Publications

Phenotypic targeting requires the ability of the drug delivery system to discriminate over cell populations expressing a particular receptor combination. Such selectivity control can be achieved using multiplexed-multivalent carriers often decorated with multiple ligands. Here, we demonstrate that the promiscuity of a single ligand can be leveraged to create multiplexed-multivalent carriers achieving phenotypic targeting. We show how the cellular uptake of poly(2-(methacryloyloxy)ethyl phosphorylcholine)-poly(2-(diisopropylamino)ethyl methacry-late) (PMPC-PDPA) polymersomes varies depending on the receptor expression among different cells. We investigate the PMPC-PDPA polymersome insertion at the single chain/receptor level using all-atom molecular modeling. We propose a theoretical statistical mechanics-based model for polymersome-cell association that explicitly considers the interaction of the polymersome with the cell glycocalyx shedding light on its effect on the polymersome binding. We validate our model experimentally and show that the binding energy is a nonlinear function, allowing us to tune the interaction by varying the radius and degree of polymerization. Finally, we show that PMPC-PDPA polymersomes can be used to target monocytes in vivo due to their promiscuous interaction with SRB1, CD36, and CD81.© 2022 The Authors. Published by American Chemical Society.

JTD Keywords: binding, cd36, multivalency, ph, scavenger receptor, sr-bi, B type-i

Polypeptide-based nanoparticles offer unique advantages from a nanomedicine perspective such as biocompatibility, biodegradability, and stimuli-responsive properties to (patho)physiological conditions. Conventionally, self-assembled polypeptide nanostructures are prepared by first synthesizing their constituent amphiphilic polypeptides followed by postpolymerization self-assembly. Herein, we describe the one-pot synthesis of oxidation-sensitive supramolecular micelles and vesicles. This was achieved by polymerization-induced self-assembly (PISA) of the N-carboxyanhydride (NCA) precursor of methionine using poly(ethylene oxide) as a stabilizing and hydrophilic block in dimethyl sulfoxide (DMSO). By adjusting the hydrophobic block length and concentration, we obtained a range of morphologies from spherical to wormlike micelles, to vesicles. Remarkably, the secondary structure of polypeptides greatly influenced the final morphology of the assemblies. Surprisingly, wormlike micellar morphologies were obtained for a wide range of methionine block lengths and solid contents, with spherical micelles restricted to very short hydrophobic lengths. Wormlike micelles further assembled into oxidation-sensitive, self-standing gels in the reaction pot. Both vesicles and wormlike micelles obtained using this method demonstrated to degrade under controlled oxidant conditions, which would expand their biomedical applications such as in sustained drug release or as cellular scaffolds in tissue engineering.

JTD Keywords: alpha-amino-acid, hydrogels, leuchs anhydrides, platform, polypeptides, transformation, triggered cargo release, Amino acids, Amphiphilics, Biocompatibility, Biodegradability, Block lengths, Controlled drug delivery, Dimethyl sulfoxide, Ethylene, Gels, Hydrophobicity, Medical nanotechnology, Methionine, Micelles, Morphology, One-pot synthesis, Organic solvents, Oxidation, Physiological condition, Polyethylene oxides, Post-polymerization, Ring-opening polymerization, Scaffolds (biology), Self assembly, Stimuli-responsive properties, Supramolecular chemistry, Supramolecular gels, Supramolecular micelles, Wormlike micelle

Purpose: This paper aims to explore how the cross-fertilization of knowledge and technologies in EU-funded research projects, including serious games and gamification, is influenced by the following variables: multidisciplinarity, knowledge base and organizations (number and diversity). The interrelation of actors and projects form a network of innovation. The largest contribution to cross-fertilization comes from the multidisciplinary nature of projects and the previous knowledge and technology of actors. The analysis draws on the understanding of how consortia perform as an innovation network, what their outcomes are and what capabilities are needed to reap value. Design/methodology/approach: All the research projects including serious games and/or gamification, funded by the EU-Horizon 2020 work programme, have been analyzed to test the hypotheses in this paper. The study sample covers the period between 2014 and 2016 (June), selecting the 87 research projects that comprised 519 organizations as coordinators and participants, and 597 observations – because more organizations participate in more than one project. The data were complemented by documentary and external database analysis. Findings: To create cross-fertilization of knowledge and technologies, the following emphasis should be placed on projects: partners concern various disciplines; partners have an extensive knowledge base for generating novel combinations and added-value technologies; there is a diverse typology of partners with unique knowledge and skills; and there is a limited number of organizations not too closely connected to provide cross-fertilization. Research limitations/implications: First, the database sample covers a period of 30 months. The authors’ attention was focused on this period because H2020 prioritized for the first time the serious games and gamification with two specific calls (ICT-21–14 and ICT-24–16) and, second, for the explosion of projects including these technologies in the past years (Adkins, 2017). These facts can be understood as a way to push the research to higher technology readiness levels (TRLs) and introducing the end-user in the co-creation and co-development along the value chain. Second, an additional limitation makes reference to the European focus of the projects, missing strong regional initiatives not identified and studied. Originality/value: This paper has attempted to explore and define theoretically and empirically the characteristics found in the cross-fertilization of collaborative research projects, emphasizing which variables, and how, need to be stimulated to benefit more multidisciplinary consortia and accelerate the process of innovation. © 2021, Manel González-Piñero, Cristina Páez-Avilés, Esteve Juanola-Feliu and Josep Samitier.

JTD Keywords: absorptive-capacity, business model, cross-fertilization of knowledge, diversity, front-end, impact, innovation systems, knowledge management, management research, science, social networks, team, technology, Cross-fertilization of knowledge, Innovation, Knowledge management, Management research, Research-and-development, Technology

Background & AimsLiver stiffness is increased in advanced chronic liver disease (ACLD) and accurately predicts prognosis in this population. Recent data suggest that extracellular matrix stiffness per se may modulate the phenotype of liver cells. We aimed at investigating the effect of matrix stiffness on the phenotype of liver cells of rats with cirrhosis, assessing its influence on their response to antifibrotic strategies and evaluating associated molecular mechanisms.

JTD Keywords: Chronic liver disease, Hepatocyte, HSC, LSEC, Stiffness

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

JTD Keywords: Tissue differentiation, Computational analysis, Mechanical conditions, Bone regeneration, Weight-bearing, Proliferation, Osteoblast, Stiffness, Ingrowth, Scaffold