Distribution of tetracyclines and sulfonamides resistance genes around a smallholder pig farm: Modeling and attribution.

Livestock farm is a major source of antibiotics and antibiotic resistance genes (ARGs) pollution. ARGs can directly enter the environment through runoff and air deposition. The impact extent and the driving factors require further investigation to inform effective policies and actions to mitigate their spread. This study investigated a smallholder pig farm and its surrounding areas to understand the spread of ARGs. Topsoil samples were collected from 56 different sites within one kilometer of the farm, and a comprehensive analysis was conducted to reveal effects of soil properties, antibiotic residues, microbiome, mobilome on the variation of typical ARGs. The results confirmed that the ARGs reduced exponentially with increasing distance from the farm, with a goodness of fit (R2) of 0.7 for total ARGs. For tetracyclines (TC) and sulfonamides (SA) resistance genes, the fitting R2 exceeded 0.9. Model estimates allowed for quantitative comparisons of in-farm increments, out-farm background levels, and spread abilities of ARGs with distinct resistance mechanisms. SA-specific resistance genes (SRGs, 0.097 copies/16S rRNA gene) and TC-specific resistance genes (TRGs, 0.036 copies/16S rRNA gene) showed higher within-farm increases compared to multidrug resistance genes (MDRGs, 0.020 copies/16S rRNA gene). MDRGs, however, had a higher background level and a greater impact distance (0.18 km, 4.4 times the farm radius). Additionally spread abilities of TRGs varied by resistance mechanism, with ribosome protection proteins showing greater spread than TC inactivating enzymes and TC efflux pumps, likely due to different fitness costs. Correlation analysis and structural equation modeling indicated that changes in bacterial community composition and mobilome are primary factors influencing ARGs variation during their spread. Abiotic factors like soil nutrients and antibiotics also selectively enriched ARGs within the farm. These findings provide insights into the ARGs dissemination and could inform strategies to prevent their spread from smallholder livestock farms.

A comparison of measurement properties between EORTC QLU-C10D and FACT-8D in patients with hematological malignances.

OBJECTIVE: To perform a comparison of the measurement properties of two cancer-specific Multi-Attribute Utility Instruments (MAUIs), EORTC QLU-C10D and FACT-8D, in Chinese patients with hematologic malignancies (HM). METHODS: We conducted a longitudinal study on patients with HM in China, using QLU-C10D and FACT-8D at baseline and follow-up (3-4 months from baseline). We assessed: (i) convergent validity using Spearman's rank correlation test (r) with EQ-5D-5L; (ii) clinical-groups validity by differentiating cancer stages, overall health assessment (OHA), Eastern Cancer Oncology Group (ECOG) performance status, and mental health status. We also examined clinical validity with effect size (ES) and relative efficiency (RE); (iii) responsiveness to changes in patient self-perception using receiver operating characteristics (ROC) curves and area under the curves (AUC); and (iv) agreement using intraclass correlation coefficients (ICC) and visualized with Bland-Altman plot. RESULTS: Among the 308 patients with HM at baseline, 131 completed the follow-up survey. Agreement between the two measures was high (ICC = 0.76). Both measures were highly correlated with EQ-5D-5 L and significantly differentiated (p < 0.001) among groups categorized by cancer stage, OHA performance status, and mental health. ESs for QLU-C10D were numerically higher for cancer stage, OHA, and performance status (ES = 0.53-1.49), whereas ES was higher for FACT-8D and mental health status (ES = 1.35). Responsiveness was higher for QLU-C10D (AUC = 0.84) compared to FACT-8D (AUC = 0.78). CONCLUSION: Both QLU-C10D and FACT-8D are valid cancer-specific MAUIs for evaluating patients with HM. However, scholars should consider their slight differences in focus when choosing between the two measures.

Assessing the reliability of a novel cancer-specific multi-attribute utility instrument (FACT-8D) and comparing its validity to EQ-5D-5L in colorectal cancer patients.

