Enhancement of subunit vaccine delivery with zinc-carnosine coordination polymer through the addition of mannan.

Vaccines represent a pivotal health advancement for preventing infection. However, because carrier systems with repeated administration can invoke carrier-targeted immune responses that diminish subsequent immune responses (e.g., PEG antibodies), there is a continual need to develop novel vaccine platforms. Zinc carnosine microparticles (ZnCar MPs), which are composed of a one-dimensional coordination polymer formed between carnosine and the metal ion zinc, have exhibited efficacy in inducing an immune response against influenza. However, ZnCar MPs' limited suspendability hinders clinical application. In this study, we address this issue by mixing mannan, a polysaccharide derived from yeast, with ZnCar MPs. We show that the addition of mannan increases the suspendability of this promising vaccine formulation. Additionally, since mannan is an adjuvant, we illustrate that the addition of mannan increases the antibody response and T cell response when mixed with ZnCar MPs. Mice vaccinated with mannan + OVA/ZnCar MPs had elevated serum IgG and IgG1 levels in comparison to vaccination without mannan. Moreover, in the mannan + OVA/ZnCar MPs vaccinated group, mucosal washes demonstrated increased IgG, IgG1, and IgG2c titers, and antigen recall assays showed enhanced IFN-γ production in response to MHC-I and MHC-II immunodominant peptide restimulation, compared to the vaccination without mannan. These findings suggest that the use of mannan mixed with ZnCar MPs holds potential for subunit vaccination and its improved suspendability further promotes clinical translation.

Impacto económico del uso de patiromer en enfermedad renal crónica o insuficiencia cardíaca para el tratamiento de la hiperpotasemia crónica en España / Economic impact of the use of patiromer in chronic kidney disease or heart failure for the treatment of chronic hyperkalemia in Spain

Introducción La hiperpotasemia crónica tiene consecuencias negativas a medio y largo plazo, condicionando generalmente la suspensión de fármacos nefro y cardioprotectores, en pacientes con enfermedad renal crónica (ERC) e insuficiencia cardíaca (IC), como son los inhibidores del sistema renina-angiotensina-aldosterona. Existe una alternativa a la suspensión o reducción de dosis de estos tratamientos y es la administración de quelantes del potasio. El objetivo de este estudio es estimar el impacto económico que supondría el uso de patiromer en pacientes con ERC o IC e hiperpotasemia en España. Material y métodos Se ha estimado el impacto económico anual del uso de patiromer desde la perspectiva de la sociedad española, comparando 2 escenarios: pacientes con ERC o IC e hiperpotasemia tratada con patiromer y sin patiromer. Los costes se han actualizado a euros de 2020, utilizando el índice de precios de consumo de Sanidad. Se han considerado los costes directos sanitarios relacionados con el uso de recursos (el tratamiento con inhibidores del sistema renina-angiotensina-aldosterona, la progresión de la ERC, los eventos cardiovasculares y la hospitalización por hiperpotasemia), los costes directos no sanitarios (cuidados informales: costes derivados del tiempo de dedicación por parte de los familiares del paciente), los costes indirectos (pérdidas de productividad laboral), así como un coste intangible (por mortalidad prematura). Se realizó un análisis de sensibilidad determinístico para validar la consistencia de los resultados del estudio. Resultados El coste medio anual por paciente en el escenario sin patiromer es de 9.834,09 € y 10.739,37 € en ERC e IC, respectivamente. El uso de patiromer supondría un ahorro de costes superior al 30% en ambas enfermedades. En el caso de la ERC, el mayor ahorro procede del retraso de la progresión de la ERC (AU)

