Hierarchical fibrous structures for muscle-inspired soft-actuators:A review

Inspired by Nature, one of the most ambitious challenge in soft robotics is to design actuators capable of reaching performances comparable to the skeletal muscles. Considering the perfectly balanced features of natural muscular tissue in terms of linear contraction, force‐to‐weight ratio, scalability and morphology, scientists have been working for many years on mimicking this structure. Focusing on the biomimicry, this review investigates the state‐of‐the‐art of synthetic fibrous, muscle‐inspired actuators that, aiming to enhance their mechanical performances, are hierarchically designed from the nanoscale up to the macroscale. In particular, this review focuses on those hierarchical fibrous actuators that enhance their biomimicry employing a linear contraction strategy, closely resembling the skeletal muscles actuation system. The literature analysis shows that bioinspired artificial muscles, developed up to now, only in part comply with skeletal ones. The manipulation and control of the matter at the nanoscale allows to realize ordered structures, such as nanofibers, used as elemental actuators characterized by high strains but moderate force levels. Moreover, it can be foreseen that scaling up the nanostructured materials into micro‐ and macroscale hierarchical structures, it is possible to realize linear actuators characterized by suitable levels of force and displacement

Antagonism of the prokineticin system prevents and reverses allodynia and inflammation in a mouse model of diabetes

Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro- and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease

MORPHOLOGICALLY BIO-INSPIRED HIERARCHICAL NYLON 6,6 ELECTROSPUN STRUCTURES FOR SOFT-ROBOTICS APPLICATIONS

The last decades have seen an increasing attention on a new, ground-breaking field, soft-robotics [1]. Soft-robotics tries to overcome the limits of classical rigid robots, developing bioinspired structures with compliant and soft materials. Skeletal muscle is a biological, hierarchically arranged fibrous structure (Fig A), suitable to inspire innovative soft actuators. The possibility to mimic muscles and soft tissues has been demonstrated through the use of the electrospinning technique [2]. The aim of the present study was to develop and characterize innovative muscle-inspired, hierarchically arranged electrospun structures made of Nylon 6,6 for soft-robotics applications. In order to mimic skeletal muscle myofibrils [3], mats of aligned Nylon 6,6 nanofibers were electrospun on a rotating drum collector. To reproduce skeletal muscle fibers and fascicles morphology [3], the mats were cut in stripes and wrapped up on the drum, producing bundles of axially aligned nanofibers. The bundles were then pulled out from the drum, obtaining ring-shaped bundles. To mimic a whole skeletal muscle with its epimysium membrane [3], 2-levels hierarchical structure was developed (Fig B). Several bundles were aligned and packed together using a nanofibrous sheath produced through an innovative electrospinning setup [4]. Finally, in order to mimic also the skeletal muscle fascicles and perimysium [3], a 3-levels hierarchical structure was obtained by grouping together three 2-levels hierarchical structures, produced as previously described, with an additional electrospun sheath (Fig C). A morphological investigation of the different electrospun structures was carried out with scanning electron microscopy (SEM) and high-resolution x-ray tomography (XCT). The alignment of the nanofibers of the electrospun sheaths and the internal bundles, was quantified with a previously validated methodology [5]. The bundles and the 2-levels hierarchical structures were also mechanically characterized with a monotonic tensile test. The level of alignment of the nanofibers in the sheaths has proved to be tuneable by modifying the electrospinning parameters. The electrospun sheaths are also capable to tighten the structures wrapped inside, reducing their cross-sectional area and improving the apparent mechanical strength and stiffness. The high-resolution imaging confirmed that the mean diameters of the different hierarchical structures were comparable to the corresponding structures of biological skeletal muscle [3]. The directionality analysis on both bundles and sheaths nanofibers showed comparable levels of alignment with corresponding skeletal muscles fibrous tissues [3]. The mechanical test on the structures revealed a non-linear behaviour typical of soft tissue. The 2- levels hierarchical structures showed mechanical properties roughly proportional to the number of single bundles incorporated (with a possible underestimation of the ultimate strength, due to a stress concentration at the grips). In conclusion, this innovative electrospinning approach to produce hierarchically-arranged structures will be suitable to develop muscle-inspired assemblies. We will explore the possibility of incorporating adequate contracting ability so as to build soft actuators

Health impact assessment by the implementation of Madrid City air-quality plan in 2020

