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Nanbiosis

Stable nanovesicles for the delivery of microRNA in cancer treatment

  • Nanovesicles, known as quatsomes, have been successfully engineered to encapsulate and deliver microRNAs for the treatment of tumors.
  • These nanovesicles are produced by a simple GMP compliant process, an unavoidable requirement for the clinical use of new drug candidates.
  • The study, published in Small, has been highlighted in the Women in Materials Science issue of Advanced Materials.

“The beauty of these quatsomes nanovesicles is that they can be easily engineered for the delivery of a variety of nucleic acids. Importantly, they are stable at room temperature, which avoids problems associated to cold chain requirements, says Nora Ventosa, Scientific Director of NANBIOSIS U6.

MicroRNAs (also known as miRNAs) are small RNA molecules that can interfere with the stability of other RNA molecules (specifically, messenger RNA). They have many potential therapeutic uses due to the central role they play in major diseases. However, these molecules are still infrequently used in patients due to their instability in the bloodstream and their poor ability to reach specific tissues. A potential strategy to improve the clinical delivery of miRNAs in the body is to encapsulate them in tiny carriers that compensate its current shortcomings, without side effects and offering other complementary functions.

To this end, researchers have developed and designed especially for this application nanostructures, known as quatsomes, composed by two closed lipid layers. In a new publication in Small, which is highlighted in the “Women in Materials Science” Issue of Advanced Materials, researchers present a newly engineered formulation of quatsomes that have a controlled structure, composition and pH sensitiveness. 

The study is the result of an interdisciplinary team of researchers from the Institute of Materials Science of Barcelona, ICMAB-CSIC, the Vall d’Hebron Research Institute (VHIR)-UAB,  the Institute for Bioengineering of Catalonia (IBEC), the Barcelona Institute of Science and Technology (BIST),  the CIBER network on Bioengineering, Biomaterails and Nanomedicine (CIBER-BBN), the company Nanomol Technologies SL, the Technion-Israel Institute of Technology and the Institute for Complex Molecular Systems (ICMS).

“In this study we have collaborated with hospitals, research networks and companies. The successful results obtained illustrate the importance of collaboration across fields and beyond the academic system” says Ventosa.

These new quatsomes can be coupled with the miRNA and injected intravenously into the body to be delivered in neuroblastoma primary tumors or in frequent sites of metastasis, such as the liver or lung, with a higher success and stability than if the miRNA were injected by itself. Once delivered, the miRNA has an effect on the cell proliferation and survival-related gens in the tumors, decreasing the tumor’s growth rate.

Many properties make quatsomes a good fit for these applications: they are less than 150 nm in size and are stable in a liquid solution for more than 6 months; they also have tunable pH sensitiveness, which means that different pH levels around can trigger different responses.

Quatsome production and their physicochemical characterization has been performed by the ICTS “NANBIOSIS,” more specifically in the Biomaterial Processing and Nanostructuring Unit (U6), Unit of the CIBER in Bioengineering, Biomaterials & Nanomedicne (CIBER-BBN) located at the Institute of Materials Science of Barcelona (ICMAB-CSIC) and led by Nora Ventosa

The production of these nanovesicles has been optimized with their final application in mind and to make sure they can be used in clinics. Through a green and scalable one-step process, named DELOS, researchers have designed a procedure that is fully compliant with Good Manufacturing Practice (GMP) guidelines stablished by the European Union. “It is time to translate our scientific findings for the benefit of patients” says Ariadna Boloix, VHIR researcher.

The development of miRNA delivery systems containing an active targeting for neuroblastoma is performed under the frame of a CIBER-BBN valorization project “Targeted Quatsome nanocarriers for the delivery of microRNA for neuroblastoma therapy” (TAG-SMARTLY), coordinated by the Nanomol group in collaboration with the Multivalent Systems for Nanomedicine (MS4N) group of the CIBER-BBN at IQAC-CSIC and the Synthesis of Peptides Unit of Nanbiosis (U3).

In this publication, the functionality of quatsomes in delivering miRNAs is demonstrated with a specific extracranial solid tumor common in pediatric cases of cancer known as neuroblastoma, which is responsible for roughly 15 % of all pediatric cancer deaths and lacks therapies for high-risk patients. The results show that quatsomes protect the miRNA from degradation and increase its presence on liver, lung and xenografted neuroblastoma tumors, amongst other tissues.