Introduction Chronic hyperkalemia has negative consequences in the medium and long term, and determines the suspension of nephro and cardioprotective drugs, such as renin–angiotensin–aldosterone system inhibitors (RAASi). There is an alternative to the suspension or dose reduction of these treatments: the administration of potassium chelators. The aim of this study is to estimate the economic impact of the use of patiromer in patients with chronic kidney disease (CKD) or heart failure (HF) and hyperkalemia in Spain. Materials and method The annual economic impact of the use of patiromer has been estimated from the perspective of the Spanish society. Two scenarios were compared: patients with CKD or HF and hyperkalemia treated with and without patiromer. The costs have been updated to 2020 euros, using the Health Consumer Price Index. Direct healthcare costs related to the use of resources (treatment with RAASi, CKD progression, cardiovascular events and hospitalization due to hyperkalemia), direct non-healthcare costs (informal care: costs derived from time dedicated by patient's relatives), the indirect costs (productivity loss), as well as an intangible cost (due to premature mortality) were considered. A deterministic sensitivity analysis was performed to validate the robustness of the study results. Results The mean annual cost per patient in the scenario without patiromer is €9834.09 and €10,739.37 in CKD and HF, respectively. The use of patiromer would lead to cost savings of over 30% in both diseases. The greatest savings in CKD come from the delay in the progression of CKD. While in the case of HF, 80.1% of these savings come from premature mortality reduction. The sensitivity analyses carried out show the robustness of the results, obtaining savings in all cases (AU)

Nanodiamond-based multifunctional platform for oral chemo-photothermal combinational therapy of orthotopic colon cancer.

Combination therapy system has become a promising strategy for achieving favorable antitumor efficacy. Herein, a novel oral drug delivery system with colon localization and tumor targeting functions was designed for orthotopic colon cancer chemotherapy and photothermal combinational therapy. The polydopamine coated nanodiamond (PND) was used as the photothermal carrier, through the coupling of sulfhydryl-polyethylene glycol-folate (SH-PEG-FA) on the surface of PND to achieve systematic colon tumor targeting, curcumin (CUR) was loaded as the model drug, and then coated with chitosan (CS) to achieve the long gastrointestinal tract retention and colon localization functions to obtain PND-PEG-FA/CUR@CS nanoparticles. It has high photothermal conversion efficiency and good photothermal stability and exhibited near-infrared (NIR) laser-responsive drug release behavior. Folate (FA) modification effectively promotes the intracellular uptake of nanoparticles by CT26 cells, and the combination of chemotherapy and photothermal therapy (CT/PTT) can enhance cytotoxicity. Compared with free CUR group, nanoparticles prolonged the gastrointestinal tract retention time, accumulated more in colon tumor tissues, and exhibited good photothermal effect in vivo. More importantly, the CT/PTT group exhibited satisfactory tumor growth inhibition effects with good biocompatibility in vivo. In summary, this oral drug delivery system is an efficient platform for chemotherapy and photothermal combinational therapy of orthotopic colon cancer.

Cyclic poly(ß-amino ester)s with enhanced gene transfection activity synthesized through intra-molecular cyclization.

Topological structure plays a critical role in gene delivery of cationic polymers. Cyclic poly(ß-amino ester)s (CPAEs) are successfully synthesized via sequential Michael addition and free radical initiating ring-closure reaction. The CPAEs exhibit superior gene transfection efficiency and safety profile compared to their linear counterparts.

Polymer-hybrid nanosystems for antiviral applications: Current advances.

The emergence of many new viruses in recent times has resulted in a significant scientific challenge for discovering drugs and vaccines that effectively treat and prevent viral diseases. Nanotechnology has opened doors to prevent the spread of several diseases, including those caused by viruses. Polymer-hybrid nanodevices are a class of nanotechnology platforms for biomedical applications that present synergistic properties among their components, with improved performance compared to conventional forms of therapy. Considering the growing interest in this emerging field and the promising technological advantages of polymer-hybrid nanodevices, this work presents the current status of these systems in the context of prevention and treatment of viral diseases. A brief description of the different types of polymer-hybrid nanodevices highlighting some peculiar characteristics such as their composition, biodistribution, delivery of antigens, and overall immune responses in systemic tissues are discussed. Finally, the work presents the future trends for new nanotechnological hybrid materials based on polymers and perspectives for clinical use.

Ultrasound-Enhanced Reactive Oxygen Species Responsive Charge-Reversal Polymeric Nanocarriers for Efficient Pancreatic Cancer Gene Delivery.

