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by Keyword: biomimetic

Oliver-Cervelló L, Martin-Gómez H, Mandakhbayar N, Jo YW, Cavalcanti-Adam EA, Kim HW, Ginebra MP, Lee JH, Mas-Moruno C, (2022). Mimicking Bone Extracellular Matrix: From BMP-2-Derived Sequences to Osteogenic-Multifunctional Coatings Advanced Healthcare Materials 11, 2201339

Cell-material interactions are regulated by mimicking bone extracellular matrix on the surface of biomaterials. In this regard, reproducing the extracellular conditions that promote integrin and growth factor (GF) signaling is a major goal to trigger bone regeneration. Thus, the use of synthetic osteogenic domains derived from bone morphogenetic protein 2 (BMP-2) is gaining increasing attention, as this strategy is devoid of the clinical risks associated with this molecule. In this work, the wrist and knuckle epitopes of BMP-2 are screened to identify peptides with potential osteogenic properties. The most active sequences (the DWIVA motif and its cyclic version) are combined with the cell adhesive RGD peptide (linear and cyclic variants), to produce tailor-made biomimetic peptides presenting the bioactive cues in a chemically and geometrically defined manner. Such multifunctional peptides are next used to functionalize titanium surfaces. Biological characterization with mesenchymal stem cells demonstrates the ability of the biointerfaces to synergistically enhance cell adhesion and osteogenic differentiation. Furthermore, in vivo studies in rat calvarial defects prove the capacity of the biomimetic coatings to improve new bone formation and reduce fibrous tissue thickness. These results highlight the potential of mimicking integrin-GF signaling with synthetic peptides, without the need for exogenous GFs.© 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.

JTD Keywords: adhesion formation, bmp-2, cell adhesions, in-vivo, integrin, mesenchymal stem-cells, morphogenetic protein-2, multifunctionality, osteoblastic differentiation, osteogenic differentiation, rgd-dwiva, rgd-peptides, titanium biofunctionalization, titanium surfaces, Biomimetic peptides, Cell adhesions, Marrow stromal cells, Multifunctionality, Osteogenic differentiation, Rgd-dwiva, Titanium biofunctionalization


Raymond, Y, Lehmann, C, Thorel, E, Benitez, R, Riveiro, A, Pou, J, Manzanares, MC, Franch, J, Canal, C, Ginebra, MP, (2022). 3D printing with star-shaped strands: A new approach to enhance in vivo bone regeneration Biomaterials Advances 137, 212807

Concave surfaces have shown to promote bone regeneration in vivo. However, bone scaffolds obtained by direct ink writing, one of the most promising approaches for the fabrication of personalized bone grafts, consist mostly of convex surfaces, since they are obtained by microextrusion of cylindrical strands. By modifying the geometry of the nozzle, it is possible to print 3D structures composed of non-cylindrical strands and favor the presence of concave surfaces. In this work, we compare the in vivo performance of 3D-printed calcium phosphate scaffolds with either conventional cylindrical strands or star-shaped strands, in a rabbit femoral condyle model. Mono cortical defects, drilled in contralateral positions, are randomly grafted with the two scaffold configurations, with identical composition. The samples are explanted eight weeks post-surgery and assessed by ??-CT and resin embedded histological observations. The results reveal that the scaffolds containing star-shaped strands have better osteoconductive properties, guiding the newly formed bone faster towards the core of the scaffolds, and enhance bone regeneration, although the increase is not statistically significant (p > 0.05). This new approach represents a turning point towards the optimization of pore shape in 3D-printed bone grafts, further boosting the possibilities that direct ink writing technology offers for patient-specific applications.

JTD Keywords: 3d printing, Architecture, Biomimetic calcium phosphate, Bone regeneration, Calcium-phosphate scaffolds, Geometry, Growth, Implants, In vivo, Induction, Microporosity, Osteoinduction, Pore architecture, Scaffold, Surfaces, Tissue


Tauber, F, Vouloutsi, V, Mura, A, Speck, T, (2022). Editorial: Living machines: from biological models to soft machines Bioinspiration & Biomimetics 17, 030201

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.

JTD 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


Konka J, Buxadera-Palomero J, Espanol M, Ginebra M-P, (2021). 3D printing of hierarchical porous biomimetic hydroxyapatite scaffolds: Adding concavities to the convex filaments Acta Biomaterialia 134, 744-759

