Raquel Yotti, Carlos III Health Institute, Director
Ramón Martínez Máñez, CIBER-BBN Scientific Director
Chair: Raimon Jané
Atrial flutter and atrial fibrillation – Modeling meets biosignal analysis
Olaf Dössel, Karlsruhe Institute of Technology
Chair: M. Pilar Marco
Xavier Trepat, Institute for Bioengineering of Catalonia (IBEC)
Chair: Ramón Martínez Máñez
Hybrid (nano)materials for biomedical applications
Luisa De Cola, University of Milan
Chair: Ramon Mangues
Chair: Ramón Martínez Máñez
María Luz Martínez Chantar, CIC BIOGUNE
Chair: Simó Schwartz
Drug delivery across biological barriers for combatting and preventing infectious diseases
Claus-Michael Lehr, Helmholtz Institute for Pharmaceutical Research, Saarland
Chair: Ramón Martínez Máñez
Nuria Oliver, Commissioner for the President of the Valencian Region
Chair: M. Pilar Marco
Gema Martínez Navarrete, Miguel Hernández University & Gustavo Puras, University of Basque Country
Chair: José Becerra
Nuria Vilaboa, La Paz Hospital, Madrid
Chair: Jaume Veciana
Smart-4-Fabry European project was conceived to bring a peptide-functionalized nanoliposomal formulation of α-galactosidase enzyme, developed under the frame of an interdisciplinary CIBER-BBN project, to pre-clinical regulatory testing for the treatment of Fabry disease.
In this communication will be disclosed the keys of the successful implementation of this project and the contribution of the Singular Scientific and Technical Infrastructure (ICTS) NANBIOSIS to them.
The ideal moment to withdraw respiratory supply of patients under Mechanical Ventilation (MV) at Intensive Care Units (ICU), is not easy to be determined for clinicians. Although the Spontaneous Breathing Trial (SBT) provides a measure of the patients' readiness, there is still around 15-20% of predictive failure rate. This work explores both Heart Rate Variability (HRV) and Cardiopulmonary Coupling (CPC) estimates as complementary information for readiness prediction. The CPC is related to how the mechanisms regulating respiration and cardiac pumping are working simultaneously, and it is defined from HRV in combination with respiratory information. Three different techniques are used to measure CPC, including Orthogonal Subspace Projections, Dynamic Mutual Information and Time-Frequency Coherence.
Twenty-two patients undergoing SBT in pressure support ventilation were analysed in the 24 hours previous to the SBT. Twelve had a successful weaning and ten failed the SBT or needed reintubation, being both considered as failed weaning. Results indicate that variables such as heart rate, respiratory frequency, and the parameters derived from HRV do not differ in patients with successful or failed weaning. However, significant statistical differences were found for the CPC parameters, throughout the whole recordings, comparing the values of the two groups. In addition, observations during the night prior to SBT, which is the moment where CPC mechanisms are stronger, is the moment where differences are higher. This is probably because patients with failed weaning might be experiencing more apnea events during the night, which is directly related to a reduced RSA.
Therefore, results suggest that the traditional measures could be used in combination with these CPC biomarkers to help clinicians better predict if patients are ready to be weaned.
Atherosclerosis plaque is one of the major health problems worldwide, it is the leading cause of death according to the world health organisation. One of the main problems is the detection of early, very small plaques by non-invasive imaging techniques. At this early stage is when preventive measures and therapeutic approaches could be more effective. Currently there are no tracers able to detect the plaque at this early stage.
Our collaboration is focused on the development of a new concept for the diagnosis of early stage atherosclerosis plaques. Our target marker is oxidized low-density lipoprotein (oxLDL), that plays an important role in the initiation and progression of atherosclerosis. Our contrast agent is a functionalized 68Ga iron oxide nanoparticle that provides simultaneous PET and T1-MRI signals. For the selective accumulation of our particles in the desired areas we use a bioorthogonal reaction between trans-cyclooctene (TCO) and tetrazine (TZ) derivatives.
To test the validity of our design, a mouse model of atherosclerosis was sequentially injected with trans-cyclooctene-modified antibodies against oxidized LDL followed by a tetrazine functionalized 68Ga iron oxide nanoparticles. Our results demonstrate the ability of this approach to unambiguously detect atherosclerosis.