OBJECTIVE: To examine the test-retest reliability of the Functional Assessment of Cancer Therapy - 8 Dimension (FACT-8D) for the first time, and to conduct a head-to-head comparison of the distribution properties and validity between the FACT-8D and EQ-5D-5L in Colorectal Cancer (CRC) Patients. METHODS: We conducted a longitudinal study on Chinese CRC patients, employing Functional Assessment of Cancer Therapy-General (FACT-G) and EQ-5D-5L at baseline, and FACT-G during follow-up (2-7 days from baseline). Utility scores for FACT-8D were derived from all available value sets (Australia, Canada and USA), while EQ-5D-5L scores were obtained from corresponding value sets for various countries. We assessed convergent validity using pairwise polychoric correlations between the FACT-8D and EQ-5D-5L; known-groups validity by discriminating participants' clinical characteristics, and effect size (ES) was tested; test-retest reliability for FACT-8D using kappa and weighted Kappa for choice consistency, and intraclass correlation coefficient (ICC) and Bland-Altman method for utility consistency. RESULTS: Among the 287 patients with CRC at baseline, 131 were included in the retest analysis. The utility scores of FACT-8D were highly positively correlated with EQ-5D-5L across various country value sets (r = 0.65-0.77), and most of the dimensions of FACT-8D and EQ-5D-5L were positively correlated. EQ-5D-5L failed to discriminate known-groups in cancer stage across all value sets, whereas both were significant in FACT-8D (ES = 0.35-0.48, ES = 0.38-0.52). FACT-8D showed good test-retest reliability (Cohen's weighted Kappa = 0.494-0.722, ICC = 0.748-0.786). CONCLUSION: The FACT-8D can be used as a valid and reliable instrument for clinical evaluation of patients with CRC, outperforming EQ-5D-5L in differentiating clinical subgroups and showing promise for cancer practice and research.

Recently, the Multi-Attribute Utility in Cancer Consortium developed the Functional Assessment of Cancer Therapy − 8 Dimension (FACT-8D), a new cancer-specific multi-attribute utility instrument based on the Functional Assessment of Cancer Therapy - General (FACT-G). This addresses the FACT-G's limitation in directly generating utility values, which has broad application prospects in cost-utility analysis within the field of oncology. To our knowledge, this is the first study to examine the test-retest reliability of FACT-8D and to conduct a head-to-head comparison of its distribution properties and validity against the EQ-5D-5L in colorectal cancer (CRC) patients. The results indicate that FACT-8D is a valid and reliable instrument for clinical evaluation of CRC patients, demonstrating superior performance in differentiating between known clinical groups compared to the generic MAUI EQ-5D-5L, and is a promising instrument for use in cancer practice and research.

Fluoranthene slow down sulfamethazine migration in soil via π-π interaction to increase the abundance of antibiotic resistance genes.

Sulfonamide antibiotics and polycyclic aromatic hydrocarbons (PAHs) often coexist in soil, leading to compound pollution through various pathways. This study focuses on sulfamethazine (SMZ) and PAHs (fluoranthene) as the subject for compound pollution research. Using a soil-groundwater simulation system, we investigated the migration characteristics of SMZ under coexistence with fluoranthene (Fla) and observed variations in the abundance of antibiotic resistance genes (ARGs). Through molecular docking simulations and isothermal adsorption experiments, we discovered that Fla bound with SMZ via π-π interactions, resulting in a 20.9% increase in the SMZ soil-water partition coefficient. Under compound conditions, the concentration of SMZ in surface soil could reach 1.4 times that of SMZ added alone, with an 13.4% extension in SMZ half-life. The deceleration of SMZ's vertical migration rate placed additional stress on surface soil microbiota, leading to a proliferation of ARGs by 66.3%-125.8%. Moreover, under compound pollution, certain potential hosts like Comamonadaceae and Gemmatimonas exhibited a significant positive correlation with resistance genes such as sul 1 and sul 2. These findings shed light on the impact of PAHs on sulfonamide antibiotic migration and the abundance of ARGs. They also provide theoretical insights for the development of technologies aimed at mitigating compound pollution in soil.

Economic Evaluation of COVID-19 Immunization Strategies: A Systematic Review and Narrative Synthesis.