Inefficient intracellular gene release and transfection limit nonviral gene delivery applications in cancer therapy. Reactive oxygen species (ROS) responsive nonviral gene delivery is the most widely explored strategy for such applications, yet the development of fast and safe ROS responsive nanocarriers proves to be a challenge because of the intracellular chemical equilibrium of high ROS and glutathione levels. Here, we report an ultrasound-enhanced ROS responsive charge-reversal polymeric nanocarrier (BTIL) for fast and efficient pancreatic cancer gene delivery. The BTIL is composed of B-PDEAEA/DNA polyplex-based cores and IR780-loaded liposome coatings. The IR780 is able to produce an excess of ROS under low intensity ultrasound irradiation, thus disequilibrating the chemical equilibrium of ROS and glutathione, and promoting the ROS-responsive positive-to-negative charge-reversal of the B-PDEAEA polymer. This charge conversion results in fast polyplex dissociation and intracellular gene release, inducing efficient gene transfection and cancer cell apoptosis. Moreover, following the intravenous administration, BTIL maintains a stable and long circulation in the bloodstream, achieves orthotopic pancreatic ductal adenocarcinoma distribution, and exhibits potent antitumor activity with negligible side effects. Our results reveal the proposed strategy to be both promising and universal for the development of fast and safe ROS responsive nonviral gene delivery in cancer therapy.

Assessment of Patiromer Monotherapy for Hyperkalemia in an Acute Care Setting.

Importance: Hyperkalemia is a common electrolyte disorder in hospitalized patients; however, the clinical usefulness of administering patiromer for reduction of serum potassium levels in this setting is unknown. Objective: To evaluate the outcomes associated with patiromer as monotherapy in patients with acute hyperkalemia in an acute care setting. Design, Setting, and Participants: This cohort study used electronic health record data from adult patients treated with patiromer for acute hyperkalemia in emergency departments, inpatient units, and intensive care units at an urban, academic medical center in the Bronx, New York, between January 30, 2018, and December 30, 2019. Data analysis was conducted between June 2020 and February 2021. Exposures: A single dose of oral patiromer (8.4 g, 16.8 g, or 25.2 g). Main Outcomes and Measure: The primary outcome was the mean absolute reduction in serum potassium level from baseline at 3 distinct time intervals after patiromer administration: 0 to 6 hours, greater than 6 to 12 hours, and greater than 12 to 24 hours. Key secondary outcomes were the incidence of hypokalemia and potassium reduction stratified by baseline potassium level and care setting. Results: Among 881 encounters of patiromer treatment, the mean (SD) age of patients was 67.4 (14.4) years; 463 encounters (52.6%) were for male patients, and most (338 [38.4%]) were for patients who identified as non-Hispanic Black. The mean (SD) baseline serum potassium level was 5.60 (0.35) mEq/L (to convert to mmol/L, multiply by 1.0), and within the first 6 hours after patiromer administration, the mean (SD) potassium reduction was 0.50 (0.56) mEq/L (P < .001). Both absolute and relative potassium reduction from baseline varied across baseline hyperkalemia severity but not by care setting. The lowest dose of patiromer (8.4 g) was used in 721 encounters (81.8%), and in 725 encounters (82.3%), no further doses of a potassium binder were required. Hypokalemia was noted in 2 encounters (0.2%) at 24 hours after patiromer administration. Conclusions and Relevance: In this cohort study of patients with acute, non-life-threatening hyperkalemia, a single dose of patiromer was associated with a significant decrease in serum potassium levels and a low incidence of hypokalemia. These findings suggest that patiromer monotherapy may be useful in an institutional setting for managing elevated potassium levels and minimizing the risk of hypokalemia associated with other potassium control measures.

Low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet versus traditional dietary advice for functional dyspepsia: a randomized controlled trial.

