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Kadkhodaie-Elyaderani A, de Lama-Odría MC, Rivas M, Martínez-Rovira I, Yousef I, Puiggalí J, Del Valle LJ, (2022). Medicated Scaffolds Prepared with Hydroxyapatite/Streptomycin Nanoparticles Encapsulated into Polylactide Microfibers International Journal Of Molecular Sciences 23,

The preparation, characterization, and controlled release of hydroxyapatite (HAp) nanopar-ticles loaded with streptomycin (STR) was studied. These nanoparticles are highly appropriate for the treatment of bacterial infections and are also promising for the treatment of cancer cells. The analyses involved scanning electron microscopy, dynamic light scattering (DLS) and Z-potential measurements, as well as infrared spectroscopy and X-ray diffraction. Both amorphous (ACP) and crystalline (cHAp) hydroxyapatite nanoparticles were considered since they differ in their release behavior (faster and slower for amorphous and crystalline particles, respectively). The encapsulated nanoparticles were finally incorporated into biodegradable and biocompatible polylactide (PLA) scaf-folds. The STR load was carried out following different pathways during the synthesis/precipitation of the nanoparticles (i.e., nucleation steps) and also by simple adsorption once the nanoparticles were formed. The loaded nanoparticles were biocompatible according to the study of the cytotoxicity of extracts using different cell lines. FTIR microspectroscopy was also employed to evaluate the cytotoxic effect on cancer cell lines of nanoparticles internalized by endocytosis. The results were promising when amorphous nanoparticles were employed. The nanoparticles loaded with STR increased their size and changed their superficial negative charge to positive. The nanoparticles’ crystallinity decreased, with the consequence that their crystal sizes reduced, when STR was incorporated into their structure. STR maintained its antibacterial activity, although it was reduced during the adsorption into the nanoparticles formed. The STR release was faster from the amorphous ACP nanoparticles and slower from the crystalline cHAp nanoparticles. However, in both cases, the STR release was slower when incorporated in calcium and phosphate during the synthesis. The biocompatibility of these nanoparticles was assayed by two approximations. When extracts from the nanoparticles were evaluated in cultures of cell lines, no cytotoxic damage was observed at concen-trations of less than 10 mg/mL. This demonstrated their biocompatibility. Another experiment using FTIR microspectroscopy evaluated the cytotoxic effect of nanoparticles internalized by endocytosis in cancer cells. The results demonstrated slight damage to the biomacromolecules when the cells were treated with ACP nanoparticles. Both ACP and cHAp nanoparticles were efficiently encapsulated in PLA electrospun matrices, providing functionality and bioactive properties. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords: antibiotics, antimicrobial activity, behavior, cytotoxicity, delivery, drug, drug delivery, hydroxyapatite nanoparticles, in-vitro, mechanisms, mitochondria, polylactide, release, streptomycin, Antimicrobial activity, Cancer stem-cells, Cytotoxicity, Drug delivery, Hydroxyapatite nanoparticles, Polylactide, Streptomycin


Matamoros-Angles, A, Hervera, A, Soriano, J, Marti, E, Carulla, P, Llorens, F, Nuvolone, M, Aguzzi, A, Ferrer, I, Gruart, A, Delgado-Garcia, JM, Del Rio, JA, (2022). Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability Bmc Biology 20, 17

Background Cellular prion protein (PrP(C)) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. However, increasing knowledge about the participation of PrP(C) in prion pathogenesis contrasts with puzzling data regarding its natural physiological role. PrP(C) is expressed in a number of tissues, including at high levels in the nervous system, especially in neurons and glial cells, and while previous studies have established a neuroprotective role, conflicting evidence for a synaptic function has revealed both reduced and enhanced long-term potentiation, and variable observations on memory, learning, and behavior. Such evidence has been confounded by the absence of an appropriate knock-out mouse model to dissect the biological relevance of PrP(C), with some functions recently shown to be misattributed to PrP(C) due to the presence of genetic artifacts in mouse models. Here we elucidate the role of PrP(C) in the hippocampal circuitry and its related functions, such as learning and memory, using a recently available strictly co-isogenic Prnp(0/0) mouse model (Prnp(ZH3/ZH3)). Results We performed behavioral and operant conditioning tests to evaluate memory and learning capabilities, with results showing decreased motility, impaired operant conditioning learning, and anxiety-related behavior in Prnp(ZH3/ZH3) animals. We also carried in vivo electrophysiological recordings on CA3-CA1 synapses in living behaving mice and monitored spontaneous neuronal firing and network formation in primary neuronal cultures of Prnp(ZH3/ZH3) vs wildtype mice. PrP(C) absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the Prnp(ZH3/ZH3) hippocampus. In addition, we observed a delay in neuronal maturation and network formation in Prnp(ZH3/ZH3) cultures. Conclusion Our results demonstrate that PrP(C) promotes neuronal network formation and connectivity. PrP(C) mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion may underlie an epileptogenic-susceptible brain that fails to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.

