Publications

Here, we report DNA-based synthetic nanostructures decorated with enzymes (hereafter referred to as DNA-enzyme swimmers) that self-propel by converting the enzymatic substrate to the product in solution. The DNA-enzyme swimmers are obtained from tubular DNA structures that self-assemble spontaneously by the hybridization of DNA tiles. We functionalize these DNA structures with two different enzymes, urease and catalase, and show that they exhibit concentration-dependent movement and enhanced diffusion upon addition of the enzymatic substrate (i.e., urea and H2O2). To demonstrate the programmability of such DNA-based swimmers, we also engineer DNA strands that displace the enzyme from the DNA scaffold, thus acting as molecular brakes on the DNA swimmers. These results serve as a first proof of principle for the development of synthetic DNA-based enzyme-powered swimmers that can self-propel in fluids.

JTD Keywords: Design, Motor, Shapes

Micro/nanomotors (MNMs) have evolved from single self-propelled entities to versatile systems capable of performing one or multiple biomedical tasks. When single MNMs self-assemble into coordinated swarms, either under external control or triggered by chemical reactions, they offer advantages that individual MNMs cannot achieve. These benefits include intelligent multitasking and adaptability to changes in the surrounding environment. Here, we provide our perspective on the evolution of MNMs, beginning with the development of enzymatic MNMs since the first theoretical model was proposed in 2005. These enzymatic MNMs hold immense promise in biomedicine due to their advantages in biocompatibility and fuel availability. Subsequently, we introduce the design and application of single motors in biomedicine, followed by the control of MNM swarms and their biomedical applications. In the end, we propose viable solutions for advancing the development of MNM swarms and anticipate valuable insights into the creation of more intelligent and controllable MNM swarms for biomedical applications.; Micro/nanomotor swarms propelled by diverse mechanisms.

JTD Keywords: Active particles, Actuation, Behaviors, Biocompatibility, Biomedical applications, Coordination reactions, Design and application, Diffusion, External control, Medical applications, Micromotors, Motion, Nanomotors, Powered nanomotors, Propulsion, Self-assemble, Surrounding environment, Theoretical modeling, Versatile system, Viable solutions

Applications of sodium alginate (Alg) and polyacrylic acid (PAA) hydrogels in biomedicine are well-known. These are predefined by the strength and weakness of their properties, which in turn depend on the chemical structure and the architecture of their crosslinks. In this work, Alg biopolymer has been grafted to synthetic PAA that has been chemically crosslinked using N,N '-methylene-bisacrylamide (MBA) to produce a pH responsive hydrogel with adhesive property. The double crosslinking network, which combines MBA-mediated covalent crosslinks and ionic crosslinks in Alg domains, results in an elastic modulus that resembles that of highly anisotropic and viscoelastic human skin. After addressing the influence of the dual network onto the Alg-g-PAA hydrogel properties, a prospection of its potential as an adhesive has been made considering different surfaces (rubber, paper steel, porcine skin, etc). The bonding energy onto porcine skin, 32.6 +/- 4.6 J/m2, revealed that the Alg-g-PAA hydrogel can be proposed in the biomedical field as tissue adhesive for wound healing applications. Finally, the hydrogel has been semi-interpenetrated with poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PEDOT-MeOH) chains through a chemical oxidative polymerization process. The resulting hydrogel, Alg-g- PAA/PEDOT-MeOH, which is even more porous than Alg-g-PAA, in addition to being electro-responsive, maintains adhesive properties.

JTD Keywords: Adhesion properties, Adhesion properties,biomedical applications,bonding energy,dual network,conducting hydrogel, Adhesive properties, Adhesives, Biomedical applications, Biopolymers, Bonding energies, Bonding energy, Chemical bonds, Conducting hydrogels, Crosslinking, Dual network, Hydrogels, Medical applications, Methylenebisacrylamide, Poly(acrylic acid), Porcine skin, Property, Rational design,film, Sodium alginate

Tubular structures made of elastic helical fibers are widely found in nature and in technology. The complex and highly nonlinear mechanical properties of such assemblies have been understood either through minimal models or through complex simulations describing each individual fiber and their interactions. Here, inspired by Chebyshev's geometric model of nets, we propose and experimentally validate a modeling framework that treats tubular braided meshes as continuum surfaces corresponding to the virtual envelope defined by the fibers. The key idea is to relate surface geometry and fiber kinematics, enabling us to follow large deformations. This theory is amenable to efficient computations and, in axisymmetric cases, the problem reduces to finding two scalar fields defined over 1D segments. We validate our model against experiments of axial compression, revealing the existence of a plateau with vanishing stiffness in the axial force-displacement curve, a feature that could prove particularly useful in applications where an applied compressive force needs to be held constant even against settlements of the compressed object.

JTD Keywords: Braided mesh, Chebyshev nets, Computational mechanics, Design, Elastic rods, Envelope surface, Equilibrium, Hélices, Muscle

We report a simple approach to fabricate free-standing perforated 2D nanomembranes hosting well-ordered 1D metallic nanostructures to obtain hybrid materials with nanostructured surfaces for flexible electronics. Nanomembranes are formed by alternatively depositing perforated poly(lactic acid) (PLA) and poly(3,4-ethylenedioxythiophene) layers. Copper metallic nanowires (NWs) were incorporated into the nanoperforations of the top PLA layer by electrodeposition and further coated with silver via a transmetallation reaction. The combination of 2D polymeric nanomembranes and aligned 1D metallic NWs allows merging the flexibility and conformability of the ultrathin soft polymeric nanomembranes with the good electrical properties of metals for biointegrated electronic devices. Thus, we were able to tailor the nanomembrane surface chemistry as it was corroborated by SEM, EDX, XPS, CV, EIS and contact angle. The obtained hybrid nanomembranes were flexible and conformable showing sensing capacity towards H2O2 with good linear concentration range (0.35–10 mM), sensitivity (120 µA cm?2 mM?1) and limit of detection (7 ?m). Moreover, the membranes showed good stability, reproducibility and selectivity towards H2O2.