BACKGROUND AND AIM: Prospective trials evaluating efficacy of specific diet restriction in functional dyspepsia (FD) are scarce. We aimed to assess efficacy of low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet in FD, compared with traditional dietary advice (TDA). METHODS: In this prospective, single-blind trial, patients with FD (Rome IV) were randomized into low FODMAP diet (LFD) and TDA groups, for 4 weeks (phase I). In phase II (4-12 weeks), LFD group was advised systematic re-introduction of FODMAPs. Symptom severity and quality of life were assessed using "Short-Form Nepean Dyspepsia Index (SF-NDI)." Primary outcome was symptomatic response (symptom score reduction of ≥ 50%), at 4 weeks. Study was registered with CTRI (2019/06/019852). RESULTS: Of 184 patients screened, 105 were randomized to LFD (n = 54) and TDA (n = 51) groups. At 4 weeks, both groups showed significant reduction in SF-NDI symptom scores compared with baseline, with no significant difference in inter-group response rates [LFD: 66.7% (36/54); TDA: 56.9% (29/51); P = 0.32]. On sub-group analysis, patients with postprandial distress syndrome or bloating had significantly better symptomatic response with LFD (P = 0.04). SF-NDI quality of life scores improved significantly in both groups. On multivariate analysis, factors predicting response to LFD were bloating and male gender. Incidences of adverse events (minor) were similar in both groups. CONCLUSIONS: In patients with FD, LFD and TDA lead to significant symptomatic and quality of life improvement. Patients with postprandial distress syndrome or bloating respond significantly better to LFD. Therefore, dietary advice for FD should be individualized according to FD subtype.

Fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs), but not gluten, elicit modest symptoms of irritable bowel syndrome: a double-blind, placebo-controlled, randomized three-way crossover trial.

BACKGROUND: Irritable bowel syndrome (IBS) has been associated with diets rich in fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs), and gluten. Most previous studies have been single-blind and have focused on the elimination of FODMAPs or provocation with single FODMAPs. The effect of gluten is unclear, large trials isolating the effect of gluten from that of FODMAPs are needed. OBJECTIVES: The aims of this study were to ensure high intakes of a wide range of FODMAPs, gluten, or placebo, and to evaluate the effects on IBS symptoms using the IBS-severity scoring system (IBS-SSS). METHODS: The study was carried out with a double-blind, placebo-controlled, randomized 3-way crossover design in a clinical facility in Uppsala from September 2018 to June 2019. In all, 110 participants fulfilling the IBS Rome IV criteria, with moderate to severe IBS, were randomly assigned; 103 (90 female, 13 male) completed the trial. Throughout, IBS participants maintained a diet with minimal FODMAP content and no gluten. Participants were block-randomly assigned to 1-wk interventions with FODMAPs (50 g/d), gluten (17.3 g/d), or placebo, separated by 1-wk washout. All participants who completed ≥1 intervention were included in the intention-to-treat analysis. RESULTS: In participants with IBS (n = 103), FODMAPs caused higher IBS-SSS scores (mean 240 [95% CI: 222, 257]) than placebo (198 [180, 215]; P = 0.00056) or gluten (208 [190, 226]; P = 0.013); no differences were found between the placebo and gluten groups (P = 1.0). There were large interindividual differences in IBS-SSS scores associated with treatment. No adverse events were reported. CONCLUSION: In participants with IBS, FODMAPs had a modest effect on typical IBS symptoms, whereas gluten had no effect. The large interindividual differences in responses to the interventions warrant further detailed studies to identify possible underlying causes and enable individual prediction of responses. This trial was registered at www.clinicaltrials.gov as NCT03653689.

Overexpression of PDE4D in mouse liver is sufficient to trigger NAFLD and hypertension in a CD36-TGF-ß1 pathway: therapeutic role of roflumilast.

Emerging evidence has shown that nonalcoholic fatty liver disease (NAFLD) may be both a consequence and a cause of hypertension. Recent studies have demonstrated that phosphodiesterase 4 (PDE4)-cAMP signaling represents a pathway relevant to the pathophysiology of metabolic disorders. This study aims to investigate the impact and the underlying mechanism of PDE4 in the pathogenesis of NAFLD and its associated hypertension. Here we demonstrated that high-fat-diet (HFD) fed mice developed NAFLD and hypertension, with an associated increase in hepatic PDE4D expression, which can be prevented and even reversed by PDE4 inhibitor roflumilast. Furthermore, we demonstrated that hepatic overexpression of PDE4D drove significant hepatic steatosis and elevation of blood pressure. Mechanistically, PDE4D activated fatty acid translocase CD36 signaling which facilitates hepatic lipid deposition, resulting in TGF-ß1 production by hepatocytes and excessive TGF-ß1 signaling in vessels and consequent hypertension. Specific silencing of TGF-ß1 in hepatocytes by siRNA using poly (ß-amino ester) nanoparticles significantly normalized hepatic PDE4D overexpression-activated TGF-ß1 signaling in vessels and hypertension. Together, the conclusions indicated that PDE4D plays an important role in the pathogenesis of NAFLD and associated hypertension via activation of CD36-TGF-ß1 signaling in the liver. PDE4 inhibitor such as roflumilast, which is clinically approved for chronic obstructive pulmonary disease (COPD) treatment, has the potential to be used as a preventive or therapeutic drug against NAFLD and associated hypertension in the future.