Porosity plays a key role on the osteogenic performance of bone scaffolds. Direct Ink Writing (DIW) allows the design of customized synthetic bone grafts with patient-specific architecture and controlled macroporosity. Being an extrusion-based technique, the scaffolds obtained are formed by arrays of cylindrical filaments, and therefore have convex surfaces. This may represent a serious limitation, as the role of surface curvature and more specifically the stimulating role of concave surfaces in osteoinduction and bone growth has been recently highlighted. Hence the need to design strategies that allow the introduction of concave pores in DIW scaffolds. In the current study, we propose to add gelatin microspheres as a sacrificial material in a self-setting calcium phosphate ink. Neither the phase transformation responsible for the hardening of the scaffold nor the formation of characteristic network of needle-like hydroxyapatite crystals was affected by the addition of gelatin microspheres. The partial dissolution of the gelatin resulted in the creation of spherical pores throughout the filaments and exposed on the surface, increasing filament porosity from 0.2 % to 67.9 %. Moreover, the presence of retained gelatin proved to have a significant effect on the mechanical properties, reducing the strength but simultaneously giving the scaffolds an elastic behavior, despite the high content of ceramic as a continuous phase. Notwithstanding the inherent difficulty of in vitro cultures with this highly reactive material an enhancement of MG-63 cell proliferation, as well as better spreading of hMSCs was recorded on the developed scaffolds. Statement of significance: Recent studies have stressed the role that concave surfaces play in tissue regeneration and, more specifically, in osteoinduction and osteogenesis. Direct ink writing enables the production of patient-specific bone grafts with controlled architecture. However, besides many advantages, it has the serious limitation that the surfaces obtained are convex. In this article, for the first time we develop a strategy to introduce concave pores in the printed filaments of biomimetic hydroxyapatite by incorporation and partial dissolution of gelatin microspheres. The retention of part of the gelatin results in a more elastic behavior compared to the brittleness of hydroxyapatite scaffolds, while the needle-shaped nanostructure of biomimetic hydroxyapatite is maintained and gelatin-coated concave pores on the surface of the filaments enhance cell spreading. © 2021 The Authors

JTD Keywords: 3d printing, bioceramics, biomimetic, bone, bone regeneration, concavity, concavity, bone regeneration, gelatin, hydrogel, hydroxyapatite, microspheres, osteoinduction, porosity, porous filament, substitutes, tissue-growth, 3d printing, Biomimetic, Calcium-phosphate scaffolds, Concavity, bone regeneration, Gelatin, Hydroxyapatite, Porous filament


Konka, J, Espanol, M, Bosch, BM, de Oliveira, E, Ginebra, MP, (2021). Maturation of biomimetic hydroxyapatite in physiological fluids: a physicochemical and proteomic study Materials Today Bio 12,

Biomimetic calcium-deficient hydroxyapatite (CDHA) as a bioactive material exhibits exceptional intrinsic osteoinductive and osteogenic properties because of its nanostructure and composition, which promote a favorable microenvironment. Its high reactivity has been hypothesized to play a relevant role in the in vivo performance, mediated by the interaction with the biological fluids, which is amplified by its high specific surface area. Paradoxically, this high reactivity is also behind the in vitro cytotoxicity of this material, especially pro-nounced in static conditions. The present work explores the structural and physicochemical changes that CDHA undergoes in contact with physiological fluids and to investigate its interaction with proteins. Calcium-deficient hydroxyapatite discs with different micro/nanostructures, coarse (C) and fine (F), were exposed to cell-free complete culture medium over extended periods of time: 1, 7, 14, 21, 28, and 50 days. Precipitate formation was not observed in any of the materials in contact with the physiological fluid, which would indicate that the ionic exchanges were linked to incorporation into the crystal structure of CDHA or in the hydrated layer. In fact, CDHA experienced a maturation process, with a progressive increase in crystallinity and the Ca/P ratio, accompanied by an uptake of Mg and a B-type carbonation process, with a gradual propagation into the core of the samples. However, the reactivity of biomimetic hydroxyapatite was highly dependent on the specific surface area and was amplified in nanosized needle-like crystal structures (F), whereas in coarse specimens the ionic exchanges were restricted to the surface, with low penetration in the material bulk. In addition to showing a higher protein adsorption on F substrates, the proteomics study revealed the existence of protein selectivity to-ward F or C microstructures, as well as the capability of CDHA, and more remarkably of F-CDHA, to concentrate specific proteins from the culture medium. Finally, a substantial improvement in the material's ability to support cell proliferation was observed after the CDHA maturation process.

JTD Keywords: calcium phosphates, ion exchange, nanostructure, protein adsorption, Biological-systems, Biomaterials, Biomimetic hydroxyapatites, Biomimetics, Bone-formation, Calcium deficient hydroxyapatite, Calcium phosphate, Calcium phosphates, Cell proliferation, Crystal structure, Crystallinity, Crystals structures, Culture medium, Growth, High reactivity, Hydroxyapatite, In-vitro, Ion exchange, Ionic exchange, Molecular biology, Nanocrystalline apatites, Nanostructure, Nanostructures, Octacalcium phosphate, Physicochemical studies, Physiological fluids, Physiology, Protein adsorption, Proteins, Proteomic studies, Raman spectroscopy, Serum-albumin, Specific surface area


Guix M, Mestre R, Patiño T, de Corato M, Fuentes J, Zarpellon G, Sánchez S, (2021). Biohybrid soft robots with self-stimulating skeletons Science Robotics 6,

Bioinspired hybrid soft robots that combine living and synthetic components are an emerging field in the development of advanced actuators and other robotic platforms (i.e., swimmers, crawlers, and walkers). The integration of biological components offers unique characteristics that artificial materials cannot precisely replicate, such as adaptability and response to external stimuli. Here, we present a skeletal muscle–based swimming biobot with a three-dimensional (3D)–printed serpentine spring skeleton that provides mechanical integrity and self-stimulation during the cell maturation process. The restoring force inherent to the spring system allows a dynamic skeleton compliance upon spontaneous muscle contraction, leading to a cyclic mechanical stimulation process that improves the muscle force output without external stimuli. Optimization of the 3D-printed skeletons is carried out by studying the geometrical stiffnesses of different designs via finite element analysis. Upon electrical actuation of the muscle tissue, two types of motion mechanisms are experimentally observed: directional swimming when the biobot is at the liquid-air interface and coasting motion when it is near the bottom surface. The integrated compliant skeleton provides both the mechanical self-stimulation and the required asymmetry for directional motion, displaying its maximum velocity at 5 hertz (800 micrometers per second, 3 body lengths per second). This skeletal muscle–based biohybrid swimmer attains speeds comparable with those of cardiac-based biohybrid robots and outperforms other muscle-based swimmers. The integration of serpentine-like structures in hybrid robotic systems allows self-stimulation processes that could lead to higher force outputs in current and future biomimetic robotic platforms. Copyright © 2021 The Authors, some rights reserved;