JTD Keywords: biointegrated sensors, designs, electronics, fabrication, free-standing films, h2o2, metallic nanowires, nanoparticles, nanowires, sensor, skin, Hydrogen-peroxide, Perforated nanomembranes

JTD Keywords: alignment, bioresorbable stents, cells, design, electrospinning, everolimus, impact, in-vitro, poly(l-lactic-co-e-caprolactone), proliferation, release, sirolimus, Scaffold topography, Solvent-cast direct-writing

A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid β (Aβ40) aggregation, were evaluated for the inhibition of tau protein aggregation. All compounds exhibited a good activity, and eight of them (5-8, 10, 14, 15 and 20) shared comparable low micromolar inhibitory potency versus Aβ40 aggregation and human acetylcholinesterase (AChE), while inhibiting human butyrylcholinesterase (BChE) even at submicromolar concentration. Compound 20 showed outstanding biological data, inhibiting tau protein and Aβ40 aggregation with IC50 = 1.8 and 1.3 μM, respectively. Moreover, at 0.1-10 μM it also exhibited neuroprotective activity against tau toxicity induced by okadoic acid in human neuroblastoma SH-SY5Y cells, that was comparable to that of estradiol and PD38. In preliminary toxicity studies, these interesting results for compound 20 are somewhat conflicting with a narrow safety window. However, compound 10, although endowed with a little lower potency for tau and Aβ aggregation inhibition additionally demonstrated good inhibition of ChEs and rather low cytotoxicity. Compound 4 is also worth of note for its high potency as hBChE inhibitor (IC50 = 7 nM) and for the three order of magnitude selectivity versus hAChE. Molecular modelling studies were performed to explain the different behavior of compounds 4 and 20 towards hBChE. The observed balance of the inhibitory potencies versus the relevant targets indicates the thioxanthene-9-one derivatives as potential MTDLs for AD therapy, provided that the safety window will be improved by further structural variations, currently under investigation.Copyright © 2023 Elsevier Masson SAS. All rights reserved.

JTD Keywords: a? and tau aggregation inhibition, ache and bche inhibition, aggregation, alzheimer?s disease, butyrylcholinesterase, design, drugs, dual inhibitors, fibrillization, multitarget-directed ligands (mtdls), peptide, polyphenols, potent, rivatives, Ache and bche inhibition, Alzheimer's disease, Amyloid-beta, Aβ and tau aggregation inhibition, Multitarget-directed ligands (mtdls), Thioxanthene-9-one and xanthen-9-one de, Thioxanthene-9-one and xanthen-9-one derivatives

JTD Keywords: biocompatibility, blends, design, dopamine detection, electrocatalytic oxidation, electrodes, polymers, sensor, Additive manufacturing, Surface

CRENKA [Cys-Arg-(NMe)Glu-Lys-Ala, where (NMe)Glu refers to N-methyl-Glu], an anti-cancer pentapeptide that induces prostate tumor necrosis and significant reduction in tumor growth, was engineered to increase the resistance to endogenous proteases of its parent peptide, CREKA (Cys-Arg-Glu-Lys-Ala). Considering their high tendency to aggregate, the self-assembly of CRENKA and CREKA into well-defined and ordered structures has been examined as a function of peptide concentration and pH. Spectroscopic studies and atomistic molecular dynamics simulations reveal significant differences between the secondary structures of CREKA and CRENKA. Thus, the restrictions imposed by the (NMe)Glu residue reduce the conformational variability of CRENKA with respect to CREKA, which significantly affects the formation of well-defined and ordered self-assembly morphologies. Aggregates with poorly defined morphology are obtained from solutions with low and moderate CREKA concentrations at pH 4, whereas well-defined dendritic microstructures with fractal geometry are obtained from CRENKA solutions with similar peptide concentrations at pH 4 and 7. The formation of dendritic structures is proposed to follow a two-step mechanism: (1) pseudo-spherical particles are pre-nucleated through a diffusion-limited aggregation process, pre-defining the dendritic geometry, and (2) such pre-nucleated structures coalesce by incorporating conformationally restrained CRENKA molecules from the solution to their surfaces, forming a continuous dendritic structure. Instead, no regular assembly is obtained from solutions with high peptide concentrations, as their dynamics is dominated by strong repulsive peptide-peptide electrostatic interactions, and from solutions at pH 10, in which the total peptide charge is zero. Overall, results demonstrate that dendritic structures are only obtained when the molecular charge of CRENKA, which is controlled through the pH, favors kinetics over thermodynamics during the self-assembly process.