OBJECTIVES: This study aimed to systematically assess global economic evaluation studies on COVID-19 vaccination, offer valuable insights for future economic evaluations, and assist policymakers in making evidence-based decisions regarding the implementation of COVID-19 vaccination. METHODS: Searches were performed from January 2020 to September 2023 across seven English databases (PubMed, Web of Science, MEDLINE, EBSCO, KCL-Korean Journal Dataset, SciELO Citation Index, and Derwent Innovations Index) and three Chinese databases (Wanfang Data, China Science and Technology Journal, and CNKI). Rigorous inclusion and exclusion criteria were applied. Data were extracted from eligible studies using a standardized data collection form, with the reporting quality of these studies assessed using the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022). RESULTS: Of the 40 studies included in the final review, the overall reporting quality was good, evidenced by a mean score of 22.6 (ranging from 10.5 to 28). Given the significant heterogeneity in fundamental aspects among the studies reviewed, a narrative synthesis was conducted. Most of these studies adopted a health system or societal perspective. They predominantly utilized a composite model, merging dynamic and static methods, within short to medium-term time horizons to simulate various vaccination strategies. The research strategies varied among studies, investigating different doses, dosages, brands, mechanisms, efficacies, vaccination coverage rates, deployment speeds, and priority target groups. Three pivotal parameters notably influenced the evaluation results: the vaccine's effectiveness, its cost, and the basic reproductive number (R0). Despite variations in model structures, baseline parameters, and assumptions utilized, all studies identified a general trend that COVID-19 vaccination is cost-effective compared to no vaccination or intervention. CONCLUSIONS: The current review confirmed that COVID-19 vaccination is a cost-effective alternative in preventing and controlling COVID-19. In addition, it highlights the profound impact of variables such as dose size, target population, vaccine efficacy, speed of vaccination, and diversity of vaccine brands and mechanisms on cost effectiveness, and also proposes practical and effective strategies for improving COVID-19 vaccination campaigns from the perspective of economic evaluation.

Poly(amino acid)-based drug delivery nanoparticles eliminate Methicillin resistant Staphylococcus aureus via tunable release of antibiotic.

Bacterial infections threaten public health, and novel therapeutic strategies critically demand to be explored. Herein, poly(amino acid) (PAA)-based drug delivery nanoparticles (NPs) were designed for eliminating Methicillin resistant Staphylococcus aureus (MRSA) via tunable release of antibiotic. Using N-acryloyl amino acids (valine, valine methyl ester, aspartic acid, serine) as monomers, four kinds of amphiphilic PAAs were synthesized via photoinduced electron/energy transfer-reversible addition fragmentation chain-transfer (PET-RAFT) polymerization and were further assembled into nano-sized delivery systems. Their assemble behavior was drove mainly by hydrophobic/hydrophilic interaction, which determined the particle size, efficacy of drug loading and release; but numerous hydrogen bonding (HB) interaction also played an important role in regulating morphologies of the NPs and enriching drug-binding capacity. By changing the HB- and hydrophobic-interaction of the PAAs, the particle sizes (240.7 nm-302.7 nm), the drug loading efficiency (9.57%-19.76%), and the Rifampicin (Rif) release rate (49.6%-69.7%) of the PAA-based NPs could be tunable. Specially, the antimicrobial properties of the Rif-loaded NPs are found to be related to the release of Rif, which was determined by its hydrophobic interaction with hydrophobic blocks and HB interaction with hydrophilic blocks. These studies provide a new outlook for the design of delivery systems for the therapy of bacterial infection.

A Universal Strategy to Construct High-Performance Homo- and Heterogeneous Microgel Assembly Bioinks.

Three dimensional (3D) extrusion bioprinting aims to replicate the complex architectures and functions of natural tissues and organs. However, the conventional hydrogel and new-emerging microgel bioinks are both difficult in achieving simultaneously high shape-fidelity and good maintenance of cell viability/function, leading to limited amount of qualified hydrogel/microgel bioinks. Herein, a universal strategy is reported to construct high-performance microgel assembly (MA) bioinks by using epigallocatechin gallate-modified hyaluronic acid (HA-EGCG) as coating agent and phenylboronic acid grafted hyaluronic acid (HA-PBA) as assembling agent. HA-EGCG can spontaneously form uniform coating on the microgel surface via mussel-inspired chemistry, while HA-PBA quickly forms dynamic phenylborate bonds with HA-EGCG, conferring the as-prepared MA bioinks with excellent rheological properties, self-healing, and tissue-adhesion. More importantly, this strategy is applicable to various microgel materials, enabling the preparation of homo- and heterogeneous MA (homo-MA and hetero-MA) bioinks and the hierarchical printing of complicated structures with high fidelity by integration of different microgels containing multiple materials/cells in spatial and compositional levels. It further demonstrates the printing of breast cancer organoid in vitro using homo-MA and hetero-MA bioinks and its preliminary application for drug testing. This universal strategy offers a new solution to construct high-performance bioinks for extrusion bioprinting.