Clinical Studies Reporting on Vascular Graft Coatings for the Prevention of Aortic Graft Infection: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this study was to investigate the efficacy of vascular graft coatings used in the aortic position to prevent vascular graft infection (VGI). METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines using a pre-registered protocol (CRD42020206436). Eligible studies used a vascular graft coating in the aortic position and reported on VGI. A search was performed in MEDLINE (PubMed), Embase, Web of Science, and the Cochrane Library. Primary outcome parameters were VGI, patency, and mortality. Pooled estimates of VGI were calculated using odds ratio (OR) and 95% confidence intervals (CIs) wherever possible. Quality assessment was performed with the Newcastle-Ottawa Assessment Scale and the Revised Cochrane risk of bias tool for randomised trials. RESULTS: In total, 6 873 papers were identified. Only eight studies were included. Six of eight studies (75%) reported on known antimicrobial coating strategies such as antibiotics (n = 3) and silver (n = 3). In the other two studies, polymer coated grafts were used. Only three of eight studies compared coated with uncoated grafts (two antibiotic and one silver). Two randomised controlled trials reported on the effect of rifampicin soaked (1 mg/mL) grafts and showed no significant effect in the early (2 months; OR 0.69, 95% CI 0.29 - 1.62) or late (2 years; OR 0.73, 95% CI 0.23 - 2.32) post-operative periods. A retrospective cohort study focusing on the effect of silver coated grafts did not reveal any advantage (OR 0.19, 95% CI 0.02 - 1.64). Two polymer coated grafts were not considered to have a potential benefit in the prevention of VGIs. CONCLUSION: Clinical studies reporting on the antibacterial effect of vascular graft coatings in the aortic position to prevent VGI are scarce. For silver and antibiotic coatings, no significant protection for VGI was observed. New types of grafts or long acting coating strategies are mandatory to prevent this complication in the future.

Scaffold 3D-Printed from Metallic Nanoparticles-Containing Ink Simultaneously Eradicates Tumor and Repairs Tumor-Associated Bone Defects.

Bone metastasis occurs in about 70% of breast cancer patients. The surgical resection of metastatic tumors often leads to bone erosion and destruction, which greatly hinders the treatment and prognosis of breast cancer patients with bone metastasis. Herein, a bifunctional scaffold 3D-printed from nanoink is fabricated to simultaneously eliminate the tumor cells and repair the tumor-associated bone defects. The metallic polydopamine (PDA) nanoparticles (FeMg-NPs) may effectively load and sustainably release the metal ions Fe3+ and Mg2+ in situ. Fe3+ exerts a chemodynamic therapy to synergize with the photothermal therapy induced by PDA with effective photothermal conversion under NIR laser, which efficiently eliminates the bone-metastatic tumor. Meanwhile, the sustained release of osteoinductive Mg2+ from the bony porous 3D scaffold enhances the new bone formation in the bone defects. Taken together, the implantation of scaffold (FeMg-SC) 3D-printed from the FeMg-NPs-containing nanoink provides a novel strategy to simultaneously eradicate bone-metastatic tumor and repair the tumor-associated bone defects.