JTD Keywords: aggregation, amphiphilic peptides, breast-cancer, cells, design, oxidative stress, resistance, strategy, Molecular-dynamics

Growing evidence suggests that the physical properties of the cellular microenvironment influence cell migration. However, it is not currently understood how active physical remodelling by cells affects migration dynamics. Here we report that cell clusters seeded on deformable collagen-I networks display persistent collective migration despite not showing any apparent intrinsic polarity. Clusters generate transient gradients in collagen density and alignment due to viscoelastic relaxation of the collagen networks. Combining theory and experiments, we show that crosslinking collagen networks or reducing cell cluster size results in reduced network deformation, shorter viscoelastic relaxation time and smaller gradients, leading to lower migration persistence. Traction force and Brillouin microscopy reveal asymmetries in force distributions and collagen stiffness during migration, providing evidence of mechanical cross-talk between cells and their substrate during migration. This physical model provides a mechanism for self-generated directional migration on viscoelastic substrates in the absence of internal biochemical polarity cues.; Cell clusters mechanically reorganize viscoelastic collagen networks, resulting in transient gradients in collagen density, alignment and stiffness that promote spontaneous persistent migration.

JTD Keywords: Cell-migration, Design, Invasion, Limits, Mechanics, Microscopy, Morphogenesis, Motility, Rear, Rigidity

Nanosized artificial antigen-presenting cells (aAPCs), synthetic immune cell mimics that aim to activate T cells ex or in vivo, offer an effective alternative to cellular immunotherapies. However, comprehensive studies that delineate the effect of nano-aAPC topology, including nanoparticle morphology and ligand density, are lacking. Here, we systematically studied the topological effects of polymersome-based aAPCs on T cell activation. We employed an aAPC library created from biodegradable poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-PDLLA) polymersomes with spherical or tubular shape and variable sizes, which were functionalized with αCD3 and αCD28 antibodies at controlled densities. Our results indicate that high ligand density leads to enhancement in T cell activation, which can be further augmented by employing polymersomes with larger size. At low ligand density, the effect of both polymersome shape and size was more pronounced, showing that large elongated polymersomes better activate T cells compared to their spherical or smaller counterparts. This study demonstrates the capacity of polymersomes as aAPCs and highlights the role of topology for their rational design.

JTD Keywords: antibody density, artificial antigen-presenting cells, biodegradable polymersomes, design, expansion, immunotherapy, nano-immunotherapy, nanoparticle morphology, t cell activation, Biodegradable polymersomes, Nanoparticle morphology, Synthetic dendritic cells

Upon coming into contact with the biological environment, nanostructures are immediately covered by biomolecules, particularly by proteins forming the so-called "protein corona" (PC). The phenomenon of PC formation has gained great attention in recent years due to its implication in the use of nanostructures in biomedicine. In fact, it has been shown that the formation of the PC can impact the performance of nanostructures by reducing their stability, causing aggregation, increasing their toxicity, and providing unexpected and undesired nanostructure-cell interactions. In this work, we decided to study for the first time the formation and the evolution of PC on the surface of nanostructured lipid carriers loaded with superparamagnetic iron oxide nanoparticles, before and after the crossing of an in vitro model of the blood-brain barrier (BBB). Combining confocal microscopy, direct STochastic Optical Reconstruction Microscopy (dSTORM), and proteomic analysis, we were able to carry out a complete analysis of the PC formation and evolution. In particular, we highlighted that PC formation is a fast process, being formed around particles even after just 1 min of exposure to fetal bovine serum. Moreover, PC formed around particles is extremely heterogeneous: while some particles have no associated PC at all, others are completely covered by proteins. Lastly, the interaction with an in vitro BBB model strongly affects the PC composition: in particular, a large amount of the proteins forming the initial PC is lost after the BBB passage and they are partially replaced by new proteins derived from both the brain endothelial cells and the cell culture medium. Altogether, the obtained data could potentially provide new insights into the design and fabrication of lipid nanostructures for the treatment of central nervous system disorders.

JTD Keywords: design, impact, Nanoparticles

Alzheimer's disease and Type 2 diabetes are pathological processes associated to ageing. Moreover, there are evidences supporting a mechanistic link between Alzheimer's disease and insulin resistance (one of the first hallmarks of Type 2 diabetes). Regarding Alzheimer's disease, amyloid beta-peptide aggregation into beta-sheets is the main hallmark of Alzheimer's disease. At monomeric state, amyloid beta-peptide is not toxic but its function in brain, if any, is unknown. Here we show, by in silico study, that monomeric amyloid beta-peptide 1-40 shares the tertiary structure with insulin and is thereby able to bind and activate insulin receptor. We validated this prediction experimentally by treating human neuroblastoma cells with increasing concentrations of monomeric amyloid. beta-peptide 1-40. Our results confirm that monomeric amyloid beta-peptide 1-40 activates insulin receptor autophosphorylation, triggering downstream enzyme phosphorylarions and the glucose Transporter 4 translocation to the membrane. On the other hand, neuronal insulin resistance is known to be associated to Alzheimer's disease since early stages. We thus modelled the docking of oligomeric amyloid peptide 1-40 to insulin receptor. We found that oligomeric amyloid. beta-peptide 1-40 blocks insulin receptor, impairing its activation. It was confirmed in vitro by observing the lack of insulin receptor autophosphorylation, and also the impairment of insulin-induced intracellular enzyme activations and the glucose Transporter 4 translocation to the membrane. By biological system analysis, we have carried out a mathematical model recapitulating the process that turns amyloid beta-peptide binding to insulin receptor from the physiological to the pathophysiological regime. Our results suggest that monomeric amyloid beta-peptide 1-40 contributes to mimic insulin effects in the brain, which could be good when neurons have an extra requirement of energy beside the well-known protective effects on insulin intracellular signalling, while its accumulation and subsequent oligomerization blocks the insulin receptor producing insulin resistance and compromising neuronal metabolism and protective pathways.