A head-to-head comparison of the measurement properties of EQ-5D-3L and EQ-5D-5L in Chinese family caregivers of cancer patients.

BACKGROUND: Although both EQ-5D-3L(3L) and EQ-5D-5L(5L) have demonstrated good measurement properties in several patient populations, there is currently limited evidence comparing the measurement properties of 3L and 5L in family caregivers (FCs) of cancer patients. PURPOSE: This study aimed to compare the measurement properties of 3L and 5L in a sample of family caregivers of cancer patients. METHODS: A consecutive sample of FCs of cancer patients recruited from three tertiary hospitals were invited to complete the two versions of the EQ-5D in two rounds of interviews. We compared i) the ceiling effect using the McNemar's test, ii) test-retest reliability using intraclass correlation coefficient (ICC) and Cohen's Kappa, iii) convergent validity using Spearman's rank correlation coefficient, iv) known-group validity using F-statistic, v) and discriminant capacity using ordinal logistic regression. RESULTS: A total of 416 FCs completed the baseline questionnaire and 120 caregivers completed the follow-up questionnaire. Ceiling effects were smaller in 5L (12.5%) than in 3L (20.7%). The convergent validity (r = 0.344-0.771), known-groups validity (Fratio5L/3L = 2.06-4.09), discriminant capacity (ES = 0.341-0.396), and test-retest reliability (ICC = 0.725) of the 5L were slightly better than those of the 3L in China. CONCLUSION: The current study found both 3L and 5L to be suitable for use by FCs of cancer patients. However, 5L showed superior measurement properties compared to 3L and therefore could be the preferred instrument when EQ-5D data of cancer patients FCs is required.

A novel bioartificial pancreas fabricated via islets microencapsulation in anti-adhesive core-shell microgels and macroencapsulation in a hydrogel scaffold prevascularized in vivo.

Islets transplantation is a promising treatment for type 1 diabetes mellitus. However, severe host immune rejection and poor oxygen/nutrients supply due to the lack of surrounding capillary network often lead to transplantation failure. Herein, a novel bioartificial pancreas is constructed via islets microencapsulation in core-shell microgels and macroencapsulation in a hydrogel scaffold prevascularized in vivo. Specifically, a hydrogel scaffold containing methacrylated gelatin (GelMA), methacrylated heparin (HepMA) and vascular endothelial growth factor (VEGF) is fabricated, which can delivery VEGF in a sustained style and thus induce subcutaneous angiogenesis. In addition, islets-laden core-shell microgels using methacrylated hyaluronic acid (HAMA) as microgel core and poly(ethylene glycol) diacrylate (PEGDA)/carboxybetaine methacrylate (CBMA) as shell layer are prepared, which provide a favorable microenvironment for islets and simultaneously the inhibition of host immune rejection via anti-adhesion of proteins and immunocytes. As a result of the synergistic effect between anti-adhesive core-shell microgels and prevascularized hydrogel scaffold, the bioartificial pancreas can reverse the blood glucose levels of diabetic mice from hyperglycemia to normoglycemia for at least 90 days. We believe this bioartificial pancreas and relevant fabrication method provide a new strategy to treat type 1 diabetes, and also has broad potential applications in other cell therapies.

Wearable Dual-Signal NH3 Sensor with High Sensitivity for Non-invasive Diagnosis of Chronic Kidney Disease.

