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Grechuta, K., Rubio Ballester, B., Espín Munne, R., Usabiaga Bernal, T., Molina Hervás, B., Mohr, B., Pulvermüller, F., San Segundo, R., Verschure, P., (2019). Augmented dyadic therapy boosts recovery of language function in patients with nonfluent aphasia Stroke 50, (5), 1270-1274

Background and Purpose- Evidence suggests that therapy can be effective in recovering from aphasia, provided that it consists of socially embedded, intensive training of behaviorally relevant tasks. However, the resources of healthcare systems are often too limited to provide such treatment at sufficient dosage. Hence, there is a need for evidence-based, cost-effective rehabilitation methods. Here, we asked whether virtual reality-based treatment grounded in the principles of use-dependent learning, behavioral relevance, and intensity positively impacts recovery from nonfluent aphasia. Methods- Seventeen patients with chronic nonfluent aphasia underwent intensive therapy in a randomized, controlled, parallel-group trial. Participants were assigned to the control group (N=8) receiving standard treatment or to the experimental group (N=9) receiving augmented embodied therapy with the Rehabilitation Gaming System for aphasia. All Rehabilitation Gaming System for aphasia sessions were supervised by an assistant who monitored the patients but did not offer any elements of standard therapy. Both interventions were matched for intensity and materials. Results- Our results revealed that at the end of the treatment both groups significantly improved on the primary outcome measure (Boston Diagnostic Aphasia Examination: control group, P=0.04; experimental group, P=0.01), and the secondary outcome measure (lexical access-vocabulary test: control group, P=0.01; experimental group, P=0.007). However, only the Rehabilitation Gaming System for aphasia group improved on the Communicative Aphasia Log ( P=0.01). The follow-up assessment (week 16) demonstrated that while both groups retained vocabulary-related changes (control group, P=0.01; experimental group, P=0.007), only the Rehabilitation Gaming System for aphasia group showed therapy-induced improvements in language ( P=0.01) and communication ( P=0.05). Conclusions- Our results demonstrate the effectiveness of Rehabilitation Gaming System for aphasia for improving language and communication in patients with chronic aphasia suggesting that current challenges faced by the healthcare system in the treatment of stroke might be effectively addressed by augmenting traditional therapy with computer-based methods. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02928822.

Keywords: Aphasia, Embodied training, Neurological rehabilitation, Virtual reality


Infante, Elvira, Stannard, Andrew, Board, Stephanie J., Rico-Lastres, Palma, Rostkova, Elena, Beedle, Amy E. M., Lezamiz, Ainhoa, Wang, Yong Jian, Gulaidi Breen, Samuel, Panagaki, Fani, Sundar Rajan, Vinoth, Shanahan, Catherine, Roca-Cusachs, Pere, Garcia-Manyes, Sergi, (2019). The mechanical stability of proteins regulates their translocation rate into the cell nucleus Nature Physics Epub ahead of print

A cell’s ability to react to mechanical stimuli is known to be affected by the transport of transcription factors, the proteins responsible for regulating transcription of DNA into RNA, across the membrane enveloping its nucleus. Yet the molecular mechanisms by which mechanical cues control this process remain unclear. Here we show that one such protein, myocardin-related transcription factor A (MRTFA), is imported into the nucleus at a rate that is inversely correlated with its nanomechanical stability, but independent of its thermodynamic stability. Attaching mechanically stable proteins to MRTFA results in reduced gene expression and the subsequent slowing down of cell migration. We conclude that the mechanical unfolding of proteins regulates their nuclear translocation rate, and highlight the role of the nuclear pore complex as a selective mechanosensor that is capable of detecting forces as low as 10 pN. The modulation of the mechanical stability of transcription factors may represent a general strategy for the control of gene expression.

Keywords: Biological physics, Biophysics, Chemistry, Nanoscience and technology


Lozano-García, M., Estrada, L., Jané, R., (2019). Performance evaluation of fixed sample entropy in myographic signals for inspiratory muscle activity estimation Entropy 21, (2), 183

Fixed sample entropy (fSampEn) has been successfully applied to myographic signals for inspiratory muscle activity estimation, attenuating interference from cardiac activity. However, several values have been suggested for fSampEn parameters depending on the application, and there is no consensus standard for optimum values. This study aimed to perform a thorough evaluation of the performance of the most relevant fSampEn parameters in myographic respiratory signals, and to propose, for the first time, a set of optimal general fSampEn parameters for a proper estimation of inspiratory muscle activity. Different combinations of fSampEn parameters were used to calculate fSampEn in both non-invasive and the gold standard invasive myographic respiratory signals. All signals were recorded in a heterogeneous population of healthy subjects and chronic obstructive pulmonary disease patients during loaded breathing, thus allowing the performance of fSampEn to be evaluated for a variety of inspiratory muscle activation levels. The performance of fSampEn was assessed by means of the cross-covariance of fSampEn time-series and both mouth and transdiaphragmatic pressures generated by inspiratory muscles. A set of optimal general fSampEn parameters was proposed, allowing fSampEn of different subjects to be compared and contributing to improving the assessment of inspiratory muscle activity in health and disease.

Keywords: Electromyography, Fixed sample entropy, Mechanomyography, Non-invasive physiological measurements, Oesophageal electromyography, Respiratory muscle


Pittolo, Silvia, Lee, Hyojung, Lladó, Anna, Tosi, Sébastien, Bosch, Miquel, Bardia, Lídia, Gómez-Santacana, Xavier, Llebaria, Amadeu, Soriano, Eduardo, Colombelli, Julien, Poskanzer, Kira E., Perea, Gertrudis, Gorostiza, Pau, (2019). Reversible silencing of endogenous receptors in intact brain tissue using two-photon pharmacology Proceedings of the National Academy of Sciences of the United States of America Epub ahead of print

The physiological activity of proteins is often studied with loss-of-function genetic approaches, but the corresponding phenotypes develop slowly and can be confounding. Photopharmacology allows direct, fast, and reversible control of endogenous protein activity, with spatiotemporal resolution set by the illumination method. Here, we combine a photoswitchable allosteric modulator (alloswitch) and 2-photon excitation using pulsed near-infrared lasers to reversibly silence metabotropic glutamate 5 (mGlu5) receptor activity in intact brain tissue. Endogenous receptors can be photoactivated in neurons and astrocytes with pharmacological selectivity and with an axial resolution between 5 and 10 µm. Thus, 2-photon pharmacology using alloswitch allows investigating mGlu5-dependent processes in wild-type animals, including synaptic formation and plasticity, and signaling pathways from intracellular organelles.

Keywords: Photopharmacology, Photoactivation, Pharmacological selectivity, Functional silencing, 2-photon pharmacology


Muro, Silvia, (2018). Alterations in cellular processes involving vesicular trafficking and implications in drug delivery Biomimetics 3, (3), 19

Endocytosis and vesicular trafficking are cellular processes that regulate numerous functions required to sustain life. From a translational perspective, they offer avenues to improve the access of therapeutic drugs across cellular barriers that separate body compartments and into diseased cells. However, the fact that many factors have the potential to alter these routes, impacting our ability to effectively exploit them, is often overlooked. Altered vesicular transport may arise from the molecular defects underlying the pathological syndrome which we aim to treat, the activity of the drugs being used, or side effects derived from the drug carriers employed. In addition, most cellular models currently available do not properly reflect key physiological parameters of the biological environment in the body, hindering translational progress. This article offers a critical overview of these topics, discussing current achievements, limitations and future perspectives on the use of vesicular transport for drug delivery applications.