Keywords: anxiety, behavior, cellular prion protein, epilepsy, hippocampus, Anxiety, Behavior, Cellular prion protein, Developmental expression, Epilepsy, Gene-expression, Hippocampus, Kainate-induced seizures, Lacking, Ltp, Memory, Messenger-rna, Motor behavior, Mouse, Prp


Beltrán G, Navajas D, García-Aznar JM, (2022). Mechanical modeling of lung alveoli: From macroscopic behaviour to cell mechano-sensing at microscopic level Journal Of The Mechanical Behavior Of Biomedical Materials 126, 105043

The mechanical signals sensed by the alveolar cells through the changes in the local matrix stiffness of the extracellular matrix (ECM) are determinant for regulating cellular functions. Therefore, the study of the mechanical response of lung tissue becomes a fundamental aspect in order to further understand the mechanosensing signals perceived by the cells in the alveoli. This study is focused on the development of a finite element (FE) model of a decellularized rat lung tissue strip, which reproduces accurately the mechanical behaviour observed in the experiments by means of a tensile test. For simulating the complex structure of the lung parenchyma, which consists of a heterogeneous and non-uniform network of thin-walled alveoli, a 3D model based on a Voronoi tessellation is developed. This Voronoi-based model is considered very suitable for recreating the geometry of cellular materials with randomly distributed polygons like in the lung tissue. The material model used in the mechanical simulations of the lung tissue was characterized experimentally by means of AFM tests in order to evaluate the lung tissue stiffness on the micro scale. Thus, in this study, the micro (AFM test) and the macro scale (tensile test) mechanical behaviour are linked through the mechanical simulation with the 3D FE model based on Voronoi tessellation. Finally, a micro-mechanical FE-based model is generated from the Voronoi diagram for studying the stiffness sensed by the alveolar cells in function of two independent factors: the stretch level of the lung tissue and the geometrical position of the cells on the extracellular matrix (ECM), distinguishing between pneumocyte type I and type II. We conclude that the position of the cells within the alveolus has a great influence on the local stiffness perceived by the cells. Alveolar cells located at the corners of the alveolus, mainly type II pneumocytes, perceive a much higher stiffness than those located in the flat areas of the alveoli, which correspond to type I pneumocytes. However, the high stiffness, due to the macroscopic lung tissue stretch, affects both cells in a very similar form, thus no significant differences between them have been observed. © 2021 The Authors

Keywords: Afm, Animal cell, Animal experiment, Animal model, Animal tissue, Article, Biological organs, Cell function, Cells, Computational geometry, Cytology, Extracellular matrices, Extracellular matrix, Geometry, High stiffness, Human, Lung alveolus cell type 1, Lung alveolus cell type 2, Lung parenchyma, Lung tissue, Male, Mechanical behavior, Mechanical modeling, Mechanical simulations, Mechanosensing, Model-based opc, Nonhuman, Physical model, Rat, Rigidity, Stiffness, Stiffness matrix, Tensile testing, Thin walled structures, Three dimensional finite element analysis, Tissue, Type ii, Voronoi tessellations


Raymond Y, Bonany M, Lehmann C, Thorel E, Benítez R, Franch J, Espanol M, Solé-Martí X, Manzanares MC, Canal C, Ginebra MP, (2021). Hydrothermal processing of 3D-printed calcium phosphate scaffolds enhances bone formation in vivo: a comparison with biomimetic treatment Acta Biomaterialia 135, 671-688

Hydrothermal (H) processes accelerate the hydrolysis reaction of α-tricalcium phosphate (α-TCP) compared to the long-established biomimetic (B) treatments. They are of special interest for patient-specific 3D-printed bone graft substitutes, where the manufacturing time represents a critical constraint. Altering the reaction conditions has implications for the physicochemical properties of the reaction product. However, the impact of the changes produced by the hydrothermal reaction on the in vivo performance was hitherto unknown. The present study compares the bone regeneration potential of 3D-printed α-TCP scaffolds hardened using these two treatments in rabbit condyle monocortical defects. Although both consolidation processes resulted in biocompatible scaffolds with osseointegrative and osteoconductive properties, the amount of newly formed bone increased by one third in the hydrothermal vs the biomimetic samples. B and H scaffolds consisted mostly of high specific surface area calcium-deficient hydroxyapatite (38 and 27 m2 g-1, respectively), with H samples containing also 10 wt.% β-tricalcium phosphate (β-TCP). The shrinkage produced during the consolidation process was shown to be very small in both cases, below 3%, and smaller for H than for B samples. The differences in the in vivo performance were mainly attributed to the distinct crystallisation nanostructures, which proved to have a major impact on permeability and protein adsorption capacity, using BSA as a model protein, with B samples being highly impermeable. Given the crucial role that soluble proteins play in osteogenesis, this is proposed to be a relevant factor behind the distinct in vivo performances observed for the two materials. Statement of significance: The possibility to accelerate the consolidation of self-setting calcium phosphate inks through hydrothermal treatments has aroused great interest due to the associated advantages for the development of 3D-printed personalised bone scaffolds. Understanding the implications of this approach on the in vivo performance of the scaffolds is of paramount importance. This study compares, for the first time, this treatment to the long-established biomimetic setting strategy in terms of osteogenic potential in vivo in a rabbit model, and relates the results obtained to the physicochemical properties of the 3D-printed scaffolds (composition, crystallinity, nanostructure, nanoporosity) and their interaction with soluble proteins.