JTD Keywords: actuators, design, fabrication, mechanics, mems, myotubes, platform, tissue, 3d printers, Agricultural robots, Biological components, Biomimetic processes, Electrical actuation, Geometrical stiffness, Intelligent robots, Liquefied gases, Liquid-air interface, Mechanical integrity, Mechanical stimulation, Muscle, Muscle contractions, Phase interfaces, Robotics, Serpentine, Springs (components), Threedimensional (3-d)


Oliver-Cervelló L, Martin-Gómez H, Reyes L, Noureddine F, Ada Cavalcanti-Adam E, Ginebra MP, Mas-Moruno C, (2021). An Engineered Biomimetic Peptide Regulates Cell Behavior by Synergistic Integrin and Growth Factor Signaling Advanced Healthcare Materials 10,

© 2020 Wiley-VCH GmbH Recreating the healing microenvironment is essential to regulate cell–material interactions and ensure the integration of biomaterials. To repair bone, such bioactivity can be achieved by mimicking its extracellular matrix (ECM) and by stimulating integrin and growth factor (GF) signaling. However, current approaches relying on the use of GFs, such as bone morphogenetic protein 2 (BMP-2), entail clinical risks. Here, a biomimetic peptide integrating the RGD cell adhesive sequence and the osteogenic DWIVA motif derived from the wrist epitope of BMP-2 is presented. The approach offers the advantage of having a spatial control over the single binding of integrins and BMP receptors. Such multifunctional platform is designed to incorporate 3,4-dihydroxyphenylalanine to bind metallic oxides with high affinity in a one step process. Functionalization of glass substrates with the engineered peptide is characterized by physicochemical methods, proving a successful surface modification. The biomimetic interfaces significantly improve the adhesion of C2C12 cells, inhibit myotube formation, and activate the BMP-dependent signaling via p38. These effects are not observed on surfaces displaying only one bioactive motif, a mixture of both motifs or soluble DWIVA. These data prove the biological potential of recreating the ECM and engaging in integrin and GF crosstalk via molecular-based mimics.

JTD Keywords: binding, biomaterials, biomimetic peptides, bone, cell adhesion, cell differentiation, differentiation, dwiva, multifunctional coatings, osseointegration, osteoblasts, rgd, surface, surface functionalization, Biomimetic peptides, Cell adhesion, Cell differentiation, Dwiva, Matrix-bound bmp-2, Rgd, Surface functionalization


Riccobelli, D., Noselli, G., Arroyo, M., DeSimone, A., (2020). Mechanics of axisymmetric sheets of interlocking and slidable rods Journal of the Mechanics and Physics of Solids 141, 103969

In this work, we study the mechanics of metamaterial sheets inspired by the pellicle of Euglenids. They are composed of interlocking elastic rods which can freely slide along their edges. We characterize the kinematics and the mechanics of these structures using the special Cosserat theory of rods and by assuming axisymmetric deformations of the tubular assembly. Through an asymptotic expansion, we investigate both structures that comprise a discrete number of rods and the limit case of a sheet composed by infinitely many rods. We apply our theoretical framework to investigate the stability of these structures in the presence of an axial load. Through a linear analysis, we compute the critical buckling force for both the discrete and the continuous case. For the latter, we also perform a numerical post-buckling analysis, studying the non-linear evolution of the bifurcation through finite elements simulations.

JTD Keywords: Biomimetic structures, Elastic structures, Helical rods, Mechanical instabilities, Metamaterials, Post-buckling analysis


De Corato, M., Pagonabarraga, I., Abdelmohsen, L. K. E. A., Sánchez, S., Arroyo, M., (2020). Spontaneous polarization and locomotion of an active particle with surface-mobile enzymes Physical Review Fluids 5, (12), 122001

We examine a mechanism of locomotion of active particles whose surface is uniformly coated with mobile enzymes. The enzymes catalyze a reaction that drives phoretic flows but their homogeneous distribution forbids locomotion by symmetry. We find that the ability of the enzymes to migrate over the surface combined with self-phoresis can lead to a spontaneous symmetry-breaking instability whereby the homogeneous distribution of enzymes polarizes and the particle propels. The instability is driven by the advection of enzymes by the phoretic flows and occurs above a critical Péclet number. The transition to polarized motile states occurs via a supercritical or subcritical pitchfork bifurcations, the latter of which enables hysteresis and coexistence of uniform and polarized states.

JTD Keywords: Biomimetic & bio-inspired materials, Locomotion, Surface-driven phase separation


Vouloutsi, Vasiliki, Mura, Anna, Tauber, F., Speck, T., Prescott, T. J., Verschure, P., (2020). Biomimetic and Biohybrid Systems 9th International Conference, Living Machines 2020, Freiburg, Germany, July 28–30, 2020, Proceedings , Springer, Cham (Lausanne, Switzerland) 12413, 1-428

This book constitutes the proceedings of the )th International Conference on Biomimetic and Biohybrid Systems, Living Machines 2020, held in Freiburg, Germany, in July 2020. Due to COVID-19 pandemic the conference was held virtually. The 32 full and 7 short papers presented in this volume were carefully reviewed and selected from 45 submissions. They deal with research on novel life-like technologies inspired by the scientific investigation of biological systems, biomimetics, and research that seeks to interface biological and artificial systems to create biohybrid systems.

