (VEGF) and a slow release of oxygen from calcium peroxide (CPO), thereby regulating the microenvironment for islet survival. This helps to improve insufficient subcutaneous vascularization and reduce islet death due to hypoxia post-transplantation. By pre-implanting VEGF-CPO scaffolds subcutaneously into diabetic rats, a sufficiently vascularized site is formed, thereby ensuring early survival of transplanted islets. In a word, the VEGF-CPO scaffold shows good biocompatibility both in vitro and in vivo, avoids the adverse effects on the implanted islets, and displays promising clinical transformation prospects.

Nanoparticles exhibiting virus-mimic surface topology for enhanced oral delivery.

The oral delivery of nano-drug delivery systems (Nano-DDS) remains a challenge. Taking inspirations from viruses, here we construct core-shell mesoporous silica nanoparticles (NPs, ~80 nm) with virus-like nanospikes (VSN) to simulate viral morphology, and further modified VSN with L-alanine (CVSN) to enable chiral recognition for functional bionics. By comparing with the solid silica NPs, mesoporous silica NPs and VSN, we demonstrate the delivery advantages of CVSN on overcoming intestinal sequential barriers in both animals and human via multiple biological processes. Subsequently, we encapsulate indomethacin (IMC) into the nanopores of NPs to mimic gene package, wherein the payloads are isolated from bio-environments and exist in an amorphous form to increase their stability and solubility, while the chiral nanospikes multi-sited anchor and chiral recognize on the intestinal mucosa to enhance the penetrability and ultimately improve the oral adsorption of IMC. Encouragingly, we also prove the versatility of CVSN as oral Nano-DDS.

A rat liver cell atlas reveals intrahepatic myeloid heterogeneity.

The large size and vascular accessibility of the laboratory rat (Rattus norvegicus) make it an ideal hepatic animal model for diseases that require surgical manipulation. Often, the disease susceptibility and outcomes of inflammatory pathologies vary significantly between strains. This study uses single-cell transcriptomics to better understand the complex cellular network of the rat liver, as well as to unravel the cellular and molecular sources of inter-strain hepatic variation. We generated single-cell and single-nucleus transcriptomic maps of the livers of healthy Dark Agouti and Lewis rat strains and developed a factor analysis-based bioinformatics analysis pipeline to study data covariates, such as strain and batch. Using this approach, we discovered transcriptomic variation within the hepatocyte and myeloid populations that underlie distinct cell states between rat strains. This finding will help provide a reference for future investigations on strain-dependent outcomes of surgical experiment models.

Inorganic-Organic Hybrid Multifunctional Solid Electrolyte Interphase Layers for Dendrite-Free Sodium Metal Anodes.

Constructing a stable and robust solid electrolyte interphase (SEI) is crucial for achieving dendrite-free sodium metal anodes and high-performance sodium batteries. However, maintaining the integrity of SEI during prolonged cycle life under high current densities poses a significant challenge. In this study, we propose an integrated multifunctional SEI layer with inorganic/organic hybrid construction (IOHL-Na) to enhance the durability of sodium metal anode during reduplicative plating/stripping processes. The inorganic components with high mechanical strength and strong sodiophilicity demonstrate optimized ionic conduction efficiency and dendrite inhibition ability. Simultaneously, the organic component contributes to the formation of a dense and elastic membrane structure, preventing fracture and delamination issues during volume fluctuations. The symmetrical batteries of IOHL-Na achieve stable cycling over 2000 hours with an extremely low voltage hysteresis of around 15.8 mV at a high current density of 4 mA cm-2 . Moreover, the Na-O2 batteries sustain exceptional long-term stability and impressive capacity retention, exploiting a promising approach for constructing durable SEI and dendrite-free sodium metal anodes.

Mesoporous silica nanoparticles with chiral pattern topological structure function as "antiskid tires" on the intestinal mucosa to facilitate oral drugs delivery.