Keywords: 3d printing, behavior, biomimetic, bone scaffolds, calcium phosphate, deficient hydroxyapatite, design, graft, hydrothermal, in vivo, morbidity, osteoinduction, porosity, standard, tricalcium phosphate, 3d printing, Biomimetic, Bone scaffolds, Calcium phosphate, Fibula free-flap, Hydrothermal, In vivo


del-Mazo-Barbara L, Ginebra MP, (2021). Rheological characterisation of ceramic inks for 3D direct ink writing: A review JOURNAL OF THE EUROPEAN CERAMIC SOCIETY 41, 18-33

3D printing is a competitive manufacturing technology, which has opened up new possibilities for the fabrication of complex ceramic structures and customised parts. Extrusion-based technologies, also known as direct ink writing (DIW) or robocasting, are amongst the most used for ceramic materials. In them, the rheological properties of the ink play a crucial role, determining both the extrudability of the paste and the shape fidelity of the printed parts. However, comprehensive rheological studies of printable ceramic inks are scarce and may be difficult to understand for non-specialists. The aim of this review is to provide an overview of the main types of ceramic ink formulations developed for DIW and a detailed description of the more relevant rheological tests for assessing the printability of ceramic pastes. Moreover, the key rheological parameters are identified and linked to printability aspects, including the values reported in the literature for different ink compositions.

Keywords: 3-dimensional structures, behavior, deposition, direct ink writing, freeform fabrication, gelation, glass scaffolds, mechanical-properties, printability, rheology, robocasting, suspensions, 3d printing, Direct ink writing, Phosphate scaffolds, Printability, Rheology, Robocasting


Elosegui-Artola A, (2021). The extracellular matrix viscoelasticity as a regulator of cell and tissue dynamics Current Opinion In Cell Biology 72, 10-18

The extracellular matrix mechanical properties regulate processes in development, cancer, and fibrosis. Among the distinct mechanical properties, the vast majority of research has focused on the extracellular matrix's elasticity as the primary determinant of cell and tissue behavior. However, both cells and the extracellular matrix are not only elastic but also viscous. Despite viscoelasticity being a universal feature of living tissues, our knowledge of the influence of the extracellular matrix's viscoelasticity in cell behavior is limited. This mini-review describes some of the recent findings that have highlighted the role of the extracellular matrix's viscoelasticity in cell and tissue dynamics.

Keywords: behavior, cell adhesion, cell mechanics, cell migration, deformability, extracellular matrix, extracellular matrix mechanics, fluidity, forces, hydrogels, mechanobiology, mechanotransduction, tissue mechanics, viscoelasticity, viscosity, Cell adhesion, Cell mechanics, Cell migration, Extracellular matrix, Extracellular matrix mechanics, Fluidity, Mechanobiology, Mechanotransduction, Migration, Tissue mechanics, Viscoelasticity, Viscosity


García-Mintegui C, Córdoba LC, Buxadera-Palomero J, Marquina A, Jiménez-Piqué E, Ginebra MP, Cortina JL, Pegueroles M, (2021). Zn-Mg and Zn-Cu alloys for stenting applications: From nanoscale mechanical characterization to in vitro degradation and biocompatibility Bioactive Materials 6, 4430-4446

In the recent decades, zinc (Zn) and its alloys have been drawing attention as promising candidates for bioresorbable cardiovascular stents due to its degradation rate more suitable than magnesium (Mg) and iron (Fe) alloys. However, its mechanical properties need to be improved in order to meet the criteria for vascular stents. This work investigates the mechanical properties, biodegradability and biocompatibility of Zn-Mg and Zn-Cu alloys in order to determine a proper alloy composition for optimal stent performance. Nanoindentation measurements are performed to characterize the mechanical properties at the nanoscale as a function of the Zn microstructure variations induced by alloying. The biodegradation mechanisms are discussed and correlated to microstructure, mechanical performance and bacterial/cell response. Addition of Mg or Cu alloying elements refined the microstructure of Zn and enhanced yield strength (YS) and ultimate tensile strength (UTS) proportional to the volume fraction of secondary phases. Zn-1Mg showed the higher YS and UTS and better performance in terms of degradation stability in Hanks’ solution. Zn-Cu alloys presented an antibacterial effect for S. aureus controlled by diffusion mechanisms and by contact. Biocompatibility was dependent on the degradation rate and the nature of the corrosion products.

Keywords: behavior, biocompatibility, biodegradable metals, bioresorbable metals, bioresorbable scaffold, copper, corrosion properties, elastic-modulus, galvanic corrosion, microstructure, nanoindentation, redox homeostasis, zinc, Biocompatibility, Bioresorbable metals, Galvanic corrosion, Nanoindentation, Room-temperature superplasticity, Zinc alloys


Vidal, E, Guillem-Marti, J, Ginebra, MP, Combes, C, Ruperez, E, Rodriguez, D, (2021). Multifunctional homogeneous calcium phosphate coatings: Toward antibacterial and cell adhesive titanium scaffolds SURFACE & COATINGS TECHNOLOGY 405,

