Blood derivatives awaken in regenerative medicine strategies to modulate wound healing

Blood components play key roles in the modulation of the wound healing process and, together with the provisional fibrin matrix ability to selectively bind bioactive molecules and control its spatial-temporal presentation, define the complex microenvironment that characterize this biological process. As a biomimetic approach, the use of blood derivatives in regenerative strategies has awakened as a source of multiple therapeutic biomolecules. Nevertheless, and despite their clinical relevance, blood derivatives have been showing inconsistent therapeutic results due to several factors, including proper control over their delivery mechanisms. Herein, we highlight recent trends on the use biomaterials to protect, sequester and deliver these pools of biomolecules in tissue engineering and regenerative medicine approaches. Particular emphasis is given to strategies that enable to control their spatiotemporal delivery and improve the selectivity of presentation profiles of the biomolecules derived from blood derivatives rich in platelets. Finally, we discussed possible directions for biomaterials design to potentiate the aimed regenerative effects of blood derivatives and achieve efficient therapies.BBM acknowledges the financial support from FCT/MCTES (Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia, e Ensino Superior) and the Fundo Social Europeu através do Programa Operacional do Capital Humano (FSE/POCH), PD/59/2013 for PD/BD/113807/2015. MGF acknowledges European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 706996 (PrinTendon). PB acknowledges RECOGNIZE and NORTE2020 (UTAP-ICDT/CTM-BIO/0023/2014). RMD acknowledges SFRH/BPD/112459/2015.info:eu-repo/semantics/publishedVersio

Injectable and magnetic responsive hydrogels with bioinspired ordered structures

Injectable hydrogels are particularly interesting for applications in minimally invasive tissue engineering and regenerative medicine strategies. However, the typical isotropic microstructure of these biomaterials limits their potential for the regeneration of ordered tissues. In the present work, we decorated rod-shaped cellulose nanocrystals with magnetic nanoparticles and coated these with polydopamine and polyethylene glycol polymer brushes to obtain chemical and colloidal stable nanoparticles. Then, these nanoparticles (0.1-0.5 wt %) were incorporated within gelatin hydrogels, creating injectable and magnetically responsive materials with potential for various biomedical applications. Nanoparticle alignment within the hydrogel matrix was achieved under exposure to uniform low magnetic fields (108 mT), resulting in biomaterials with directional microstructure and anisotropic mechanical properties. The biological performance of these nanocomposite hydrogels was studied using adipose tissue derived human stem cells. Cells encapsulated in the nanocomposite hydrogels showed high rates of viability demonstrating that the nanocomposite biomaterials are not cytotoxic. Remarkably, the microstructural patterns stemming from nanoparticle alignment induced the directional growth of seeded and, to a lower extent, encapsulated cells in the hydrogels, suggesting that this injectable system might find application in both cellular and acellular strategies targeting the regeneration of anisotropic tissues.Fundação para a Ciência e a Tecnologia for SFRH/BPD/112459/2015 (RD), EU’s H2020 programme for Marie Skłodowska-Curie grant agreement 706996 and for European Research Council grant agreement 772817 - MagTendon, project RECOGNIZE (UTAPICDT/CTM-BIO/0023/2014), project FOOD4CELLS (PTDC/CTM-BIO/4706/2014 - POCI-01- 0145-FEDER 016716) (PB), and project NORTE-01-0145-FEDER-000021

Human-based fibrillar nanocomposite hydrogels as bioinstructive matrices to tune stem cell behavior