The weak adhesion between nanocarriers and the intestinal mucosa was one of the main reasons caused the failure in oral delivery. Inspired by the "antiskid tires" with complex chiral patterns, mesoporous silica nanoparticles AT-R@CMSN exhibiting geometrical chiral structure were designed to improve the surface/interface roughness in nanoscale, and employed as the hosting system for insoluble drugs nimesulide (NMS) and ibuprofen (IBU). Once performing the delivery tasks, AT-R@CMSN with rigid skeleton protected the loaded drug and reduced the irritation of drug on gastrointestinal tract (GIT), while their porous structure deprived drug crystal and improved drug release. More importantly, AT-R@CMSN functioned as "antiskid tire" to produce higher friction on intestinal mucosa and substantively influenced multiple biological processes, including "contact", "adhesion", "retention", "permeation" and "uptake", compared to the achiral S@MSN, thereby improving the oral adsorption effectiveness of such drug delivery systems. By engineering AT-R@CMSN to overcome the stability, solubility and permeability bottlenecks of drugs, orally administered NMS or IBU loaded AT-R@CMSN could achieve higher relative bioavailability (705.95% and 444.42%, respectively) and stronger anti-inflammation effect. In addition, AT-R@CMSN displayed favorable biocompatibility and biodegradability. Undoubtedly, the present finding helped to understand the oral adsorption process of nanocarriers, and provided novel insights into the rational design of nanocarriers.

Chiral Nanosilica Drug Delivery Systems Stereoselectively Interacted with the Intestinal Mucosa to Improve the Oral Adsorption of Insoluble Drugs.

Chiral nanoparticles (NPs) with nanoscale rough surfaces have enormous application prospects in drug delivery. However, the stereoselective interactions between the chiral NPs and biosurfaces remain challenging and mysterious. Herein, we designed mesoporous silica nanocarriers (l/d/dl-TA-PEI@CMSN) exhibiting the same structural parameters (hydrophilic, electroneutral, spherical NPs, ∼120 nm) but different geometrical chirality as oral nanodrug delivery systems (Nano-DDS) for insoluble drugs nimesulide (NMS) and ibuprofen (IBU) and demonstrated their stereoselective interactions with the intestinal mucosa, that is, l-TA-PEI@CMSN as well as Nano-DDS in the l-configuration displayed apparent superior behaviors in multiple microprocesses associated with oral adsorption, including adhesion, penetration, adsorption, retention and uptake, causing by the stereomatching between the chiral mesostructures of NPs and the inherent chiral topologies of the biosurfaces. As hosting systems, l/d/dl-TA-PEI@CMSN effectively incorporated drugs in amorphous states and helped to overcome the stability, solubility and permeability bottlenecks of drugs. Subsequently, Nano-DDS in the l-configuration (including IBU/l-TA-PEI@CMSN and NMS/d-TA-PEI@CMSN owing to a chiral inversion) showed higher oral delivery efficiency of NMS and IBU evidenced by the larger relative bioavailability (1055.06% and 583.17%, respectively) and stronger anti-inflammatory and analgesic effects. In addition, l/d/dl-TA-PEI@CMSN were stable, nonirritative, biocompatible and biodegradable, benefiting for their clinical applications. These findings provided insights into the rational design of functionalized Nano-DDS and contributed to the further knowledge in the field of chiral pharmaceutical science.

A pH-responsive chiral mesoporous silica nanoparticles for delivery of doxorubicin in tumor-targeted therapy.

The purpose of this study was to develop a nano-drug delivery system with intelligent stimuli-responsive drug delivery in tumor microenvironment (TME). Based on chiral mesoporous silica nanoparticles (CMSN) with a chiral recognition function in our previous research, a pH-responsive CMSN (CS-CMSN) was successfully prepared by chemical modification of chitosan (CS), and the related physicochemical properties, drug release performance, potential anti-tumor effect, and biological safety were studied. The results showed that the CS-CMSN were successfully modified by CS. Moreover, CS-CMSN displayed superior encapsulation ability for doxorubicin (DOX) and exhibited controllable pH-responsive drug release properties. In particular, in a physiological environment (pH 7.4/6.5), CS shielded the nanopores, prevented DOX release, and minimized side effects on normal cells. Once the CS-CMSN was exposed to the TME (pH 5.0), the pH-sensitive moiety of CS was cleaved in an acidic environment, along with the rapid release of DOX. In vitro cell experiments further proved that DOX@CS-CMSN was more strongly taken up by 4T1 cells and could enhance the toxicity to 4T1 tumor cells as well as promote cell apoptosis. More importantly, CS-CMSN were shown to have good biosafety in vitro and in vivo. Overall, the delivery of DOX by CS-CMSN nanocarriers is a promising strategy for tumor-targeted therapy.