JTD Keywords: akt, alzheimer’s disease, amyloid β-peptide, insulin, A-beta, Aggregation, Akt, Alzheimer's disease, Alzheimers-disease, Amyloid beta-peptide, Brain, Design, Insulin, Insulin resistance, Precursor protein, Protein-protein docking, Receptor, Resistance, Site

3DNA holds promise as a carrier for drugs that can be intercalated into its core or linked to surface arms. Coupling 3DNA to an antibody targeting intercellular adhesion molecule 1 (ICAM-1) results in high lung-specific biodistributions in vivo. While the role of individual parameters on ICAM-1 targeting has been studied for other nanocarriers, it has never been examined for 3DNA or in a manner capable of revealing the hierarchic interplay among said parameters. In this study, we used 2-layer vs. 4-layer anti-ICAM 3DNA and radiotracing to examine biodistribution in mice. We found that, below saturating conditions and within the ranges tested, the density of targeting antibodies on 3DNA is the most relevant parameter driving lung targeting over liver clearance, compared to the number of antibodies per carrier, total antibody dose, 3DNA dose, 3DNA size, or the administered concentration, which influenced the dose in organs but not the lung specific-over-liver clearance ratio. Data predicts that lung-specific delivery of intercalating (core loaded) drugs can be tuned using this biodistribution pattern, while that of arm-linked (surface loaded) drugs requires a careful parametric balance because increasing anti-ICAM density reduces the number of 3DNA arms available for drug loading.

JTD Keywords: 3dna nanocarrier, acid sphingomyelinase, antibody, carrier design parameters, carriers, dna nanostructures, doxorubicin, drug type, icam-1, inflammation, lung targeting, multiparametric hierarchy, nanoparticles, size, 3dna nanocarrier, Intracellular delivery, Multiparametric hierarchy

JTD Keywords: biosensor, blood-plasma, chemistry, coatings, design, microchannel cantilever spotting, strain-promoted alkyne-azide cycloaddition, ultra-low fouling hierarchical polymer brushes, Alkyne cycloaddition, Coupling efficiency

Thermal scanning probe lithography (tSPL) is a nanofabrication method for the chemical and physical nanopatterning of a large variety of materials and polymer resists with a lateral resolution of 10 nm and a depth resolution of 1 nm. In this Primer, we describe the working principles of tSPL and highlight the characteristics that make it a powerful tool to locally and directly modify material properties in ambient conditions. We introduce the main features of tSPL, which can pattern surfaces by locally delivering heat using nanosized thermal probes. We define the most critical patterning parameters in tSPL and describe post-patterning analysis of the obtained results. The main sources of reproducibility issues related to the probe and the sample as well as the limitations of the tSPL technique are discussed together with mitigation strategies. The applications of tSPL covered in this Primer include those in biomedicine, nanomagnetism and nanoelectronics; specifically, we cover the fabrication of chemical gradients, tissue-mimetic surfaces, spin wave devices and field-effect transistors based on two-dimensional materials. Finally, we provide an outlook on new strategies that can improve tSPL for future research and the fabrication of next-generation devices.

JTD Keywords: Beam lithography, Design, Feature size, Force microscope cantilevers, Mos2, Polymer, Silicon, Speed, Thermochemical nanolithography, Tip

Biobased epoxy-derived raw materials will be essential for future coating and adhesive designs in industry. Here, a facile approach is reported towards the incorporation of limonene into an epoxy-functionalized polycarbonate and its crosslinking with a polyamine curing agent to obtain a thermoset material. For the first time, a solvent-borne adhesive with excellent film-forming, mechanical and adhesion strength properties is described.

JTD Keywords: adhesives, biobased epoxies, limonene, polycarbonate, Adhesives, Biobased epoxies, Biobased epoxy, Carbon-dioxide, Curing agents, Design in industries, Epoxides, Epoxy, Epoxy resins, Film adhesion, Film-forming, Functionalized, Limonene, Mechanical, Monomer, Monoterpenes, Oil, Oxide, Performance, Polyamines, Polycarbonate, Polycarbonates, Terpenes, Thermoset materials, Thermosets

Large doses of movement practice have been shown to restore upper extremities' motor function in a significant subset of individuals post-stroke. However, such large doses are both difficult to implement in the clinic and highly inefficient. In addition, an important reduction in upper extremity function and use is commonly seen following rehabilitation-induced gains, resulting in “rehabilitation in vain”. For those with mild to moderate sensorimotor impairment, the limited spontaneous use of the more affected limb during activities of daily living has been previously proposed to cause a decline of motor function, initiating a vicious cycle of recovery, in which non-use and poor performance reinforce each other. Here, we review computational, experimental, and clinical studies that support the view that if arm use is raised above an effective threshold, one enters a virtuous cycle in which arm use and function can reinforce each other via self-practice in the wild. If not, one enters a vicious cycle of declining arm use and function. In turn, and in line with best practice therapy recommendations, this virtuous/vicious cycle model advocates for a paradigm shift in neurorehabilitation whereby rehabilitation be embedded in activities of daily living such that self-practice with the aid of wearable technology that reminds and motivates can enhance paretic limb use of those who possess adequate residual sensorimotor capacity. Altogether, this model points to a user-centered approach to recovery post-stroke that is tailored to the participant's level of arm use and designed to motivate and engage in self-practice through progressive success in accomplishing meaningful activities in the wild. Copyright © 2022 Ballester, Winstein and Schweighofer.