Programmable Polymeric Microneedles for Combined Chemotherapy and Antioxidative Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. Antioxidative treatment combined with chemotherapy holds great promise for RA treatment, and the ability to efficiently deliver drugs and antioxidants to the RA synovial joint is highly desired. Herein, we developed a programmable polymeric microneedle (MN) platform for transdermal delivery of methotrexate (MTX) and reactive oxygen species (ROS) scavengers for RA treatment. The biodegradable MNs made of polyvinylpyrrolidone (PVP) were incorporated with polydopamine/manganese dioxide (termed PDA@MnO2) and MTX. After insertion into skin tissue, the MNs degraded, thus enabling release of loaded MTX and PDA@MnO2. The PDA@MnO2 could be utilized as an MRI contrast agent in the RA synovial microenvironment. It also acted as a robust antioxidant to remove ROS and decrease RA inflammation, which when combined with the MTX-mediated chemotherapy led to an ideal outcome for RA treatments in a murine model. This work not only represents a valuable MN-assisted RA therapeutic agent transdermal delivery approach but also opens a new avenue for chemotherapy and antioxidative synergistic treatment of RA.

Advances in Skin Wound and Scar Repair by Polymer Scaffolds.

Scars, as the result of abnormal wound-healing response after skin injury, may lead to loss of aesthetics and physical dysfunction. Current clinical strategies, such as surgical excision, laser treatment, and drug application, provide late remedies for scarring, yet it is difficult to eliminate scars. In this review, the functions, roles of multiple polymer scaffolds in wound healing and scar inhibition are explored. Polysaccharide and protein scaffolds, an analog of extracellular matrix, act as templates for cell adhesion and migration, differentiation to facilitate wound reconstruction and limit scarring. Stem cell-seeded scaffolds and growth factors-loaded scaffolds offer significant bioactive substances to improve the wound healing process. Special emphasis is placed on scaffolds that continuously release oxygen, which greatly accelerates the vascularization process and ensures graft survival, providing convincing theoretical support and great promise for scarless healing.

Polymeric long-acting drug delivery systems (LADDS) for treatment of chronic diseases: Inserts, patches, wafers, and implants.

Non-oral long-acting drug delivery systems (LADDS) encompass a range of technologies for precisely delivering drug molecules into target tissues either through the systemic circulation or via localized injections for treating chronic diseases like diabetes, cancer, and brain disorders as well as for age-related eye diseases. LADDS have been shown to prolong drug release from 24 h up to 3 years depending on characteristics of the drug and delivery system. LADDS can offer potentially safer, more effective, and patient friendly treatment options compared to more invasive modes of drug administration such as repeated injections or minor surgical intervention. Whilst there is no single technology or definition that can comprehensively embrace LADDS; for the purposes of this review, these systems include solid implants, inserts, transdermal patches, wafers and in situ forming delivery systems. This review covers common chronic illnesses, where candidate drugs have been incorporated into LADDS, examples of marketed long-acting pharmaceuticals, as well as newly emerging technologies, used in the fabrication of LADDS.

[Design of Synthetic Polymer Nanoparticles That Capture and Neutralize Target Molecules].

Protein affinity reagents that specifically and strongly bind to target molecules are widely used in disease detection, diagnosis, and therapy. Although antibodies and their fragments are the gold standard in protein-protein inhibitors (PPIs), synthetic polymers such as linear polymers, dendrimers, and nanoparticles as cost-effective PPIs have attracted great attention as alternatives to antibodies. These polymers exhibit high affinity to the target by imitating natural protein-protein interactions. However, only a few in vivo applications have been reported. Here, our recent advances in the development of synthetic polymers for in vivo application are reviewed. Poly(N-isopropylacrylamide) (pNIPAm) was used as a model of synthetic affinity reagents. Incorporation of both sulfated carbohydrate and hydrophobic monomers into lightly crosslinked pNIPAm nanoparticles (NPs) captured and neutralized vascular endothelial growth factor (VEGF) and inhibited tumor growth upon intravenous injection into tumor-bearing mice. Modification of a liposome with the pNIPAm-based linear polymer increased the polymer circulation time after intravenous injection and improved the affinity for the target. The pNIPAm-based NPs delivered by oral administration captured the target small molecules and inhibited their absorption from the intestine. Our recent findings provide useful information for the design of synthetic polymers that capture target molecules in vivo.

Facile surface functional polyetheretherketone with antibacterial and immunoregulatory activities for enhanced regeneration toward bacterium-infected bone destruction.