JTD Keywords: Artificial intelligence, Soft robotics, Biomimetics, Insect navigation, Synthetic nervous system, Computer vision, Bio-inspired materials, Visual homing, Locomotion+, Image processing, Intelligent robots, Human-robot interaction, Machine learning, Snake robot, Mobile robots, Robotic systems, Drosophila, Robots, Sensors, Signal processing


Barba, A., Diez-Escudero, A., Espanol, M., Bonany, M., Sadowska, J. M., Guillem-Marti, J., Öhman-Mägi, C., Persson, C., Manzanares, M. C., Franch, J., Ginebra, M. P., (2019). Impact of biomimicry in the design of osteoinductive bone substitutes: Nanoscale matters ACS Applied Materials and Interfaces 11, (9), 8818-8830

Bone apatite consists of carbonated calcium-deficient hydroxyapatite (CDHA) nanocrystals. Biomimetic routes allow fabricating synthetic bone grafts that mimic biological apatite. In this work, we explored the role of two distinctive features of biomimetic apatites, namely, nanocrystal morphology (plate vs needle-like crystals) and carbonate content, on the bone regeneration potential of CDHA scaffolds in an in vivo canine model. Both ectopic bone formation and scaffold degradation were drastically affected by the nanocrystal morphology after intramuscular implantation. Fine-CDHA foams with needle-like nanocrystals, comparable in size to bone mineral, showed a markedly higher osteoinductive potential and a superior degradation than chemically identical coarse-CDHA foams with larger plate-shaped crystals. These findings correlated well with the superior bone-healing capacity showed by the fine-CDHA scaffolds when implanted intraosseously. Moreover, carbonate doping of CDHA, which resulted in small plate-shaped nanocrystals, accelerated both the intrinsic osteoinduction and the bone healing capacity, and significantly increased the cell-mediated resorption. These results suggest that tuning the chemical composition and the nanostructural features may allow the material to enter the physiological bone remodeling cycle, promoting a tight synchronization between scaffold degradation and bone formation.

JTD Keywords: Biomimetic, Calcium phosphate, Carbonated apatite, Foaming, Nanostructure, Osteogenesis, Osteoinduction


Kaurin, D., Arroyo, M., (2019). Surface tension controls the hydraulic fracture of adhesive interfaces bridged by molecular bonds Physical Review Letters 123, (22), 228102

Biological function requires cell-cell adhesions to tune their cohesiveness; for instance, during the opening of new fluid-filled cavities under hydraulic pressure. To understand the physical mechanisms supporting this adaptability, we develop a stochastic model for the hydraulic fracture of adhesive interfaces bridged by molecular bonds. We find that surface tension strongly enhances the stability of these interfaces by controlling flaw sensitivity, lifetime, and optimal architecture in terms of bond clustering. We also show that bond mobility embrittles adhesions and changes the mechanism of decohesion. Our study provides a mechanistic background to understand the biological regulation of cell-cell cohesion and fracture.

JTD Keywords: Biomimetic & bio-inspired materials, Cell adhesion, Fracture, Self-healing


Martinez-Hernandez, Uriel, Vouloutsi, Vasiliki, Mura, Anna, Mangan, Michael, Asada, Minoru, Prescott, T. J., Verschure, P., (2019). Biomimetic and Biohybrid Systems 8th International Conference, Living Machines 2019, Nara, Japan, July 9–12, 2019, Proceedings , Springer, Cham (Lausanne, Switzerland) 11556, 1-384

This book constitutes the proceedings of the 8th International Conference on Biomimetic and Biohybrid Systems, Living Machines 2019, held in Nara, Japan, in July 2019. The 26 full and 16 short papers presented in this volume were carefully reviewed and selected from 45 submissions. They deal with research on novel life-like technologies inspired by the scientific investigation of biological systems, biomimetics, and research that seeks to interface biological and artificial systems to create biohybrid systems.

JTD Keywords: Artificial intelligence, Biomimetics, Computer architecture, Human robot interaction, Human-Computer Interaction (HCI), Humanoid robot, Image processing, Learning algorithms, Mobile robots, Multipurpose robots, Neural networks, Quadruped robots, Reinforcement learning, Robot learning, Robotics, Robots, Sensor, Sensors, Swarm robotics, User interfaces


Sadowska, Joanna M., Wei, Fei, Guo, Jia, Guillem-Marti, Jordi, Ginebra, Maria-Pau, Xiao, Yin, (2018). Effect of nano-structural properties of biomimetic hydroxyapatite on osteoimmunomodulation Biomaterials 181, 318-332