Keywords: Cellular vesicles, Vesicle fusion, Fission and intracellular trafficking, Drug delivery systems and nanomedicines, Transcytosis and endocytosis of drugs carriers, Disease effects on vesicular trafficking, Drug effects on vesicular trafficking, Role of the biological environment


Páez-Avilés, C., van Rijnsoever, F. J., Juanola-Feliu, E., Samitier, J., (2018). Multi-disciplinarity breeds diversity: the influence of innovation project characteristics on diversity creation in nanotechnology Journal of Technology Transfer 43, (2), 458-481

Nanotechnology is an emerging and promising field of research. Creating sufficient technological diversity among its alternatives is important for the long-term success of nanotechnologies, as well as for other emerging technologies. Diversity prevents early lock-in, facilitates recombinant innovation, increases resilience, and allows market growth. Creation of new technological alternatives usually takes place in innovation projects in which public and private partners often collaborate. Currently, there is little empirical evidence about which characteristics of innovation projects influence diversity. In this paper we study the influence of characteristics of EU-funded nanotechnology projects on the creation of technological diversity. In addition to actor diversity and the network of the project, we also include novel variables that have a plausible influence on diversity creation: the degree of multi-disciplinarity of the project and the size of the joint knowledge base of project partners. We apply topic modelling (Latent Dirichlet allocation) as a novel method to categorize technological alternatives. Using an ordinal logistic regression model, our results show that the largest contribution to diversity comes from the multi-disciplinary nature of a project. The joint knowledge base of project partners and the geographical distance between them were positively associated with technological diversity creation. In contrast, the number and diversity of actors and the degree of clustering showed a negative association with technological diversity creation. These results extend current micro-level explanations of how the diversity of an emerging technology is created. The contribution of this study could also be helpful for policy makers to influence the level of diversity in a technological field, and hence to contribute to survival of emerging technologies.

Keywords: Innovation projects, Multi-disciplinarity, Nanotechnology, Social networks, Technological diversity, Topic models


Lepora, Nathan, Verschure, P., Prescott, T. J., (2018). A roadmap for Living Machines research Living machines: A handbook of research in biomimetics and biohybrid systems (ed. Prescott, T. J., Lepora, Nathan, Verschure, P.), Oxford Scholarship (Oxford, UK) , 26-50

This roadmap identifies current trends in biomimetic and biohybrid systems together with their implications for future research and innovation. Important questions include the scale at which these systems are defined, the types of biological systems addressed, the kind of principles sought, the differences between biologically based and biologically inspired approaches, the role in the understanding of living systems, relevant application domains, common benchmarks, the relation to other fields, and developments on the horizon. We interviewed and collated answers from experts who have been involved a series of events organized by the Convergent Science Network. These answers were then collated into themes of research. Overall, we see a field rapidly expanding in influence and impact. As such, this report will provide information to researchers and scientific policy makers on contemporary biomimetics and its future, together with pointers to further reading on relevant topics within this handbook.

Keywords: Biomimetics, Biohybrid, Bio-inspiration, Biologically inspired, Roadmap, Living machines, policy


Prescott, T. J., Verschure, P. F. M. J., (2018). Living machines: An introduction Living Machines: A Handbook of Research in Biomimetic and Biohybrid Systems (ed. Prescott, T. J., Lepora, Nathan, Verschure, P.), Oxford Scholarship (Oxford, UK) , 3-14

Biomimetics is the development of novel technologies through the distillation of principles from the study of biological systems. Biohybrid systems are formed by at least one biological component—an already existing living system—and at least one artificial, newly engineered component. The development of either biomimetic or biohybrid systems requires a deep understanding of the operation of living systems, and the two fields are united under the theme of “living machines”—the idea that we can construct artifacts that not only mimic life but share some of the same fundamental principles. This chapter sets out the philosophy and history underlying this Living Machines approach and sets the scene for the remainder of this book.

Keywords: Biohybrids, Biological principles, Biomimetics, History of technology, Living machines, Technology ethics


Prescott, T. J., Lepora, Nathan, Verschure, P., (2018). Living machines: A handbook of research in biomimetics and biohybrid systems Oxford Scholarship , 1-623

Biomimetics is the development of novel technologies through the distillation of ideas from the study of biological systems. Biohybrids are formed through the combination of at least one biological component—an existing living system—and at least one artificial, newly engineered component. These two fields are united under the theme of Living Machines—the idea that we can construct artifacts that not only mimic life but also build on the same fundamental principles. The research described in this volume seeks to understand and emulate life’s ability to self-organize, metabolize, grow, and reproduce; to match the functions of living tissues and organs such as muscles, skin, eyes, ears, and neural circuits; to replicate cognitive and physical capacities such as perception, attention, locomotion, grasp, emotion, and consciousness; and to assemble all of these elements into integrated systems that can hold a technological mirror to life or that have the capacity to merge with it. We conclude with contributions from philosophers, ethicists, and futurists on the potential impacts of this remarkable research on society and on how we see ourselves.

Keywords: Novel technologies, Biomimetics, Biohybrids, Living systems, Living machines, Biological principles, Technology ethics, Societal impacts


Rodriguez-Franco, P., Brugués, A., Marin-Llaurado, A., Conte, V., Solanas, G., Batlle, E., Fredberg, J. J., Roca-Cusachs, P., Sunyer, R., Trepat, X., (2017). Long-lived force patterns and deformation waves at repulsive epithelial boundaries Nature Materials 16, (10), 1029-1036

For an organism to develop and maintain homeostasis, cell types with distinct functions must often be separated by physical boundaries. The formation and maintenance of such boundaries are commonly attributed to mechanisms restricted to the cells lining the boundary. Here we show that, besides these local subcellular mechanisms, the formation and maintenance of tissue boundaries involves long-lived, long-ranged mechanical events. Following contact between two epithelial monolayers expressing, respectively, EphB2 and its ligand ephrinB1, both monolayers exhibit oscillatory patterns of traction forces and intercellular stresses that tend to pull cell-matrix adhesions away from the boundary. With time, monolayers jam, accompanied by the emergence of deformation waves that propagate away from the boundary. This phenomenon is not specific to EphB2/ephrinB1 repulsion but is also present during the formation of boundaries with an inert interface and during fusion of homotypic epithelial layers. Our findings thus unveil a global physical mechanism that sustains tissue separation independently of the biochemical and mechanical features of the local tissue boundary.

Keywords: Biological physics, Cellular motility


Mohammadi, M. H., Obregón, R., Ahadian, S., Ramón-Azcón, J., Radisic, M., (2017). Engineered muscle tissues for disease modeling and drug screening applications Current Pharmaceutical Design , 23, (20), 2991-3004

Animal models have been the main resources for drug discovery and prediction of drugs’ pharmacokinetic responses in the body. However, noticeable drawbacks associated with animal models include high cost, low reproducibility, low physiological similarity to humans, and ethical problems. Engineered tissue models have recently emerged as an alternative or substitute for animal models in drug discovery and testing and disease modeling. In this review, we focus on skeletal muscle and cardiac muscle tissues by first describing their characterization and physiology. Major fabrication technologies (i.e., electrospinning, bioprinting, dielectrophoresis, textile technology, and microfluidics) to make functional muscle tissues are then described. Finally, currently used muscle tissue models in drug screening are reviewed and discussed.

