Institute for Bioengineering of Catalonia

Barcelona, Spain

Institute for Bioengineering of Catalonia

Barcelona, Spain

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An enzyme-propelled nanorobot: urease-coated nanotubes turn into a propulsion system in a urea-containing liquid because the enzyme breaks down the urea into gaseous products. Since the tubes always have small asymmetries, the reaction products generate a current in the fluid which propels them out of the tube like a jet. Credit: MPI for Intelligent Systems Nanorobots and other mini-vehicles might be able to perform important services in medicine one day – for example, by conducting remotely-controlled operations or transporting pharmaceutical agents to a desired location in the body. However, to date it has been hard to steer such micro- and nanoswimmers accurately through biological fluids such as blood, synovial fluid or the inside of the eyeball. Researchers at the Max Planck Institute for Intelligent Systems in Stuttgart are now presenting two new approaches for constructing propulsion systems for tiny floating bodies. In the case of one motor, the propulsion is generated by bubbles which are caused to oscillate by ultrasound. With the other, a current caused by the product of an enzymatic reaction propels a nanoswimmer. Jet aircraft have led the way. They burn fuel, eject the combustion products in one direction and as a result move in the opposite direction. Researchers at the Max Planck Institute for Intelligent Systems in Stuttgart do it in a very similar way - albeit on a much smaller scale. Their underwater-nanorobot is a single-walled nanotube made of silicon dioxide, a mere 220 nanometres (billionths of a metre) in diameter. A particle of that nature would not normally be able to propel itself in fluids. The scientists therefore coated either only the inner or the inner as well as the outer surface or of the nanotube with the enzyme urease which breaks down urea into ammonia and carbon dioxide. If a nanotube prepared in this way is introduced into a fluid containing urea, this urea is broken down at the urease-coated internal wall. The reaction products generate a current in the fluid which propels them out of the tube like a jet. As such a nanoswimmer either is thinner at one end than at the other or the the urea is not distributed homogeniously over its surface, this results in a thrust, so that the micro-swimmer experiences propulsion in the opposite direction – as in a jet aeroplane. The nanojets reached speeds of 10 micrometres per second, i.e. almost four centimetres per hour. The smallest jet engine in the world Admittedly, coating a nanorobot to achieve a chemical drive is by no means new. However, the tube now presented, with its 220 nanometre opening, represents the smallest jet propulsion system so far constructed in the world. "Our previous record, which is still in the Guinness Book of Records, was around three-times bigger", explains Samual Sanchez who leads the Smart NanoBioDevices Group at the Max Planck Institute for Intelligent Systems in Stuttgart and at the same time holds a professorship at the Institute for Bioengineering of Catalonia in Barcelona. And there is another new aspect of the nanojet which scientists from the Harbin Institute of Technology in Shenzhen in China also helped to develop: for the first time, all the materials and reaction partners used are fully biocompatible. "Previous chemical drives of this kind were usually based on a metallic catalyst at the surface of which hydrogen peroxide was broken down into hydrogen and oxygen molecules", says Sanchez. Oxygen bubbles are created in the process, which creates a thrust in the opposite direction. Both the hydrogen peroxide and the gas bubbles would have disadvantages if used in the human body. But this is not the case with the urease-coated version with its water-soluble – and therefore bubble-free – reaction products. "Urease occurs anyway in the human organism", Sanchez explains. The researchers now want to test the biocompatibility more precisely – and in the process examine whether they can succeed in implanting such micro-tubes into individual cells. "That would be necessary, of course, in order to bring drug molecules to their destination, for example", says Sanchez. While gas bubbles were still unwanted in the approach specified, they form the very centrepiece of a entirely new principle of propulsion for minirobos, which colleagues at the Institute in the Micro, Nano and Molecular Systems Group led by Peer Fischer propose. However, here the gas bubbles are not bubbling freely through the fluid and therefore cannot damage the organism. Rather, the researchers enclose the micro-bubbles in small cylindrical chambers along a plastic strip. To provide the drive, therefore, the gas bubbles expand and contract cyclically because ultrasound causes them to oscillate. As the pulsating bubbles are in chambers open on one side, they only expand through this opening. In the process, they exert a force on the opposite wall of the chamber which propels the plastic strip. In order to achieve propulsion worth mentioning, the researchers arranged several chambers with air bubbles in parallel on their polymer strip. A notable aspect: the sound wave frequency required to cause them to oscillate depends on the size of the tiny bubbles. The bigger the bubbles, the smaller the corresponding resonant frequency. The researchers used this connection to cause their swimmer to rotate alternately clockwise and anti-clockwise. To do so, they placed bubbles of different sizes on the two halves of the four, long cuboid faces divided lengthwise. Two different sound frequencies were then used in a liquid to each cause all the bubbles of one size to oscillate. In this way, the scientists generated thrusts exclusively on one-half of the cuboid face which caused it to rotate on its own axis. This small acoustically driven rotation motor with longitudinal areas each five square millimetres in size achieved up to a thousand rotations per minute in the process. "The variation in the size of the bubbles thereby enables a mini-swimmer to deliberately steer in different directions", says Tian Qiu, who also conducts research at the Max Planck Institute in Stuttgart and played an appreciable role in the study. According to Qiu, a further benefit of the new principle of propulsion is that even swimmers with a complicated geometric structure can be coated with the wafer-thin strips together with chambers for the bubbles. He goes on to explain that the use of ultrasound is also suited to optically impenetrable media such as blood. Light waves, which are also a potential control instrument for micro-drives, can achieve nothing in this case. The researchers now want to use tests in real biological media to check whether the new drive principle is also able to make the most of its advantages in practice. More information: Xing Ma et al. Bubble-Free Propulsion of Ultrasmall Tubular Nanojets Powered by Biocatalytic Reactions, Journal of the American Chemical Society (2016). DOI: 10.1021/jacs.6b06857