Immune cells are sensitive to the microstructural and textural properties of materials. Tuning the structural features of synthetic bone grafts could be a valuable strategy to regulate the specific response of the immune system, which in turn modulates the activity of bone cells. The aim of this study was to analyse the effect of the structural characteristics of biomimetic calcium deficient hydroxyapatite (CDHA) on the innate immune response of macrophages and the subsequent impact on osteogenesis and osteoclastogenesis. Murine RAW 264.7 cells were cultured, under standard and inflammatory conditions, on chemically identical CDHA substrates that varied in microstructure and porosity. The impact on osteogenesis was evaluated by incubating osteoblastic cells (SaOS-2) with RAW-CDHA conditioned extracts. The results showed that macrophages were sensitive to different textural and structural properties of CDHA. Under standard conditions, the impact of inflammatory cytokine production by RAW cells cultured on CDHA played a significant role in the degradation of substrates, suggesting the impact of resorptive behaviour of RAW cells on biomimetic surfaces. Osteoblast differentiation was stimulated by the conditioned media collected from RAW cells cultured on needle-like nanostructured CDHA. The results demonstrated that needle-like nanostructured CDHA was able to generate a favourable osteoimmune environment to regulate osteoblast differentiation and osteogenesis. Under inflammatory conditions, the incubation of RAW cells with less porous CDHA resulted in a decreased gene expression and release of pro-inflammatory cytokines.

JTD Keywords: Calcium phosphates, Biomimetic hydroxyapatite, Osteoimmunomodulation, Inflammation, Osteogenesis, Osteoclastogesis


Raymond, Santiago, Maazouz, Yassine, Montufar, Edgar B., Perez, Roman A., González, Borja, Konka, Joanna, Kaiser, Jozef, Ginebra, Maria-Pau, (2018). Accelerated hardening of nanotextured 3D-plotted self-setting calcium phosphate inks Acta Biomaterialia 75, 451-462

Direct ink writing (DIW) techniques open up new possibilities for the fabrication of patient-specific bone grafts. Self-setting calcium phosphate inks, which harden at low temperature, allow obtaining nanostructured scaffolds with biomimetic properties and enhanced bioactivity. However, the slow hardening kinetics hampers the translation to the clinics. Different hydrothermal treatments for the consolidation of DIW scaffolds fabricated with an α-tricalcium phosphate /pluronic F127 ink were explored, comparing them with a biomimetic treatment. Three different scaffold architectures were analysed. The hardening process, associated to the conversion of α-tricalcium phosphate to hydroxyapatite was drastically accelerated by the hydrothermal treatments, reducing the time for complete reaction from 7 days to 30 minutes, while preserving the scaffold architectural integrity and retaining the nanostructured features. β-tricalcium phosphate was formed as a secondary phase, and a change of morphology from plate-like to needle-like crystals in the hydroxyapatite phase was observed. The binder was largely released during the treatment. The hydrothermal treatment resulted in a 30% reduction of the compressive strength, associated to the residual presence of β-tricalcium phosphate. Biomimetic and hydrothermally treated scaffolds supported the adhesion and proliferation of rat mesenchymal stem cells, indicating a good suitability for bone tissue engineering applications. Statement of Significance: 3D plotting has opened up new perspectives in the bone regeneration field allowing the customisation of synthetic bone grafts able to fit patient-specific bone defects. Moreover, this technique allows the control of the scaffolds’ architecture and porosity. The present work introduces a new method to harden biomimetic hydroxyapatite 3D-plotted scaffolds which avoids high-temperature sintering. It has two main advantages: i) it is fast and simple, reducing the whole fabrication process from the several days required for the biomimetic processing to a few hours; and ii) it retains the nanostructured character of biomimetic hydroxyapatite and allows controlling the porosity from the nano- to the macroscale. Moreover, the good in vitro cytocompatibility results support its suitability for cell-based bone regeneration therapies.

JTD Keywords: Calcium phosphate, Hydroxyapatite, Biomimetic, Bone regeneration, 3D plotting, Direct ink writing, Bone graft


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.

JTD 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.

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


Vouloutsi, Vasiliki, Halloy, José, Mura, Anna, Mangan, Michael, Lepora, Nathan, Prescott, T. J., Verschure, P., (2018). Biomimetic and Biohybrid Systems 7th International Conference, Living Machines 2018, Paris, France, July 17–20, 2018, Proceedings , Springer International Publishing (Lausanne, Switzerland) 10928, 1-551

This book constitutes the proceedings of the 7th International Conference on Biomimetic and Biohybrid Systems, Living Machines 2018, held in Paris, France, in July 2018. The 40 full and 18 short papers presented in this volume were carefully reviewed and selected from 60 submissions. The theme of the conference targeted at the intersection of research on novel life-like technologies inspired by the scientific investigation of biological systems, biomimetics, and research that seeks to interface biological and artificial systems to create biohybrid systems.

JTD Keywords: Artificial neural network, Bio-actuators, Bio-robotics, Biohybrid systems, Biomimetics, Bipedal robots, Earthoworm-like robots, Robotics, Decision-making, Tactile sensing, Soft robots, Locomotion, Insects, Sensors, Actuators, Robots, Artificial intelligence, Neural networks, Motion planning, Learning algorithms


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.