Reference article:

Engineering pH-Sensitive Stable Nanovesicles for Delivery of MicroRNA Therapeutics Ariadna Boloix, Natalia Feiner-Gracia, Mariana Köber, Javier Repetto, Rosa Pascarella, Aroa Soriano, Marc Masanas, Nathaly Segovia, Guillem Vargas-Nadal, Josep Merlo-Mas, Dganit Danino, Inbal Abutbul-Ionita, Laia Foradada, Josep Roma, Alba Córdoba, Santi Sala, Josep Sánchez de Toledo, Soledad Gallego, Jaume Veciana, Lorenzo Albertazzi, Miguel F. Segura*, Nora Ventosa* Small, 18, 3, 2022 DOI: 10.1002/smll.202101959

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Nanoligent, whoes founders are leaders of NANBIOSIS units, raises €1M in Series Seed financing

Barcelona, Spain – Milan, Italy, February 3rd, 2022 – Nanoligent SL, a biotech company specialized in the development of nanotechnology-based cancer treatments, today announces the completion of the first closing of a Seed financing round of €1M. The round has been led by members of Italian Angels for Growth, the largest network of business angels in Italy, through the investment vehicle Nanolinvest, and AVANTECA Partners, a Swiss privately held asset management firm, both specialized in supporting innovative early-stage life-science companies primarily in Europe. An equity campaign, is still ongoing on Doorway, an online investment platform, thus promising to provide additional funding for the company.

NANOLIGENTis spin off from the Universidad Autónoma de Barcelona and Research Institute of the Hospital de Sant Pau – IIB Sant Pau that was created by the Directors of NANBIOSIS Units U18. Nanotoxicology Unit, Ramón Mangues and U1. Protein Production Platform (PPP), Antoni Villaverde, together with Esther Vázquez and Manuel Rodriguez

Nanoligent, is focused on the development of new drugs for the treatment of more than 20 different metastatic cancer types. The lead molecule is based on the targeted elimination of cancer cells overexpressing the CXCR4 receptor, a recognized biomarker for poor prognosis and therapy resistance. Nanoligent is developing a new proprietary nano-technological platform, with the potential to overcome current limitations of Antibody-Drug-Conjugates. The CXCR4 is overexpressed in a significant number of patients of more than 20 different tumors.

The financing will allow Nanoligent to complete the pre-clinical development in a variety of tumor types and to move its lead candidate into pre-IND stage.

The investor syndicate will join the Nanoligent’s Board which will consist of: Michele Marzola (IAG), Michael Milos (Avanteca Partners), Manuel Rodríguez (Chairman) and Montserrat Cano (CEO).

“We started the evaluation of a possible investment in Nanoligent one year ago and since then we have received enthusiastic responses from Key Opinion Leaders and Industry Experts. It has been a real pleasure working with the team at Nanoligent; we are impressed by their scientific depth and professional responses. We are continuing our fundraise for this deal together with Doorway, a fintech investing platform”, said Michele Marzola who together with Alessandro Toniolo are co-champions from IAG in this investment.

“We are fascinated by the technological capabilities of the platform and the professionalism of the team. The whole process was an intense, productive and very professional exchange. We are looking forward to partner with the management of Nanoligent to develop this highly innovative platform, which has the potential to transform cancer therapy” said Michael Milos from AVANTECA Partners.

“It is our great pleasure to welcome Michele Marzola and Michael Milos, whose expertise and experience will be a valuable addition to the company to accomplish its ambitious development plans over the next 18 months” said Montserrat Cano, CEO of Nanoligent.

Doorway, at its turn, is very happy to continue fundraising with its qualified community for such an innovative technology that can achieve a significant impact in the treatment of many cancers, being Nanoligent a perfect example of Doorway’s vision of “business with an impact”.

About Nanoligent

Nanoligent was founded in 2017 by co-founder and Chairman Manuel Rodriguez Mariscal, as a spin-off coming from more than 10 years of fruitful collaboration between the Nanobiotechnology group at the Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, co-lead by full professor Antonio Villaverde and Principal Investigator Esther Vázquez, and the Oncogenesis and Antitumor Drug Group at the Biomedical Research Institut Sant Pau of the Hospital de la Santa Creu i Sant Pau, headed by full professor Ramon Mangues, the three of them also co-founders of the company. Montserrat Cano joined the company in 2020, with more than 15 years of experience in pharma and biotech companies. The aim of the company is to develop a pioneering technological platform based on protein-drug nanoconjugates to target metastasis across several tumor types.