Marco S.,Institute for Bioengineering of Catalonia | Marco S.,University of Barcelona
Analytical and Bioanalytical Chemistry | Year: 2014

Over the last two decades, electronic nose research has produced thousands of research works. Many of them were describing the ability of the e-nose technology to solve diverse applications in domains ranging from food technology to safety, security, or health. It is, in fact, in the biomedical field where e-nose technology is finding a research niche in the last years. Although few success stories exist, most described applications never found the road to industrial or clinical exploitation. Most described methodologies were not reliable and were plagued by numerous problems that prevented practical application beyond the lab. This work emphasizes the need of external validation in machine olfaction. I describe some statistical and methodological pitfalls of the e-nose practice and I give some best practice recommendations for researchers in the field. [Figure not available: see fulltext.] © 2014 Springer-Verlag Berlin Heidelberg.


Roca-Cusachs P.,Institute for Bioengineering of Catalonia | Roca-Cusachs P.,University of Barcelona | Sunyer R.,Institute for Bioengineering of Catalonia | Trepat X.,Institute for Bioengineering of Catalonia | And 2 more authors.
Current Opinion in Cell Biology | Year: 2013

For an organism to develop, for a wound to heal, or for a tumor to invade, cells must be able to migrate following directional cues. It is widely accepted that directed cell migration is enabled by cellular sensing of local gradients in the concentration of chemical factors. The main molecular players involved in this mode of cellular guidance-chemotaxis-have been identified and the combination of modeling and experimental approaches is progressively unveiling a clear picture of the underlying mechanisms. Evidence obtained over the past decade has shown that cells can also be guided by mechanical stimuli such as physical forces or gradients in extracellular matrix stiffness. Mechanical guidance, which we refer here globally as mechanotaxis, is also thought to drive processes in development, cancer, and wound healing, but experimental evidence is scattered and mechanisms remain largely unknown. Here we use the better understood process of chemotaxis as a reference to define the building blocks that are required for cell guidance, and then discuss how these building blocks might be organized in mechanotaxis. We show that both chemotaxis and mechanotaxis involve an exquisite interplay between physical and chemical mechanisms to sense gradients, establish polarization, and drive directed migration. © 2013 Elsevier Ltd.


Trepat X.,Institute for Bioengineering of Catalonia
Comprehensive Physiology | Year: 2012

Cell migration is fundamental to establishing and maintaining the proper organization of multicellular organisms. Morphogenesis can be viewed as a consequence, in part, of cell locomotion, from large-scale migrations of epithelial sheets during gastrulation, to the movement of individual cells during development of the nervous system. In an adult organism, cell migration is essential for proper immune response, wound repair, and tissue homeostasis, while aberrant cell migration is found in various pathologies. Indeed, as our knowledge of migration increases, we can look forward to, for example, abating the spread of highly malignant cancer cells, retarding the invasion of white cells in the inflammatory process, or enhancing the healing of wounds. This article is organized in two main sections. The first section is devoted to the single-cell migrating in isolation such as occurs when leukocytes migrate during the immune response or when fibroblasts squeeze through connective tissue. The second section is devoted to cells collectively migrating as part of multicellular clusters or sheets. This second type of migration is prevalent in development, wound healing, and in some forms of cancer metastasis. © 2012 American Physiological Society