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


Caballero, D., Samitier, J., (2017). Topological control of extracellular matrix growth: A native-like model for cell morphodynamics studies ACS Applied Materials & Interfaces 9, (4), 4159-4170

The interaction of cells with their natural environment influences a large variety of cellular phenomena, including cell adhesion, proliferation, and migration. The complex extracellular matrix network has challenged the attempts to replicate in vitro the heterogeneity of the cell environment and has threatened, in general, the relevance of in vitro studies. In this work, we describe a new and extremely versatile approach to generate native-like extracellular matrices with controlled morphologies for the in vitro study of cellular processes. This general approach combines the confluent culture of fibroblasts with microfabricated guiding templates to direct the three-dimensional growth of well-defined extracellular networks which recapitulate the structural and biomolecular complexity of features typically found in vivo. To evaluate its performance, we studied fundamental cellular processes, including cell cytoskeleton organization, cell-matrix adhesion, proliferation, and protrusions morphodynamics. In all cases, we found striking differences depending on matrix architecture and, in particular, when compared to standard two-dimensional environments. We also assessed whether the engineered matrix networks influenced cell migration dynamics and locomotion strategy, finding enhanced migration efficiency for cells seeded on aligned matrices. Altogether, our methodology paves the way to the development of high-performance models of the extracellular matrix for potential applications in tissue engineering, diagnosis, or stem-cell biology.

JTD Keywords: Biomimetics, Cell migration, Engineered cell-derived matrices, Extracellular matrix, In vitro model


Sadowska, J. M., Guillem-Marti, J., Montufar, E. B., Espanol, M., Ginebra, M. P., (2017). Biomimetic versus sintered calcium phosphates: The in vitro behavior of osteoblasts and mesenchymal stem cells Tissue Engineering Part A , 23, (23-24), 1297-1309

The fabrication of calcium phosphates using biomimetic routes, namely, precipitation processes at body temperature, results in distinct features compared to conventional sintered calcium phosphate ceramics, such as a high specific surface area (SSA) and micro-or nanometric crystal size. The aim of this article is to analyze the effects of these parameters on cell response, focusing on two bone cell types: rat mesenchymal stem cells (rMSCs) and human osteoblastic cells (SaOS-2). Biomimetic calcium-deficient hydroxyapatite (CDHA) was obtained by a low temperature setting reaction, and α-Tricalcium phosphate (α-TCP) and β-Tricalcium phosphate were subsequently obtained by sintering CDHA either at 1400°C or 1100°C. Sintered stoichiometric hydroxyapatite (HA) was also prepared using ceramic routes. The materials were characterized in terms of SSA, skeletal density, porosity, and pore size distribution. SaOS-2 cells and rMSCs were seeded either directly on the surfaces of the materials or on glass coverslips subsequently placed on top of the materials to expose the cells to the CaP-induced ionic changes in the culture medium, while avoiding any topography-related effects. CDHA produced higher ionic fluctuations in both cell culture media than sintered ceramics, with a strong decrease of calcium and a release of phosphate. Indirect contact cell cultures revealed that both cell types were sensitive to these ionic modifications, resulting in a decrease in proliferation rate, more marked for CDHA, this effect being more pronounced for rMSCs. In direct contact cultures, good cell adhesion was found on all materials, but, while cells were able to proliferate on the sintered calcium phosphates, cell number was significantly reduced with time on biomimetic CDHA, which was associated to a higher percentage of apoptotic cells. Direct contact of the cells with biomimetic CDHA resulted also in a higher alkaline phosphatase activity for both cell types compared to sintered CaPs, indicating a promotion of the osteoblastic phenotype.

JTD Keywords: Biomimetic hydroxyapatite, Calcium phosphate, Mesenchymal stem cell, Osteoblast


Ziyatdinov, Andrey, Fonollosa, Jordi, Fernández, Luis, Gutiérrez-Gálvez, Agustín, Marco, Santiago, Perera, Alexandre, (2015). Data set from gas sensor array under flow modulation Data in Brief 3, 131-136

Abstract Recent studies in neuroscience suggest that sniffing, namely sampling odors actively, plays an important role in olfactory system, especially in certain scenarios such as novel odorant detection. While the computational advantages of high frequency sampling have not been yet elucidated, here, in order to motivate further investigation in active sampling strategies, we share the data from an artificial olfactory system made of 16 MOX gas sensors under gas flow modulation. The data were acquired on a custom set up featured by an external mechanical ventilator that emulates the biological respiration cycle. 58 samples were recorded in response to a relatively broad set of 12 gas classes, defined from different binary mixtures of acetone and ethanol in air. The acquired time series show two dominant frequency bands: the low-frequency signal corresponds to a conventional response curve of a sensor in response to a gas pulse, and the high-frequency signal has a clear principal harmonic at the respiration frequency. The data are related to the study in [1], and the data analysis results reported there should be considered as a reference point.

JTD Keywords: Gas sensor array, MOX sensor, Flow modulation, Early detection, Biomimetics, Respiration, Sniffing


Sánchez-Ferrero, Aitor, Mata, Álvaro, Mateos-Timoneda, Miguel A., Rodríguez-Cabello, José C., Alonso, Matilde, Planell, Josep, Engel, Elisabeth, (2015). Development of tailored and self-mineralizing citric acid-crosslinked hydrogels for in situ bone regeneration Biomaterials 68, 42-53

Bone tissue engineering demands alternatives overcoming the limitations of traditional approaches in the context of a constantly aging global population. In the present study, elastin-like recombinamers hydrogels were produced by means of carbodiimide-catalyzed crosslinking with citric acid, a molecule suggested to be essential for bone nanostructure. By systematically studying the effect of the relative abundance of reactive species on gelation and hydrogel properties such as functional groups content, degradation and structure, we were able to understand and to control the crosslinking reaction to achieve hydrogels mimicking the fibrillary nature of the extracellular matrix. By studying the effect of polymer concentration on scaffold mechanical properties, we were able to produce hydrogels with a stiffness value of 36.13 ± 10.72 kPa, previously suggested to be osteoinductive. Microstructured and mechanically-tailored hydrogels supported the growth of human mesenchymal stem cells and led to higher osteopontin expression in comparison to their non-tailored counterparts. Additionally, tailored hydrogels were able to rapidly self-mineralize in biomimetic conditions, evidencing that citric acid was successfully used both as a crosslinker and a bioactive molecule providing polymers with calcium phosphate nucleation capacity.