Fluorine Substitution Promotes Air-Stability of P'2-Type Layered Cathodes for Sodium-Ion Batteries.

As one of the most promising cathode materials in sodium-ion batteries, manganese-based layered oxides have aroused wide attention due to their high specific capacity and plentiful reserves. However, they are plagued by poor air stability rooting in water/Na+ exchange and adverse structural reconstruction, hindering their practical applications. Herein, it is demonstrated that utilizing fluorine to substitute oxygen atoms can narrow the interlayer spacing of novel P'2-Na0.67 MnO1.97 F0.03 (NMOF) cathode material, which resists the attack of water molecules, significantly prolonging exposure time in air. Density functional theory (DFT) calculation results indicate that fluorine substitution alleviates the insertion of water molecules and spontaneous extraction of Na+ effectively. Benefiting from the structural modulation, NMOF can deliver a high specific capacity of 227.1 mAh g-1 at 20 mA g-1 and a promising capacity retention of 84.0% after 100 cycles at 200 mA g-1 . This facile and available strategy provides a feasible way to strengthen the air-stability and expands the scope of practical applications of layered oxide cathodes.

Fluorination Treatment of Conjugated Protonated Polyanilines for High-Performance Sodium Dual-Ion Batteries.

The overall performance of dual-ion batteries (DIBs) is strongly linked to anions storage properties of cathodes. Whereas high energy/power densities and stabilities for DIBs are limited by cathodes. To overcome these barriers, we have designed a novel fluoridized-polyaniline-H+ /carbon nanotubes (FPHC) as cathode for high-efficiency PF6 - storage. F- in PF6 - is easy to form covalent bond with H on -NH- in FPHC, so that PF6 - can stably coordinate with FPHC, showing a symmetrical structure. FPHC cathode shows a highly reversible capacity of 73 mAh g-1 at 2 A g-1 after 2000 cycles, which provides a solid base for the advanced sodium dual-ion batteries (SDIBs) (310 Wh kg-1 /7720 W kg-1 ). Besides, the relative pouch-type SDIB can drive a vacuum cleaner model with an electric machine. This work may shed light on an up-and-coming strategy of robust cathodes for SDIBs.

A randomized controlled trial to evaluate efficacy and safety of early conversion to a low-dose calcineurin inhibitor combined with sirolimus in renal transplant patients.

BACKGROUND: The calcineurin inhibitor (CNI)-based immune maintenance regimen that is commonly used after renal transplantation has greatly improved early graft survival after transplantation; however, the long-term prognosis of grafts has not been significantly improved. The nephrotoxicity of CNI drugs is one of the main risk factors for the poor long-term prognosis of grafts. Sirolimus (SRL) has been employed as an immunosuppressant in clinical practice for over 20 years and has been found to have no nephrotoxic effects on grafts. Presently, the regimen and timing of SRL application after renal transplantation vary, and clinical data are scarce. Multicenter prospective randomized controlled studies are particularly rare. This study aims to investigate the effects of early conversion to a low-dose CNI combined with SRL on the long-term prognosis of renal transplantation. METHODS: Patients who receive four weeks of a standard regimen with CNI + mycophenolic acid (MPA) + glucocorticoid after renal transplantation in multiple transplant centers across China will be included in this study. At week 5, after the operation, patients in the experimental group will receive an additional administration of SRL, a reduction in the CNI drug doses, withdrawal of MPA medication, and maintenance of glucocorticoids. In addition, patients in the control group will receive the maintained standard of care. The patients' vital signs, routine blood tests, routine urine tests, blood biochemistry, serum creatinine, BK virus (BKV)/ cytomegalovirus (CMV), and trough concentrations of CNI drugs and SRL at the baseline and weeks 12, 24, 36, 48, 72, and 104 after conversion will be recorded. Patient survival, graft survival, and estimated glomerular filtration rate will be calculated, and concomitant medications and adverse events will also be recorded. CONCLUSION: The study data will be utilized to evaluate the efficacy and safety of early conversion to low-dose CNIs combined with SRL in renal transplant patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800017277.

