Interfaces for Neural Repair

Laboratory of Interfaces for Neural Repair

 

Principal investigator: Elisa López Dolado. MD, PhD.

E-mail: elopez@sescam.jccm.es

 

Co-principal investigator: María Concepción Serrano López-Terradas. PhD, (ICMM-CSIC).

E-mail: mc.terradas@csic.es

 

 

The Laboratory of Interfaces for Neural Repair (LINER) was born as an independent research laboratory in the Hospital Nacional de Parapléjicos in January, 2017. LINER research focuses on the design and development of new biomaterials useful to serve as interfaces with the injured central neural tissue and able to represent novel therapeutic alternatives for the treatment of spinal cord injury (SCI). Among the materials currently under investigation, both graphene oxide due to its extraordinary physic-chemical properties and natural polymers (e.g. chitosan, gelatin, hyaluronic acid) due to their high biocompatibility deserve special attention. Work in the laboratory includes: (1) Design, fabrication, characterization and functionalization of biomaterials, (2) Biocompatibility assessment by using in vitromodels with neural cell cultures and (3) In vivo studies in experimental models of spinal cord injury in rats. The multidisciplinary expertise of the research team allows the creation of an enriched environment in which knowledge from basic science (Materials Science, Molecular and Cell Biology, Neuroscience, Histology, Pathologic Anatomy) is combined with the understanding of the clinical problem from the daily practice with SCI patients.

 

A few months after its creation in 2014, LINER began a collaboration with the Individualized and Translational Medicine in Inflammation and Cancer Groupof the Department of Medicine and Medical Specialties of the University of Alcalá (UAH, Spain), with the aim of elucidating the alterations of the inflammatory immune system in patients with chronic spinal cord injury, their pathogenic and clinical relevance and possible therapeutic modulations. This collaboration was initiated and has been maintained through uninterrupted funding since 2014 through FIS projects.

 

In July, 25th, 2017, we created the Joint Research Unit “Design and development of biomaterials for neural repair” between the National Hospital for Paraplegics and the Institute of Materials Science in Madrid (CSIC).Through this unit, we maintain an intensive collaboration between LINER from this hospital and the Group of Materials for Medicine and Biotechnology (MAMBIO) from the ICMM-CSIC, for which Dr M. Concepción Serrano is a member. Other groups from our hospital such as Experimental Neurophysiology and Neuronal Circuits, Neuroinflammation and Neuroimmuno-Repair also collaborate within the frame of this Research Unit.

 

 

Selected publications

 

Books:

 

- Engineering biomaterials for neural applications: Targetting traumatic brain and spinal cord injuries. López-Dolado E and Serrano MC (Editors). Springer-Nature 2022.ISBN: 978-3-030-81400-7.

 

 

Articles in Clinical Research:

 

- Rios-León M et al. (2022) Pediatric health and life domain priorities: A national survey of people with spinal cord injury and their parents and caregivers. Journal of Spinal Cord Medicine, Ahead of Print.

 

- De Los Reyes-Guzmán A et al. (2021) RehabHand: Oriented-tasks serious games for upper limb rehabilitation by using Leap Motion Controller and target population in spinal cord injury. NeuroRehabilitation 48: 365–373.

 

- López-Dolado E et al. (2020 )Lessons learned from the coronavirus disease 2019 (Covid-19) outbreak in a monographic center for spinal cord injury. Spinal Cord 58:517-519.

 

- Rodríguez-Cola M et al. (2020) Clinical features of coronavirus disease 2019 (COVID-19) in a cohort of patients with disability due to spinal cord injury. Spinal Cord Series and Cases 6: 39.

 

- Calvo E et al. (2020) Why does COVID-19 affect patients with spinal cord injury milder? A case-control study: Results from two observational cohorts. Journal of Personalized Medicine 10:1-13.

 

 

Articles in Translational Research:

 

- Grassner L et al. (2022) A New Score Based on the International Standards for Neurological Classification of Spinal Cord Injury for Integrative Evaluation of Changes in Sensorimotor Functions. Journal of Neurotrauma 39:613-626.