Keywords: Cardiac muscle, Drug screening, Engineering muscle, Human pharmacological response, Physiological similarity, Skeletal muscle


Fernanda, Andrade, Pedro, Fonte, Ana, Costa, Cassilda Cunha, Reis, Rute, Nunes, Andreia, Almeida, Domingos, Ferreira, Mireia, Oliva, Bruno, Sarmento, (2016). Pharmacological and toxicological assessment of innovative self-assembled polymeric micelles as powders for insulin pulmonary delivery Nanomedicine 11, (17), 2305-2317

Aim: Explore the use of polymeric micelles in the development of powders intended for pulmonary delivery of biopharmaceuticals, using insulin as a model protein. Materials & methods: Formulations were assessed in vitro for aerosolization properties and in vivo for efficacy and safety using a streptozotocin-induced diabetic rat model. Results: Powders presented good aerosolization properties like fine particle fraction superior to 40% and a mass median aerodynamic diameter inferior of 6 μm. Endotracheally instilled powders have shown a faster onset of action than subcutaneous administration of insulin at a dose of 10 IU/kg, with pharmacological availabilities up to 32.5% of those achieved by subcutaneous route. Additionally, micelles improved the hypoglycemic effect of insulin. Bronchoalveolar lavage screening for toxicity markers (e.g., lactate dehydrogenase, cytokines) revealed no signs of lung inflammation and cytotoxicity 14 days postadministration. Conclusion: Developed powders showed promising safety and efficacy characteristics for the systemic delivery of insulin by pulmonary administration.

Keywords: Fine particle fraction, Inhalation, Insulin, In vivo, Pharmacological availability, Polymeric micelles, Pulmonary toxicity


Morales, R., Badesa, F. J., Garcia-Aracil, N., Aranda, J., Casals, A., (2015). Autoadaptive neurorehabilitation robotic system assessment with a post-stroke patient Revista Iberoamericana de Automatica e Informatica Industrial , 12, (1), 92-98

This paper presents a new rehabilitation system that is able to adapt its performance to patient's psychophysiological state during the execution of robotic rehabilitation tasks. Using this approach, the motivation and participation of the patient during rehabilitation activity can be maximized. In this paper, the results of the study with healthy subjects presented in (Badesa et al., 2014b) have been extended for using them with patients who have suffered a stroke. In the first part of the article, the different components of the adaptive system are exposed, as well as a comparison of different machine learning techniques to classify the patient's psychophysiological state between three possible states: stressed, average excitation level and relaxed are presented. Finally, the results of the auto-adaptive system which modifies the behavior of the rehabilitation robot and virtual task in function of measured physiological signals are shown for a patient in the chronic phase of stroke.

Keywords: Physiological state multimodal interfaces rehabilitation robotics control


Comelles, J., Hortigüela, V., Martínez, Elena, Riveline, D., (2015). Methods for rectifying cell motions in vitro: Breaking symmetry using microfabrication and microfluidics Methods in Cell Biology - Biophysical Methods in Cell Biology (ed. Wilson, L., Tran, P.), Academic Press (Santa Barbara, USA) 125, 437-452

Cell motility is an important phenomenon in cell biology, developmental biology, and cancer. Here we report methods that we designed to identify and characterize external factors which direct cell motions by breaking locally the symmetry. We used microfabrication and microfluidics techniques to impose and combine mechanical and chemical cues to moving fibroblasts. Gradients can thereby be engineered at the cellular scale and this approach has allowed to disentangle roles of the nucleus and protrusion activity in setting cell directions.

Keywords: Adhesion, Biological physics, Cell motility, Gradient, Ratchet


Castaño, O., Sachot, N., Xuriguera, E., Engel, E., Planell, J. A., Park, J. H., Jin, G. Z., Kim, T. H., Kim, J. H., Kim, H. W., (2014). Angiogenesis in bone regeneration: Tailored calcium release in hybrid fibrous scaffolds ACS Applied Materials & Interfaces 6, (10), 7512-7522

In bone regeneration, silicon-based calcium phosphate glasses (Bioglasses) have been widely used since the 1970s. However, they dissolve very slowly because of their high amount of Si (SiO2 > 45%). Recently, our group has found that calcium ions released by the degradation of glasses in which the job of silicon is done by just 5% of TiO2 are effective angiogenic promoters, because of their stimulation of a cell-membrane calcium sensing receptor (CaSR). Based on this, other focused tests on angiogenesis have found that Bioglasses also have the potential to be angiogenic promoters even with high contents of silicon (80%); however, their slow degradation is still a problem, as the levels of silicon cannot be decreased any lower than 45%. In this work, we propose a new generation of hybrid organically modified glasses, ormoglasses, that enable the levels of silicon to be reduced, therefore speeding up the degradation process. Using electrospinning as a faithful way to mimic the extracellular matrix (ECM), we successfully produced hybrid fibrous mats with three different contents of Si (40, 52, and 70%), and thus three different calcium ion release rates, using an ormoglass–polycaprolactone blend approach. These mats offered a good platform to evaluate different calcium release rates as osteogenic promoters in an in vivo subcutaneous environment. Complementary data were collected to complement Ca2+ release analysis, such as stiffness evaluation by AFM, ζ-potential, morphology evaluation by FESEM, proliferation and differentiation analysis, as well as in vivo subcutaneous implantations. Material and biological characterization suggested that compositions of organic/inorganic hybrid materials with a Si content equivalent to 40%, which were also those that released more calcium, were osteogenic. They also showed a greater ability to form blood vessels. These results suggest that Si-based ormoglasses can be considered an efficient tool for calcium release modulation, which could play a key role in the angiogenic promoting process.

Keywords: Biological materials, Blood vessels, Calcium, Electrospinning, Glass, Hybrid materials, Silicon oxides, Sol-gel process, Sol-gels, Angiogenesis, Biological characterization, Calcium phosphate glass, Calcium-sensing receptors, Degradation process, Extracellular matrices, Organic/inorganic hybrid materials, ormoglasses, Silicon


Melo, E., Cárdenes, N., Garreta, E., Luque, T., Rojas, M., Navajas, D., Farré, R., (2014). Inhomogeneity of local stiffness in the extracellular matrix scaffold of fibrotic mouse lungs Journal of the Mechanical Behavior of Biomedical Materials , 37, 186-195

Lung disease models are useful to study how cell engraftment, proliferation and differentiation are modulated in lung bioengineering. The aim of this work was to characterize the local stiffness of decellularized lungs in aged and fibrotic mice. Mice (2- and 24-month old; 14 of each) with lung fibrosis (N=20) and healthy controls (N=8) were euthanized after 11 days of intratracheal bleomycin (fibrosis) or saline (controls) infusion. The lungs were excised, decellularized by a conventional detergent-based (sodium-dodecyl sulfate) procedure and slices of the acellular lungs were prepared to measure the local stiffness by means of atomic force microscopy. The local stiffness of the different sites in acellular fibrotic lungs was very inhomogeneous within the lung and increased according to the degree of the structural fibrotic lesion. Local stiffness of the acellular lungs did not show statistically significant differences caused by age. The group of mice most affected by fibrosis exhibited local stiffness that were ~2-fold higher than in the control mice: from 27.2±1.64 to 64.8±7.1. kPa in the alveolar septa, from 56.6±4.6 to 99.9±11.7. kPa in the visceral pleura, from 41.1±8.0 to 105.2±13.6. kPa in the tunica adventitia, and from 79.3±7.2 to 146.6±28.8. kPa in the tunica intima. Since acellular lungs from mice with bleomycin-induced fibrosis present considerable micromechanical inhomogeneity, this model can be a useful tool to better investigate how different degrees of extracellular matrix lesion modulate cell fate in the process of organ bioengineering from decellularized lungs.

