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Organ-on-chip monitoring. Breakthrough technological approximations

Organ-on-chip (OOC) is the term used to define a microfluidic 3D culture model that contains continuously perfused chambers inhabited by living cells. OOC are considered as very promising tools for investigating many aspects of human physiology and pathophysiology as well as drug testing platforms with future progressions to be used for precision medicine.

As the complexity of OOC systems increases, the necessity to integrate relevant assessment methods to provide information about cell physiology, secreted metabolites as well as pharmacodynamics drug responses also increases. Dr. Rosa Villa, who leads NANBIOSIS U8 Nano Technology Unit and the Biomedical Applications Group of the Institute of Microelectronics of Barcelona and CIBER in Bioengineering, Biomaterials and Nanomedicine, works on different engineering approaches to develop physical and chemical sensors that can be integrated into the OOC devices. The group considers that sensors integration is a requirement that must be taken into consideration in an OOC platform giving the necessary assessment of the OOC platforms in a continuous and real-time

An overview of the most relevant works of the Biomonitoring Group and NANBIOSIS Unit 8 have been presented by Mar Alvarez and Gemma Gabriel, researchers of
NANBIOSIS U8 Nano Technology in the conference on Engineering Multicellular Systems organized by EMBL – IBEC that took place in La Pedrera Auditorium, in Barcelona, from 10-12th February 2020.

It has been presented a device fabricated for that mimics Retina. In this novel microfluidic device cells are arranged in parallel compartments and are highly interconnected through a grid of microgrooves, which facilitates paracrine signaling and heterotypic cell–cell contact between multiple tissues. In the field of Brain, TEER barrier monitoring is mandatory. An interdigitated electrodes (IDE) configuration where the entire cell culture area contributes equally to the measurement, has been integrated in a custom-made bioreactor. This configuration, besides being more accurate for measuring the TEER, also allows the minimal electrode coverage, so that the optical visualization of the cell culture is maximized. The control and monitoring of dissolved oxygen (DO) is key for most of the OOC. The integration of oxygen sensors in an Liver-On-a-Chip system to achieve in-situ and real-time monitoring of oxygen zonation along the cell culture microfluidic chamber. A miniaturized sensing device compatible with microfluidic technology to measure simultaneously dissolved oxygen, pH, Na+ and K+, able to be connected in the input or output of a cell culture system has been developed for Kidney monitoring.

References

[1]   Yeste J, García-Ramírez M, Illa X, Guimerà A, Hernández C, Simó R, Villa R, “A compartmentalized microfluidic chip with crisscross microgrooves and electrophysiological electrodes for modeling the blood–retinal barrier” Lab on a Chip 18 (2018) 95-105

[2] Yeste J, Martínez-Gimeno L, Illa X, Laborda P, Guimerà A, Sánchez-Marín JP, Villa R, Giménez I “A perfusion chamber for monitoring transepithelial NaCl transport in an in vitro model of the renal tubule “, Biotechnology and Bioengineering 115 (2018) 1604-1613

[3] Moya A, Ortega-Ribera M, Guimerà X, Sowade E, Zea M, Illa X, Ramon E, Villa R, Gracia-Sancho J, Gabriel G., “Online oxygen monitoring using integrated inkjet-printed sensors in a Liver-On-a-Chip system” Lab on a Chip (2018),18, 2023-2035

[4]Moya A, Illa X, Gimenez I, Lazo-Fernandez Y, Villa R, Errachid A, Gabriel G. “Miniaturized multiparametric flexible platform for the simultaneous monitoring of ionic compounds: Application in real urine” Sensors and Actuators B: Chemical 255 (2018) 2861-2870

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Challenges in precision medicine

Transfiere, the European Forum for Science, Technology and Innovation,  the bigest professional and multisectoral forum for the transfer of knowledge and technology held in Spain, took place last February 12 and 13 in Malaga in its 9th edition.

Among the events held at Transfiere, there has been a round table organized by all health-related platforms under the title: Challenges in precision medicine on the 12th at 6pm.

Maria Luisa García Martín, Scientific Director of NANBIOSIS U28 of Nanoimaging Unit and head of Nano-Imagen  facilities at BIONAND, was invited by the Nanomedicine platform, NanomedSpain as a speaker at the aforementioned round table to discuss metabolomics and cancer. The rest of the participants were:

• Amelia Martín Uranga. Responsible for the Innovative Medicines Platform (Pharmaindustry) – Data protection in precision medicine.