Synergistic Effect of 3D Flexible Framework with Sodiophilic Mesoporous SnO2 Nanosheet Arrays on Dendrite-Free Sodium Metal Batteries.

Although tremendous efforts have been dedicated to promote the electrochemical stability of sodium metal batteries (SMBs), the uncontrollable dendrites growth and inevitable side reactions at the sodium (Na) anode/electrolyte interface have not been effectively resolved. In this work, a flexible and functionalized 3D framework with mesoporous SnO2 nanosheet arrays (SnO2@CC-12) is fabricated to serve as a sodiophilic matrix toward dendrite-free Na metal anode. The mesoporous SnO2 nanosheet arrays provide abundant sodiophilic sites and sufficient internal voids, which can not only accelerate electron transport to reduce the local current density of Na anode surface but also manipulate the Na+ flux deposition to suppress the growth of Na dendrites. Therefore, the SnO2@CC-12-Na symmetric cell exhibits an ultralow overpotential of 9 mV and superior Na plating/stripping stability over 2200 h at 1.0 mA cm-2. Moreover, the full cells using Na3V2(PO4)3 cathode show favorable high-rate performance and impressive long cycling stability with 95.1% capacity retention over 1000 cycles at 500 mA g-1. This work may provide a new insight into the design of functionalized interface layer with high sodiophilicity toward dendrite-free SMBs.

Inorganic Electrolyte for Low-Temperature Aqueous Sodium Ion Batteries.

Aqueous sodium ion batteries have received widespread attention due to their great application potential and high safety. However, the serious capacity fading under low temperature dramatically restricts their practical application. Compared to flammable and toxic organic antifreezing additives, addition of common cheap inorganic inert additives to improve low-temperature performance is of interest scientifically. Herein, low-cost calcium chloride is served as antifreezing additive in 1 m NaClO4 aqueous electrolyte due to its strong interaction with water molecules. The freezing point of the optimized electrolyte is significantly reduced to below -50 °C with an ultrahigh ionic conductivity (7.13 mS cm-1 ) at -50 °C. All pure inorganic composition of the full battery delivers a high capacity of 74.5 mAh g-1 under 1 C (1 C = 150 mA g-1 ) at -30 °C. More importantly, when tested under 10 C at -30 °C, the battery can achieve an ultralong cycling stability of 6000 cycles with no obvious capacity decay, indicating fast Na+ transport under low temperature. Significantly, this work provides an easy-to-operate strategy by adding cheap inorganic salt to develop high-performance low-temperature aqueous batteries.

Reduced Complications after Arterial Reconnection in a Rat Model of Orthotopic Liver Transplantation.

The rat orthotopic liver transplantation (OLT) model is a powerful tool to study acute and chronic rejection. However, it is not a complete representation of human liver transplantation due to the absence of arterial reconnection. Described here is a modified transplantation procedure that includes the incorporation of hepatic artery (HA) reconnection, leading to a marked improvement in transplant outcomes. With a mean anhepatic time of 12 min and 14 s, HA reconnection results in improved perfusion of the transplanted liver and an increase in long-term recipient survival from 37.5% to 88.2%. This protocol includes the use of 3D-printed cuffs and holders to connect the portal vein and infrahepatic inferior vena cava. It can be implemented for studying multiple aspects of liver transplantation, from immune response and infection to technical aspects of the procedure. By incorporating a simple and practical method for arterial reconnection using a microvascular technique, this modified rat OLT protocol closely mimics aspects of human liver transplantation and will serve as a valuable and clinically relevant research model.