Epithelial repair and regeneration are driven by collective cell migration and division. Both cellular functions involve tightly controlled mechanical events, but how physical forces regulate cell division in migrating epithelia is largely unknown. In this collaboration we show that cells dividing in the migrating zebrafish epicardium exert large cell-extracellular matrix (ECM) forces during cytokinesis. These forces point towards the division axis and are exerted through focal adhesions that connect the cytokinetic ring to the underlying ECM. When subjected to high loading rates, these cytokinetic focal adhesions prevent closure of the contractile ring, leading to multi-nucleation through cytokinetic failure. By combining a clutch model with experiments on substrates of different rigidity, ECM composition and ligand density, we show that failed cytokinesis is triggered by adhesion reinforcement downstream of increased myosin density. The mechanical interaction between the cytokinetic ring and the ECM thus provides a mechanism for the regulation of cell division and polyploidy that may have implications in regeneration and cancer.
Metabolism reprogramming is considered a hallmark of cancer. The study of bladder cancer (BC) metabolism could be the key to developing new strategies for diagnosis and therapy. This work aimed to identify tissue and urinary metabolic signatures as biomarkers of BC and get further insight into BC tumor biology through the study of gene-metabolite networks and the integration of metabolomics and transcriptomics data. The metabolic profile allowed for the classification of BC tissue samples with a sensitivity and specificity of 100%. The most discriminant metabolites for BC tissue samples reflected alterations in amino acids, glutathione, and taurine metabolic pathways. Transcriptomic data supported metabolomic results and revealed a predominant downregulation of metabolic genes belonging to phosphorylative oxidation, tricarboxylic acid cycle, and amino acid metabolism. The urinary profiling study showed a relation with taurine and other amino acids perturbed pathways observed in BC tissue samples, and classified BC from non-tumor urine samples with good sensitivities (91%) and specificities (77%). This urinary profile could be used as a non-invasive tool for BC diagnosis and follow-up.
Breast carcinoma being the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. Among one million cases of breast cancer diagnosed each year, approximately 15 % are characterized as triple-negative (triple negative breast cancer, TNBC), lacking the expression of estrogen receptor (ER), progesterone receptor (PgR) and HER2/neu receptor. Absence of effective therapies, younger age of onset, and early metastatic spread have contributed to the poor prognoses and outcomes associated with this malignancy. Evidences that breast cancer maintenance, resistance to therapy and metastatic disease are sustained by cancer stem cells (CSC) are recently accumulating. In breast cancer, these cells correspond to a small fraction of cells within the tumor that express stem cell markers (CD44+/CD24-/low/lin-) and have the ability to grow as spheres and differentiate into defined progenies, and initiate and sustain tumor growth in vivo. In this regard, new therapies against TNBC should compile two requirements: (i) reduce the toxicity seen in combination therapies and most importantly, (ii) specifically target and eliminate CSCs. Following this concept, in the PENTRI project we first explored ligands of cell surface proteins overexpressed in populations of TNBC cells, including nucleolin, CXCR1, CMKLR1 or chemerin receptor and CD44v6 as well as CSC-specific drugs such niclosamide, citral and 8-quinolinol. Then, different peptide and protein constructs were developed to ensure the feasibility of the CSC targeting in TNBC in vitro and in vivo models. Finally, different drug delivery systems were tested in relevant in vivo models, including targeted and un-targeted polymeric micelles for the delivery of CSC-specific drugs, second-generation protein nanoparticles incorporating the policationic RKRKRKRK motif and the PE24 therapeutic domain, CD44-targerted inclusion bodies with p31 or Oncomyc as therapeutic domain. Overall, our results indicate that addressing CSC population, by means of specific therapeutic entities and targeting-moieties, increases the therapeutic window of either classic or novel anti-cancer therapies in TNBC.
The urgent need of more efficient therapeutic platforms in cancer push towards the development of nanoscale drugs targeting metastatic stem cells. We have approached this issue by the design of modular, fully functional proteins with the ability to self-assemble into nanoparticles of controlled size and to target and internalize cancer stem cells through solvent-exposed specific receptors. These nanoparticles have been tailored as vehicles for conventional anti-tumor drugs, to increase their selectivity and decrease their toxicity through an improved biodistribution. However, the same protein-based platform can be re-designed into tumor-targeted, intrinsically therapeutic protein-only nanoparticles. In absence of any external vehicle, these materials perform as both drug and carrier simply by incorporating a therapeutic domain with anti-tumor activity. On the other hand, these protein drugs are delivered by conventional venous administration but also from a novel type of artificial secretory granuls that act as long-term protein depots. Administered as subcutaneous nano-implants they release, in a time-prolonged way, efficient tumor-targeted nanoparticles, in a protocol that can expand in time the need of doses in the administration regimen. This new therapeutic protein platform has probed potent antimetastatic activity in colorectal cancer, AML and lymphoma orthotopic mouse models, improving conventional chemotherapy achievements.
