In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

Recent research has demonstrated that all body fluids assessed contain substantial amounts of vesicles that range in size from 30 to 1000 nm and that are surrounded by phospholipid membranes containing different membrane microdomains such as lipid rafts and caveolae. The most prominent representatives of these so-called extracellular vesicles (EVs) are nanosized exosomes (70-150 nm), which are derivatives of the endosomal system, and microvesicles (100-1000 nm), which are produced by outward budding of the plasma membrane. Nanosized EVs are released by almost all cell types and mediate targeted intercellular communication under physiological and pathophysiological conditions. Containing cell-type-specific signatures, EVs have been proposed as biomarkers in a variety of diseases. Furthermore, according to their physical functions, EVs of selected cell types have been used as therapeutic agents in immune therapy, vaccination trials, regenerative medicine, and drug delivery. Undoubtedly, the rapidly emerging field of basic and applied EV research will significantly influence the biomedicinal landscape in the future. In this Perspective, we, a network of European scientists from clinical, academic, and industry settings collaborating through the H2020 European Cooperation in Science and Technology (COST) program European Network on Microvesicles and Exosomes in Health and Disease (ME-HAD), demonstrate the high potential of nanosized EVs for both diagnostic and therapeutic (i.e., theranostic) areas of nanomedicine.

Titanium and titanium alloys exhibit a unique combination of strength and biocompatibility, which enables their use in medical applications and accounts for their extensive use as implant materials in the last 50 years. Currently, a large amount of research is being carried out in order to determine the optimal surface topography for use in bioapplications, and thus the emphasis is on nanotechnology for biomedical applications. It was recently shown that titanium implants with rough surface topography and free energy increase osteoblast adhesion, maturation and subsequent bone formation. Furthermore, the adhesion of different cell lines to the surface of titanium implants is influenced by the surface characteristics of titanium; namely topography, charge distribution and chemistry. The present review article focuses on the specific nanotopography of titanium, i.e. titanium dioxide (TiO2) nanotubes, using a simple electrochemical anodisation method of the metallic substrate and other processes such as the hydrothermal or sol-gel template. One key advantage of using TiO2 nanotubes in cell interactions is based on the fact that TiO2 nanotube morphology is correlated with cell adhesion, spreading, growth and differentiation of mesenchymal stem cells, which were shown to be maximally induced on smaller diameter nanotubes (15 nm), but hindered on larger diameter (100 nm) tubes, leading to cell death and apoptosis. Research has supported the significance of nanotopography (TiO2 nanotube diameter) in cell adhesion and cell growth, and suggests that the mechanics of focal adhesion formation are similar among different cell types. As such, the present review will focus on perhaps the most spectacular and surprising one-dimensional structures and their unique biomedical applications for increased osseointegration, protein interaction and antibacterial properties.

Abstract. Phospholipid membrane forming a closed surface and decorated with anisotropic inclusions is considered. The inclusions are free to redistribute laterally over the membrane and to orient in the plane of the membrane according to the local membrane curvature. A phenomenological expression for the energy of the interaction between an inclusion and local curvature of the surrounding membrane is proposed. Considering this single-inclusion energy, and assuming thermodynamic equilibrium, the free energy of the inclusions, and the consistently related lateral and orientational distributions of the inclusions are obtained using statistical mechanical methods. For a vesicle shape with given surface area, enclosed volume, and total amount of inclusions, the free energy is in general given in a nonlocal form (i.e. it can not be expressed as an integral of its area density over the membrane area). The limits of weak and strong orientational ordering are considered. Specifically, it is shown that in the shape sequence representing the formation of an exovesicle the effect of the membrane curvature on the orientation of the inclusions may stabilize the shape where the exovesicle and the cell are connected by a narrow neck. PACS. 05.70.Np Interface and surface thermodynamics -87.16.Dg Membranes, bilayers and vesiclesThe system considered is composed of a continuum of phospholipid molecules into which anisotropic laterally mobile molecules are embedded. It was determined that embedding a molecule into the membrane may involve several kT of energy [1]. Thus it can be expected that the embedded molecules may considerably influence the membrane free energy and also the equilibrium vesicle shape. The effect of the embedded molecules on the vesicle shape was also observed in experiments [2,3].In previous works, nonuniform lateral distribution of the embedded molecules was theoretically described by taking into account the interdependence between the local membrane curvature and the lateral density of the embedded molecules [4,5], while orientation of the anisotropic embedded molecules in the local curvature field was studied [6] by considering the area density of the embedded molecules to be uniform. In this work we present a consistent description of both, the nonuniform lateral distribution and the orientational ordering of the membrane constituents.Below we employ the term inclusion for an entity consisting of the embedded molecule and some lipids that are significantly distorted due to the presence of the embeda e-mail: vera.kralj-iglic@biofiz.mf.uni-lj.si b Present address: Dept. of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA ded molecule. It is imagined that there exists a local membrane shape (and orientation) which fits the inclusion. We will refer to this shape as to the intrinsic shape of the inclusion. As the region where the configuration of the lipid molecules is significantly distorted is small with respect to the lateral membrane dimensions [7], the inclusions are fo...

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