Keywords: Ageing, Atomic force microscopy, Decellularization, Lung fibrosis, Tissue engineering, Atomic force microscopy, Biological organs, Peptides, Sodium dodecyl sulfate, Sodium sulfate, Tissue engineering, Ageing, Decellularization, Extracellular matrices, Healthy controls, Inhomogeneities, Lung fibrosis, Micro-mechanical, Statistically significant difference, Mammals, bleomycin, adventitia, animal experiment, animal model, article, atomic force microscopy, bleomycin-induced pulmonary fibrosis, cell fate, controlled study, extracellular matrix, female, intima, lung alveolus, lung fibrosis, lung mechanics, mechanical probe, microenvironment, mouse, nonhuman, pleura, priority journal, rigidity, tissue engineering


Hoyo, J., Guaus, E., Oncins, G., Torrent-Burgués, J., Sanz, F., (2013). Incorporation of Ubiquinone in supported lipid bilayers on ITO Journal of Physical Chemistry B , 117, (25), 7498-7506

Ubiquinone (UQ) is one of the main electron and proton shuttle molecules in biological systems, and dipalmitoylphosphatidylcholine (DPPC) is one of the most used model lipids. Supported planar bilayers (SPBs) are extensively accepted as biological model membranes. In this study, SPBs have been deposited on ITO, which is a semiconductor with good electrical and optical features. Specifically, topographic atomic force microscopy (AFM) images and force curves have been performed on SPBs with several DPPC:UQ ratios to study the location and the interaction of UQ in the SPB. Additionally, cyclic voltammetry has been used to understand the electrochemical behavior of DPPC:UQ SPBs. Obtained results show that, in our case, UQ is placed in two main different positions in SPBs. First, between the DPPC hydrophobic chains, fact that originates a decrease in the breakthrough force of the bilayer, and the second between the two leaflets that form the SPBs. This second position occurs when increasing the UQ content, fact that eventually forms UQ aggregates at high concentrations. The formation of aggregates produces an expansion of the SPB average height and a bimodal distribution of the breakthrough force. The voltammetric response of UQ depends on its position on the bilayer.

Keywords: Bimodal distribution, Biological models, Dipalmitoyl phosphatidylcholine, Electrochemical behaviors, Hydrophobic chains, Supported lipid bilayers, Supported planar bilayers, Voltammetric response


Giraldo, B. F., Chaparro, J. A., Caminal, P., Benito, S., (2013). Characterization of the respiratory pattern variability of patients with different pressure support levels Engineering in Medicine and Biology Society (EMBC) 35th Annual International Conference of the IEEE , IEEE (Osaka, Japan) , 3849-3852

One of the most challenging problems in intensive care is still the process of discontinuing mechanical ventilation, called weaning process. Both an unnecessary delay in the discontinuation process and a weaning trial that is undertaken too early are undesirable. In this study, we analyzed respiratory pattern variability using the respiratory volume signal of patients submitted to two different levels of pressure support ventilation (PSV), prior to withdrawal of the mechanical ventilation. In order to characterize the respiratory pattern, we analyzed the following time series: inspiratory time, expiratory time, breath duration, tidal volume, fractional inspiratory time, mean inspiratory flow and rapid shallow breathing. Several autoregressive modeling techniques were considered: autoregressive models (AR), autoregressive moving average models (ARMA), and autoregressive models with exogenous input (ARX). The following classification methods were used: logistic regression (LR), linear discriminant analysis (LDA) and support vector machines (SVM). 20 patients on weaning trials from mechanical ventilation were analyzed. The patients, submitted to two different levels of PSV, were classified as low PSV and high PSV. The variability of the respiratory patterns of these patients were analyzed. The most relevant parameters were extracted using the classifiers methods. The best results were obtained with the interquartile range and the final prediction errors of AR, ARMA and ARX models. An accuracy of 95% (93% sensitivity and 90% specificity) was obtained when the interquartile range of the expiratory time and the breath duration time series were used a LDA model. All classifiers showed a good compromise between sensitivity and specificity.

Keywords: autoregressive moving average processes, feature extraction, medical signal processing, patient care, pneumodynamics, signal classification, support vector machines, time series, ARX, autoregressive modeling techniques, autoregressive models with exogenous input, autoregressive moving average model, breath duration time series, classification method, classifier method, discontinuing mechanical ventilation, expiratory time, feature extraction, final prediction errors, fractional inspiratory time, intensive care, interquartile range, linear discriminant analysis, logistic regression analysis, mean inspiratory flow, patient respiratory volume signal, pressure support level, pressure support ventilation, rapid shallow breathing, respiratory pattern variability characterization, support vector machines, tidal volume, weaning trial, Analytical models, Autoregressive processes, Biological system modeling, Estimation, Support vector machines, Time series analysis, Ventilation


Jané, R., Lazaro, J., Ruiz, P., Gil, E., Navajas, D., Farre, R., Laguna, P., (2013). Obstructive Sleep Apnea in a rat model: Effects of anesthesia on autonomic evaluation from heart rate variability measures CinC 2013 Computing in Cardiology Conference (CinC) , IEEE (Zaragoza, Spain) , 1011-1014

Rat model of Obstructive Sleep Apnea (OSA) is a realistic approach for studying physiological mechanisms involved in sleep. Rats are usually anesthetized and autonomic nervous system (ANS) could be blocked. This study aimed to assess the effect of anesthesia on ANS activity during OSA episodes. Seven male Sprague-Dawley rats were anesthetized intraperitoneally with urethane (1g/kg). The experiments were conducted applying airway obstructions, simulating 15s-apnea episodes for 15 minutes. Five signals were acquired: respiratory pressure and flow, SaO2, ECG and photoplethysmography (PPG). In total, 210 apnea episodes were studied. Normalized power spectrum of Pulse Rate Variability (PRV) was analyzed in the Low Frequency (LF) and High Frequency (HF) bands, for each episode in consecutive 15s intervals (before, during and after the apnea). All episodes showed changes in respiratory flow and SaO2 signal. Conversely, decreases in the amplitude fluctuations of PPG (DAP) were not observed. Normalized LF presented extremely low values during breathing (median=7,67%), suggesting inhibition of sympathetic system due to anesthetic effect. Subtle increases of LF were observed during apnea. HRV and PPG analysis during apnea could be an indirect tool to assess the effect and deep of anesthesia.