Existing biologically inert or unmodified implants to treat infectious bone defects or osteomyelitis still cannot effectively solve bacterial infection and osseointegration. In this work, a simple co-deposition strategy was developed to modify porous polyetheretherketone (PEEK) with improved antibacterial activity and controllable immunoregulatory ability. After PEEK was treated by H2SO4 to obtain porous PEEK (SPEEK), the self-polymerization of dopamine was operated on SPEEK in the solution of dopamine and gentamicin sulfate (GS) to prepare polydopamine (pDA) and GS layer-modified SPEEK (labeled as SPEEK-pDA-GS). The morphology, surface property, and molecular structure of SPEEK-pDA-GS were investigated. Besides the antibacterial property of SPEEK-pDA-GS ascribed to the successful immobilization of GS, SPEEK-pDA-GS exhibited promoted osseointegration through the results of mineralization, alkaline phosphatase (ALP) levels and osteogenic gene expression. Furthermore, the evaluation of the cell proliferation suggested that SPEEK-pDA-GS possessed the biocompatibility and the immunoregulatory ability that induced macrophages to anti-inflammatory M2 phenotype. Using rat as model, in vivo results containing X-ray, µ-CT, immunohistochemistry, and pathological analysis showed the excellent healing effect of SPEEK-pDA-GS on bone defect with infection with biological safety. This work illustrates a new insight into the simple and effective modification of PEEK and other implants with antibacterial, immunoregulatory, and osseointegration abilities for clinical requirement.

Psychological and Gastrointestinal Symptoms of Patients with Irritable Bowel Syndrome Undergoing a Low-FODMAP Diet: The Role of the Intestinal Barrier.

A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (LFD) improves both gastrointestinal (GI) symptoms and the psychological profile of patients with irritable bowel syndrome with diarrhea (IBS-D). The effects of 12 weeks of LFD on GI symptom and psychological profiles in relation to inflammation and the involvement of the intestinal barrier were studied in twenty IBS-D patients. The IBS Severity Scoring System, the Symptom Checklist-90-Revised, the Italian version of the 36-Item Short-Form Health Survey, the IBS-Quality of Life (QoL) questionnaire, and the Psychophysiological questionnaire were administered. The GI barrier function was assessed by sugar absorption test, the serum and fecal zonulin levels, and the serum levels of intestinal fatty-acid binding protein and diamine oxidase. Interleukins (ILs) and lipopolysaccharide (LPS) serum levels were evaluated along with dysbiosis. At the end of LFD, GI symptoms, psychological state (mainly anxiety, somatization, psychoticism, and interpersonal sensitivity), and QoL significantly improved in these patients. Simultaneously, an improvement in small intestinal permeability and intestinal mucosal integrity occurred, while IL-6, Il-10, LPS, and fermentative dysbiosis significantly decreased. The LFD can modify the immune-inflammatory features and enhance intestinal permeability and mucosal integrity, thus determining a concurrent improvement in the clinical and psychological conditions.

Co-Delivery of Doxorubicin and Chloroquine by Polyglycerol Functionalized MoS2 Nanosheets for Efficient Multidrug-Resistant Cancer Therapy.

2D MoS2 has shown a great potential in biomedical applications, due to its superior loading capacity, photothermal property, and biodegradation. In this work, polyglycerol functionalized MoS2 nanosheets with photothermal and pH dual-stimuli responsive properties are used for the co-delivery of doxorubicin and chloroquine and treatment of multidrug-resistant HeLa (HeLa-R) cells. The polyglycerol functionalized MoS2 nanosheets with 80 nm average size show a high biocompatibility and loading efficiency (≈90%) for both drugs. The release of drugs from the nanosheets at pH 5.5 is significantly promoted by laser irradiation leading to efficient destruction of incubated HeLa-R cells. In vitro evaluation shows that the designed nanoplatform has a high ability to kill HeLa-R cells. Confocal experiments demonstrate that the synthesized drug delivery system enhances the cellular uptake of DOX via folic acid targeting ligand. Taking advantage of the combined properties including biocompatibility and targeting ability as well as high loading capacity and photothermal release, this multifunctional nanosystem is a promising candidate for anticancer therapy.