Nanoparticle Uptake in a Spontaneous and Immunocompetent Woodchuck Liver Cancer Model.

There is a tremendous focus on the application of nanomaterials for the treatment of cancer. Nonprimate models are conventionally used to assess the biomedical utility of nanomaterials. However, these animals often lack an intact immunological background, and the tumors in these animals do not develop spontaneously. We introduce a preclinical woodchuck hepatitis virus-induced liver cancer model as a platform for nanoparticle (NP)-based in vivo experiments. Liver cancer development in these out-bred animals occurs as a result of persistent viral infection, mimicking human hepatitis B virus-induced HCC development. We highlight how this model addresses key gaps associated with other commonly used tumor models. We employed this model to (1) track organ biodistribution of gold NPs after intravenous administration, (2) examine their subcellular localization in the liver, (3) determine clearance kinetics, and (4) characterize the identity of hepatic macrophages that take up NPs using RNA-sequencing (RNA-seq). We found that the liver and spleen were the primary sites of NP accumulation. Subcellular analyses revealed accumulation of NPs in the lysosomes of CD14+ cells. Through RNA-seq, we uncovered that immunosuppressive macrophages within the woodchuck liver are the major cell type that take up injected NPs. The woodchuck-HCC model has the potential to be an invaluable tool to examine NP-based immune modifiers that promote host anti-tumor immunity.

Rose-like Nanocomposite of Fe-Ni Phosphides/Iron Oxide as Efficient Catalyst for Oxygen Evolution Reaction.

In order to accelerate the reaction rate of water splitting, it is of immense importance to develop low-cost, stable and efficient catalysts. In this study, the facile synthesis of a novel rose-like nanocomposite catalyst (Ni2 P/Fe2 P/Fe3 O4 ) is reported. The synthesis process includes a solvothermal step and a phosphatization step to combine iron oxides and iron-nickel phosphides. Ni2 P/Fe2 P/Fe3 O4 performs well in catalyzing oxygen evolution reaction, with a very low overpotential of 365 mV to reach 10 mA cm-2 current density. The Tafel slope is as low as 59 mV dec-1 . Ni2 P/Fe2 P/Fe3 O4 has a large double-layer capacitance that contributes to a high electrochemically active area. Moreover, this catalyst is very stable for long-term use. Therefore, the Ni2 P/Fe2 P/Fe3 O4 catalyst has a high potential for use in oxygen evolution reactions.

Early detection and integral resection are keys to extend survival in patients suffered from primary angiosarcoma of the spleen: A care-compliant case report and literature review.

RATIONALE: Primary angiosarcoma of the spleen (PAS) is a very rare malignant neoplasm that originates from endothelial cells of the splenic blood vessels. Without typical clinical presentations and specific radiological features, PAS is very difficult to be early identified and 1-year mortality is extremely high. Late detection and spleen rupture are considered as the most important risk factors for early metastasis. PATIENT CONCERNS: Without any obvious symptom, a 35-year-old woman was admitted with splenic neoplasm that was accidentally discovered through a routine physical examination. DIAGNOSES: The patient was first diagnosed as lymphoma by laboratory tests and imaging studies, but changed to PAS by histological examinations after the surgery. INTERVENTIONS: After careful preoperational assessment, a laparoscopic-assisted splenectomy was scrutinously performed and the entire spleen was removed without any rupture. OUTCOMES: The postoperative followed-up was uneventful until 3 years later, when she sought medical attention due to persisting back pain. Bone metastasis was consequently identified and the symptom was quickly alleviated after radiation therapy. However, intra-abdominal metastases leading to intestinal obstruction occurred 4.5 years after surgery. Following short palliative treatment, the patient passed away 4 years and 9 months after the operation due to multiple organ failure. LESSONS: PAS is an uncommon and aggressive splenic disease. Once suspected, PAS require prompt and precise surgical procedures to remove the tumor origin. Laparoscopic-assisted splenectomy was technically feasible and therapeutically harmless for PAS treatment compared with open surgery as long as the spleen was removed intact. However, more evaluation of this option will be needed due to limited experience by now. Early discovery, precautious plan, meticulous operation, close follow-up, and comprehensive treatment may significantly prolong the living period of this fatal disease.