Keywords: electrocardiography, fluctuations, medical disorders, medical signal detection, medical signal processing, neurophysiology, photoplethysmography, pneumodynamics, sleep, ECG, SaO2 flow, SaO2 signal, airway obstructions, amplitude fluctuations, anesthesia effects, anesthetized nervous system, autonomic evaluation, autonomic nervous system, breathing, heart rate variability, high-frequency bands, low-frequency bands, male Sprague-Dawley rats, normalized power spectrum, obstructive sleep apnea, photoplethysmography, physiological mechanisms, pulse rate variability, rat model, respiratory flow, respiratory pressure, signal acquisition, sympathetic system inhibition, time 15 min, time 15 s, Abstracts, Atmospheric modeling, Computational modeling, Electrocardiography, Rats, Resonant frequency


Fumagalli, Laura, Esteban-Ferrer, Daniel, Cuervo, Ana, Carrascosa, Jose L., Gomila, Gabriel, (2012). Label-free identification of single dielectric nanoparticles and viruses with ultraweak polarization forces Nature Materials Nature Publishing Group 11, (9), 743-826

Label-free detection of the material composition of nanoparticles could be enabled by the quantification of the nanoparticles’ inherent dielectric response to an applied electric field. However, the sensitivity of dielectric nanoscale objects to geometric and non-local effects makes the dielectric response extremely weak. Here we show that electrostatic force microscopy with sub-piconewton resolution can resolve the dielectric constants of single dielectric nanoparticles without the need for any reference material, as well as distinguish nanoparticles that have an identical surface but different inner composition. We unambiguously identified unlabelled ~10unm nanoparticles of similar morphology but different low-polarizable materials, and discriminated empty from DNA-containing virus capsids. Our approach should make the in situ characterization of nanoscale dielectrics and biological macromolecules possible.

Keywords: Biological materials, Nanoscale materials, Characterisation and analytical techniques, Computation, modelling and theory


Serra-Picamal, Xavier, Conte, Vito, Vincent, Romaric, Anon, Ester, Tambe, Dhananjay T., Bazellieres, Elsa, Butler, James P., Fredberg, Jeffrey J., Trepat, Xavier, (2012). Mechanical waves during tissue expansion Nature Physics Nature Publishing Group 8, (8), 628-634

The processes by which an organism develops its shape and heals wounds involve expansion of a monolayer sheet of cells. The mechanism underpinning this epithelial expansion remains obscure, despite the fact that its failure is known to contribute to several diseases, including carcinomas, which account for about 90% of all human cancers. Here, using the micropatterned epithelial monolayer as a model system, we report the discovery of a mechanical wave that propagates slowly to span the monolayer, traverses intercellular junctions in a cooperative manner and builds up differentials of mechanical stress. Essential features of this wave generation and propagation are captured by a minimal model based on sequential fronts of cytoskeletal reinforcement and fluidization. These findings establish a mechanism of long-range cell guidance, symmetry breaking and pattern formation during monolayer expansion.

Keywords: Biological physics


Juanola-Feliu, E., Colomer-Farrarons, J., Miribel-Català , P., Samitier, J., Valls-Pasola, J., (2012). Market challenges facing academic research in commercializing nano-enabled implantable devices for in-vivo biomedical analysis Technovation , 32, (3-4), 193-204

This article reports on the research and development of a cutting-edge biomedical device for continuous in-vivo glucose monitoring. This entirely public-funded process of technological innovation has been conducted at the University of Barcelona within a context of converging technologies involving the fields of medicine, physics, chemistry, biology, telecommunications, electronics and energy. The authors examine the value chain and the market challenges faced by in-vivo implantable biomedical devices based on nanotechnologies. In so doing, they trace the process from the point of applied research to the final integration and commercialization of the product, when the social rate of return from academic research can be estimated. Using a case-study approach, the paper also examines the high-tech activities involved in the development of this nano-enabled device and describes the technology and innovation management process within the value chain conducted in a University-Hospital-Industry-Administration-Citizens framework. Here, nanotechnology is seen to represent a new industrial revolution, boosting the biomedical devices market. Nanosensors may well provide the tools required for investigating biological processes at the cellular level in vivo when embedded into medical devices of small dimensions, using biocompatible materials, and requiring reliable and targeted biosensors, high speed data transfer, safely stored data, and even energy autonomy.

Keywords: Biomedical device, Diabetes, Innovation management, Nanobiosensor, Nanotechnology, Research commercialization, Technology transfer, Academic research, Applied research, Barcelona, Biocompatible materials, Biological process, Biomedical analysis, Biomedical devices, Cellular levels, Converging technologies, Glucose monitoring, High-speed data transfer, Implantable biomedical devices, Implantable devices, In-vivo, Industrial revolutions, Innovation management, Medical Devices, Nanobiosensor, Rate of return, Research and development, Technological innovation, Value chains, Biological materials, Biomedical engineering, Biosensors, Commerce, Data transfer, Earnings, Engineering education, Glucose, Implants (surgical), Industrial research, Innovation, Medical problems, Nanosensors, Nanotechnology, Technology transfer, Equipment


Gustavsson, J., Ginebra, M. P., Planell, J., Engel, E., (2012). Osteoblast-like cellular response to dynamic changes in the ionic extracellular environment produced by calcium-deficient hydroxyapatite Journal of Materials Science-Materials in Medicine , 23, (10), 2509-2520

Solution-mediated reactions due to ionic substitutions are increasingly explored as a strategy to improve the biological performance of calcium phosphate-based materials. Yet, cellular response to well-defined dynamic changes of the ionic extracellular environment has so far not been carefully studied in a biomaterials context. In this work, we present kinetic data on how osteoblast-like SAOS-2 cellular activity and calcium-deficient hydroxyapatite (CDHA) influenced extracellular pH as well as extracellular concentrations of calcium and phosphate in standard in vitro conditions. Since cells were grown on membranes permeable to ions and proteins, they could share the same aqueous environment with CDHA, but still be physically separated from the material. In such culture conditions, it was observed that gradual material-induced adsorption of calcium and phosphate from the medium had only minor influence on cellular proliferation and alkaline phosphatase activity, but that competition for calcium and phosphate between cells and the biomaterial delayed and reduced significantly the cellular capacity to deposit calcium in the extracellular matrix. The presented work thus gives insights into how and to what extent solution-mediated reactions can influence cellular response, and this will be necessary to take into account when interpreting CDHA performance both in vitro and in vivo.

Keywords: Alkaline-phosphatase activity, Saos-2 cells, In-vitro, bone mineralization, Biological basis, Differentiation, Culture, Matrix, Proliferation, Topography


Giraldo, B.F., Gaspar, B.W., Caminal, P., Benito, S., (2012). Analysis of roots in ARMA model for the classification of patients on weaning trials Engineering in Medicine and Biology Society (EMBC) 34th Annual International Conference of the IEEE , IEEE (San Diego, USA) , 698-701

One objective of mechanical ventilation is the recovery of spontaneous breathing as soon as possible. Remove the mechanical ventilation is sometimes more difficult that maintain it. This paper proposes the study of respiratory flow signal of patients on weaning trials process by autoregressive moving average model (ARMA), through the location of poles and zeros of the model. A total of 151 patients under extubation process (T-tube test) were analyzed: 91 patients with successful weaning (GS), 39 patients that failed to maintain spontaneous breathing and were reconnected (GF), and 21 patients extubated after the test but before 48 hours were reintubated (GR). The optimal model was obtained with order 8, and statistical significant differences were obtained considering the values of angles of the first four poles and the first zero. The best classification was obtained between GF and GR, with an accuracy of 75.3% on the mean value of the angle of the first pole.