OBJECTIVES: Air pollutant concentrations in many urban areas are still above the legal and recommended limits that are set to protect the citizens' health. Madrid is one of the cities where traffic causes high NO2 levels. In this context, Madrid City Council launched the Air Quality and Climate Change Plan for the city of Madrid (Plan A), a local strategy approved by the previous government in 2017. The aim of this study was to conduct a quantitative health impact assessment to evaluate the number of premature deaths that could potentially be prevented by the implementation of Plan A in Madrid in 2020, at both citywide and within-city level. The main purpose was to support decision-making processes in order to maximize the positive health impacts from the implementation of Plan A measures. METHODS: The Regional Statistical Office provided information on population and daily mortality in Madrid. For exposure assessment, we estimated PM2.5, NO2 and O3 concentration levels for Madrid city in 2012 (baseline air-quality scenario) and 2020 (projected air-quality scenario based on the implementation of Plan A), by means of an Eulerian chemical-transport model with a spatial resolution of 1 km × 1 km and 30 vertical levels. We used the concentration-response functions proposed by two relevant WHO projects to calculate the number of attributable annual deaths corresponding to all non-accidental causes (ICD-10: A00-R99) among all-ages and the adult population (>30 years old) for each district and for Madrid city overall. This health impact assessment was conducted dependant on health-data availability. RESULTS: In 2020, the implementation of Plan A would imply a reduction in the Madrid citywide annual mean PM2.5 concentration of 0.6 μg/m3 and 4.0 μg/m3 for NO2. In contrast, an increase of 1 μg/m3 for O3 would be expected. The annual number of all-cause deaths from long-term exposure (95% CI) that could be postponed in the adult population by the expected air-pollutant concentration reduction was 88 (57-117) for PM2.5 and 519 (295-750) for NO2; short-term exposure accounted for 20 (7-32) for PM2.5 and 79 (47-111) for NO2 in the total population. According to the spatial distribution of air pollutants, the highest mortality change estimations were for the city centre - including Madrid Central and mainly within the M-30 ring road -, as compared to peripheral districts. The positive health impacts from the reductions in PM2.5 and NO2 far exceeded the adverse mortality effects expected from the increase in O3. CONCLUSIONS: Effective implementation of Plan A measures in Madrid city would bring about an appreciable decline in traffic-related air-pollutant concentrations and, in turn, would lead to significant health-related benefits.This HIA study was funded by the European Project ICARUS (Integrated Climate forcing and Air pollution Reduction in Urban Systems; Horizon 2020, GA N° 690105) and by SaludAire-España (Contaminación atmosférica y salud en España: morbilidad en atención primaria y mortalidad; Carlos III Health Institute, AESI grant PI18CIII/00022). Air-quality modelling was funded by the Madrid City Council (Environment and Mobility Division of the General Directorate of Sustainability and Environmental Control) within the framework for the development and assessment of Plan A.S

European Parliament Pilot Project on Exposure to Indoor air Chemicals and Possible Health Risks

This report outlines the results of the 2-year pilot project on indoor air quality and potential health effects executed by the Joint Research Centre and funded by the European Parliament via the Directorate-General Health and Consumer Protection. It had four distinct objectives as follows: 1) to identify and quantify the main air pollutants present in public buildings, including indoor environments where children frequently stay, like schools and kindergartens, 2) to identify the main sources of these pollutants, applying source apportionment analyses, 3) to estimate people¿s exposure to these pollutants while working and/or living in these areas and combined with micro-environmental activity patterns during the day, 4) to evaluate possible health risks due to (chronic) exposure to air pollutants, in particular, for children. The results indicate that indoor air pollution concentrations are consistently higher than the respective outdoor ones for the chemical families this study focused on. Differences attributable to variation in consumer behaviour, climate and type of building materials used, have been identified in the indoor:outdoor ratio of primary pollutants across Europe. These differences account for small variance in the corresponding health risk to the local population across the EU.JRC.I.5-Physical and chemical exposure

Dataset on biomimetic hierarchically arranged nanofibrous structures resembling the architecture and the passive mechanical properties of skeletal muscles: a step forward towards artificial muscles

The present database contains the data presented and discussed in the paper “Biomimetic hierarchically arranged nanofibrous structures resembling the architecture and the passive mechanical properties of skeletal muscles: a step forward towards artificial muscle” by Carlo Gotti, Alberto Sensini, Gianmaria Fornaia, Chiara Gualandi, Andrea Zucchelli and Maria Letizia Focarete, accepted for publication in the journal Frontiers in Bioengineering and Biotechnology (2020, doi 10.3389/fbioe.2020.00767). The paper describes an approach for the biomimetic design of engineered muscle, that makes use of an elastomeric polyurethane with suitable mechanical performances, processed with the electrospinning technology, to produce a hierarchically arranged nanofibrous structure resembling the architecture and passive biomechanical properties of skeletal muscles. Scaffolds morphology and physical properties are studied and a detailed analysis of material mechanical properties is performed, taking into account the different levels of increasing complexity, going from mats to bundles and finally the hierarchical nanofibrous electrospun structure (HNES). Data include the thermal characterization of the pristine PU pellets (thermogravimetric and differential scanning calorimetry analysis), force-displacement data obtained through mechanical tensile tests along with the different geometrical and physical characterization of the samples, the results of the mechanical characterization, data on the nanofibrous alignment and the outcome of a statistical analysis

Phase II trial of bevacizumab and dose/dense chemotherapy with cisplatin and metronomic daily oral etoposide in advanced non-small-cell-lung cancer patients.