Enucleation of pancreatic cystadenomas.

BACKGROUND: Optimal surgical treatment of pancreatic cystadenomas is controversial due to the rarity of the tumors and paucity of studies regarding long-term outcomes. This is especially true for large pancreatic cystadenomas. The objective of this study was to determine the safety and effectiveness of treating pancreatic cystadenomas by enucleation. METHODS: Eleven cases of pancreatic mucinous or serous cystadenomas were selected for enucleation according to the following criteria: (1) the benign nature of the tumors was ascertained preoperatively and intraoperatively, (2) small tumors or larger tumors no more than 6 cm in diameter growing outwardly with small tumor beds, and (3) the main pancreatic duct was not in jeopardy of damage by enucleation. The patients' demographics, tumor features, morbidity, and follow-up results were retrospectively reviewed and analyzed. RESULTS: Among 11 cases, three were serous cystadenomas and eight were mucinous cystadenomas; the average size of the neoplasms was 4.8 cm (ranging from 3 to 6 cm). Two cases were complicated by the development of fistulas postoperatively and one had an incision infection. All cases were followed up from 23 to 67 months, which revealed no neoplasm recurrence or new onset of diabetes mellitus; one patient developed a pseudocyst in the body 30 months after enucleation. CONCLUSIONS: It is safe and effective to perform enucleation for well-selected benign pancreatic cystadenomas even if the tumor size is as large as 6 cm, and the endocrine or exocrine function of the pancreas is maintained as much as possible.

[Liver transplantation in end-stage liver disease with portal vein thrombosis].

OBJECTIVE: To summarize the experience in the managements of portal vein thrombosis (PVT) and to evaluate the impact of PVT on intraoperative course and postoperative outcome in liver transplantation. METHODS: Between May 1995 and September 2007, 194 orthotopic liver transplantations were performed, of which 24 cases presented portal vein thrombosis. There were 12 patients with grade I, 9 with grade II, 2 with grade III and 1 with grade IV. The management of PVT depended mainly on its extent. Ligation of the collateral circulation, especially spontaneous or surgical splenorenal shunt, was made as approaches to improve portal flow.Heparin or low-molecule-weight heparin as a prophylactic anticoagulation therapy was maintained during and after operation if prothrombin time is less than eighteen seconds. Follow-up Doppler ultrasonography was used daily in the early postoperative period. Risk factors and variables associated with the transplant and the post-transplant period were analyzed and compared with 170 patients transplanted without PVT. RESULTS: Surgical techniques were eversion thromboendovenectomy in 21 patients with PVT grades I and II, extra-anatomic mesenteric graft in 2 with grade III, and anastomosis to a collateral vein in 1 with grade IV. The study demonstrated more RBC transfusions [(15.2 +/- 11.8) U vs. (8.6 +/- 6.6) U, P = 0.006], longer surgery procedures [(492 +/- 89) min vs. (403 +/- 105) min, P = 0.001] and hospital stay [(32.4 +/- 13.5) d vs. (22.1 +/- 9.1) d, P = 0.001] in the PVT group. However, there were no differences in overall morbidity (58.3% vs. 50.6%, P = 0.478), hospital mortality (8.3% vs.6.5%, P = 0.73) and 1-year survival (87.5% vs. 89.4%, P = 0.778). The incidence of rethrombosis was higher in the PVT group (8.3% vs.1.2%, P = 0.021). Two cases rethrombosis were successfully cured by percutaneous thrombolysis, balloon angioplasty, and stent placement. CONCLUSION: Portal thrombosis is associated with greater operative complexity and rethrombosis, but has no influence on overall morbidity and mortality in liver transplantation.