These discoveries are the result of an extensive and enriching collaboration between the groups of Ramon Mangues, from the Research Institute of the Hospital de la Santa Cruz y San Pablo, and the group of Esther Vázquez and Antonio Villaverde in the Autonomous University of Barcelona. This collaboration has been driven through 4 intramural seminal projects: NANOSCAPE (coordinated by U. Unzueta), 4NANOMETS (coordinated by R. Mangues), NANOREMOTE (coordinated by E. Vázquez) and VENOM4CANCER (coordinated by A. Villaverde), that acted as seeds to obtain additional funding from external funding agencies.
Catheter ablation may be curative and is an effective treatment option for scar-related VT patients in whom antiarrhythmic drug therapy is ineffective. During catheter ablation using electanatomical mapping (EAM) systems, voltage mapping helps in identifying the arrhythmogenic substrate of scar-related ventricular arrhytmias (VAs). Slow conducting channels (SCCs), defined by the presence of electrogram (EGM) signals with delayed components (EGM-DC), are responsible for sustaining VAs and constitute potential ablation targets. However, voltage mapping, is time-consuming, requiring a manual analysis of all EGMs to detect SCCs, and its accuracy is limited by electric far-field. We introduce and evaluate a signal processing algorithm that automatically identifies EGM-DC, classifies EAM mapping points, and creates new voltage maps, named “Slow Conducting Channel Maps” (SCC-Maps).
Retrospective analysis of EAM maps from 20 patients (10 ischemic, 10 with arrhythmogenic right ventricular dysplasia/cardiomyopathy) was performed. EAM voltage maps were acquired during sinus rhythm and used for guiding ablation. Preprocedural contrast enhanced cardiac magnetic resonance (Ce-CMR) imaging was available for the ischemic population. The ability of EAM voltage maps, Ce-CMR maps and the proposed SCC maps in identifying SCCs was compared and their agreement was evaluated. The proposed SCC-Maps identify a superior number of SCCs compared to EAM voltage maps and comparable with Ce-CMR maps in the ischemic population. We conclude that the SCC-Mapping algorithm allows an operator-independent analysis of EGM signals showing better identification of the arrhythmogenic substrate characteristics when compared to EAM voltage maps.
Recently, novel definitions of Alzheimer’s disease (AD) and the concept of resilience to AD have emerged. For research purposes, Alzheimer’s disease is defined as the presence of abnormal levels of biomarkers for the pathological hallmarks of the disease, namely amyloid-β and tau, irrespective of cognition. Besides, the heterogeneity in cognitive impairment that can be observed in different individuals with similar levels of AD pathology is explained through the concepts of ‘resistance’ and ‘resilience’ to AD. ‘Resistance’ stands for factors that promote avoiding the onset of AD pathologies whereas ‘resilience’ encompasses the concept of being able to better coping with such pathologies.
This presentation will review the novel research diagnostic framework and the concepts of resistance and resilience to AD, along with novel insights on protective and risk factors obtained in the study of the ALFA cohort from the Pasqual Maragall Foundation.
Complex diseases such those that affect to the retina require a coordinated and multidisciplinary approach to design safe and efficient therapeutic strategies. We present a successful intramural collaboration project for the design and evaluation of novel non-viral vectors based on cationic niosomes to face retinal diseases by gene therapy approach.
Cell macroencapsulation has shown a great potential overcoming the low survival of the transplanted pancreatic islets in the Type 1 Diabetes Mellitus (T1DM) treatment, as it avoids the need for lifelong immunosuppression. It is still not completely known how these devices interact with the host immune system when implanted. However, their surface properties seem to be crucial factors for a successful implant. In this context, the hydrophilicity and porosity of the surface of the macrocapsules are two of the most important properties that can affect the functionality of the graft; hydrophilicity defines the interactions with the host's immune cells, while the porosity determines the biosafety of the device while conditioning the oxygen, nutrients and insulin diffusion. Here, we report a novel β-cell macroencapsulation system that combines an injectable alginate hydrogel with an external 3D-printed implantable device. This external macrocapsule protects the inner hydrogel containing cells, while allowing the precise location of the implant in the body. In addition, it would allow the easy extraction of the grafted cells in the case the implant fails or the renewal of the therapeutic cells is required. This study evaluates the biological effect of the macroencapsulation devices' surface properties (hydrophilicity and porosity). We studied two different pore sizes and hydrophilicities in four different devices containing rat INS1E β-cells embedded in alginate hydrogels. All the devices showed great biocompatibility, although the hydrophilic ones exhibited higher fibroblast adhesion, which could potentially enhance the fibrotic response when implanted. Importantly, INS1E cells did not escape from the devices, denoting high biosafety. Cells grown within all devices and maintained their insulin secretory function. However, the hydrophobic device with a smaller pore size showed better cell viability values and, therefore, it might be the best candidate for the development of a safe β-cell replacement therapy in T1DM.