Bevacizumab, is a humanized monoclonal antibody to vasculo-endothelial- growth-factor, with anticancer activity in non-small-cell-lung cancer (NSCLC) patients. Our previous results from a dose/finding phase I trial in NSCLC patients, demonstrated the anti-angiogenic effects and toxicity of a newest bevacizumab-based combination with fractioned cisplatin and daily oral etoposide. We designed a phase II trial to evaluate in advanced NSCLC patients the antitumor activity and the safety of this novel regimen. In particular, 45 patients (36 males and 9 females), with a mean age of 54 years, an ECOG ≤2, stage III B/IV and NSCLC (28 adenocarcinomas, 11 squamous-cell carcinomas, 2 large-cell carcinomas, 4 undifferentiated carcinomas), were enrolled. They received cisplatin (30 mg/sqm, days 1-3), oral etoposide (50 mg, days 1-15) and bevacizumab (5 mg/kg, day 3) every 3 weeks (mPEBev regimen). Patients who achieved an objective response or stable disease received maintenance treatment with bevacizumab in combination with erlotinib until progression. Grade I-II hematological, mucosal toxicity and alopecia were the most common adverse events. The occurrence of infections (17%), thromboembolic events (4.4%) and severe mood depression (6.7%) was also recorded. A partial response was achieved in 31 (68.8%) patients, disease remained stable in 8 (17.8%) and disease progressed in 6 (13.3%) with a progression-free-survival of 9.53 months (95% CI, 7.7-11.46). Our bio-chemotherapy regimen resulted very active in advanced NSCLC, however, the toxicity associated with the treatment requires strict selection of the patients to enroll in future studies. © 2011 Landes Bioscience

Dose/dense metronomic chemotherapy with fractioned cisplatin and oral daily etoposide enhances the anti-angiogenic effects of bevacizumab and has strong antitumor activity in advanced non-small-cell-lung cancer patients.

Background: We designed a translational clinical trial to investigate whether a dose/dense chemotherapy regimen is able to enhance in patients with non-small-cell-lung-cancer, the anti-angiogenic, and anti-tumor activity of bevacizumab, a murine/human monoclonal antibody to the vasculo-endothelial-growth-factor (VEGF) Patients and Methods: Forty-eight patients (42 males and 6 females) with stage IIIB/IV non-small-cell-lung-cancer, a mean age of 68 years, and ECOG ≤ 2 were enrolled in the study. They received every three weeks fractioned cisplatinum (30 mg/sqm, days 1-3) and oral etoposide (50 mg, days 1-15) and were divided in 5 cohorts receiving different bevacizumab dosages [0; 2.5; 5; 7.5; and 10 mg/kg] on the day 3. Results: The combined treatment was able of inducing a significant decline in the blood-perfusion of primary tumor (NMR-study); in serum levels of VEGF, angiopoietin-1, thrombospondin-1; and in the number of VEGF-transporting cells. In the group of 40 patients who received bevacizumab ther..

Bayesian Algorithm Implementation in a Real Time Exposure Assessment Model on Benzene with Calculation of Associated Cancer Risks

The objective of the current study was the development of a reliable modeling platform to calculate in real time the personal exposure and the associated health risk for filling station employees evaluating current environmental parameters (traffic, meteorological and amount of fuel traded) determined by the appropriate sensor network. A set of Artificial Neural Networks (ANNs) was developed to predict benzene exposure pattern for the filling station employees. Furthermore, a Physiology Based Pharmaco-Kinetic (PBPK) risk assessment model was developed in order to calculate the lifetime probability distribution of leukemia to the employees, fed by data obtained by the ANN model. Bayesian algorithm was involved in crucial points of both model sub compartments. The application was evaluated in two filling stations (one urban and one rural). Among several algorithms available for the development of the ANN exposure model, Bayesian regularization provided the best results and seemed to be a promising technique for prediction of the exposure pattern of that occupational population group. On assessing the estimated leukemia risk under the scope of providing a distribution curve based on the exposure levels and the different susceptibility of the population, the Bayesian algorithm was a prerequisite of the Monte Carlo approach, which is integrated in the PBPK-based risk model. In conclusion, the modeling system described herein is capable of exploiting the information collected by the environmental sensors in order to estimate in real time the personal exposure and the resulting health risk for employees of gasoline filling stations