Implants for orthopedic applications need to be biocompatible and bioactive, with mechanical properties similar to those of surrounding natural bone. Given this scenario titanium (Ti) scaffolds obtained by Direct Ink Writing technique offer the opportunity to manufacture customized structures with controlled porosity and mechanical properties. Considering that 3D Ti scaffolds have a significant surface area, it is necessary to develop strategies against the initial bacterial adhesion in order to prevent infection in the early stages of the implantation, while promoting cell adhesion to the scaffold. The challenge is not only achieving a balance between antibacterial activity and osseointegration, it is also to develop a homogeneous coating on the inner and outer surface of the scaffold. The purpose of this work was the development of a single-step electrodeposition process in order to uniformly cover Ti scaffolds with a layer of calcium phosphate (CaP) loaded with chlorhexidine digluconate (CHX). Scaffold characterization was assessed by scanning electron microscopy, Energy dispersive X-ray spectroscopy, X-ray diffraction, micro-Raman microscopy and compressive strength tests. Results determined that the surface of scaffolds was covered by plate-like and whisker-like calcium phosphate crystals, which main phases were octacalcium phosphate and brushite. Biological tests showed that the as-coated scaffolds reduced bacteria adhesion (73 +/- 3% for Staphylococcus aureus and 70 +/- 2% for Escherichia coli). In vitro cell studies and confocal analysis revealed the adhesion and spreading of osteoblast-like SaOS-2 on coated surfaces. Therefore, the proposed strategy can be a potential candidate in bone replacing surgeries.

Keywords: Antibacterial, Bacterial, Behavior, Biocompatibility, Calcium phosphate coating, Chlorhexidine, Chlorhexidine digluconate, Deposition, Electrodeposition, Hydroxyapatite coatings, Implants, One-step pulse electrodeposition, Plasma-spray, Release, Surface, Titanium scaffolds


Redondo-Morata, Lorena, Losada-Pérez, Patricia, Giannotti, Marina Inés, (2020). Lipid bilayers: Phase behavior and nanomechanics Current Topics in Membranes (ed. Levitan, Irena, Trache, Andreea), Academic Press (Berlin, Germany) 86, 1-55

Lipid membranes are involved in many physiological processes like recognition, signaling, fusion or remodeling of the cell membrane or some of its internal compartments. Within the cell, they are the ultimate barrier, while maintaining the fluidity or flexibility required for a myriad of processes, including membrane protein assembly. The physical properties of in vitro model membranes as model cell membranes have been extensively studied with a variety of techniques, from classical thermodynamics to advanced modern microscopies. Here we review the nanomechanics of solid-supported lipid membranes with a focus in their phase behavior. Relevant information obtained by quartz crystal microbalance with dissipation monitoring (QCM-D) and atomic force microscopy (AFM) as complementary techniques in the nano/mesoscale interface is presented. Membrane morphological and mechanical characterization will be discussed in the framework of its phase behavior, phase transitions and coexistence, in simple and complex models, and upon the presence of cholesterol.

Keywords: Lipid phase behavior, Phase transition, Phase coexistence, Nanomechanics, Thermodynamics, Atomic force microscopy (AFM), Quartz crystal microbalance with dissipation monitoring (QCM-D)


Bos, J. J., Vinck, M., Marchesi, P., Keestra, A., van Mourik-Donga, L. A., Jackson, J. C., Verschure, P., Pennartz, C. M. A., (2019). Multiplexing of self and other information in hippocampal ensembles Cell Reports 29, (12), 3859-3871.e6

In addition to coding a subject’s location in space, the hippocampus has been suggested to code social information, including the spatial position of conspecifics. “Social place cells” have been reported for tasks in which an observer mimics the behavior of a demonstrator. We examine whether rat hippocampal neurons may encode the behavior of a minirobot, but without requiring the animal to mimic it. Rather than finding social place cells, we observe that robot behavioral patterns modulate place fields coding animal position. This modulation may be confounded by correlations between robot movement and changes in the animal’s position. Although rat position indeed significantly predicts robot behavior, we find that hippocampal ensembles code additional information about robot movement patterns. Fast-spiking interneurons are particularly informative about robot position and global behavior. In conclusion, when the animal’s own behavior is conditional on external agents, the hippocampus multiplexes information about self and others.

Keywords: CA1, Decoding, Information theory, Interneuron, Mutual information, Place cells, Place field, Tobot, Docial behavior, Tetrode


Blithikioti, C., Miquel, L., Batalla, A., Rubio, B., Maffei, G., Herreros, I., Gual, A., Verschure, P., Balcells-Oliveró, M., (2019). Cerebellar alterations in cannabis users: A systematic review Addiction Biology 24, (6), 1121-1137

Cannabis is the most used illicit substance in the world. As many countries are moving towards decriminalization, it is crucial to determine whether and how cannabis use affects human brain and behavior. The role of the cerebellum in cognition, emotion, learning, and addiction is increasingly recognized. Because of its high density in CB1 receptors, it is expected to be highly affected by cannabis use. The aim of this systematic review is to investigate how cannabis use affects cerebellar structure and function, as well as cerebellar-dependent behavioral tasks. Three databases were searched for peer-reviewed literature published until March 2018. We included studies that focused on cannabis effects on cerebellar structure, function, or cerebellar-dependent behavioral tasks. A total of 348 unique records were screened, and 40 studies were included in the qualitative synthesis. The most consistent findings include (1) increases in cerebellar gray matter volume after chronic cannabis use, (2) alteration of cerebellar resting state activity after acute or chronic use, and (3) deficits in memory, decision making, and associative learning. Age of onset and higher exposure to cannabis use were frequently associated with increased cannabis-induced alterations. Chronic cannabis use is associated with alterations in cerebellar structure and function, as well as with deficits in behavioral paradigms that involve the cerebellum (eg, eyeblink conditioning, memory, and decision making). Future studies should consider tobacco as confounding factor and use standardized methods for assessing cannabis use. Paradigms exploring the functional activity of the cerebellum may prove useful as monitoring tools of cannabis-induced impairment.