 About Italian Angels for Growth

IAG, founded in 2007, is a leader in the Italian seed venture capital: more than 270 protagonists of the entrepreneurial, financial and industrial world that invest time, skills and capital for the growth of innovative startups. Italian Angels for Growth, in more than ten years of activity, has analyzed more than 6,500 startups and its members have made over 100 investments, for a total of over 300 million euros invested by IAG members and co-investors. IAG business angels support innovative projects financially by investing their own capital, but at the same time, thanks to the mix of skills of the members, support the founders of the startups in the definition of the business model in all its aspects.

 About AVANTECA Partners

AVANTECA Partners is a Swiss-based, privately held asset management company that invests in early-stage life science companies.

Related News

A new pathway for the prevention of metastasis in colorectal cancer in humans is open: a nanomedicine that selectively eliminates metastatic stem cells

Nanoligent obtains the first prize in the Tech Transfer Competition in the ONCO Emergence forum

Nanoligent, the spin off created by the Directors of Units 1 and 18 of NANBIOSIS, awarded for the best company in Health Sciences given by the law firm RCD

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Multivalent self-assembled platforms for the delivery of chemotherapeutic drugs

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.

Dr. Miriam Royo, who leads NANBIOSIS unit 3 of Synthesis of Peptide, explains one of the projects in which the ICTS is involved in relation with cancer therapy.

The improvement of solubility and stability of clinically approved chemotherapeutic drugs still represent a big challenge in cancer therapy. In fact, many of these drugs have low water solubility, which forces to administer larger volume doses to achieve the desired biological effect, and increases the side effects suffered from patients. The active principle can be chemically modified to increase the solubility, and administered as prodrug which, however, has to be enzymatically metabolized to have therapeutic effect and only a low percentage of the free drug is achieved. Moreover, some of the chemotherapeutic drugs are unstable at physiological conditions due to their chemical structure, and rapidly degrades before reaching the tumor tissue, further reducing the effectiveness of the treatment. Drugs commonly used in clinical chemotherapy treatments for advanced colorectal cancer and triple negative breast cancer, such as SN38, 5-fluorouracil (5-FU) and paclitaxel (PTX), have presented these problems, which affect their efficacy and tolerance to treatment by patients.

Drug delivery nanosystems based on biocompatible polyethylene glycol (PEG)-based multivalent platforms conjugated to hydrophobic drugs (SN38, PTX among others) are developed by the Multivalent Systems for Nanomedicine (MS4N) goup of Centro de Investigación Biom´dcia en Red (CIBER-BBN) at the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC). The resulting water-soluble conjugates have also the ability to self-assemble in aqueous media in nanoscale micellar structures improving the pharmacokinetic profile of drugs. In these systems, the intact active principle can be released in a controlled manner thanks to the presence of degradable bonds, between the drug and the polymer, which are sensitive to chemical or biological stimuli, favoring its accumulation in tumor.

Systems containing only one drug (SN38 or PTX) for monotherapy and two different drugs (as SN38 and 5-FU) for combined therapy treatments are developed to improve the therapeutic efficacy of the free drugs and decrease their secondary effects.  The multivalence nature of these systems also allows the possibility to add targeting agents, such as tumor specific peptide ligands thus increasing the specificity of the platforms towards the cancer cells. These peptide ligands have been produced at the Synthesis of Peptides Unit (U3) of NANBIOSIS.

This project (RTI2018-093831-B-I00) is funded by MICIN/AEI/10.13039/501100011033 and by “ERDF A way to of making Europe and performed in collaboration with Dr. Ibane Abasolo group of CIBER-BBN at Vall d’Hebron Research Institute (VHIR) and the In Vivo Experimental Platform (U20) of NANBIOSIS under the frame of CIBER BBN intramural collaborative projects (PolyPlaTher, Colocomb and Nanomets).

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Submissions open for Special Issue of MDPI on Fluorescent Organic Nanoparticles for Bioimaging and Theragnostics

Nora Ventosa and Mariana Köber, from NANBIOSIS Unit 6 of CIBER-BBN and ICMAB-CSIC, and Judit Morlà-Folch, from the BioMedical Engineering and Imaging Institute at the Icahn School of Medicine at Mount Sinai, New York, are editors of the Special Issue of MDPI Pharmaceutics.