JTD Keywords: compensatory movement, computational neurorehabilitation, decision-making, individuals, learned non-use, learned nonuse, monkeys, neurorehabilitation, recovery, rehabilitation, stroke, stroke patients, wearable sensors, wrist, Arm movement, Article, Cerebrovascular accident, Clinical decision making, Clinical practice, Clinical study, Compensatory movement, Computational neurorehabilitation, Computer model, Daily life activity, Decision-making, Experimental study, Human, Induced movement therapy, Learned non-use, Musculoskeletal function, Neurorehabilitation, Paresis, Sensorimotor function, Stroke, Stroke rehabilitation, User-centered design, Vicious cycle, Virtuous cycle, Wearable sensors

Remarkable progress in bioengineering over the past two decades has enabled the formulation of fundamental design principles for a variety of medical and non-medical applications. These advancements have laid the foundation for building multicellular engineered living systems (M-CELS) from biological parts, forming functional modules integrated into living machines. These cognizant design principles for living systems encompass novel genetic circuit manipulation, self-assembly, cell–cell/matrix communication, and artificial tissues/organs enabled through systems biology, bioinformatics, computational biology, genetic engineering, and microfluidics. Here, we introduce design principles and a blueprint for forward production of robust and standardized M-CELS, which may undergo variable reiterations through the classic design-build-test-debug cycle. This Review provides practical and theoretical frameworks to forward-design, control, and optimize novel M-CELS. Potential applications include biopharmaceuticals, bioreactor factories, biofuels, environmental bioremediation, cellular computing, biohybrid digital technology, and experimental investigations into mechanisms of multicellular organisms normally hidden inside the “black box” of living cells.

JTD Keywords: cell-fate specification, endothelial-cells, escherichia-coli, extracellular-matrix, gene-expression noise, nuclear hormone-receptors, pluripotent stem-cells, primitive endoderm, transcription factors, Artificial tissues, Assembly cells, Biological parts, Biological systems, Bioremediation, Blood-brain-barrier, Cell engineering, Cell/matrix communication, Design principles, Environmental technology, Functional modules, Fundamental design, Genetic circuits, Genetic engineering, Living machines, Living systems, Medical applications, Molecular biology, Synthetic biology

The dizzying life of the homeostatic intestinal epithelium is governed by a complex interplay between fate, form, force and function. This interplay is beginning to be elucidated thanks to advances in intravital and ex vivo imaging, organoid culture, and biomechanical measurements. Recent discoveries have untangled the intricate organization of the forces that fold the monolayer into crypts and villi, compartmentalize cell types, direct cell migration, and regulate cell identity, proliferation and death. These findings revealed that the dynamic equilibrium of the healthy intestinal epithelium relies on its ability to precisely coordinate tractions and tensions in space and time. In this review, we discuss recent findings in intestinal mechanobiology, and highlight some of the many fascinating questions that remain to be addressed in this emerging field.Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

JTD Keywords: crypt fission, designer matrices, differentiation, growth, gut, migration, model, scaffold, tissue mechanics, Biophysics, Cell migration, Cell movement, Cell proliferation, Ex vivo study, Human tissue, Intestinal mucosa, Intestine epithelium, Monolayer culture, Organoid, Organoids, Review, Stem-cell, Tension, Traction therapy

Underpowered trials risk inaccurate results. Recruitment to stroke rehabilitation randomised controlled trials (RCTs) is often a challenge. Statistical simulations offer an important opportunity to explore the adequacy of sample sizes in the context of specific outcome measures. We aimed to examine and compare the adequacy of stroke rehabilitation RCT sample sizes using the Barthel Index (BI) or modified Rankin Scale (mRS) as primary outcomes.We conducted computer simulations using typical experimental event rates (EER) and control event rates (CER) based on individual participant data (IPD) from stroke rehabilitation RCTs. Event rates are the proportion of participants who experienced clinically relevant improvements in the RCT experimental and control groups. We examined minimum sample size requirements and estimated the number of participants required to achieve a number needed to treat within clinically acceptable boundaries for the BI and mRS.We secured 2350 IPD (18 RCTs). For a 90% chance of statistical accuracy on the BI a rehabilitation RCT would require 273 participants per randomised group. Accurate interpretation of effect sizes would require 1000s of participants per group. Simulations for the mRS were not possible as a clinically relevant improvement was not detected when using this outcome measure.Stroke rehabilitation RCTs with large sample sizes are required for accurate interpretation of effect sizes based on the BI. The mRS lacked sensitivity to detect change and thus may be unsuitable as a primary outcome in stroke rehabilitation trials.Copyright © 2021 Elsevier Inc. All rights reserved.

JTD Keywords:  , barthel index, design, increasing value, modified rankin scale, randomised controlled trials, recruitment, reducing waste, reliability, sample size calculations, simulations, stroke rehabilitation, Adult, Article, Barthel index, Calculation, Computer simulation, Controlled study, Effect size, Female, Human, Human experiment, Major clinical study, Male, Modified rankin scale, Numbers needed to treat, Outcome assessment, Randomised controlled trials, Randomized controlled trial, Randomized controlled-trials, Rankin scale, Recruitment, Rehabilitation, Sample size, Sample size calculations, Simulations, Stroke rehabilitation