NH3 gas in human exhaled breath contains abundant physiological information related to human health, especially chronic kidney disease (CKD). Unfortunately, up to now, most wearable NH3 sensors show inevitable defects (low sensitivity, easy to be interfered by the environment, etc.), which may lead to misdiagnosis of CKD. To solve the above dilemma, a nanoporous, heterogeneous, and dual-signal (optical and electrical) wearable NH3 sensor mask is developed successfully. More specifically, a polyacrylonitrile/bromocresol green (PAN/BCG) nanofiber film as a visual NH3 sensor and a polyacrylonitrile/polyaniline/reduced graphene oxide (PAN/PANI/rGO) nanofiber film as a resistive NH3 sensor are constructed. Due to the high specific surface area and abundant NH3 binding sites of these two nanofiber films, they exhibit good NH3 sensing performance. However, although the visual NH3 sensor (PAN/BCG nanofiber film) is simple without the need of any detecting facilities and quite stable when temperature and humidity change, it shows poor sensitivity and resolution. In comparison, the resistive NH3 sensor (PAN/PANI/rGO nanofiber film) is of high sensitivity, fast response, and good resolution, but its electrical signal is easily interfered by the external environment (such as humidity, temperature, etc.). Considering that the sensing principles between a visual NH3 sensor and resistive NH3 sensor are significantly different, a wearable dual-signal NH3 sensor containing both a visual NH3 sensor and resistive NH3 sensor is further explored. Our data prove that the two sensing signals in this dual-signal NH3 sensor mask can not only work well without interference with each other but also complement each other to improve the sensing accuracy, indicating its potential application in non-invasive diagnosis of CKD.

Dual-targeted poly(amino acid) nanoparticles deliver drug combinations on-site: an intracellular synergistic strategy to eliminate intracellular bacteria.

Multi-drug combinations are a common strategy for the treatment of intracellular bacterial infections. However, different internalized pathways and the accumulation of the composite drugs at different subcellular organelles very much reduce their efficacy. Herein, an intracellular synergistic strategy is proposed, which is realized by on-site delivery of a drug combination using a macrophage/intracellular bacterium-dual targeted drug delivery system (DDS). The DDS is fabricated by encapsulating vancomycin (Van) and curcumin (Cur) into poly(α-N-acryloyl-phenylalanine)-block-poly(ß-N-acryloyl-D-aminoalanine-co-2-O-acetyl-α-D-mannosyloxy) nanoparticles, denoted by (Van + Cur)@F(AM) NPs. Mannose ligands on (Van + Cur)@F(AM) NPs trigger their specific internalization in macrophages, while aminoalanine moieties subsequently drive the NPs to target intracellular methicillin-resistant Staphylococcus aureus (MRSA). Thereafter, Van and Cur are durably released in a synergistic dose at the residence site of intracellular MRSA. Under this intracellular synergistic effect, (Van + Cur)@F(AM) NPs show superior elimination efficiency in vitro and in vivo compared to the control groups, including free Van, (Van + Cur), the DDS encapsulated Van and the DDSs separately-encapsulated Van and Cur. Furthermore, (Van + Cur)@F(AM) NPs significantly enhance the in vivo antibacterial capacity by modulating the immune response. Therefore, this dual-targeted DDS-assisted intracellular synergistic antibacterial strategy of drug combination is an effective therapeutic against intracellular bacteria.

Lipid Giant Vesicles Engulf Living Bacteria Triggered by Minor Enhancement in Membrane Fluidity.

Antibacterial amphiphiles normally kill bacteria by destroying the bacterial membrane. Whether and how antibacterial amphiphiles alter normal cell membrane and lead to subsequent effects on pathogen invasion into cells have been scarcely promulgated. Herein, by taking four antibacterial gemini amphiphiles with different spacer groups to modulate cell-mimic phospholipid giant unilamellar vesicles (GUVs), bacteria adhesion on the modified GUVs surface and bacteria engulfment process by the GUVs are clearly captured by confocal laser scanning microscopy. Further characterization shows that the enhanced cationic surface charge of GUVs by the amphiphiles determines the bacteria adhesion amount, while the involvement of amphiphile in GUVs results in looser molecular arrangement and concomitant higher fluidity in the bilayer membranes, facilitating the bacteria intruding into GUVs. This study sheds new light on the effect of amphiphiles on membrane bilayer and the concurrent effect on pathogen invasion into cell mimics and broadens the nonprotein-mediated endocytosis pathway for live bacteria.

Multimorbidity and catastrophic health expenditure: Evidence from the China Health and Retirement Longitudinal Study.