The Special Issue on Fluorescent Organic Nanoparticles for Bioimaging and Theragnostics belongs to the “Nanomedicine and Nanotechnology” section and has a deadline for manuscript submissions on 25 July 2022.

The guest editors explain the main topic of this Special Edition:

“Fluorescence-based techniques play an essential role in the study of biological events in tissues and animals due to their specificity and noninvasive nature. However, realizing the whole potential of today’s fluorescence imaging and detection in terms of speed, resolution, and sensitivity, requires fluorescent labels that combine stability, a very high brightness, and a high photostability.

In this regard, novel, bright and stable organic fluorescent nanoparticles have evolved rapidly during the last few years, allowing further development of novel, experimental treatments and imaging strategies, including photodynamic therapy or image-guided surgery.

These results shine a spotlight on fluorescent nanomaterials as promising candidates for imaging and theragnostics in several health disorders. In this Special Issue, we invite authors to report on their recently developed, fluorescent, organic nanoparticles for imaging, diagnostics, and the treatment of diseases.”

If you have a relevant manuscript, you can submit it at MDPI in the submission form before 25 July 2022. All papers will be peer-reviewed, and research articles, review articles or short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website. More information on submission here

About the Pharmaceutics MDPI Journal

Pharmaceutics (ISSN 1999-4923) is an online open access journal on the science and technology of pharmaceutics and biopharmaceutics. The scientific community, the wider community and the general public have unlimited and free access to the content as soon as a paper is published; this open access to your research ensures your findings are shared with the widest possible audience. Please consider publishing your impressive work in this high quality journal. We would be pleased to welcome you as one of our authors.” – Editor-in-Chief Prof. Dr. Yvonne Perrie from the Strathclyde Institute of Pharmacy and Biomedical Sciences at the University of Strathclyde.

Source of information: ICMAB-CSIC

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U26-E07. MRS*DRYMAG3017-Flexiscan

Equipment Features:

Description: 3T preclinical imaging equipment with PET ClipOn attached.

Technical specifications: Imaging equipment with superconducting magnet, capable of varying the angle from 0 to 90º, without cryogenics of 3 Teslas; mouth diameter of 170mm; 600 mT/m gradients with 5% linearity; 30 mm DSV for Homogeneity and 0.05 ppm/hour for stability; 350 Kg of total weight.

Applications:

Acquisition and viewing of in vivo images of mice and rats as well as other beings or materials of similar size.

  • Qualitative and quantitative studies (relaxation times T1 and T2 and even making maps) at the brain level and other organs.
  • Cardiological sequences: diffusion, determination of blood volume…
    Anatomical and functional studies of different organs (for example: renal, abdominal, liver…).
  • Bone-level imaging, distinguish between bone material from soft tissue.
    Fat suppression techniques.
  • Oncological studies to detect and locate tumors and volume calculation.
  • Carry out studies on fruits and vegetables (grapes, kiwi, tomato, seeds…).
  • Perform studies with/without contrast (Gadolinium) and see the differences between the 2 images.
  • Thanks to the possibility of rotating the equipment in a vertical position, images of plants can be obtained (because by their nature, they have to be in a vertical orientation, such as a stem).
  • Ex-vivo studies can also be carried out vertically and in this way we maintain the integrity of the organ (eg heart).
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Best Emergeging Researcher Award in the Biomedical Area to Edorta Santos

Edorta Santos Vizcaíno has been awarded as Best Emerging Researcher in the biomedical area by the Bioaraba Health Research Institute in the XXII edition of the Research and Innovation Conference.

This award aims to recognize the work of researchers under the age of 40 who carry out their research activity in any public center of the Araba Health Network (OSI ARABA UNIVERSITY HOSPITAL / BIOARABA). The main award´’s criteria are the quality of the research carried out, active participation in public and private research projects, fidelity to the line of biomedical research and the usefulness and interest of the research developed for the environment are valued. The award also carries a financial endowment destined to continue promoting the research career of the awarded person.