 

- Diaz D, López-Dolado E et al.(2021) Systemic inflammation and the breakdown of intestinal homeostasis are key events in chronic spinal cord injury patients. International Journal of Molecular Science 22:744.

 

 

Articles in Basic Science:

 

- Domínguez-Bajo A et al. (2021) Nanostructured gold electrodes promote neural maturation and network connectivity. Biomaterials 279: 121186.

 

- Girão A et al. (2020) 3D Reduced graphene oxide scaffolds with a combinatorial fibrous-porous architecture for neural tissue engineering. ACS Applied Materials and Interfaces 12: 38962 - 38975.

 

- Domínguez-Bajo A et al. (2020) Graphene oxide microfibers promote regenerative responses after chronic implantation in the cervical injured spinal cord. ACS Biomaterials Science and Engineering 6: 2401 - 2414.

 

- Domínguez-Bajo A et al. (2020) Interfacing neurons with nanostructured electrodes modulates synaptic circuit features. Advanced Biosystems 2000117: 1 – 13.

 

- Domínguez-Bajo A et al.(2019) Myelinated axons and functional blood vessels populate mechanically compliant rGO foams in chronic cervical hemisected rats. Biomaterials 192: 461 - 474.

 

- López-Dolado E et al. (2016) Immunomodulatory and angiogenic responses induced by graphene oxide scaffolds in chronic spinal hemisected rats. Biomaterials 99: 72-81.

 

- Hernández-Balaguera E et al.(2016) Obtaining electrical equivalent circuits of biological tissues using the current interruption method, circuit theory and fractional calculus. RSC Advances 6: 22312-22319.

 

- López-Dolado E et al.(2015) Subacute tissue response to 3D graphene oxide scaffolds implanted in the injured rat spinal cord. Advanced Healthcare Materials 4: 1861-1868. Portada posterior invitada.

 

 

Research team

 

 

Elisa López Dolado (PhD in Neuroscience, Universidad Autónoma de Madrid, 2012)

 

María Concepción Serrano López-Terradas (PhD in Biology, Universidad Complutense de Madrid, 2006)

 

Yasmina Hernández, Technician in Pathologic Anatomy and Cytology, lab manager

 

Mar Atienza. Physician in Rehabilitation

 

Raquel Madroñero, Physician in Rehabilitation

 

Esther Benayas, PhD student visitor (ICMM-CSIC)

 

Julia Martínez. PhD studentvisitor (ICMM-CSIC)

 

 

 

 

Current research lines and active projects

 

1. Piezo4Spine Project: Piezo-driven theramesh: A revolutionary multifaceted actuator to repair the injured spinal cord. Duration: 01/01/2023 – 31/12/2026. Total budget: 3.5 M€. SESCAM budget: 622 k€. Funding agency: European Commission (Horizon Europe-PathFinder Call). Coordinator: M. Concepción Serrano (CSIC). Principal investigator SESCAM: Juliana M. Rosa (GNEC-HNP). Principal investigator LINER: Elisa López-Dolado. The main objective of this project is the design and development of a novel therapeutic mesh targetter against Piezo mechanoreceptors and fibroglial scarring for spinal cord injury.

 

 

2. PID2020-113480RB-I00 Project: Smart magnetic bio-implants for neural regeneration: Application to spinal cord injury. Duration: 01/09/2021 – 31/08/2024. Budget: 217.8 k€. Fundingagency: MICINN (AEI, Retos de la Sociedad). Principal investigators: M. Concepción Serrano y Sabino Veintemillas (ICMM-CSIC). The main objective of this project is the design, development and characterization of novel bioimplants based on magnetic hydrogels able to efficiently promote, in combination with motor training, neural repair in the injured spinal cord mediating a significant functional recovery.