Data from the World Health Organization indicates that musculoskeletal conditions are the leading contributor to disability worldwide affecting between 20 to 33% of people. Musculoskeletal conditions range from those that arise suddenly and are short-lived such as fractures, to lifelong conditions associated with persistent pain and disability. While the prevalence of musculoskeletal conditions increases with age, younger people are also affected. Although many musculoskeletal conditions can be managed in primary care, some of them require of surgical intervention. In such cases, and especially in tissues with a limited capacity of self-repair as cartilage and tendon, regenerative medicine approaches became significantly relevant. In this intramural collaboration, we developed nanopatterned cell carriers of tunable cell adhesive properties that improve mesenchymal stem cell preconditioning in vitro towards tendon and cartilage tissues. Preliminary results on the implantation of the obtained cell constructs in vivo show increased efficiency in the regeneration of cartilage defects..
The previous studies carried out by the participant groups had shown the excellent biocompatibility of fibrin-based hydrogels loaded with nanomaterials that transduce photon energy into heat, such as gold hollow nanoparticles (HGNPs) or CuS nanoparticles (CuSNP). Also, we had shown that NIR-responsive fibrin hydrogels comprising HGNPs or CuSNP can serve as reliable platforms for triggering in vitro and in vivo heat-inducible transgene expression from cells incorporated in the hydrogels. In the course of this intramural collaboration, we have shown that remote NIR activation of these scaffolds can induce the production of transgenic bone morphogenetic protein 2 (BMP-2), resulting in enhanced bone regeneration, as tested in a murine model of orthotopic ossification. Using a layer-by-layer functionalization approach, we prepared HGNPs coated with a positively charged copolymer that enabled thrombin conjugation. Thrombin-conjugated HGNP conduct in situ fibrin polymerization, facilitating the process of generating photothermal matrices that can function as scaffolds capable of controlling heat-induced transgene expression. Finally, we have also explored photothermal scaffolds based on synthetic and biological polymers, cryogels and recombinant elastomers, respectively, that are able to sustain transgenic activity.
Infectious diseases are on the raise and increasing challenge to human health with mortality rates predicted to soon exceed those of cancer and other diseases. While antimicrobial resistance is increasing, the number of new antibiotics and even the number of companies engaging in those is decreasing. Besides the need for new targets and molecules for anti-infective compounds, such as e.g. pathoblockers, there is also a need to deliver those across biological barriers preventing access to the target site. Relevant barriers in this context are the body’s outer epithelia, in particular of the gut, the skin and the lung, but also host cell membranes, the bacterial cell envelope as well as non-cellular barriers, such as mucus and bacterial biofilm. The lecture will provide an introduction into this emerging field of drug delivery research with focus on novel nanomedicines as innovative human cell- and tissue models as alternative to animal testing.
Despite the substantial progress that has been made in biomaterials synthesis and functionalization, the challenge to develop injectable hydrogel with delivery properties is still mostly unmet.
Towards this aim, we reported novel biocompatible hydrogels that are formed in physiological conditions, and can be injected using non-invasive surgery in different part of the animal body. The materials contain breakable particles, able to respond to an external stimulus, and to release on demand drugs but also large biomolecules such as enzymes and proteins.
The hydrogels that contain such nanoparticles are perfectly biocompatible and can be made degradable. Cells are able to populate and proliferate in the matrices and even stem cells are able to grow and differentiate. We have demonstrated that the excellent biocompatibility of the systems allowed their use in different applications such as wound repair, as support for tumor resection and more recently for fistula filler.