Edorta Santos Vizcaíno (NANBIOSIS Unit 10 “Drug Formulation”) has a degree in Biochemistry and a doctorate in Pharmacy, with an international mention and an extraordinary award, from the UPV / EHU. He has been part of the research group NanoBioCel of the UPV / EHU, Consolidated Group of Excellence of the Basque university system, since 2006. In the same way, he is a member of the Center for Biomedical Research in Network for Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), a consortium dependent on the Carlos III Health Institute through the Ministry of Science and Innovation, and the Bioaraba Health Research Institute. Edorta has extensive experience in cell therapy and drug delivery systems. During the last years, his research has focused on the biomedical application of different biomaterials (for example, alginate, gelatin, collagen), mesenchymal stem cells (MSC) and their secretome (extracellular vesicles and soluble factors), in order to exert a immunomodulatory and regenerative effect in the treatment of immune-mediated inflammatory diseases (for example, inflammatory bowel disease, IBD) and the regeneration of chronic wounds, among other applications.

Bioaraba‘s mission is to develop research and innovation of excellence and quality that allows the translation of its results aimed at solving the health problems of the population, also promoting scientific research and for this, it annually carries out the Research and Innovation Conference.

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New fluorescent nanovesicles for intracellular biomarker detection

A new work by researchers from the CIBER-BBN at the Barcelona Institute of Materials Science ICMAB-CSIC, together with a team from the University of Rome Tor Vergata, presents new nanovesicles capable of crossing biological barriers such as cell membranes, maintaining their sensory capacity, making them attractive probes for intracellular biomarker detection.

“The development of probes capable of detecting the biological environment and signaling the presence of a specific target molecule is a challenge with relevance in a variety of biomedical applications, from drug administration to diagnostic tools” says Mariana Köber, one of those responsible of the investigation together with Nora Ventosa and Alessandro Porchetta from the University of Rome Tor Vergata.

In this work, which has been published in Advanced Functional Materials, the design of functionalized fluorescent nanovesicles with biomimetic DNA capable of translating their binding with a target molecule into an optical output is presented, through a change in the transfer of resonance energy. Förster (FRET) and fluorescent emission. These Quatsomes (QS) nanovesicles are an emerging class of highly stable small unilamellar vesicles ≈50–100 nm in diameter, formed by the self-assembly of ionic surfactants and sterols in aqueous media. Their high stability, also in body fluids, unilaminarity and particle-to-particle homogeneity make them an attractive soft material for detection applications. “QS nanovesicles are loaded with fluorescent waves based on amphiphilic nucleic acids to produce programmable FRET active nanovesicles that function as highly sensitive signal transducers,” she explains.

The CIBER-BBN researchers have participated in the characterization of the photophysical properties of these nanovesicles and the highly selective detection of clinically relevant microRNAs with sensitivity in the nanomolar range has been demonstrated. This production of nanovesicles and their physicochemical characterization has been carried out thanks to the services of ICTS NANBIOSIS, through its unit 6 of Biomaterials Processing and Nanostructuring at the ICMAB-CSIC.

According to the authors, the proposed strategy could easily be adapted to the detection of different biomarkers: “we hope to achieve a bioimaging platform for the detection of a wide range of nucleic acids and other clinically relevant molecules in body fluids or directly in cells, thanks to the ability of Quatsomes for intracellular delivery. “

  • Figure: Schematic representation of the DNA-grafted QS nanovesicles. Adv Funct Materials, Volume: 31, Issue: 46, First published: 11 August 2021, DOI: (10.1002 / adfm.202103511)

Article of reference

Marianna Rossetti, Lorenzo Stella, Judit Morlà-Folch, Sara Bobone, Ariadna Boloix, Lorena Baranda, Danila Moscone, Mònica Roldán, Jaume Veciana, Miguel F. Segura, Mariana Köber… Engineering DNA-Grafted Quatsomes as Stable Nucleic Acid-Responsive Fluorescent Nanovesicles . https://doi.org/10.1002/adfm.202103511

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The activity of Peptide T22 as antimicrobial drug opens new possibilities for the local control of bacterial infections related to tumors

Researchers of NANBIOSIS Units 1 and 18, from CIBER-BBN at the Institut de Biotecnologia i de Biomedicina (IBB-UAB) and the Institut de Recerca Sant Pau (IIB-Sant Pau) presents the finding of a significant antimicrobial activity in the targeting peptide T22, which is used for antitumor therapy directed against CXCR4 + stem cells, with clinical interest in more than 20 types of human cancer, including colorectal cancer.

The study describes how said activity has a significant effect on several bacterial species of clinical importance: “we have detected antimicrobial activity associated with T22 and inhibition of biofilm formation on Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, explains Antonio Villaverde, one of the coordiantors of the study . The researcher adds that “the T22 peptide does not show cytotoxicity on mammalian cells or hemolytic activity and is active when it is shown in protein nanoparticles through genetic fusion.”