Keywords: Behavior, Cannabis use, Cerebellum, Cognitive function, Structure


Grechuta, Klaudia, Ulysse, Laura, Rubio Ballester, Belén, Verschure, Paul, (2019). Self beyond the body: Action-driven and task-relevant purely distal cues modulate performance and body ownership Frontiers in Human Neuroscience 13, Article 91

Our understanding of body ownership largely relies on the so-called Rubber Hand Illusion (RHI). In this paradigm, synchronous stroking of the real and the rubber hands leads to an illusion of ownership of the rubber hand provided that it is physically, anatomically, and spatially plausible. Self-attribution of an artificial hand also occurs during visuomotor synchrony. In particular, participants experience ownership over a virtual or a rubber hand when the visual feedback of self-initiated movements follows the trajectory of the instantiated motor commands, such as in the Virtual Hand Illusion (VHI) or the moving Rubber Hand Illusion (mRHI). Evidence yields that both when the cues are triggered externally (RHI) and when they result from voluntary actions (VHI and mRHI), the experience of ownership is established through bottom-up integration and top-down prediction of proximodistal cues (visuotactile or visuomotor) within the peripersonal space. It seems, however, that depending on whether the sensory signals are externally (RHI) or self-generated (VHI and mRHI), the top-down expectation signals are qualitatively different. On the one hand, in the RHI the sensory correlations are modulated by top-down influences which constitute empirically induced priors related to the internal (generative) model of the body. On the other hand, in the VHI and mRHI body ownership is actively shaped by processes which allow for continuous comparison between the expected and the actual sensory consequences of the actions. Ample research demonstrates that the differential processing of the predicted and the reafferent information is addressed by the central nervous system via an internal (forward) model or corollary discharge. Indeed, results from the VHI and mRHI suggest that, in action-contexts, the mechanism underlying body ownership could be similar to the forward model. Crucially, forward models integrate across all self-generated sensory signals including not only proximodistal (i.e., visuotactile or visuomotor) but also purely distal sensory cues (i.e., visuoauditory). Thus, if body ownership results from a consistency of a forward model, it will be affected by the (in)congruency of purely distal cues provided that they inform about action-consequences and are relevant to a goal-oriented task. Specifically, they constitute a corrective error signal. Here, we explicitly addressed this question. To test our hypothesis, we devised an embodied virtual reality-based motor task where action outcomes were signaled by distinct auditory cues. By manipulating the cues with respect to their spatial, temporal and semantic congruency, we show that purely distal (visuoauditory) feedback which violates predictions about action outcomes compromises both performance and body ownership. These results demonstrate, for the first time, that body ownership is influenced by not only externally and self-generated cues which pertain to the body within the peripersonal space but also those arising outside of the body. Hence, during goal-oriented tasks body ownership may result from the consistency of forward models.

Keywords: Body ownership, Internal forward model, Goal-oriented behavior, Multisensory integration, Top-down prediction


Gugutkov, D., Gustavsson, J., Cantini, M., Salmeron-Sánchez, M., Altankov, G., (2017). Electrospun fibrinogen-PLA nanofibres for vascular tissue engineering Journal of Tissue Engineering and Regenerative Medicine 11, (10), 2774-2784

Here we report on the development of a new type of hybrid fibrinogen-polylactic acid (FBG-PLA) nanofibres (NFs) with improved stiffness, combining the good mechanical properties of PLA with the excellent cell recognition properties of native FBG. We were particularly interested in the dorsal and ventral cell response to the nanofibres' organization (random or aligned), using human umbilical endothelial cells (HUVECs) as a model system. Upon ventral contact with random NFs, the cells developed a stellate-like morphology with multiple projections. The well-developed focal adhesion complexes suggested a successful cellular interaction. However, time-lapse analysis shows significantly lowered cell movements, resulting in the cells traversing a relatively short distance in multiple directions. Conversely, an elongated cell shape and significantly increased cell mobility were observed in aligned NFs. To follow the dorsal cell response, artificial wounds were created on confluent cell layers previously grown on glass slides and covered with either random or aligned NFs. Time-lapse analysis showed significantly faster wound coverage (within 12 h) of HUVECs on aligned samples vs. almost absent directional migration on random ones. However, nitric oxide (NO) release shows that endothelial cells possess lowered functionality on aligned NFs compared to random ones, where significantly higher NO production was found. Collectively, our studies show that randomly organized NFs could support the endothelization of implants while aligned NFs would rather direct cell locomotion for guided neovascularization.