Background: Population aging accompanied by multimorbidity imposes a great burden on households and the healthcare system. This study aimed to determine the incidence and determinants of catastrophic health expenditure (CHE) in the households of old people with multimorbidity in China. Methods: Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS) conducted in 2018, with 3,511 old people (≥60 years) with multimorbidity responding to the survey on behalf of their households. CHE was identified using two thresholds: ≥10% of out-of-pocket (OOP) health spending in total household expenditure (THE) and ≥40% of OOP health spending in household capacity to pay (CTP) measured by non-food household expenditure. Logistic regression models were established to identify the individual and household characteristics associated with CHE incidence. Results: The median values of THE, OOP health spending, and CTP reached 19,900, 1,500, and 10,520 Yuan, respectively. The CHE incidence reached 31.5% using the ≥40% CTP threshold and 45.6% using the ≥10% THE threshold. It increased by the number of chronic conditions reported by the respondents (aOR = 1.293-1.855, p < 0.05) and decreased with increasing household economic status (aOR = 1.622-4.595 relative the highest quartile, p < 0.001). Hospital admissions over the past year (aOR = 6.707, 95% CI: 5.186 to 8.674) and outpatient visits over the past month (aOR = 4.891, 95% CI: 3.822 to 6.259) of the respondents were the strongest predictors of CHE incidence. The respondents who were male (aOR = 1.266, 95% CI: 1.054 to 1.521), married (OR = 1.502, 95% CI: 1.211 to 1.862), older than 70 years (aOR = 1.288-1.458 relative to 60-69 years, p < 0.05), completed primary (aOR = 1.328 relative to illiterate, 95% CI: 1.079 to 1.635) or secondary school education (aOR = 1.305 relative to illiterate, 95% CI: 1.002 to 1.701), lived in a small (≤2 members) household (aOR = 2.207, 95% CI: 1.825 to 2.669), and resided in the northeast region (aOR = 1.935 relative to eastern, 95% CI: 1.396 to 2.682) were more likely to incur CHE. Conclusion: Multimorbidity is a significant risk of CHE. Household CHE incidence increases with the number of reported chronic conditions. Socioeconomic and regional disparities in CHE incidence persist in China.

Prognostic Modeling of Lung Adenocarcinoma Based on Hypoxia and Ferroptosis-Related Genes.

Background: It is well known that hypoxia and ferroptosis are intimately connected with tumor development. The purpose of this investigation was to identify whether they have a prognostic signature. To this end, genes related to hypoxia and ferroptosis scores were investigated using bioinformatics analysis to stratify the risk of lung adenocarcinoma. Methods: Hypoxia and ferroptosis scores were estimated using The Cancer Genome Atlas (TCGA) database-derived cohort transcriptome profiles via the single sample gene set enrichment analysis (ssGSEA) algorithm. The candidate genes associated with hypoxia and ferroptosis scores were identified using weighted correlation network analysis (WGCNA) and differential expression analysis. The prognostic genes in this study were discovered using the Cox regression (CR) model in conjunction with the LASSO method, which was then utilized to create a prognostic signature. The efficacy, accuracy, and clinical value of the prognostic model were evaluated using an independent validation cohort, Receiver Operator Characteristic (ROC) curve, and nomogram. The analysis of function and immune cell infiltration was also carried out. Results: Here, we appraised 152 candidate genes expressed not the same, which were related to hypoxia and ferroptosis for prognostic modeling in The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) cohort, and these genes were further validated in the GSE31210 cohort. We found that the 14-gene-based prognostic model, utilizing MAPK4, TNS4, WFDC2, FSTL3, ITGA2, KLK11, PHLDB2, VGLL3, SNX30, KCNQ3, SMAD9, ANGPTL4, LAMA3, and STK32A, performed well in predicting the prognosis in lung adenocarcinoma. ROC and nomogram analyses showed that risk scores based on prognostic signatures provided desirable predictive accuracy and clinical utility. Moreover, gene set variance analysis showed differential enrichment of 33 hallmark gene sets between different risk groups. Additionally, our results indicated that a higher risk score will lead to more fibroblasts and activated CD4 T cells but fewer myeloid dendritic cells, endothelial cells, eosinophils, immature dendritic cells, and neutrophils. Conclusion: Our research found a 14-gene signature and established a nomogram that accurately predicted the prognosis in patients with lung adenocarcinoma. Clinical decision-making and therapeutic customization may benefit from these results, which may serve as a valuable reference in the future.

Dual-Cascade Responsive Nanoparticles Enhance Pancreatic Cancer Therapy by Eliminating Tumor-Resident Intracellular Bacteria.