For the develiopment of this research protein production was partially performed by the unit 1 of the ICTS NANBIOSIS, Protein Production Platform (PPP).

In short, the discovery of T22 as AMP is of interest, not only because of its addition to the catalog of antibacterial drugs, but its clinical uses could allow its combined and multivalent application in complex clinical conditions, such as colorectal cancer, which could benefit from the synchronous destruction of cancer stem cells and local bacterial biofilms.

The stable collaboration between the NBT group led by Esther Vazquez and Antonio Villaverde, the GOA group led by Ramón Mangues and the spin-off of the UAB Nanoligent, develops systemic targeted therapies using T22 to functionalize different types of cytotoxic nanoparticles, with which the destruction of metastatic stem cells and the consequent reduction in the number of metastases. “The dual activity of T22 as a targeting agent and as an antimicrobial drug may offer a new local treatment route, through which bacterial infections related to the development and progression of tumors are controlled locally,” the authors conclude.

Article of reference:

Naroa Serna, José V. Carratalá, Oscar Conchillo-Solé, Carlos Martínez-Torró, Ugutz Unzueta, Ramón Mangues, Neus Ferrer-Miralles, Xavier Daura, Esther Vázquez, and Antonio Villaverde. 2021. “Antibacterial Activity of T22, a Specific Peptidic Ligand of the Tumoral Marker CXCR4” Pharmaceutics 13, no. 11: 1922. https://doi.org/10.3390/pharmaceutics13111922

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DNA nanotechnologists are in mourning

At the end of the XXth century Nanotechnology appeared as one of the more powerful technologies for the future. At that time material sciences were able to produce nanomaterials with exquisite size control and atomic force, microscopy was able to visualize objects in the nanoscale and photolithography arrived to their physical limits in the preparation of computer chips threatening Moore’s law. This empirical law saying that as transistor components shrank, the number per chip doubled about every 18 months, was acting from 1971  (Intel’s first chip) to billions in the present times. 

At these times, one crucial development was the discovery of the first self-assembling DNA structures, leaded by Ned Seeman, who died recently at age 75. Being a crystallographer interested in DNA-protein structures, Ned though that a good way to obtain crystals of DNA-protein complexes was to prepare crystal networks of DNA where proteins bind. (In the classical approach of obtaining protein crystals small oligonucleotides bind). In this way in 1982 he described the idea of making lattices from DNA junctions. In 1991 he obtained a DNA cube, the first tridimensional DNA nanostructure receiving the 1995 Feynman Prize in Nanotechnology. But the most impressive development was the so-called “DNA tile systems” published in 1998.

The figure shows a bidimensional array made by his former Ph.D. student Alejandra Garibotti in our laboratory in Barcelona. In the tile system two or more tiles (each one made out of 5 oligonucleotides) are designed to self-assemble one next to the other by their sticky ends making a large lattice or bidimensional crystal having a tunable shape and size defined by the tiles.

Later on in 2009, Ned was able to demonstrate the achievement of three-dimensional DNA crystals. These developments settle the foundations for the development of DNA origami, DNA computation, DNA nanoelectronics and DNA nanorobotics earning the Kavli Prize in Nanoscience in 2010. The immense creativity of Ned is not only an active value for mankind but also an example for old and new scientists.

By Ramón Eritja, Scientific Director of NANBIOSIS U29, January 10th, 2022

U29.-Oligonucleotide-Synthesis-Platform
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New graphene-based neural probes improve detection of epileptic brain signals

A study published in Nature Nanotechnology shows that flexible brain probes made of graphene micro-transistors can be used to record pathological brain signals associated with epilepsy with excellent fidelity and high spatial resolution. This research was led by the Institute of Microelectronics of Barcelona (IMB-CNM-CSIC), the Catalan Institute of Nanoscience and Nanotechnology (ICN2) and the University College London Queen Square Institute of Neurology (UK).

The ability to record and map the full range of brain signals using electrophysiological probes will greatly advance our understanding of brain diseases and aid the clinical management of patients with diverse neurological disorders. However, current technologies are limited in their ability to accurately obtain with high spatial fidelity ultraslow brain signals. In a paper published today in Nature Nanotechnology, an international team of researchers report a flexible neural probe made of graphene-based field-effect transistors capable of recording the full spectrum of brain signals, including infraslow; and demonstrate the ability of these devices to detect with high fidelity electrographic signatures of the epileptic brain.