The extracellular matrix (ECM)-biomimetic fibrillar structure of platelet lysate (PL) gels along with its enriched milieu of biomolecules has drawn significant interest in regenerative medicine applications. However, PL-based gels have poor structural stability which severely limits its performance as a bioinstructive biomaterial. Here, rod-shaped cellulose nanocrystals (CNC) are used as a novel approach to modulate the physical and biochemical microenvironment of PL gels enabling their effective use as injectable human-based cell scaffolds with a level of biomimicry that is difficult to recreate with synthetic biomaterials. The incorporation of CNC (0 to 0.61 wt.%) into the PL fibrillar network during the coagulation cascade leads to decreased fiber branching, increased interfiber porosity (from 66 to 83%) and modulate fiber (from 1.4 ± 0.7 to 27 ± 12 kPa) and bulk hydrogel (from 18 ± 4 to 1256 ± 82 Pa) mechanical properties. As result of these physicochemical alterations, nanocomposite PL hydrogels resist to the typical extensive clot retraction (from 76 ± 1 to 24 ± 3 at Day 7) and show favored retention of PL bioactive molecules. The feedback of these cues on the fate of human adipose-derived stem cells is evaluated, showing how it can be explored to modulate the commitment of encapsulated stem cells toward different genetic phenotypes without the need for additional external biological stimuli. These fibrillar nanocomposite hydrogels allow therefore to explore the outstanding biological properties of human-based PL as an efficient engineered ECM which can be tailored to trigger specific regenerative pathways in minimal invasive strategies.The authors thank the Hospital da Prelada (Porto, Portugal) for providing adipose tissue samples. The authors acknowledge the financial support from project Recognize (UTAP-ICDT/CTM-BIO/0023/2014), project NORTE-01-0145FEDER-000021 supported by the Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), the European Union Framework Programme for Research and Innovation HORIZON 2020, under the TEAMING Grant agreement No. 739572 – The Discoveries CTR EU, Forecast 668983, Marie Skłodowska-Curie grant agreement No. 706996 (PrinTendon) and CHEM2NATURE 692333; FCT/MCTES (Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia, e Ensino Superior) and the Fundo Social Europeu através do Programa Operacional do Capital Humano (FSE/POCH) in the framework of PhD grant PD/59/2013 – PD/BD/113807/2015 for BBM, Post-Doc grant SFRH/BPD/112459/2015 for R.D.info:eu-repo/semantics/publishedVersio

Searches for Ultra-High-Energy Photons at the Pierre Auger Observatory

The Pierre Auger Observatory, being the largest air-shower experiment in the world, offers an unprecedented exposure to neutral particles at the highest energies. Since the start of data taking more than 18 years ago, various searches for ultra-high-energy (UHE, $E\gtrsim10^{17}\,\text{eV}$) photons have been performed: either for a diffuse flux of UHE photons, for point sources of UHE photons or for UHE photons associated with transient events like gravitational wave events. In the present paper, we summarize these searches and review the current results obtained using the wealth of data collected by the Pierre Auger Observatory.Comment: Review article accepted for publication in Universe (special issue on ultra-high energy photons

A combined fit of energy spectrum, shower depth distribution and arrival directions to constrain astrophysical models of UHECR sources

The combined fit of the measured energy spectrum and distribution of depths of shower maximum of ultra-high-energy cosmic rays is known to constrain the parameters of astrophysical scenarios with homogeneous source distributions. Further measurements show that the cosmic-ray arrival directions agree better with the directions and fluxes of catalogs of starburst galaxies and active galactic nuclei than with isotropy. Here, we present a novel combination of both analyses. For that, a three-dimensional universe model containing a nearby source population and a homogeneous background source distribution is built, and its parameters are adapted using a combined fit of the energy spectrum, depth of shower maximum distribution and energy-dependent arrival directions. The model takes into account a symmetric magnetic field blurring, source evolution and interactions during propagation. We use simulated data, which resemble measurements of the Pierre Auger Observatory, to evaluate the method’s sensitivity. With this, we are able to verify that the source parameters as well as the fraction of events from the nearby source population and the size of the magnetic field blurring are determined correctly, and that the data is described by the fitted model including the catalog sources with their respective fluxes and three-dimensional positions. We demonstrate that by combining all three measurements we reach the sensitivity necessary to discriminate between the catalogs of starburst galaxies and active galactic nuclei

Status and performance of the underground muon detector of the Pierre Auger Observatory