The limited drug penetration and robust bacteria-mediated drug inactivation in pancreatic cancer result in the failure of chemotherapy. To fight against these issues, a dual-cascade responsive nanoparticle (sNP@G/IR) that can sequentially trigger deep penetration, killing of intratumor bacteria, and controlled release of chemo-drug, is reported. sNP@G/IR consists of a hyaluronic acid (HA) shell and glutathione (GSH)-responsive polymer-core (NP@G/IR), that encapsulates gemcitabine (Gem) and photothermal agent (IR1048). The polymer core, as an antibiotic alternative, is tailored to exert optimal antibacterial activity and selectivity. sNP@G/IR actively homes in on the tumor due to the CD44 targeting of the HA shell, which is subsequently degraded by the hyaluronidase in the extracellular matrix. The resultant NP@G/IR in decreased size and reversed charge facilitates deep tumor penetration. After cellular endocytosis, the exposed guanidine on NP@G/IR kills intracellular bacteria through disrupting cell membranes. Intracellular GSH further triggers the controlled release of the cargo. Thus, the protected Gem eventually induces cell apoptosis. Under laser irradiation, the hyperthermia of IR1048 helps further elimination of tumors and bacteria. Moreover, sNP@G/IR activates immune response, thereby reinforcing anticancer capacity. Therefore, this dual-cascade responsive sNP@G/IR eliminates tumor-resident intracellular bacteria and augments drug delivery efficacy, providing a new avenue for improving cancer therapy.

Enhancing Boiling Heat Transfer on a Superheated Surface by Surfactant-Laden Droplets.

Boiling, one of the most common phase-change heat transfer methods, is widely used in nuclear power plants, spacecraft, integrated circuits, and other situations, where rapid and efficient heat transfer is crucial. However, boiling heat transfer is efficient only in a specific surface temperature range when a droplet impacts a superheated surface. Here, we enhance the boiling heat transfer and extend this temperature range by adding a tiny amount of surfactant. We find that surfactants can weaken the Kelvin effect of boiling bubbles, and thus reduce the onset of boiling driven temperature and significantly enhance the maximum vaporization rate of the droplet effectively. In particular, different from previous studies, we find that the surfactants at lower concentrations can increase the Leidenfrost temperature of the droplets. All the above effects jointly expand the temperature range of effective boiling heat transfer. This study sheds new light on the role of surfactants in the boiling process and offers a new medium to promote heat-transfer applications.

Co-transplantation of Islets-Laden Microgels and Biodegradable O2-Generating Microspheres for Diabetes Treatment.

Pancreatic islets transplantation is an optimal alternative to exogenous insulin injection for long-term effective type 1 diabetes treatment. However, direct islets transplantation without any protection can induce cell necrosis due to severe host immune rejection. Insufficient O2 supply induced by the lack of capillary network at the early stage of islets transplantation is another critical constraint limiting islets survival and insulin-secretion function. In this paper, we design a novel co-transplantation system composed of islets-laden nanocomposite microgels and O2-generating microspheres. In particular, nanocomposite microgels confer the encapsulated islets with simultaneous physical protection and chemical anti-inflammation/immunosuppression by covalently anchoring rapamycin-loaded cyclodextrin nanoparticles to microgel network. Meanwhile, O2-generating microspheres prepared by blending inorganic peroxides in biodegradable polycaprolactone and polylactic acid can generate in situ O2 gas and thus avoid hypoxia environment around transplanted islets. In vivo therapeutic effect of diabetic mice proves the reversion of the high blood glucose level back to normoglycemia and superior glucose tolerance for at least 90 days post co-transplantation. In brief, the localized drug and oxygen codelivery, as well as physical protection provided by our co-transplantation system, has the potential to overcome to a large extent the inflammatory, hypoxia, and host immune rejection after islets transplantation. This new strategy may have wider application in other cell replacement therapies.

A versatile strategy to construct free-standing multi-furcated vessels and a complicated vascular network in heterogeneous porous scaffolds via combination of 3D printing and stimuli-responsive hydrogels.