Epilepsy is the most common serious brain disorder worldwide, with up to 30% of people unable to control their seizures using traditional anti-epileptic drugs. For drug-refractory patients, epilepsy surgery may be a viable option. Surgical removal of the area of the brain where the seizures first start can result in seizure freedom; however, the success of surgery relies on accurately identifying the seizure onset zone (SOZ).  Epileptic signals span over a wide range of frequencies –much larger than the band monitored in conventional EEG.  Electrographic biomarkers of a SOZ include very fast oscillations as well as infraslow activity and direct-current (DC) shifts. The latter, in particular, can provide very relevant information associated with seizure onset but are seldom used due to the poor performance of current probes to record these types of slow brain signals. Application of this technology will allow researchers to investigate the role infraslow oscillations play in promoting susceptibility windows for the transition to seizure, as well as improving detection of clinically relevant electrophysiological biomarkers associated with epilepsy.

The graphene depth neural probe (gDNP) developed by the authors of this research consists of a millimetre-long linear array of micro-transistors imbedded in a micrometre-thin polymeric flexible substrate. The flexible gDNP devices were chronically implanted in small animal models of seizures and epilepsy. The implanted devices provided outstanding spatial resolution and very rich wide bandwidth recording of epileptic brain signals over weeks. In addition, extensive chronic biocompatibility tests confirmed no significant tissue damage and neuro-inflammation, attributed to the biocompatibility of the used materials, including graphene, and the flexible nature of the gDNP device.

Future clinical translation of this technology offers the possibility to identify and confine much more precisely the zones of the brain responsible for seizure onset before surgery, leading to less extensive resections and better outcomes. Ultimately, this technology can also be applied to improve our understanding of other neurological diseases associated with ultraslow brain signals, such as traumatic brain injury, stroke and migraine.

“The development of this graphene-based neurotechnology was possible thanks to the microfabrication capacities of the Micro and Nanofabrication Clean Room”, explains Anton Guimerà about the Unique Science and Technology Infrastructure (ICTS) recognized by the Ministry of Science and Innovation.

This study was led by ICREA Prof. Jose A Garrido, head of the ICN2 Advanced Electronic Materials and Devices Group, Dr Anton Guimerà-Brunet, from the Institute of Microelectronics of Barcelona (IMB-CNM-CSIC) and CIBER-BBN and researcher of NANBIOSIS Unit 8 Micro-nanotechnology unit, and Dr Rob Wykes, from the University College London Queen Square Institute of Neurology (UK) & the Nanomedicine Lab of the University of Manchester (UK). First author of the paper is Dr Andrea Bonaccini Calia, a former member of Prof. Garrido’s group. This study was conducted in the frame of the EU project Graphene Flagship. It benefited from multidisciplinary collaborations and received valuable contributions from researchers at the Nanomedicine Lab of the University of Manchester (UK), the Universitat Autònoma de Barcelona (Spain) and g.tec medical engineering GmbH (Austria).

The authors acknoledged the participation of NANBIOSIS Unit 8 Micro-nanotechnology unit, (from CIBER-BBN at IMB-CNM-CSIC) led by Dr. Rosa Villa, in the research in the article of reference.

Reference article:

Andrea Bonaccini Calia, Eduard Masvidal-Codina, Trevor M. Smith, Nathan Schäfer, Daman Rathore, Elisa Rodríguez-Lucas, Xavi Illa, Jose M. De la Cruz, Elena Del Corro, Elisabet Prats-Alfonso, Damià Viana, Jessica Bousquet, Clement Hébert, Javier Martínez-Aguilar, Justin R. Sperling, Matthew Drummond, Arnab Halder, Abbie Dodd, Katharine Barr, Sinead Savage, Jordina Fornell, Jordi Sort, Christoph Guger, Rosa Villa, Kostas Kostarelos, Rob Wykes, Anton Guimerà-Brunet, and Jose A. Garrido, Full bandwidth electrophysiology of seizures and epileptiform activity enabled by flexible graphene micro-transistor depth neural probes. Nature Nanotechnology, 2021. https://www.nature.com/articles/s41565-021-01041-9

Source of information: IMB-CNM-CSIC

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