• Beatriz Palomo. Coordinator of Biotechnology Markets Platform Responsible for projects and the ASEBIO Health Area

• Patricia Fernández. Coordinator of the Vet + i-Spanish Technology Platform for Animal Health Foundation

• Antonio Riobás. Medical Director and Health Advisor at Biocrew – Aspects of meso and micro-management in relation to the incorporation of Precision Medicine. Spain and its challenges.

Among subjects discussed, ethical aspects, data protection, limitations and challenges to overcome, the role of patients and clinicians, as well as the role of new technologies, such as metabolomics, in precision medicine, Maria Luisa García shared her experience about  the role of magnetic resonance metabolomics in the precision medicine of the futue, focused on tumor diagnosis.

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Mechanism and Consequences of the Impaired Hif-1α Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose

NANBIOSIS has been informed about a recent publication in the pretigious scientific magzine SCIENTIFIC REPORTS (Q1) of Nature Research group, mentioning NANBIOSIS Unit 17 in the Methods section:

Immunofluorescence analysis: Detection was performed by using a Leica SP5 confocal microscope (Leica Microsystems, Wetzlar, Germany), through the Confocal Microscopy Service of the ICTS ‘NANBIOSIS’ Unit 17 of the Biomedical Research Networking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) at the University of Alcalá, Madrid, Spain. HIF-1α-dependent immunofluorescence intensity was quantified after digital capture using image-J software.

The Leica TCS-SP5 confocal microscope with especial features allows studying interactions between cells/tissues and materials. Indeed, the experience of the research group in charge of this service makes it a unique service for the study of cells and tissues and the interactions between various materials and cell components as well as between implants/scaffolds and tissues of the recipient organism. 

Article of reference:

Mechanism and Consequences of the Impaired Hif-1α Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose. Coral García-Pastor, Selma Benito-Martínez, Victoria Moreno-Manzano, Ana B. Fernández-Martínez, Francisco Javier Lucio-Cazaña. SCIENTIFIC REPORTS, (2019) 9:15868 | https://doi.org/10.1038/s41598-019-52310-6

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VII Course of Microscopic and Piezoelectric Techniques in Dentistry: Endodontics, Implantology and Prosthetics

CCMIJU has organised the VII Course of Microscopic and Piezoelectric Techniques in Dentistry: Endodontics, Implantology and Prosthetics, which wil take place at JUMISC from March 3 till June 27 2020 under the Direction of Alberto Anta Escudero. (Profesor of the UPV-EHU), Gorka Santamaría Arrieta (Professor of the UPV-EHU), Jon Eskurza Pérez (Endodontics Specialist. Private Clinic) and Francisco Miguel Sánchez Margallo (Deputy Scientific Director of NANBIOSIS)

The general objective of the course is the knowledge of the enodontology magnification, necessary materials and instruments and related ergonomic aspects. Training in magnification in dentistry

Frurther information: Programm and inscriptions

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NANBIOSIS #WOMEN IN SCIENCE

In order to achieve full and equitable access and participation in science for women and girls, and also to achieve gender equality and the empowerment of women and girls, the United Nations General Assembly decided to proclaim in 2016 (resolution A / RES / 70/212) February 11 as the International Day of Women and Girls in Science.

We want to take this day to congratulate all the women who lead research and innovation and contribute to the breakdown of the barriers that still exist, especially to the scientists from NANBIOSIS ICTS.

Happy International Day of Women and Girls in Science!

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A new smart drug that finds and kills metastasis cells could be applied in 23 types of cancer

Researchers of two CIBER-BBN Units of the ICTS NANBIOSIS  U18 Nanotoxicology Unit at Hospital Sant Pau. and U1, Protein Production Platform (PPP), at the  Institute of Biotechnology and biomedicine of the Autonomous University of Barcelona (IBB–UAB), led by Prof Ramón Mangues, have developed a new drug that selectively removes metastatic stem cells, inducing a powerful metastasis prevention effect.