Tolerances in the fabrication of metal oxide (MOX) gas sensors lead to inter-device variability in baseline and sensitivity, even for sensors of the same fabrication batch. This has traditionally forced the use of individual calibration models (ICMs) built specifically for each sensor unit, which requires an expensive and time-consuming calibration process and hinders sensor replacement. We propose Global calibration models (GCMs) built using the responses of multiple sensor units, and then applied to a new sensor unit that is not part of the calibration set. GCM have been already successfully applied to transfer calibration models between sensor arrays (electronic noses) for classification tasks. In this work, we investigate the use of such models for regression purposes in temperature-modulated sensors, aiming at the quantification of low concentrations of carbon monoxide (CO) in the presence of variable humidity levels (20–80% r.h. at 26 ± 1 °C). Using a laboratory dataset containing data from 6 replicas of the FIS SB-500–12 model, we evaluate the performance of global models built with data from 1 to 4 sensors when applied to unseen sensor units. Results show that the performance of global models improves with an increasing number of sensors in the calibration set, approaching the performance of individual calibration models (1.38 ± 0.15 ppm for GCM; 1.05 ± 0.24 ppm for ICM), and surpassing their performance only if few calibration conditions per sensor are available (2.09 ± 0.10 ppm for GCM;; 2.76 ± 0.22 ppm for ICM, if only 5 samples per sensor are used).

JTD Keywords: design, recognition, Arrays

JTD Keywords: added value chemicals, amino-acids, catalytic-hydrogenation, climate, design, electrochemical reduction, electroreduction, green co2 conversion to ethanol, nitrogen, photocatalytic reduction, polarized hydroxyapatite, recycling co2, sea-level, Acetone, Added value chemicals, Added-value chemicals, C-c coupling, Calcium apatites, Carbon dioxide, Carbon-dioxide, Co 2 reduction, Co2 reduction, Ethanol, Green co2 conversion to ethanol, Hard tissues, Hydroxyapatite, Mixtures, Morphology, Morphology and composition, Naturally occurring, Organic carbon, Phosphate minerals, Polarized hydroxyapatite, Recycling co2

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, Animals, Biomimetic, Biomimetics, Bone regeneration, Bone scaffolds, Calcium phosphate, Calcium phosphates, Fibula free-flap, Humans, Hydrothermal, In vivo, Osteogenesis, Printing, three-dimensional, Rabbits, Tissue scaffolds

Tricyclic chemical structures are the core of many important drugs targeting all neurotransmitter pathways. These medicines enable effective therapies to treat from peptic ulcer disease to psychiatric disorders. However, when administered systemically, they cause serious adverse effects that limit their use. To obtain localized and on-demand pharmacological action using light, we have designed photoisomerizable ligands based on azobenzene that mimic the tricyclic chemical structure and display reversibly controlled activity. Pseudo-analogues of the tricyclic antagonist pirenzepine demonstrate that this is an effective strategy in muscarinic acetylcholine receptors, showing stronger inhibition upon illumination both in vitro and in cardiac atria ex vivo. Despite the applied chemical modifications to make pirenzepine derivatives sensitive to light stimuli, the most potent candidate of the set, cryptozepine-2, maintained a moderate but promising M-1 vs M-2 subtype selectivity. These photoswitchable crypto-azologs of tricyclic drugs might open a general way to spatiotemporally target their therapeutic action while reducing their systemic toxicity and adverse effects.

JTD Keywords: Binding, Dose-response relationship, drug, Drug design, Humans, M1, Molecular structure, Muscarinic antagonists, Pirenzepine, Rat-brain, Receptor, Receptors, muscarinic, Structure-activity relationship

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)

Enzyme-powered nanomotors are an exciting technology for biomedical applications due to their ability to navigate within biological environments using endogenous fuels. However, limited studies into their collective behavior and demonstrations of tracking enzyme nanomotors in vivo have hindered progress toward their clinical translation. Here, we report the swarming behavior of urease-powered nanomotors and its tracking using positron emission tomography (PET), both in vitro and in vivo. For that, mesoporous silica nanoparticles containing urease enzymes and gold nanoparticles were used as nanomotors. To image them, nanomotors were radiolabeled with either I on gold nanoparticles or F-labeled prosthetic group to urease. In vitro experiments showed enhanced fluid mixing and collective migration of nanomotors, demonstrating higher capability to swim across complex paths inside microfabricated phantoms, compared with inactive nanomotors. In vivo intravenous administration in mice confirmed their biocompatibility at the administered dose and the suitability of PET to quantitatively track nanomotors in vivo. Furthermore, nanomotors were administered directly into the bladder of mice by intravesical injection. When injected with the fuel, urea, a homogeneous distribution was observed even after the entrance of fresh urine. By contrast, control experiments using nonmotile nanomotors (i.e., without fuel or without urease) resulted in sustained phase separation, indicating that the nanomotors’ self-propulsion promotes convection and mixing in living reservoirs. Active collective dynamics, together with the medical imaging tracking, constitute a key milestone and a step forward in the field of biomedical nanorobotics, paving the way toward their use in theranostic applications. 124 18

JTD Keywords: cell, reversal, silica nanoparticles, size, step, transport, Administration, intravesical, Animals, Equipment design, Female, Gold, Metal nanoparticles, Mice, Mice, inbred c57bl, Motion, Phantoms, imaging, Positron emission tomography computed tomography, Precision medicine, Propelled micromotors, Robotics, Translational research, biomedical, Urease, Urinary bladder

© 2020 The Authors Although the concept of selective delivery has been postulated over 100 years ago, no targeted nanomedicine has been clinically approved so far. Nanoparticles modified with targeting ligands to promote the selective delivery of therapeutics towards a specific cell population have been extensively reported. However, the rational design of selective particles is still challenging. One of the main reasons for this is the lack of quantitative theoretical and experimental understanding of the interactions involved in cell targeting. In this review, we discuss new theoretical models and experimental methods that provide a quantitative view of targeting. We show the new advancements in multivalency theory enabling the rational design of super-selective nanoparticles. Furthermore, we present the innovative approaches to obtain key targeting parameters at the single-cell and single molecule level and their role in the design of targeting nanoparticles. We believe that the combination of new theoretical multivalent design and experimental methods to quantify receptors and ligands aids in the rational design and clinical translation of targeted nanomedicines.