Atrial arrhythmia is the most frequent arrhythmia of the human heart. Millions of patients are affected. Still, the etiology of AFlut and AFib is not well understood. Ablation is a good measure to stop AFlut and AFib, but success rates are – depending on the specific case – around 60% to 70%. Computer simulations can contribute to better comprehension. In particular modeling of fibrotic tissue and modeling of initiation and perpetuation of depolarization waves are important topics. On the other hand, the measurement of electrograms (EGM) inside the heart with multichannel catheters becomes more advanced. 20.000 EGMs can be measured in the atria of patients in about 15min. This demands for advanced biosignal analysis. New algorithms to extract spatiotemporal information of depolarization waves from multichannel EGMs are needed. Sometimes they are inspired by computer simulations. Thus, new measurement techniques, better algorithms of biosignal analysis and improved computer simulations go hand in hand striving for better patient outcome
On March 12, the World Health Organization declared a pandemic following the exponential increase of SARS-CoV-2 cases. The rapid spread of the virus is due to both its high infectivity and the free circulation of unrecognized infectious cases. Thus, diagnostic testing is a key element for a rapid management of symptomatic patients and to detect asymptomatic patients and further prevent dissemination of the virus. In my presentation, a review of the COVID-19 diagnostic approaches, discussing both direct and indirect microbiological diagnoses will be performed. Diagnostic accuracy varies according to time elapsed since symptom onset and has evolved together with understanding of the COVID-19 disease. Taking into account all these variables will allow determining the most adequate diagnostic test to use and how to optimize diagnostic testing for COVID-19. Methods to direct detection of the virus following RNA or protein (antigen) detection will be assessed. Rapid as well as high-throughput RT-PCR methods and others such as LAMP or CRISPR will be analyzed. Finally, the indirect diagnosis based on antibodies detection will also be examined.
Although the elicitation of humoral immune responses against different viral proteins is rapid and occurs in most individuals after infection, its magnitude is highly variable among them and positively correlates with COVID-19 disease severity. This rapid response is characterized by the almost concomitant appearance of virus-specific IgG, IgA and IgM antibodies that contain neutralizing antibodies directed against different epitopes of the Spike glycoprotein. Of particularly interest, the antibodies against the partially exposed domain of the Spike that interacts with the cellular receptor ACE2 (the receptor binding domain, RBD) are present in most infected individuals and are able to block viral entry and infectivity. Neutralizing anti-RBD antibodies are able to protect different animal species when administered before virus exposure; therefore, its elicitation is the main target of current vaccine approaches and their clinical use as recombinant monoclonal antibodies is being explored. Current project are yielding promising results, however the length of the generated humoral responses and their efficacy at protecting against infection or disease progression are still open questions.
In my talk, I will describe the work that we have done within the Commissioner for AI Strategy and Data Science against COVID-19 for the President of the Valencian Region. As commissioner, I have led a multi-disciplinary team of 20+ scientists who have volunteered since March 2020. We have been working on 4 large areas: (1) human mobility modeling; (2) computational epidemiological models (both metapopulation and individual models); (3) predictive models; (4) citizen surveys, with the launch of the covid19impactsurvey, one of the largest citizen surveys about COVID-19 to date (https://covid19impactsurvey.org)
I will describe some of the work we have carried out in each of these areas and will share the lessons learned in this very special initiative of collaboration between the civil society at large (through the survey), the scientific community (through the Expert Group) and a public administration (through the Commissioner at the Presidency level)
Many diseases need site focused treatments, as the most efficient drugs lead to systemic toxicity or experience inferior biodistribution. Using nanoparticles as drug carriers may overcome some of these drawbacks. These nanoparticles must overcome many different biological barriers to reach their final target at the disease site. Often, nanoparticle-based approaches rely on the EPR effect, which is observed in cancer and in inflammations, but is unpredictable and not an optimal strategy. To address unmet healthcare needs with innovative nanotechnology-base solutions for the benefit of the patients, nanomedicine needs to work in synergy with other Key Enabling Technologies (KETs) and Digital Technologies in health in a cross-KET approach. Examples will be given to illustrate this clinical need-focused, technology-pull thinking.
BNN is a non-profit research organization owned by the BioNanoNet Association. We are responsible and devoted for pursuing the objectives of the Association, taking special care of the needs and requests of our members. The BioNanoNet Association aims to strengthen innovative research by promoting cooperation and creating synergies among people working in the fields of Health & Safety, Data & Sustainability and Enabling Technologies.
By connecting our members to national and international strategic stakeholders, together we establish and coordinate thematic platforms that lead initiatives in different fields. As a consequence, we jointly contribute to shape the R&D&I landscape in Europe. BNN’s core competences are distributed along different services that we implement not only to benefit the association members but also external customers and partnerships. BNN’s competences will be presented, as key factor of success of our on-going initiatives and projects with the aim to look for future cross-collaborations and/or initiatives.
ONLINE, 16-17 November 2020
Actualizada a 10 de junio de 2020
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