Besides the participation of the “NANBIOSIS” ICTS Units
U1 Protein Production Platform where Protein production was partially performed and U18 Nantoxicology Unit where Biodistribution studies were performed, all in vivo experiments were performed by the Unit 20 In Vivo Experimental Platform of CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN)

The researchers have ceated inclusion bodies of amyloid and nanostructured fibers that, when administered subcutaneously in mice, release soluble cytotoxic nanoparticles continuously. These nanoparticles are carriers of the exotoxin of Pseudomonas aeruginosa that manages to maintain a stable concentration of this nanomedicine in the blood and tissues. Dr. Mangues explains that “this new pharmaceutical form of subcutaneous administration for sustained release allows high doses of this nanopharmaceutical to be administered, at prolonged intervals (weeks in mice and probably months in humans) without toxicity at the injection site or in normal tissues, while generating a powerful antimetastatic effect. Apart from being controlled-release systems, these nanoparticles incorporate a ligand that interacts with the receptor (CXCR4), present at high levels in the membrane of metastatic stem cells capable of generating metastases (CMM CXCR4 +). Once the new pharmaceutical form is administered subcutaneously in mice with metastatic colorectal cancer, this ligand directs each nanoparticle released by this structure to the tumor tissues, increasing their uptake, to specifically internalize in the CXCR4 + CMMs and induce their selective destruction. “This effect achieves a notable reduction in tumor size in the colon while blocking the development of lymph node, lung, liver and peritoneal metastases, without appreciable uptake or toxicity in non-tumor tissues” continous the researchers.

The researchers estimate that this new therapeutic strategy will have a high clinical impact by reducing the requirement of its hospital administration, which most antitumor drugs have, and blocking metastatic dissemination, responding to an unmet clinical need. On the other hand, this new pharmaceutical form, which combines sustained release with targeting to the CXCR4 receptor, could be used in the treatment of at least 23 types of cancer that also express high levels of this receptor in tumor cells.

The new therapy offers an answer to the urgent medical need to inhibit the development of metastases, which represents the leading cause of death in cancer patients. The selective destruction of tumor and metastatic cells increases the therapeutic index of nanomedicine, obtaining a potent antimetastatic effect without generating associated adverse effects, which differentiates it from most of the currently used antitumor drugs.


Article of reference

María Virtudes Céspedes, Olivia Cano‐Garrido, Patricia Álamo, Rita Sala, Alberto Gallardo, Naroa Serna, Aïda Falgàs, Eric Voltà‐Durán, Isolda Casanova, Alejandro Sánchez‐Chardi, Hèctor López‐Laguna, Laura Sánchez‐García, Julieta M. Sánchez, Ugutz Unzueta, Esther Vázquez, Ramón Mangues, Antonio Villaverde. Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci Adv.Mater.2019, 1907348

https://doi.org/10.1002/adma.201907348

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Ethylcellulose nanoparticles as new “in vitro” tool for cell transfection

Researchers of NANBIOSIS U12 Nanostructured liquid characterization unit and U29 Oligonucleotide Synthesis Platform (OSP) of CIBER-BBN at IQAC-CSIC have obtained successfully ethylcellulose nanoparticles with positive zeta potential formed from nano-emulsion complexation with an antisense oligonucleotide which result very promising complexes for “in vitro” cell transfection.

A new non-viral gene delivery vector has been developed, based on ethylcellulose, an easily available and low cost carbohydrate polymer, “generally recognized as safe” by the FDA. Although ethylcellulose is nonionic, positively charged nanoparticle dispersions have been obtained using nano-emulsion templates in cationic:non-ionic surfactant-based systems. The nanoparticles have been successfully complexed with negatively charged phosphorothioate antisense oligonucleotides. These short nucleic acid chains are advantageous as they show improved cell penetration ability and higher resistance to degradation by nucleases. The nanoparticle:oligonucleotide complexes obtained show suitable transfection efficiency and are promising for “in vitro” gene transfection purposes.

This research has been developed through the close collaboration between the Colloidal and Interfacial Chemistry group led by Dr. Carlos Rodríguez Abreu, and the Nucleic Acids Chemistry group led by Dr. Ramon Eritja as well as the NANBIOSIS U12 and U29 Units. Both groups belong to the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC) and the CIBER-BBN.

Article of reference: Leitner, S.; Grijalvo, S.; Solans, C.; Eritja, R.; Garcia-Celma, M. J.; Caldero, G., Ethylcellulose nanoparticles as a new “in vitro” transfection tool for antisense oligonucleotide delivery CARBOHYDRATE POLYMERS 229,1, 115451, 2020; DOI: 10.1016/j.carbpol.2019.115451

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NANBIOSIS research to fight cancer

Twenty years ago, the 4 February was declared World Cancer Day with the global challenge of cancer would not be forgotten. Since then, huge progress has been made to understand, prevent, diagnose, and treat cancer.