JTD Keywords: binding-kinetics, biological identity, biomolecular corona, blood-brain-barrier, drug-delivery, gold nanoparticles, multivalency, nanotechnology, protein corona, quantitative characterization, rational design, super-selectivity, superresolution microscopy, tumor heterogeneity, Ligand-receptor interactions, Multivalency, Nanotechnology, Quantitative characterization, Rational design, Super-selectivity

Engineered immunoglobulin-G molecules (IgGs) are of wide interest for the development of detection elements in protein-based biosensors with clinical applications. The strategy usually employed for the de novo design of such engineered IgGs consists on merging fragments of the three-dimensional structure of a native IgG, which is immobilized on the biosensor surface, and of an antibody with an exquisite target specificity and affinity. In this work conventional and accelerated classical molecular dynamics (cMD and aMD, respectively) simulations have been used to propose two IgG-like antibodies for COVID-19 detection. More specifically, the crystal structure of the IgG1 B12 antibody, which inactivates the human immunodeficiency virus-1, has been merged with the structure of the antibody CR3022 Fab tightly bounded to SARS-CoV-2 receptor-binding domain (RBD) and the structure of the 5309 antibody Fab fragment complexed with SARS-CoV-2 RBD. The two constructed antibodies, named IgG1-CR3022 and IgG1-S309, respectively, have been immobilized on a stable gold surface through a linker. Analyses of the influence of both the merging strategy and the substrate on the stability of the two constructs indicate that the IgG1-S309 antibody better preserves the neutralizing structure than the IgG1-CR3022 one. Overall, results indicate that the IgG1-S309 is appropriated for the generation of antibody based sensors for COVID-19 diagnosis. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.

JTD Keywords: cr3022, igg1, molecular engineering, s309, Antibodies, Antibody engineering, Biosensors, Chemical detection, Clinical application, Cov, Cr3022, Crystal structure, Design, Diseases, Gold nanoparticles, Igg1, Igg1 antibody, Immobilization, Immunoglobulin g, Immunosensor, In-silico, Merging, Molecular dynamics, Molecular engineering, Orientation, Protein-based biosensors, Receptor-binding domains, S309, Sars, Sensor, Spike protein, Target, Vaccine, Viruses

Learning programming and robotics offers the opportunity to practice problem-solving, creativity, and team-work and it provides important competencies to train for the 21st century. However, programming can be challenging, and children may encounter difficulties in learning the syntax or using the coding environment. To address this issue, we have developed a methodology for teaching programming, design and robotics based on inquiry-based learning and hands-on oriented activities together with visual programming. We have applied and evaluated this new methodology within the extracurricular activity of an international elementary school in Barcelona. Our findings showed acquisition and learning of technical language, understanding of electronics devices, understanding the mapping of coding into action via the robot’s behavior. This suggests that our approach is a valid and effective teaching methodology for the instructional design of robotics and programming.

JTD Keywords: Educational technology, Instructional design, Robotics

Articular cartilage tissue possesses poor ability to regenerate; as the lesion progresses, it extends to the underlying subchondral bone and an osteochondral (OC) defect appears complicating the therapeutic approaches. Cartilage tissue engineering has become a very active research area capable of contributing to medical technology innovation. In this regard, the development of new biomaterials in combination with cells represents one of the best alternatives for the treatment of OC injuries. In the last decades, the strategies have been designed without considering the cartilage as a complex tissue with a functionally stratified three-dimensional structure. Today, efforts are focused on creating a starting point in the process of cartilage formation with the development of a multiphase implants that recapitulates the cartilage as an OC unit, which improves its integration. This chapter will focus on a review of tissue engineering based on multiphase designs for cartilage and OC injuries, highlighting the importance of the biomaterial selection, and also the relevance of a biomimetic approach to reach a suitable microenvironment for the differentiation and maturation of the chondral tissue.

JTD Keywords: Osteochondral regeneration, Cartilage tissue engineering, Multiphasic designs, Biofunctionalization, Vascularization

One of the challenges of the robotics community is to develop robots that behave more and more autonomously. Therefore, it is necessary to establish new design criteria, as well as more complex methodologies supporting the analysis of associated risks. The procedure described in this paper includes civil liability as an additional criterion to validate the safety of a surgical robot. In order to understand the concept, a methodology is presented through the description of a simple case. This work aims to establish the basis for a further implementation.

JTD Keywords: Design methodology, Product development, Product liability, Safety, Robotic surgery, Cognitive robotics

Biosensors' research filed has clearly been changing towards the production of multifunctional and innovative design concepts to address the needs related with sensitivity and selectivity of the devices. More recently, waveguide biosensors, that do not require any label procedure to detect biomolecules adsorbed on its surface, have been pointed out as one of the most promising technologies for the production of biosensing devices with enhanced performance. Moreover the combination of optical and electrochemical measurements through the integration of transparent and conducting oxides in the multilayer structures can greatly enhance the biosensors' sensitivity. Furthermore, the integration of polymeric substrates may bring powerful advantages in comparison with silicon based ones. The biosensors will have a lower production costs being possible to disposable them after use ("one use sensor chip"). This research work represents a preliminary study about the influence of substrate temperature on the overall properties of ITO thin films deposited by DC magnetron sputtering onto 0,5 mm thick PMMA sheets.