Keywords: Electrospun nanofibers, Endothelial cells, Fibrinogen, Guided cellular behavior, Polylactic acid, Vascular tissue engineering


Pacheco, D., Sánchez-Fibla, M., Duff, A., Verschure, P. F. M. J., (2017). A spatial-context effect in recognition memory Frontiers in Behavioral Neuroscience 11, Article 143

We designed a novel experiment to investigate the modulation of human recognition memory by environmental context. Human participants were asked to navigate through a four-arm Virtual Reality (VR) maze in order to find and memorize discrete items presented at specific locations in the environment. They were later on tested on their ability to recognize items as previously presented or new. By manipulating the spatial position of half of the studied items during the testing phase of our experiment, we could assess differences in performance related to the congruency of environmental information at encoding and retrieval. Our results revealed that spatial context had a significant effect on the quality of memory. In particular, we found that recognition performance was significantly better in trials in which contextual information was congruent as opposed to those in which it was different. Our results are in line with previous studies that have reported spatial-context effects in recognition memory, further characterizing their magnitude under ecologically valid experimental conditions.

Keywords: Context effects, Recognition memory, Spatial behavior, Spatial memory and navigation, Virtual reality


Tomas-Roig, J., Piscitelli, F., Gil, V., del Río, J. A., Moore, T. P., Agbemenyah, H., Salinas-Riester, G., Pommerenke, C., Lorenzen, S., Beißbarth, T., Hoyer-Fender, S., Di Marzo, V., Havemann-Reinecke, U., (2016). Social defeat leads to changes in the endocannabinoid system: An overexpression of calreticulin and motor impairment in mice Behavioural Brain Research , 303, 34-43

Prolonged and sustained stimulation of the hypothalamo-pituitary-adrenal axis have adverse effects on numerous brain regions, including the cerebellum. Motor coordination and motor learning are essential for animal and require the regulation of cerebellar neurons. The G-protein-coupled cannabinoid CB1 receptor coordinates synaptic transmission throughout the CNS and is of highest abundance in the cerebellum. Accordingly, the aim of this study was to investigate the long-lasting effects of chronic psychosocial stress on motor coordination and motor learning, CB1 receptor expression, endogenous cannabinoid ligands and gene expression in the cerebellum. After chronic psychosocial stress, motor coordination and motor learning were impaired as indicated the righting reflex and the rota-rod. The amount of the endocannabinoid 2-AG increased while CB1 mRNA and protein expression were downregulated after chronic stress. Transcriptome analysis revealed 319 genes differentially expressed by chronic psychosocial stress in the cerebellum; mainly involved in synaptic transmission, transmission of nerve impulse, and cell-cell signaling. Calreticulin was validated as a stress candidate gene. The present study provides evidence that chronic stress activates calreticulin and might be one of the pathological mechanisms underlying the motor coordination and motor learning dysfunctions seen in social defeat mice.

Keywords: Psychosocial stress, Cerebellum, Calreticulin, Endocannabinoid system, Behavior, RNA seq.


Eckelt, Kay, Masanas, Helena, Llobet, Artur, Gorostiza, P., (2014). Automated high-throughput measurement of body movements and cardiac activity of Xenopus tropicalis tadpoles Journal of Biological Methods , 1, (2), e9

Xenopus tadpoles are an emerging model for developmental, genetic and behavioral studies. A small size, optical accessibility of most of their organs, together with a close genetic and structural relationship to humans make them a convenient experimental model. However, there is only a limited toolset available to measure behavior and organ function of these animals at medium or high-throughput. Herein, we describe an imaging-based platform to quantify body and autonomic movements of Xenopus tropicalis tadpoles of advanced developmental stages. Animals alternate periods of quiescence and locomotor movements and display buccal pumping for oxygen uptake from water and rhythmic cardiac movements. We imaged up to 24 animals in parallel and automatically tracked and quantified their movements by using image analysis software. Animal trajectories, moved distances, activity time, buccal pumping rates and heart beat rates were calculated and used to characterize the effects of test compounds. We evaluated the effects of propranolol and atropine, observing a dose-dependent bradycardia and tachycardia, respectively. This imaging and analysis platform is a simple, cost-effective high-throughput in vivo assay system for genetic, toxicological or pharmacological characterizations.

Keywords: Xenopus tropicalis, Animal behavior, Cardiac imaging, Motion analysis, Animal tracking, Hhigh-throughput in vivo assay


Vedula, Sri Ram Krishna, Ravasio, Andrea, Anon, Ester, Chen, Tianchi, Peyret, G., Ashraf, Mohammed, Ladoux, Benoit, (2014). Microfabricated environments to study collective cell behaviors Methods in Cell Biology (ed. Piel, M., Théry, M.), Academic Press 120, 235-252

Abstract Coordinated cell movements in epithelial layers are essential for proper tissue morphogenesis and homeostasis. Microfabrication techniques have proven to be very useful for studies of collective cell migration in vitro. In this chapter, we briefly review the use of microfabricated substrates in providing new insights into collective cell behaviors. We first describe the development of micropatterned substrates to study the influence of geometrical constraints on cell migration and coordinated movements. Then, we present an alternative method based on microfabricated pillar substrates to create well-defined gaps within cell sheets and study gap closure. We also provide a discussion that presents possible pitfalls and sheds light onto the important parameters that allow the study of long-term cell culture on substrates of well-defined geometries.