JTD Keywords: Biomimetic material, Biomineralisation, Bone tissue engineering, Cross-linking, Hydrogel, Mesenchymal stem cell


Ziyatdinov, Andrey, Fonollosa, Jordi, Fernánndez, Luis, Gutierrez-Gálvez, Agustín, Marco, Santiago, Perera, Alexandre, (2015). Bioinspired early detection through gas flow modulation in chemo-sensory systems Sensors and Actuators B: Chemical 206, 538-547

Abstract The design of bioinspired systems for chemical sensing is an engaging line of research in machine olfaction. Developments in this line could increase the lifetime and sensitivity of artificial chemo-sensory systems. Such approach is based on the sensory systems known in live organisms, and the resulting developed artificial systems are targeted to reproduce the biological mechanisms to some extent. Sniffing behaviour, sampling odours actively, has been studied recently in neuroscience, and it has been suggested that the respiration frequency is an important parameter of the olfactory system, since the odour perception, especially in complex scenarios such as novel odourants exploration, depends on both the stimulus identity and the sampling method. In this work we propose a chemical sensing system based on an array of 16 metal-oxide gas sensors that we combined with an external mechanical ventilator to simulate the biological respiration cycle. The tested gas classes formed a relatively broad combination of two analytes, acetone and ethanol, in binary mixtures. Two sets of low-frequency and high-frequency features were extracted from the acquired signals to show that the high-frequency features contain information related to the gas class. In addition, such information is available at early stages of the measurement, which could make the technique suitable in early detection scenarios. The full data set is made publicly available to the community.11 http://archive.ics.uci.edu/ml/datasets/Gas+sensor+array+under+flow+modulation.

JTD Keywords: Gas sensor array, MOX sensor, Flow modulation, Early detection, Biomimetics, Sniffing


Hoyo, J., Guaus, E., Torrent-Burgués, J., Sanz, F., (2015). Biomimetic monolayer films of digalactosyldiacylglycerol incorporating plastoquinone Biochimica et Biophysica Acta - Biomembranes , 1848, (6), 1341-1351

The photosynthesis is the process used by plants and bacteria cells to convert inorganic matter in organic thanks to the light energy. This process consist on several steps, being one of them the electronic transport from the photosystem II to the cytochrome thanks to plastoquinone-9 (PQ). Here we prepare membranes that mimic the characteristics and composition of natural photosynthetic cell membranes and we characterize them in order to obtain the PQ molecules position in the membrane and their electrochemical behaviour. The selected galactolipid is digalactosyldiacylglycerol (DGDG) that represents the 30% of the thylakoid membrane lipid content. The results obtained are worthful for several science fields due to the relevance of galactolipids as anti-algal, anti-viral, anti-tumor and anti-inflammatory agents and the antioxidant and free radical scavenger properties of prenylquinones. Both pure components (DGDG and PQ) and the DGDG:PQ mixtures have been studied using surface pressure-area isotherms. These isotherms give information about the film stability and indicate the thermodynamic behaviour of the mixture and their physical state. The Langmuir-Blodgett (LB) film has been transferred forming a monolayer that mimics the bottom layer of the biological membranes. This monolayer on mica has been topographically characterized using AFM and both the height and the physical state that they present have been obtained. Moreover, these monolayers have been transferred onto ITO that is a hydrophilic substrate with good optical and electrical features, so that, it is suitable for studying the electrochemical behaviour of these systems and it is a good candidate for energy producing devices.

JTD Keywords: Biomimetic membrane, Digalactosyldiacylglycerol, Electron transfer, LangmuirBlodgett film, Modified ITO electrode, Plastoquinone


Marco, S., Gutiérrez-Gálvez, A., Lansner, A., Martinez, D., Rospars, J. P., Beccherelli, R., Perera, A., Pearce, T., Vershure, P., Persaud, K., (2013). Biologically inspired large scale chemical sensor arrays and embedded data processing Proceedings of SPIE - The International Society for Optical Engineering Smart Sensors, Actuators, and MEMS VI , SPIE Digital Library (Grenoble, France) 8763, 1-15

Biological olfaction outperforms chemical instrumentation in specificity, response time, detection limit, coding capacity, time stability, robustness, size, power consumption, and portability. This biological function provides outstanding performance due, to a large extent, to the unique architecture of the olfactory pathway, which combines a high degree of redundancy, an efficient combinatorial coding along with unmatched chemical information processing mechanisms. The last decade has witnessed important advances in the understanding of the computational primitives underlying the functioning of the olfactory system. EU Funded Project NEUROCHEM (Bio-ICT-FET- 216916) has developed novel computing paradigms and biologically motivated artefacts for chemical sensing taking inspiration from the biological olfactory pathway. To demonstrate this approach, a biomimetic demonstrator has been built featuring a large scale sensor array (65K elements) in conducting polymer technology mimicking the olfactory receptor neuron layer, and abstracted biomimetic algorithms have been implemented in an embedded system that interfaces the chemical sensors. The embedded system integrates computational models of the main anatomic building blocks in the olfactory pathway: The olfactory bulb, and olfactory cortex in vertebrates (alternatively, antennal lobe and mushroom bodies in the insect). For implementation in the embedded processor an abstraction phase has been carried out in which their processing capabilities are captured by algorithmic solutions. Finally, the algorithmic models are tested with an odour robot with navigation capabilities in mixed chemical plumes.