Malandrino A.,Institute for Bioengineering of Catalonia | Noailly J.,Institute for Bioengineering of Catalonia | Lacroix D.,Institute for Bioengineering of Catalonia
PLoS Computational Biology | Year: 2011

Intervertebral disc metabolic transport is essential to the functional spine and provides the cells with the nutrients necessary to tissue maintenance. Disc degenerative changes alter the tissue mechanics, but interactions between mechanical loading and disc transport are still an open issue. A poromechanical finite element model of the human disc was coupled with oxygen and lactate transport models. Deformations and fluid flow were linked to transport predictions by including strain-dependent diffusion and advection. The two solute transport models were also coupled to account for cell metabolism. With this approach, the relevance of metabolic and mechano-transport couplings were assessed in the healthy disc under loading-recovery daily compression. Disc height, cell density and material degenerative changes were parametrically simulated to study their influence on the calculated solute concentrations. The effects of load frequency and amplitude were also studied in the healthy disc by considering short periods of cyclic compression. Results indicate that external loads influence the oxygen and lactate regional distributions within the disc when large volume changes modify diffusion distances and diffusivities, especially when healthy disc properties are simulated. Advection was negligible under both sustained and cyclic compression. Simulating degeneration, mechanical changes inhibited the mechanical effect on transport while disc height, fluid content, nucleus pressure and overall cell density reductions affected significantly transport predictions. For the healthy disc, nutrient concentration patterns depended mostly on the time of sustained compression and recovery. The relevant effect of cell density on the metabolic transport indicates the disturbance of cell number as a possible onset for disc degeneration via alteration of the metabolic balance. Results also suggest that healthy disc properties have a positive effect of loading on metabolic transport. Such relation, relevant to the maintenance of the tissue functional composition, would therefore link disc function with disc nutrition. © 2011 Malandrino et al.


Conte V.,Institute for Bioengineering of Catalonia
PloS one | Year: 2012

The article provides a biomechanical analysis of ventral furrow formation in the Drosophila melanogaster embryo. Ventral furrow formation is the first large-scale morphogenetic movement in the fly embryo. It involves deformation of a uniform cellular monolayer formed following cellularisation, and has therefore long been used as a simple system in which to explore the role of mechanics in force generation. Here we use a quantitative framework to carry out a systematic perturbation analysis to determine the role of each of the active forces observed. The analysis confirms that ventral furrow invagination arises from a combination of apical constriction and apical-basal shortening forces in the mesoderm, together with a combination of ectodermal forces. We show that the mesodermal forces are crucial for invagination: the loss of apical constriction leads to a loss of the furrow, while the mesodermal radial shortening forces are the primary cause of the internalisation of the future mesoderm as the furrow rises. Ectodermal forces play a minor but significant role in furrow formation: without ectodermal forces the furrow is slower to form, does not close properly and has an aberrant morphology. Nevertheless, despite changes in the active mesodermal and ectodermal forces lead to changes in the timing and extent of furrow, invagination is eventually achieved in most cases, implying that the system is robust to perturbation and therefore over-determined.


Brugues A.,Institute for Bioengineering of Catalonia
Nature Physics | Year: 2014

A fundamental feature of multicellular organisms is their ability to self-repair wounds through the movement of epithelial cells into the damaged area. This collective cellular movement is commonly attributed to a combination of cell crawling and 'purse-string' contraction of a supracellular actomyosin ring. Here we show by direct experimental measurement that these two mechanisms are insufficient to explain force patterns observed during wound closure. At early stages of the process, leading actin protrusions generate traction forces that point away from the wound, showing that wound closure is initially driven by cell crawling. At later stages, we observed unanticipated patterns of traction forces pointing towards the wound. Such patterns have strong force components that are both radial and tangential to the wound. We show that these force components arise from tensions transmitted by a heterogeneous actomyosin ring to the underlying substrate through focal adhesions. The structural and mechanical organization reported here provides cells with a mechanism to close the wound by cooperatively compressing the underlying substrate.