Keywords: Microfabricated substrates, Microcontact printing, Collective cell behavior, Geometrical constraints, Epithelial gap closure


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


Hernansanz, A., Amat, J., Casals, A., (2012). Virtual Robot: A new teleoperation paradigm for minimally invasive robotic surgery IEEE Conference Publications 4th IEEE RAS & EMBS International Conference on Biomedical Robotics and Biomechatronics (BioRob) , IEEE (Roma, Italy) , 749-754

This paper presents a novel teleoperation paradigm, the Virtual Robot (VR), focused on facilitating the surgeon tasks in minimally invasive robotic surgery. The VR has been conceived to increase the range of applicability of traditional master slave teleoperation architectures by means of an automatic cooperative behavior that assigns the execution of the ongoing task to the most suitable robot. From the user's point of view, the VR internal operation must be automatic and transparent. A set of evaluation indexes have been developed to obtain the suitability of each robot as well as an algorithm to determine the optimal instant of time to execute a task transfer. Several experiments demonstrate the usefulness of the VR, as well as indicates the next steps of the research.

Keywords: Cameras, Collision avoidance, Indexes, Joints, Robots, Surgery, Trajectory, Medical robotics, Surgery, Telerobotics, VR internal operation, Automatic cooperative behavior, Evaluation indexes, Master slave teleoperation architectures, Minimally invasive robotic surgery, Task transfer, Virtual robot


Gugutkov, Dencho, Gonzalez-Garcia, Cristina, Altankov, George, Salmeron-Sanchez, Manuel, (2011). Fibrinogen organization at the cell-material interface directs endothelial cell behavior Journal of Bioactive and Compatible Polymers , 26, (4), 375-387

Fibrinogen (FG) adsorption on surfaces with controlled fraction of -OH groups was investigated with AFM and correlated to the initial interaction of primary endothelial cells (HUVEC). The -OH content was tailored making use of a family of copolymers consisting of ethyl acrylate (EA) and hydroxyl ethyl acrylate (HEA) in different ratios. The supramolecular distribution of FG changed from an organized network-like structure on the most hydrophobic surface (-OH(0)) to dispersed molecular aggregate one as the fraction of -OH groups increases, indicating a different conformation by the adsorbed protein. The best cellular interaction was observed on the most hydrophobic (-OH(0)) surface where FG assembled in a fibrin-like appearance in the absence of any thrombin. Likewise, focal adhesion formation and actin cytoskeleton development was poorer as the fraction of hydroxy groups on the surface was increased. The biological activity of the surface-induced FG network to provide 3D cues in a potential tissue engineered scaffold, making use of electrospun PEA fibers (-OH(0)), seeded with human umbilical vein endothelial cells was investigated. The FG assembled on the polymer fibers gave rise to a biologically active network able to direct cell orientation along the fibers (random or aligned), promote cytoskeleton organization and focal adhesion formation.

Keywords: Fibrinogen, Cell-material interactions, HUVEC, Electrospun fibers, Fibrinogen organization, Cell-material interface, Endothelial cell behavior, Ethyl acrylate, Hydroxyl ethyl acrylate


Comelles, J., Estevez, M., Martinez, E., Samitier, J., (2010). The role of surface energy of technical polymers in serum protein adsorption and MG-63 cells adhesion Nanomedicine: Nanotechnology Biology and Medicine , 6, (1), 44-51

Polymeric materials are widely used as supports for cell culturing in medical implants and as scaffolds for tissue regeneration. However, novel applications in the biosensor field require materials to be compatible with cell growth and at the same time be suitable for technological processing. Technological polymers are key materials in the fabrication of disposable parts and other sensing elements. As such, it is essential to characterize the surface properties of technological polymers, especially after processing and sterilization. It is also important to understand how technological polymers affect cell behavior when in contact with polymer materials. Therefore, the aim of this research was to study how surface energy and surface roughness affect the biocompatibility of three polymeric materials widely used in research and industry: poly (methyl methacrylate), polystyrene, and poly(dimethylsiloxane). Glass was used as the control material. From the Clinical Editor: Polymeric materials are widely used as supports for cell culturing in medical implants and as scaffolds for tissue regeneration. The aim of this research is to study how surface energy and surface roughness affect the biocompatibility of three polymeric materials widely used in research and industry: poly(methylmethacrylate) (PMMA), polystyrene (PS), and poly(dimethylsiloxane) (PDMS).