Keywords: Analytical models, Biological system modeling, Computational modeling, Estimation, Hospitals, Poles and zeros, Ventilation, Autoregressive moving average processes, Patient care, Patient monitoring, Pneumodynamics, Poles and zeros, Ventilation, ARMA model, T-tube test, Autoregressive moving average model, Extubation process, Mechanical ventilation, Optimal model, Patient classification, Respiratory flow signal, Roots, Spontaneous breathing, Weaning trials


Garde, A., Giraldo, B.F., Jané, R., Latshang, T.D., Turk, A.J., Hess, T., Bosch, M-.M., Barthelmes, D., Hefti, J.P., Maggiorini, M., Hefti, U., Merz, T.M., Schoch, O.D., Bloch, K.E., (2012). Periodic breathing during ascent to extreme altitude quantified by spectral analysis of the respiratory volume signal Engineering in Medicine and Biology Society (EMBC) 34th Annual International Conference of the IEEE , IEEE (San Diego, USA) , 707-710

High altitude periodic breathing (PB) shares some common pathophysiologic aspects with sleep apnea, Cheyne-Stokes respiration and PB in heart failure patients. Methods that allow quantifying instabilities of respiratory control provide valuable insights in physiologic mechanisms and help to identify therapeutic targets. Under the hypothesis that high altitude PB appears even during physical activity and can be identified in comparison to visual analysis in conditions of low SNR, this study aims to identify PB by characterizing the respiratory pattern through the respiratory volume signal. A number of spectral parameters are extracted from the power spectral density (PSD) of the volume signal, derived from respiratory inductive plethysmography and evaluated through a linear discriminant analysis. A dataset of 34 healthy mountaineers ascending to Mt. Muztagh Ata, China (7,546 m) visually labeled as PB and non periodic breathing (nPB) is analyzed. All climbing periods within all the ascents are considered (total climbing periods: 371 nPB and 40 PB). The best crossvalidated result classifying PB and nPB is obtained with Pm (power of the modulation frequency band) and R (ratio between modulation and respiration power) with an accuracy of 80.3% and area under the receiver operating characteristic curve of 84.5%. Comparing the subjects from 1st and 2nd ascents (at the same altitudes but the latter more acclimatized) the effect of acclimatization is evaluated. SaO2 and periodic breathing cycles significantly increased with acclimatization (p-value <; 0.05). Higher Pm and higher respiratory frequencies are observed at lower SaO2, through a significant negative correlation (p-value <; 0.01). Higher Pm is observed at climbing periods visually labeled as PB with >; 5 periodic breathing cycles through a significant positive correlation (p-value <; 0.01). Our data demonstrate that quantification of the respiratory volum- signal using spectral analysis is suitable to identify effects of hypobaric hypoxia on control of breathing.

Keywords: Frequency domain analysis, Frequency modulation, Heart, Sleep apnea, Ventilation, Visualization, Cardiology, Medical disorders, Medical signal processing, Plethysmography, Pneumodynamics, Sensitivity analysis, Sleep, Spectral analysis, Cheyne-Stokes respiration, Climbing periods, Dataset, Heart failure patients, High altitude PB, High altitude periodic breathing, Hypobaric hypoxia, Linear discriminant analysis, Pathophysiologic aspects, Physical activity, Physiologic mechanisms, Power spectral density, Receiver operating characteristic curve, Respiratory control, Respiratory frequency, Respiratory inductive plethysmography, Respiratory pattern, Respiratory volume signal, Sleep apnea, Spectral analysis, Spectral parameters


Amigo, L. E., Fernandez, Q., Giralt, X., Casals, A., Amat, J., (2012). Study of patient-orthosis interaction forces in rehabilitation therapies IEEE Conference Publications 4th IEEE RAS & EMBS International Conference on Biomedical Robotics and Biomechatronics (BioRob) , IEEE (Roma, Italy) , 1098-1103

The design of mechanical joints that kinematically behave as their biological counterparts is a challenge that if not addressed properly can cause inadequate forces transmission between robot and patient. This paper studies the interaction forces in rehabilitation therapies of the elbow joint. To measure the effect of orthosis-patient misalignments, a force sensor with a novel distributed architecture has been designed and used for this study. A test-bed based on an industrial robot acting as a virtual exoskeleton that emulates the action of a therapist has been developed and the interaction forces analyzed.

Keywords: Force, Force measurement, Force sensors, Joints, Medical treatment, Robot sensing systems, Force sensors, Medical robotics, Patient rehabilitation, Biological counterparts, Distributed architecture, Elbow joint, Force sensor, Inadequate forces transmission, Industrial robot, Mechanical joints design, Orthosis-patient misalignments, Patient-orthosis interaction forces, Rehabilitation therapies, Robot, Test-bed, Virtual exoskeleton


van Zanten, T. S., Garcia-Parajo, M. F., (2012). Super-resolution near-field optical microscopy Comprehensive Biophysics (ed. Egelman, E. H.), Elsevier (Desdren, Germany) Volume 2: Biophysical Techniques for Characterization of Cells, 144-164

Near-field optical microscopy is a technique not limited by the laws of diffraction that enables simultaneous high-resolution fluorescence and topographic measurements at the nanometer scale. This chapter highlights the intrinsic advantages of near-field optics in the study of cellular structures. The first part of the chapter lays the foundations of the near-field concept and technical implementation of near-field scanning optical microscopy (NSOM), whereas the second part of the chapter focuses on applications of NSOM to the study of model membranes and cellular structures on the plasma membrane. The last part of the chapter discusses further directions of near-field optics, including optical antennas and fluorescence correlation spectroscopy approaches in the near-field regime.

Keywords: Biological membranes, Cell membrane nanoscale compartmentalization, Cellular nanodomains, Fluorescence correlation spectroscopy in reduced volumes, Immunoreceptor imaging, Lipid rafts, Near-field scanning optical microscopy, Optical nano-antennas, Shear force imaging, Single molecule detection, Super-resolution microscopy


Tambe, Dhananjay T., Corey Hardin, C., Angelini, Thomas E., Rajendran, Kavitha, Park, Chan Young, Serra-Picamal, Xavier, Zhou, Enhua H., Zaman, Muhammad H., Butler, James P., Weitz, David A., Fredberg, Jeffrey J., Trepat, X., (2011). Collective cell guidance by cooperative intercellular forces Nature Materials 10, (6), 469-475

Cells comprising a tissue migrate as part of a collective. How collective processes are coordinated over large multi-cellular assemblies has remained unclear, however, because mechanical stresses exerted at cell–cell junctions have not been accessible experimentally. We report here maps of these stresses within and between cells comprising a monolayer. Within the cell sheet there arise unanticipated fluctuations of mechanical stress that are severe, emerge spontaneously, and ripple across the monolayer. Within that stress landscape, local cellular migrations follow local orientations of maximal principal stress. Migrations of both endothelial and epithelial monolayers conform to this behaviour, as do breast cancer cell lines before but not after the epithelial–mesenchymal transition. Collective migration in these diverse systems is seen to be governed by a simple but unifying physiological principle: neighbouring cells join forces to transmit appreciable normal stress across the cell–cell junction, but migrate along orientations of minimal intercellular shear stress.