Mimicking complex structures of natural blood vessels and constructing vascular networks in tissue engineering scaffolds are still challenging now. Herein we demonstrate a new and versatile strategy to fabricate free-standing multi-furcated vessels and complicated vascular networks in heterogeneous porous scaffolds by integrating stimuli-responsive hydrogels and 3D printing technology. Through the sol-gel transition of temperature-responsive gelatin and conversion between two physical crosslinking networks of pH-responsive chitosan (i.e., electrostatic network between protonated chitosan and sulfate ion, crystalline network of neutral chitosan), physiologically-stable gelatin/chitosan hydrogel tubes can be constructed. While stimuli-responsive hydrogels confer the formation mechanism of the hydrogel tube, 3D printing confers the feasibility to create a multi-furcated structure and interconnected network in various heterogeneous porous scaffolds. As a consequence, biomimetic multi-furcated vessels (MFVs) and heterogeneous porous scaffolds containing multi-furcated vessels (HPS-MFVs) can be constructed precisely. Our data further confirm that the artificial blood vessel (gelatin/chitosan hydrogel tube) shows good physiological stability, mechanical strength, semi-permeability, hemocompatibility, cytocompatibility and low in vivo inflammatory response. Co-culture of hepatocyte (L02 cells) and human umbilical vein endothelial cells (HUVECs) in HPS-MFVs indicates the successful construction of a liver model. We believe that our method offers a simple and easy-going way to achieve robust fabrication of free-standing multi-furcated blood vessels and prevascularization of porous scaffolds for tissue engineering and regenerative medicine.

A Three-Dimensional-Printed Recyclable, Flexible, and Wearable Device for Visualized UV, Temperature, and Sweat pH Sensing.

Wearable devices are now recognized as a powerful tool to collect physiological and environmental information in a smart, noninvasive, and real-time manner. Despite the rapid progress of wearable devices especially wearable electronic devices, there are still several challenges that limit their further development, for example, a complicated electrical signal acquisition and processing process to eliminate the interference from the surrounding signals, bulky power supply, inevitable e-waste, and environmental pollution. Herein, we report a 3D-printed recyclable, flexible, and wearable device for visualized UV, temperature, and sweat pH sensing. Compared with wearable electronic devices, our visualized wearable device senses environmental (UV light, ambient temperature), biophysical (skin temperature), and biochemical (sweat pH) signals via stimuli-responsive color change, which does not require complicated electronic circuit design/assembly, time-consuming data processing and additional power source. In addition, this visualized wearable device is fabricated via a 3D support bath printing technology by printing UV-, temperature-, and sweat pH-sensing inks containing photochromic, thermochromic, and pH-chromic materials, respectively, into/onto sustainable starch solution, resulting in a multi-functional, recyclable, and flexible sensing device with high reproducibility. Our results reveal that UV light intensities under sunlight (0-2500 µW/cm2), ambient, and skin temperatures (0-38 °C) as well as sweat pH (4.0-7.0) can be successfully monitored.

Assembling Microgels via Dynamic Cross-Linking Reaction Improves Printability, Microporosity, Tissue-Adhesion, and Self-Healing of Microgel Bioink for Extrusion Bioprinting.

Extrusion bioprinting has been widely used to fabricate complicated and heterogeneous constructs for tissue engineering and regenerative medicine. Despite the remarkable progress acquired so far, the exploration of qualified bioinks is still challenging, mainly due to the conflicting requirements on the printability/shape-fidelity and cell viability. Herein, a new strategy is proposed to formulate a dynamic cross-linked microgel assembly (DC-MA) bioink, which can achieve both high printability/shape-fidelity and high cell viability by strengthening intermicrogel interactions through dynamic covalent bonds while still maintaining the relatively low mechanical modulus of microgels. As a proof-of-concept, microgels are prepared by cross-linking hyaluronic acid modified with methacrylate and phenylboric acid groups (HAMA-PBA) and methacrylated gelatin (GelMA) via droplet-based microfluidics, followed by assembling into DC-MA bioink with a dynamic cross-linker (dopamine-modified hyaluronic acid, HA-DA). As a result, 2D and 3D constructs with high shape-fidelity can be printed without post-treatment, and the encapsulated L929 cells exhibit high cell viability after extrusion. Moreover, the addition of the dynamic cross-linker (HA-DA) also improves the microporosity, tissue-adhesion, and self-healing of the DC-MA bioink, which is very beneficial for tissue engineering and regenerative medicine applications including wound healing. We believe the present work sheds a new light on designing new bioinks for extrusion bioprinting.