Keywords: Thin-films, Poly(methyl methacrylate), Osteoblast adhesion, Electron-microscopy, Fibronectin, Polystyrene, Oly(dimethylsiloxane), Biocompatibility, Hydroxyapatite, Behavior


Iranzo, A., Isetta, V., Molinuevo, J. L., Serradell, M., Navajas, D., Farre, R., Santamaria, J., (2010). Electroencephalographic slowing heralds mild cognitive impairment in idiopathic REM sleep behavior disorder Sleep Medicine , 11, (6), 534-539

Objective: Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) may show electroencephalographic (EEG) slowing reflecting cortical dysfunction and are at risk for developing neurological conditions characterized by cognitive dysfunction including mild cognitive impairment (MCI), dementia with Lewy bodies and Parkinson's disease with associated dementia. We hypothesized that those IRBD patients who later developed MCI had pronounced cortical EEG slowing at presentation. Methods: Power EEG spectral analysis was blindly quantified from the polysomnographic studies of 23 IRBD patients without cognitive complaints and 10 healthy controls without RBD. After a mean clinical follow-up of 2.40 +/- 1.55 years, 10 patients developed MCI (RBD + MCI) and the remaining 13 remained idiopathic. Results: Patients with RBD + MCI had marked EEG slowing (increased delta and theta activity) in central and occipital regions during wakefulness and REM sleep, particularly in the right hemisphere, when compared with controls and, to a lesser extent, with IRBD subjects who remained idiopathic. The EEG spectral pattern of the RBD + MCI group was similar to that seen in patients with dementia with Lewy bodies and Parkinson's disease associated with dementia. Conclusion: Our findings suggest that the presence of marked EEG slowing on spectral analysis might be indicative of the short-term development of MCI in patients initially diagnosed with IRBD.

Keywords: Idiopathic REM sleep behavior disorder, Power EEG spectral analysis, Mild cognitive impairment, REM sleep, Parkinson's disease, Dementia with Lewy bodies


Rajzer, I., Castano, O., Engel, E., Planell, J. A., (2010). Injectable and fast resorbable calcium phosphate cement for body-setting bone grafts Journal of Materials Science-Materials in Medicine , 21, (7), 2049-2056

In this work a calcium phosphate (CPC)/polymer blend was developed with the advantage of being moldable and capable of in situ setting to form calcium deficient hydroxyapatite under physiological conditions in an aqueous environment at body temperature. The CPC paste consists in a mix of R cement, glycerol as a liquid phase carrier and a biodegradable hydrogel such as Polyvinyl alcohol, which acts as a binder. Microstructure and mechanical analysis shows that the CPC blend can be used as an injectable implant for low loaded applications and fast adsorption requirements. The storage for commercial distribution was also evaluated and the properties of the materials obtained do not significantly change during storage at -18A degrees C.

Keywords: Clinical-applications, Composites, Regeneration, Behavior, Scaffold, Repair


Montufar, E. B., Traykova, T., Schacht, E., Ambrosio, L., Santin, M., Planell, J. A., Ginebra, M. P., (2009). Self-hardening calcium deficient hydroxyapatite/gelatine foams for bone regeneration Journal of Materials Science-Materials in Medicine 22nd European Conference on Biomaterials , Springer Netherlands (Lausanne, Switzerland) 21, (3), 863-869

In this work gelatine was used as multifunctional additive to obtain injectable self-setting hydroxyapatite/gelatine composite foams for bone regeneration. The foaming and colloidal stabilization properties of gelatine are well known in food and pharmaceutical applications. Solid foams were obtained by foaming liquid gelatine solutions at 50A degrees C, followed by mixing them with a cement powder consisting of alpha tricalcium phosphate. Gelatine addition improved the cohesion and injectability of the cement paste. After setting the foamed paste transformed into a calcium deficient hydroxyapatite. The final porosity, pore interconnectivity and pore size were modulated by modifying the gelatine content in the liquid phase.

Keywords: Phosphate cement, Gelatin, Behavior


Oncins, G., Torrent-Burgues, J., Sanz, F., (2008). Nanomechanical properties of arachidic acid Langmuir-Blodgett films Journal of Physical Chemistry C 112, (6), 1967-1974

The nanomechanical properties of Langmuir-Blodgett monolayers of arachidic acid extracted at surface pressures of 1, 15, and 35 mN/m and deposited on mica were investigated by atomic force microscopy, force spectroscopy, and lateral force microscopy. It was experimentally demonstrated that the arachidic acid molecular orientation depends on the extraction pressure. According to this, tilting angles of 50, 34, and 22 degrees with respect to the surface perpendicular were detected and identified as conformations that maximize van der Waals interactions between the arachidic acid alkyl chains. The vertical force needed to puncture the monolayers with the AFM tip strongly depends on the molecular tilting angles attained at different monolayer extraction surface pressures, obtaining values that range from 13.07 +/- 3.24 nN for 50 degrees to 22.94 +/- 5.49 nN for 22 degrees tilting angles. The different molecular interactions involved in the monolayer cohesion are discussed and quantitatively related to the experimental monolayer breakthrough forces. The friction measurements performed from low vertical forces up to monolayer disruption reveal the existence of three well-defined regimes: first, a low friction response due to the elastic deformation of the monolayer, which is followed by a sharp increase in the friction force due to the onset of a sudden plastic deformation. The last regime corresponds to the monolayer rupture and the contact between tip and substrate. The friction coefficient of the substrate is seen to depend on the monolayer extraction pressure, a fact that is discussed in terms of the relationship between the sample compactness and its rupture mechanism.

Keywords: AFM, SAM, Reflection-absortion spectroscopy, Lipid-bilayers, Frictional-properies, Molecular-structure, Thermal behavior, Nanometer-scale, Chain-length, LB films