Keywords: Biological materials, Mechanical properties


Simao, C., Mas-Torrent, M., Crivillers, N., Lloveras, V., Artés, Juan Manuel, Gorostiza, Pau, Veciana, Jaume, Rovira, C., (2011). A robust molecular platform for non-volatile memory devices with optical and magnetic responses Nature Chemistry , 3, (5), 359-364

Bistable molecules that behave as switches in solution have long been known. Systems that can be reversibly converted between two stable states that differ in their physical properties are particularly attractive in the development of memory devices when immobilized in substrates. Here, we report a highly robust surface-confined switch based on an electroactive, persistent organic radical immobilized on indium tin oxide substrates that can be electrochemically and reversibly converted to the anion form. This molecular bistable system behaves as an extremely robust redox switch in which an electrical input is transduced into optical as well as magnetic outputs under ambient conditions. The fact that this molecular surface switch, operating at very low voltages, can be patterned and addressed locally, and also has exceptionally high long-term stability and excellent reversibility and reproducibility, makes it a very promising platform for non-volatile memory devices.

Keywords: Self-assembled monolayers, Chromophore-based monolayers, Ultrathin platinum films, Carbon free-radicals, Per-million levels, Polychlorotriphenylmethyl radicals, Electron-transfer, Surface, Logic, Quantification


Garcia-Manyes, S., Redondo-Morata, L., Oncins, G., Sanz, F., (2010). Nanomechanics of lipid bilayers: Heads or tails? Journal of the American Chemical Society American Chemical Society 132, (37), 12874-12886

Understanding the effect of mechanical stress on membranes is of primary importance in biophysics. Here we use force spectroscopy AFM to quantitatively characterize the nanomechanical stability of supported lipid bilayers as a function of their chemical composition. The onset of plastic deformation reveals itself as a repetitive jump in the approaching force curve, which represents a molecular fingerprint for the bilayer mechanical stability. By systematically probing a set of chemically distinct supported lipid bilayers (SLBs), we first show that both the headgroup and tail have a decisive effect on their mechanical properties. While the mechanical stability of the probed SLBs linearly increases by 3.3 nN upon the introduction of each additional -CH2- in the chain, it exhibits a significant dependence on the phospholipid headgroup, ranging from 3 nN for DPPA to 66 nN for DPPG. Furthermore, we also quantify the reduction of the membrane mechanical stability as a function of the number of unsaturations and molecular branching in the chemical structure of the apolar tails. Finally, we demonstrate that, upon introduction of cholesterol and ergosterol, contrary to previous belief the mechanical stability of membranes not only increases linearly in the liquid phase (DLPC) but also for phospholipids present in the gel phase (DPPC). Our results are discussed in the framework of the continuum nucleation model. This work highlights the compelling effect of subtle variations in the chemical structure of phospholipid molecules on the membrane response when exposed to mechanical forces, a mechanism of common occurrence in nature.

Keywords: Atomic-force microscopy, Molecular-dynamics simulation, Aqueous-electrolyte solutions, Supported planar membranes, Phospholipid-bilayers, Biological-membranes, Physical-properties, Fluid membranes, Model membranes, Chain-length


Seira, O., Gavin, R., Gil, V., Llorens, F., Rangel, A., Soriano, E., del Rio, J. A., (2010). Neurites regrowth of cortical neurons by GSK3 beta inhibition independently of Nogo receptor 1 Journal of Neurochemistry , 113, (6), 1644-1658

P>Lesioned axons do not regenerate in the adult mammalian CNS, owing to the over-expression of inhibitory molecules such as myelin-derived proteins or chondroitin sulphate proteoglycans. In order to overcome axon inhibition, strategies based on extrinsic and intrinsic treatments have been developed. For myelin-associated inhibition, blockage with NEP1-40, receptor bodies or IN-1 antibodies has been used. In addition, endogenous blockage of cell signalling mechanisms induced by myelin-associated proteins is a potential tool for overcoming axon inhibitory signals. We examined the participation of glycogen synthase kinase 3 beta (GSK3 beta) and extracellular-related kinase (ERK) 1/2 in axon regeneration failure in lesioned cortical neurons. We also investigated whether pharmacological blockage of GSK3 beta and ERK1/2 activities facilitates regeneration after myelin-directed inhibition in two models: (i) cerebellar granule cells and (ii) lesioned entorhino-hippocampal pathway in slice cultures, and whether the regenerative effects are mediated by Nogo Receptor 1 (NgR1). We demonstrate that, in contrast to ERK1/2 inhibition, the pharmacological treatment of GSK3 beta inhibition strongly facilitated regrowth of cerebellar granule neurons over myelin independently of NgR1. Finally, these regenerative effects were corroborated in the lesioned entorhino-hippocampal pathway in NgR1-/- mutant mice. These results provide new findings for the development of new assays and strategies to enhance axon regeneration in injured cortical connections.

Keywords: Axon inhibition, Nogo Receptor complex, Organotypic slice cultures, Pharmacological treatment


Fernandez, L., Gutierrez-Galvez, A., Marco, S., (2010). Gas sensor array system inspired on the sensory diversity and redundancy of the olfactory epithelium Procedia Engineering Eurosensor XXIV Conference (ed. Jakoby, B., Vellekoop, M.J.), Elsevier Science BV (Linz, Austria) 5, (0), 25-28

This paper presents a chemical sensing system that takes inspiration from the combination of sensory diversity and redundancy at the olfactory epithelium to enhance the chemical information obtained from the odorants. The system is based on commercial MOS sensors and achieves, first, diversity trough different types of MOS along with modulation of their temperatures, and second redundancy including 12 MOS sensors for each type (12×8) combined with a high-speed multiplexing system that allows connecting 16 load resistors with each and every one of the 96 sensors in about two seconds. Exposition of the system to ethanol, ammonia, and acetone at different concentrations shows how the system is able to capture a large amount of information of the identity and the concentration of the odorant.

Keywords: Gas sensor array, Biologically inspired system, Redundancy, Diversity, MOX sensors, Temperature modulation


Fumagalli, L., Ferrari, G., Sampietro, M., Gomila, G., (2009). Quantitative nanoscale dielectric microscopy of single-layer supported biomembranes Nano Letters 9, (4), 1604-1608

We present the experimental demonstration of low-frequency dielectric constant imaging of single-layer supported biomembranes at the nanoscale. The dielectric constant image has been quantitatively reconstructed by combining the thickness and local capacitance obtained using a scanning force microscope equipped with a sub-attofarad low-frequency capacitance detector. This work opens new possibilities for studying bioelectric phenomena and the dielectric properties of biological membranes at the nanoscale.

Keywords: Atomic-force microscopy, Nnear-field microscopy, Purple membrane, Scanning capacitance, Biological-systems, Fluid, Spectroscopy, Resolution, Proteins, Dynamics


Sunyer, R., Ritort, F., Farre, R., Navajas, D., (2009). Thermal activation and ATP dependence of the cytoskeleton remodeling dynamics Physical Review E 79, (5), 51920

The cytoskeleton (CSK) is a nonequilibrium polymer network that uses hydrolyzable sources of free energy such as adenosine triphosphate (ATP) to remodel its internal structure. As in inert nonequilibrium soft materials, CSK remodeling has been associated with structural rearrangements driven by energy-activated processes. We carry out particle tracking and traction microscopy measurements of alveolar epithelial cells at various temperatures and ATP concentrations. We provide the first experimental evidence that the remodeling dynamics of the CSK is driven by structural rearrangements over free-energy barriers induced by thermally activated forces mediated by ATP. The measured activation energy of these forces is similar to 40k(B)T(r) (k(B) being the Boltzmann constant and T-r being the room temperature). Our experiments provide clues to understand the analogy between the dynamics of the living CSK and that of inert nonequilibrium soft materials.