Sandino C.,Institute for Bioengineering of Catalonia | Checa S.,Trinity College Dublin | Prendergast P.J.,Trinity College Dublin | Lacroix D.,Institute for Bioengineering of Catalonia
Biomaterials | Year: 2010

Mechanical stimuli are one of the factors that influence tissue differentiation. In the development of biomaterials for bone tissue engineering, mechanical stimuli and formation of a vascular network that transport oxygen to cells within the pores of the scaffolds are essential. Angiogenesis and cell differentiation have been simulated in scaffolds of regular porosity; however, the dynamics of differentiation can be different when the porosity is not uniform. The objective of this study was to investigate the effect of the mechanical stimuli and the capillary network formation on cell differentiation within a scaffold of irregular morphology. A porous scaffold of calcium phosphate based glass was used. The pores and the solid phase were discretized using micro computed tomography images. Cell activity was simulated within the interconnected pore domain of the scaffold using a lattice modeling approach. Compressive strains of 0.5 and 1% of total deformation were applied and two cases of mesenchymal stem cells initialization (in vitro seeding and in vivo) were simulated. Similar capillary networks were formed independently of the cell initialization mode and the magnitude of the mechanical strain applied. Most of vessels grew in the pores at the periphery of the scaffolds and were blocked by the walls of the scaffold. When 0.5% of strain was applied, 70% of the pore volume was affected by mechano-regulatory stimuli corresponding to bone formation; however, because of the lack of oxygen, only 40% of the volume was filled with osteoblasts. 40% of volume was filled with chondrocytes and 3% with fibroblasts. When the mechanical strain was increased to 1%, 11% of the pore volume was filled with osteoblasts, 59% with chondrocytes, and 8% with fibroblasts. This study has shown the dynamics of the correlation between mechanical load, angiogenesis and tissue differentiation within a scaffold with irregular morphology. © 2009 Elsevier Ltd. All rights reserved.


Byrne D.P.,Trinity College Dublin | Lacroix D.,Institute for Bioengineering of Catalonia | Prendergast P.J.,Trinity College Dublin
Journal of Orthopaedic Research | Year: 2011

In this study, a three-dimensional (3D) computational simulation of bone regeneration was performed in a human tibia under realistic muscle loading. The simulation was achieved using a discrete lattice modeling approach combined with a mechanoregulation algorithm to describe the cellular processes involved in the healing process-namely proliferation, migration, apoptosis, and differentiation of cells. The main phases of fracture healing were predicted by the simulation, including the bone resorption phase, and there was a qualitative agreement between the temporal changes in interfragmentary strain and bending stiffness by comparison to experimental data and clinical results. Bone healing was simulated beyond the reparative phase by modeling the transition of woven bone into lamellar bone. Because the simulation has been shown to work with realistic anatomical 3D geometry and muscle loading, it demonstrates the potential of simulation tools for patient-specific pre-operative treatment planning. © 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.


Sandino C.,Institute for Bioengineering of Catalonia | Lacroix D.,Institute for Bioengineering of Catalonia
Biomechanics and Modeling in Mechanobiology | Year: 2011

The control of the mechanical stimuli transmitted to the cells is critical for the design of functional scaffolds for tissue engineering. The objective of this study was to investigate the dynamics of the mechanical stimuli transmitted to the cells during tissue differentiation in an irregular morphology scaffold under compressive load and perfusion flow. A calcium phosphate-based glass porous scaffold was used. The solid phase and the fluid flow within the pores were modeled as linear elastic solid material and Newtonian fluid, respectively. In the fluid model, different levels of viscosity were used to simulate tissue differentiation. Compressive strain of 0.5% and fluid flowwith constant inlet velocity of 10μm/s or constant inlet pressure of 3Pawere applied. Octahedral shear strain and fluid shear stress were used as mechano-regulatory stimuli. For constant inlet velocity, stimuli equivalent to bone were predicted in 80% of pore volume for the case of low tissue viscosity. For the cases of high viscosity, fluctuations between stimuli equivalent to tissue formation and cell death were predicted due to the increase in the fluid shear stress when tissue started to fill pores.When constant pressure was applied, stimuli equivalent to bone were predicted in 62% of pore volume when low tissue viscosity was used and 42% when high tissue viscosity was used. This study predicted critical variations of fluid shear stress when cells differentiated. If these variations are not controlled in vitro, they can impede the formation of new matured tissue. © Springer-Verlag 2010.

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