NANBIOSIS as an ICTS (Singular Scientific and Technical infrastructures) for biomedical research plays a very important role in the fight against cancer. Some examples of the work carried out during the last year, are bellow:

Unit 20 of NANBIOSIS  at VHIR, works in several proyects reletaed to cancer as  H2020-NoCanTher: magnetic nanoparticles against pancreatic cancer through the use of hyperthermia combined with conventional treatment. H2020-Target-4-Cancer: nanotherapy based on polymeric micelles directed against specific receptors of tumor stem cells in colorectal cancer. H2020-DiamStar: nanodiamonds directed against leukemia for the potentiation of chemotherapy. FET-OPEN EvoNano: in silico and tumor-tumor models for the prediction of PK / PD and tumor efficacy of antitumor nanomedicines against tumor stem cells.

The activities of U1 of Protein Production Platform (PPP) are also strongly committed with several projects devoted to develop new, more selective and more efficient antitumoral drugs, with antimetastatic effects.
oordinated action between units U1 of Protein Production Platform (PPP),
U18 of Nanotoxicology and U29 of Nucleic Acid Synthesis, shows promising results in development of nanopharmaceuticals with a high degree of efficacy for the treatment of metastases in colon cancer

Unit 6 of NANBIOSIS Biomaterial Processing and Nanostructuring Unit  is also working on a joined initiative between CIBER-BBN and CIBER-ONC to improve the current ex vivo immune cell expansion systems to help introduce immunotherapies such as the adoptive cell therapies, which have shown complete remissions of terminal cancer patients, to the clinics overcoming the limitation of having enough therapeutic cells with novel Nanobiomaterials. Researchers of Unit 6 and researchers of Laboratory of Translational Research in Child and Adolescent Cancer from the Vall d’Hebron Research Institute (VHIR), are working on a project financed by the Spanish Government and CIBER-BBN, for the development of a new nanomedicine for the treatment of high-risk neuroblastoma, one of the most frequent childhood cancers.

In our unit U26. NMR: Biomedical Applications II,  several studies for cancer biomarker discovery are being carried out. NMR studies on biofluids for the design of novel strategies for diagnosis support, easily transferable into the clinical practice, are being developed in biofluids in the context of cancer. Urine is one of the most easily obtainable biofluid and is a non-invasive source of biomarkers. Among these studies, we can mention the good discrimination achieved between urine from bladder cancer patients before surgery (cancer) and urine after surgery (free of cancer) and in the follow up of the disease, to monitor relapses

Some of the results of these researchs have been published in scientific magazines of high impact as for exemple;

Integrative Metabolomic and Transcriptomic Analysis for the Study of Bladder Cancer Alba Loras, Cristian Suárez-Cabrera, M. Carmen Martínez-Bisbal, Guillermo Quintás , Jesús M. Paramio, Ramón Martínez-Máñez,
Salvador Gil and José Luis Ruiz-Cerdá. Cancers 2019, 11, 686; doi:10.3390/cancers11050686

Nanostructured toxins for the selective destruction of drug-resistant human CXCR4+ colorectal cancer stem cells Naroa Serna, Patricia Álamo, Prashanthi Rameshef, Daria Vinokurovaef, LauraSánchez-García, Ugutz Unzueta, Alberto Gallardo, María  Virtudes Céspedes, Esther Vázquez, Antonio Villaverde, Ramón Mangues, Jan Paul Medema. . Journal of Controlled Release.  Volume 320, 96-104, 2020 https://doi.org/10.1016/j.jconrel.2020.01.019

Controlling self-assembling and tumor cell-targeting of protein-only nanoparticles through modular protein engineering Voltà-Durán, E., Cano-Garrido, O., Serna, N. et al. C. Sci. China Mater.63, 147–156 (2020). https://doi.org/10.1007/s40843-019-9582-9

Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci, María Virtudes Céspedes  Olivia Cano‐Garrido  Patricia Álamo  Rita Sala  Alberto Gallardo  Naroa Serna  Aïda Falgàs  Eric Voltà‐Durán  Isolda Casanova  Alejandro Sánchez‐Chardi  Hèctor López‐Laguna  Laura Sánchez‐García  Julieta M. Sánchez  Ugutz Unzueta  Esther Vázquez  Ramón Mangues  Antonio Villaverde . Advanced Materiasls Número de artículo: 1907348 , Dec. 2019 https://doi.org/10.1002/adma.201907348

Artificial Inclusion Bodies for Clinical Development Julieta M. Sánchez  Hèctor López‐Laguna  Patricia Álamo  Naroa Serna  Alejandro Sánchez‐Chardi  Verónica Nolan  Olivia Cano‐Garrido  Isolda Casanova  Ugutz Unzueta  Esther Vazquez  Ramon Mangues  Antonio Villaverde, Advanced Science. 2019 https://doi.org/10.1002/advs.201902420