The Auger Muons and Infill for the Ground Array (AMIGA) is an enhancement of the Pierre Auger Observatory, whose purpose is to lower the energy threshold of the observatory down to 1016.5 eV, and to measure the muonic content of air showers directly. These measurements will significantly contribute to the determination of primary particle masses in the range between the second knee and the ankle, to the study of hadronic interaction models with air showers, and, in turn, to the understanding of the muon puzzle. The underground muon detector of AMIGA is concomitant to two triangular grids of water-Cherenkov stations with spacings of 433 and 750 m; each grid position is equipped with a 30 m2 plastic scintillator buried at 2.3 m depth. After the engineering array completion in early 2018 and general improvements to the design, the production phase commenced. In this work, we report on the status of the underground muon detector, the progress of its deployment, and the performance achieved after two years of operation. The detector construction is foreseen to finish by mid-2022

Constraining Lorentz Invariance Violation using the muon content of extensive air showers measured at the Pierre Auger Observatory

Lorentz Invariance (LI) implies that the space-time structure is the same for all observers. On the other hand, various quantum gravity theories suggest that it may be violated when approaching the Planck scale. At extreme energies, like those available in the collision of Ultra-High Energy Cosmic Rays (UHECRs) with atmosphere nuclei, one should also expect a change in the interactions due to Lorentz Invariance Violation (LIV). In this work, the effects of LIV on the development of Extensive Air Showers (EAS) have been considered. After having introduced LIV as a perturbation term in the single-particle dispersion relation, a library of simulated showers with different energies, primary particles and LIV strengths has been produced. Possible LIV has been studied using the muon content of air showers measured at the Pierre Auger Observatory. Limits on LIV parameters have been derived from a comparison between the Monte Carlo expectations and muon fluctuation measurements from the Pierre Auger Observatory

A search for ultra-high-energy photons at the Pierre Auger Observatory exploiting air-shower Universality

The Pierre Auger Observatory is the most sensitive detector to primary photons with energies above ∼ 0.2 EeV. It measures extensive air showers using a hybrid technique that combines a fluorescence detector (FD) with a ground array of particle detectors (SD). The signatures of a photon-induced air shower are a larger atmospheric depth at the shower maximum (Xmax) and a steeper lateral distribution function, along with a lower number of muons with respect to the bulk of hadron-induced background. Using observables measured by the FD and SD, three photon searches in different energy bands are performed. In particular, between threshold energies of 1–10 EeV, a new analysis technique has been developed by combining the FD-based measurement of Xmax with the SD signal through a parameter related to its muon content, derived from the universality of the air showers. This technique has led to a better photon/hadron separation and, consequently, to a higher search sensitivity, resulting in a tighter upper limit than before. The outcome of this new analysis is presented here, along with previous results in the energy ranges below 1 EeV and above 10 EeV. From the data collected by the Pierre Auger Observatory in about 15 years of operation, the most stringent constraints on the fraction of photons in the cosmic flux are set over almost three decades in energy

Study on multi-ELVES in the Pierre Auger Observatory

Since 2013, the four sites of the Fluorescence Detector (FD) of the Pierre Auger Observatory record ELVES with a dedicated trigger. These UV light emissions are correlated to distant lightning strikes. The length of recorded traces has been increased from 100 μs (2013), to 300 μs (2014-16), to 900 μs (2017-present), to progressively extend the observation of the light emission towards the vertical of the causative lightning and beyond. A large fraction of the observed events shows double ELVES within the time window, and, in some cases, even more complex structures are observed. The nature of the multi-ELVES is not completely understood but may be related to the different types of lightning in which they are originated. For example, it is known that Narrow Bipolar Events can produce double ELVES, and Energetic In-cloud Pulses, occurring between the main negative and upper positive charge layer of clouds, can induce double and even quadruple ELVES in the ionosphere. This report shows the seasonal and daily dependence of the time gap, amplitude ratio, and correlation between the pulse widths of the peaks in a sample of 1000+ multi-ELVES events recorded during the period 2014-20. The events have been compared with data from other satellite and ground-based sensing devices to study the correlation of their properties with lightning observables such as altitude and polarity