JTD Keywords: Antennal lobes, Artificial olfaction, Computational neuroscience, Olfactory bulbs, Plume tracking, Abstracting, Actuators, Algorithms, Biomimetic processes, Chemical sensors, Conducting polymers, Data processing, Flavors, Odors, Robots, Smart sensors, Embedded systems


Hoyo, J., Torrent-Burgués, J., Guaus, E., (2012). Biomimetic monolayer films of monogalactosyldiacylglycerol incorporating ubiquinone Journal of Colloid and Interface Science , 384, (1), 189-197

Ubiquinone and plastoquinone are two of the main electron and proton shuttle molecules in biological systems, and monogalactosyldiacylglycerol (MGDG) is the most abundant lipid in the thylakoid membrane of chloroplasts. Saturated MGDG, ubiquinone-10 (UQ) and MGDG:UQ mixed monolayers at the air/water interface have been studied using surface pressure-area isotherms and Brewster Angle Microscopy. Moreover, the transferred Langmuir-Blodgett films have been observed by Atomic Force Microscopy. The results show that MGDG:UQ mixtures present more fluid phase than pure MGDG, indicating a higher order degree for the later. It is also observed an important influence of UQ on the MGDG matrix before UQ collapse pressure and a low influence after this event, due to UQ expulsion from the MGDG matrix. This expulsion leads to a similar remaining UQ content for all the tested mixtures, indicating a limiting content of this molecule in the MGDG matrix at high surface pressures. The thermodynamic studies confirm the stability of the MGDG:UQ mixtures at low surface pressures, although presenting a non-ideal behaviour. Results point to consider UQ as a good candidate for studies of artificial photosynthesis.

JTD Keywords: AFM, BAM, Biomimetic films, Langmuir-Blodgett film, Monogalactosyldiacylglycerol, Ubiquinone


Jang, J. H., Castano, O., Kim, H. W., (2009). Electrospun materials as potential platforms for bone tissue engineering Advanced Drug Delivery Reviews 61, (12), 1065-1083

Nanofibrous materials produced by electrospinning processes have attracted considerable interest in tissue regeneration, including bone reconstruction. A range of novel materials and processing tools have been developed to mimic the native bone extracellular matrix for potential applications as tissue engineering scaffolds and ultimately to restore degenerated functions of the bone. Degradable polymers, bioactive inorganics and their nanocomposites/hybrids nanofibers with suitable mechanical properties and bone bioactivity for osteoblasts and progenitor/stem cells have been produced. The surface functionalization with apatite minerals and proteins/peptides as well as drug encapsulation within the nanofibers is a promising strategy for achieving therapeutic functions with nanofibrous materials. Recent attempts to endow a 3D scaffolding technique to the electrospinning regime have shown some promise for engineering 3D tissue constructs. With the improvement in knowledge and techniques of bone-targeted nanofibrous matrices, bone tissue engineering is expected to be realized in the near future.

JTD Keywords: Electrospun nanofiber, Bone tissue engineering, Biomimetic matrix, Bone bioactivity, 3D scaffolding


Manara, S., Paolucci, F., Palazzo, B., Marcaccio, M., Foresti, E., Tosi, G., Sabbatini, S., Sabatino, P., Altankov, G., Roveri, N., (2008). Electrochemically-assisted deposition of biomimetic hydroxyapatite-collagen coatings on titanium plate Inorganica Chimica Acta 361, (6), 1634-1645

A biomimetic bone-like composite, made of self-assembled collagen fibrils and carbonate hydroxyapatite nanocrystals, has been performed by an electrochemically-assisted deposition on titanium plate. The electrolytic processes have been carried out using a single type I collagen molecules suspension in a diluted Ca(NO3)(2) and NH4H2PO4 solution at room temperature and applying a constant current for different periods of time. Using the same electrochemical conditions, carbonate hydroxyapatite nanocrystals or reconstituted collagen. brils coatings were obtained. The reconstituted collagen. brils, hydroxyapatite nanocrystals and collagen fibrils/apatite nanocrystals coatings have been characterized chemically, structurally and morphologically, as well as for their ability to bind fibronectin (FN). Fourier Transform Infrared microscopy has been used to map the topographic distribution of the coating components at different times of electrochemical deposition, allowing to single out the individual deposition steps. Moreover, roughness of Ti plate has been found to affect appreciably the nucleation region of the inorganic nanocrystals. Laser scanning confocal microscopy has been used to characterize the FN adsorption pattern on a synthetic biomimetic apatitic phase, which exhibits a higher affinity when it is inter-grown with the collagen fibrils. The results offer auspicious applications in the preparation of medical devices such as biomimetic bone-like composite-coated metallic implants.

JTD Keywords: Hydroxyapatite-collagen coating, Electrochemically-assisted deposition, Micro-imaging FTIR spectroscopy, Laser scanning confocal microscopy, Biomimetic crystal growth, Fibronectin binding