JTD Keywords: ITO thin films, PMMA sheets, Waveguide biosensing devices, Biosensing devices, Conducting oxides, Dc magnetron sputtering, Electrochemical measurements, Enhanced performance, Innovative design, ITO thin films, Multilayer structures, Overall properties, PMMA sheets, Polymeric substrate, Production cost, Sensor chips, Silicon-based, Substrate temperature, Biosensors, Deposition, Design, Film preparation, Optical multilayers, Thin films, Vapor deposition, Waveguides, Substrates

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

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

A ±1.2V / 350μW integrated front-end architecture for a true/false in-vivo subcutaneous detection device is presented. The detection is focused on using three electrodes amperometric sensors. The powering and AM transcutaneous communication are based on an inductively coupled link working at 13.56 MHz. A prototype device (5.5 mm x 29.5 mm) has been implemented and fully validated.

JTD Keywords: Implantable Device, Front-End architecture, Bioelectronics, Microelectronics Design, Biosensors

The main goal of this work is to propose a haptics guideline in human-robot systems focused on the relationship between the human and robot task, the use of a physical interface and the object to manipulate. With this aim, this guideline presents two main parts: a set of heuristic indicators and a qualitative evaluation. In order to assess its ergonomic validation, an application over a well known haptics interface is presented. The final goal of this work is the study of possible applications in regular laboratory conditions in order to improve the design and use of human-robot haptic interfaces in telerobotics applications.

JTD Keywords: Haptic interface design, Human-robot interaction, Surgical applications, Teleoperation

A statistical factorial analysis approach was conducted on a poroelastic finite element model of a lumbar intervertebral disc to analyse the influence of six material parameters (permeabilities of annulus, nucleus, trabecular vertebral bone, cartilage endplate and Young's moduli of annulus and nucleus) on the displacement, fluid pore pressure and velocity fields. Three different loading modes were investigated: compression, flexion and axial rotation. Parameters were varied considering low and high levels in agreement with values found in the literature for both healthy and degenerated lumbar discs. Results indicated that annulus stiffness and cartilage endplate permeability have a strong effect on the overall fluid- and solid-phase responses in all loading conditions studied. Nucleus stiffness showed its main relevance in compression while annulus permeability influenced mainly the annular pressure field. This study confirms the permeability's central role in biphasic modelling and highlights for the lumbar disc which experiments of material property characterization should be performed. Moreover, such sensitivity study gives important guidelines in poroelastic material modelling and finite element disc validation.

JTD Keywords: Intervertebral disc, Permeability, Fractional factorial design, Design of experiments, Finite element analysis

The 2C-methylerythritol 4-phosphate (MEP) pathway for the biosynthesis of isopentenyl pyrophosphate and its isomer dimethylallyl pyrophosphate, which are the precursors of isoprenoids, is present in plants, in the malaria parasite Plasmodium falciparum and in most eubacteria, including pathogenic agents. However, the MEP pathway is absent from fungi and animals, which have exclusively the mevalonic acid pathway. Given the characteristics of the MEP pathway, its enzymes represent potential targets for the generation of selective antibacterial, antimalarial and herbicidal molecules. We have focussed on the enzyme 4-(cytidine 5'-diphospho)-2-C-methyl-D: -erythritol kinase (CMK), which catalyses the fourth reaction step of the MEP pathway. A molecular dynamics simulation was carried out on the CMK dimer complex, and protein-protein interactions analysed, considering also water-mediated interactions between monomers. In order to find small molecules that bind to CMK and disrupt dimer formation, interactions observed in the dynamics trajectory were used to model a pharmacophore used in database searches. Using an intensity-fading matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry approach, one compound was found to interact with CMK. The data presented here indicate that a virtual screening approach can be used to identify candidate molecules that disrupt the CMK-CMK complex. This strategy can contribute to speeding up the discovery of new antimalarial, antibacterial, and herbicidal compounds.

JTD Keywords: Solvent-mediated interactions, Protein-protein interactions, Molecular dynamics, Drug design, Intensisty-fading MALDI-TOF mass spectrometry

In a previous work, we studied the interaction of β-amyloid fibrils (Aβ) with gold nanoparticles (AuNP) conjugated with the peptide CLPFFD-NH2. Here, we studied the effect of changing the residue sequence of the peptide CLPFFD-NH2 on the efficiency of conjugation to AuNP, the stability of the conjugates, and the affinity of the conjugates to the Aβ fibrils. We conjugated the AuNP with CLPFFD-NH2 isomeric peptides (CDLPFF-NH2 and CLPDFF-NH2) and characterized the resulting conjugates with different techniques including UV−Vis, TEM, EELS, XPS, analysis of amino acids, agarose gel electrophoresis, and CD. In addition, we determined the proportion of AuNP bonded to the Aβ fibrils by ICP-MS. AuNP-CLPFFD-NH2 was the most stable of the conjugates and presented more affinity for Aβ fibrils with respect to the other conjugates and bare AuNP. These findings help to better understand the way peptide sequences affect conjugation and stability of AuNP and their interaction with Aβ fibrils. The peptide sequence, the steric effects, and the charge and disposition of hydrophilic and hydrophobic residues are crucial parameters when considering the design of AuNP peptide conjugates for biomedical applications.

JTD Keywords: Self-assembled monolayers, Aggregation, Dispersions, Adsorption, Particles, Design, Size