Nanostructured Nucleolin-Binding Peptide for Intracellular Drug Delivery in Triple-Negative Breast Cancer Stem Cells Mireia Pesarrodona, Laura Sánchez-García, Joaquin Seras-Franzoso, Alejandro Sánchez-Chardi, Ricardo Baltá-Foix, Patricia Cámara-Sánchez, Petra Gener,  José Juan Jara, Daniel Pulido, Naroa Serna, Simó Schwartz Jr. Miriam Royo, Antonio Villaverde, Ibane Abasolo, Esther Vazquez ACS Applied Materials & Interfaces DOI: 10.1021/acsami.9b15803  

Nanostructure Empowers Active Tumor Targeting in Ligand‐Based Molecular Delivery López‐Laguna, H., Sala, R., Sánchez, J. M., Álamo, P., Unzueta, U., Sánchez‐Chardi, A., Serna, N., Sánchez‐García, L., Voltà‐Durán, E., Mangues, R., Villaverde, A., Vázquez, E., . Part. Part. Syst. Charact. 2019, 36, 1900304. https://doi.org/10.1002/ppsc.201900304

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EUROAGE: to improve people’s quality of life and increase healthy life expectancy

The Center for Minimally Invasive Surgery (JUMISC), partner of NANBIOSIS, as the main beneficiary of the Spain-Portugal EUROAGE cross-border cooperation project that promotes active aging in the region, has presented its results and its impact on society, within the Spanish-speaking meeting ‘ Forum of Iberian Stories. 30 years of the INTERREG Spain-Portugal Cross-Border Cooperation Program (POCTEP) ’.

Specifically, the event has been organized by the agencies EFE and LUSA, and took place this past Wednesday at the headquarters of the Spanish agency in Madrid, with the support of the Directorate General for Regional Policy (DGRegio) of the European Commission.

Its objective has been to address the main achievements of the program and the new challenges demanded by the future of both territories. EUROAGE, belonging to the Cooperation Area 4 (Extremadura-Centro-Alentejo), is focused on promoting healthy autonomous life, mainly for the elderly, but also for dependent people, through the promotion of innovative initiatives based on technologies and knowledge developed by the R&D agents.

In turn, the European project promotes active aging through physical, cognitive and socio-emotional activity, with the main objective of improving people’s quality of life and increasing healthy life expectancy, at the same time that will affect the reduction of expenses, in the optimization of resources in public health systems and in the modernization of the business fabric of the sector.

Although the main beneficiary of the European project is the Jesús Usón Minimally Invasive Surgery Center, other institutions also participate, such as the Castelo Branco Polytechnic Institute, the University of Coimbra, the Extremadura Social Cluster, the University of Extremadura and the Polytechnic Institute Give Guardian

EUROAGE includes the development of materials for health literacy, applications for the improvement of physical and cognitive well-being and an integrated system for the promotion of active aging, as well as different social and welfare robots.

Source of information: Región Digital

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New book by NANBIOSIS U14: Basic research procedures in the cell therapy laboratory

Researchers of NANIOSIS Unit 14 at JUMISC have published a new book titled Basic research procedures in the cell therapy laboratory, in which some basic techniques and general principles for adult stem cell research are explained.

Stem cells are cells capable of differentiating into a wide variety of cell types and can be isolated from different tissues such as. They have regenerative and anti-inflammatory properties thanks to the secretion of paracrine factors. Currently, these cells are being widely used in clinical trials for the treatment of different diseases such as Crohn disease, multiple sclerosis, diabetes, rheumatoid arthritis or myocardial infarction.
In this book, some basic techniques and general principles for working in a research laboratory in Cellular Therapy are explained in a simplified manner. In the same way, a series of basic knowledge are exposed that must be taken into account for the correct handling of the cells and their environment.
This book is not intended to be a detailed manual of laboratory procedures or a book on cell management for clinical use, but its purpose is to describe part of the protocols developed by the Cell Therapy Unit of NANBIOSIS at the Jesús Usón Minimally Invasive Surgery Center and which have the objective of evaluating the effectiveness and safety of these cells in the preclinical setting.

Book: Basic research procedures in the cell therapy laboratory. Álvarez Pérez, Verónica, García Casado, Javier, Sánchez-Margallo, Francisco.
ISBN 13: 978-84-17959-64-7

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