Keywords: Biochemistry, Cellular biophysics, Free energy, Molecular biophysics, Physiological models


Morales, R., Riss, M., Wang, L., Gavin, R., Del Rio, J. A., Alcubilla, R., Claverol-Tinture, E., (2008). Integrating multi-unit electrophysiology and plastic culture dishes for network neuroscience Lab on a Chip 8, (11), 1896-1905

The electrophysiological characterisation of cultured neurons is of paramount importance for drug discovery, safety pharmacology and basic research in the neurosciences. Technologies offering low cost, low technical complexity and potential for scalability towards high-throughput electrophysiology on in vitro neurons would be advantageous, in particular for screening purposes. Here we describe a plastic culture substrate supporting low-complexity multi-unit loose-patch recording and stimulation of developing networks while retaining manufacturability compatible with low-cost and large-scale production. Our hybrid polydimethylsilane (PDMS)-on-polystyrene structures include chambers (6 mm in diameter) and microchannels (25 mu m x 3.7 mu m 1 mm) serving as substrate-embedded recording pipettes. Somas are plated and retained in the chambers due to geometrical constraints and their processes grow along the microchannels, effectively establishing a loose-patch configuration without human intervention. We demonstrate that off-the-shelf voltage-clamp, current-clamp and extracellular amplifiers can be used to record and stimulate multi-unit activity with the aid of our dishes. Spikes up to 50 pA in voltage-clamp and 300 mu V in current-clamp modes are recorded in sparse and bursting activity patterns characteristic of 1 week-old hippocampal cultures. Moreover, spike sorting employing principal component analysis (PCA) confirms that single microchannels support the recording of multiple neurons. Overall, this work suggests a strategy to endow conventional culture plasticware with added functionality to enable cost-efficient network electrophysiology.

Keywords: Electrophysiological characterisation, Cultured neurons, Polydimethylsilane (PDMS)-on-polystyrene structures


Gavara, N., Roca-Cusachs, P., Sunyer, R., Farre, R., Navajas, D., (2008). Mapping cell-matrix stresses during stretch reveals inelastic reorganization of the cytoskeleton Biophysical Journal , 95, (1), 464-471

The mechanical properties of the living cell are intimately related to cell signaling biology through cytoskeletal tension. The tension borne by the cytoskeleton (CSK) is in part generated internally by the actomyosin machinery and externally by stretch. Here we studied how cytoskeletal tension is modified during stretch and the tensional changes undergone by the sites of cell-matrix interaction. To this end we developed a novel technique to map cell-matrix stresses during application of stretch. We found that cell-matrix stresses increased with imposition of stretch but dropped below baseline levels on stretch release. Inhibition of the actomyosin machinery resulted in a larger relative increase in CSK tension with stretch and in a smaller drop in tension after stretch release. Cell-matrix stress maps showed that the loci of cell adhesion initially bearing greater stress also exhibited larger drops in traction forces after stretch removal. Our results suggest that stretch partially disrupts the actin-myosin apparatus and the cytoskeletal structures that support the largest CSK tension. These findings indicate that cells use the mechanical energy injected by stretch to rapidly reorganize their structure and redistribute tension.

Keywords: Cell Line, Computer Simulation, Cytoskeleton/ physiology, Elasticity, Epithelial Cells/ physiology, Extracellular Matrix/ physiology, Humans, Mechanotransduction, Cellular/ physiology, Models, Biological, Stress, Mechanical


Roca-Cusachs, P., Alcaraz, J., Sunyer, R., Samitier, J., Farre, R., Navajas, D., (2008). Micropatterning of single endothelial cell shape reveals a tight coupling between nuclear volume in G1 and proliferation Biophysical Journal , 94, (12), 4984-4995

Shape-dependent local differentials in cell proliferation are considered to be a major driving mechanism of structuring processes in vivo, such as embryogenesis, wound healing, and angiogenesis. However, the specific biophysical signaling by which changes in cell shape contribute to cell cycle regulation remains poorly understood. Here, we describe our study of the roles of nuclear volume and cytoskeletal mechanics in mediating shape control of proliferation in single endothelial cells. Micropatterned adhesive islands were used to independently control cell spreading and elongation. We show that, irrespective of elongation, nuclear volume and apparent chromatin decondensation of cells in G1 systematically increased with cell spreading and highly correlated with DNA synthesis (percent of cells in the S phase). In contrast, cell elongation dramatically affected the organization of the actin cytoskeleton, markedly reduced both cytoskeletal stiffness (measured dorsally with atomic force microscopy) and contractility (measured ventrally with traction microscopy), and increased mechanical anisotropy, without affecting either DNA synthesis or nuclear volume. Our results reveal that the nuclear volume in G1 is predictive of the proliferative status of single endothelial cells within a population, whereas cell stiffness and contractility are not. These findings show that the effects of cell mechanics in shape control of proliferation are far more complex than a linear or straightforward relationship. Our data are consistent with a mechanism by which spreading of cells in G1 partially enhances proliferation by inducing nuclear swelling and decreasing chromatin condensation, thereby rendering DNA more accessible to the replication machinery.

Keywords: Cell Line, Cell Nucleus/ physiology, Cell Proliferation, Cell Size, Computer Simulation, Endothelial Cells/ cytology/ physiology, G1 Phase/ physiology, Humans, Mechanotransduction, Cellular/ physiology, Models, Biological, Statistics as Topic


Rodriguez, Segui, Bucior, I., Burger, M. M., Samitier, J., Errachid, A., Fernàndez-Busquets, X., (2007). Application of a bio-QCM to study carbohydrates self-interaction in presence of calcium Transducers '07 & Eurosensors Xxi, Digest of Technical Papers 14th International Conference on Solid-State Sensors, Actuators and Microsystems , IEEE (Lyon, France) 1-2, 1995-1998

In the past years, the quartz crystal microbalance (QCM) has been successfully applied to follow interfacial physical chemistry phenomena in a label free and real time manner. However, carbohydrate self adhesion has only been addressed partially using this technique. Carbohydrates play an important role in cell adhesion, providing a highly versatile form of attachment, suitable for biologically relevant recognition events in the initial steps of adhesion. Here, we provide a QCM study of carbohydrates' self-recognition in the presence of calcium, based on a species-specific cell recognition model provided by marine sponges. Our results show a difference in adhesion kinetics when varying either the calcium concentration (with a constant carbohydrate concentration) or the carbohydrate concentration (with constant calcium concentration).

Keywords: Biomedical materials, Calcium, Cellular biophysics, Microbalances, Porous materials, Quartz, Surface chemistry/ bio-QCM, Carbohydrates self-interaction, Quartz crystal microbalance, Interfacial physical chemistry phenomena, Carbohydrate self adhesion, Biologically relevant recognition events, Marine sponges, Adhesion kinetics, Calcium concentration, Carbohydrate concentration, Biosensors, Biomedical materials, Surface chemistry, Cellular biophysics