 

 

3. MARGO Project: MAxillofacial bone Regeneration by 3D-printed laser-activated Graphene Oxidescaffolds. Duration: 01/06/2020 – 31/12/2023. Budget: 150 k€. Funding agency: Joint Transnational Call - FLAG-ERA 2019, European Commission. Principal Investigator: Ceferino López (ICMM-CSIC). Coordinator: Claudio Conti (Sapienza University, Rome, Italy). The main objective of this project is the design, development and in vitro evaluation of 3D scaffolds made of organic polymers and graphene, activated by laser, to promote bone healing at the jaw.

 

 

 

Past research projects

 

1. ByAxon Project: Towards an active bypass for neural reconnection. From 01/01/2017 to 31/12/2020.  Budget: ~450 k€. European Commission (Call FET-OPEN RIA). Principal investigators: M. Concepción Serrano (CSIC, WP3 leader) and Elisa López (SESCAM). Coordinator: Rodolfo Miranda (IMDEA-Nanociencia). The main objective of this project has been the design and development of a novel prototype based on sensors and electrodes fabricated by last regeneration Nanotechnology techniques and able to reconnect neural circuitries through the injured spinal cord. For further details, please check our website out: http://www.byaxon-project.eu/.

 

2. MAT2016-78857-R Project: Design and development of a bioactive 3D biomaterial made of graphene oxide and functionalized for the treatment of injured spinal cord. Duration: 30/12/2016 to31/12/2020. Budget: 121 k€. MINECO (AEI, Retos de la Sociedad, Eje A). Principal investigator: M. Concepción Serrano. The main objective of this project has been the design and development of a bioactive 3D biomaterial based on graphene oxide able to efficiently promote neural repair responses in the injured spinal cord, in combination with an active motor training, by means of a significant functional recovery.

 

3. CP13/00060 Project: Development of 3D structures based on Graphene and biofunctionalized for repairing the central nervous system. Duration: 01/01/2014 – 31/12/2016. Budget: 322.5 k€ (IP cost + research project). Funding agency: Instituto de Salud Carlos III (MICINN). Principal investigator: M. Concepción Serrano. The main objective of this project was the design and development of a 3D biomaterial based on graphene oxide to efficiently promote neural repair at the injured spinal cord.

 

 

 

Most recent and promising research findings

 

The research activity carried out by LINER was initiated in January 2014, with the research Project associated to the Miguel Servet I contract of Dr. Serrano and focused on the investigation of graphene-based materials for neural repair in the injured spinal cord. During this period, our laboratory has pioneered the exploration of the tissue responses to the implantation of a 3D porous scaffold exclusively composed of reduced graphene oxide, both at the subacute and early chronic stages. These scaffolds are characterized by a flexible and soft structure (Young’s modulus: ~1kPa), with a porosity of approximately 80% and an average pore size of 150–180 μm in length. Preliminary in vitro studies with embryonic neural progenitor cells have evidenced a high biocompatibility, with the progressive formation of highly connected neural networks composed of both neurons and glial cells (14 days).

 

 

After the implantation of these structures in the rat injured spinal cord (hemisection model at C6), tissue responses in the lesion site is mainly characterized by: 1) Increase of the mechanical stability of the lesion by means of the filling role played by the scaffold and its complete infiltration by cells and extracellular matrix proteins (collagen), thus favoring the sealing of the lesion area without significant formation of fibroglial scars (stabilization); 2) Colonization of the lesion area by macrophage populations, with a reduced number at the chronic state in comparison with the subacute phase and the evident presence of pro-reparative M2 cells (Arginase I+and/or CD163+) in close contact with the scaffold (immunomodulation); 3) Formation of mature and functional new blood vessels (laminin+, RECA-1+ and SMI-71+) infiltrating the entire 3S scaffold structure (angiogenesis) and 4) Detection of axons (neurofilament+, tubulineβIII+ and vGlut2+)of new formation inside the scaffold, in the proximities of new-formed blood vessels (axonal re-growth). Moreover, by magnetic resonance imaging, we have demonstrated a significant reduction in the number and extension of areas of perilesional damage. Finally, through the use of atomic force microscopy, we have confirmed that our graphene biomaterials do not promote mechanical damage to the contralateral hemicord.

 

 

 

Currents cientific collaborators

 

- Prof. María Teresa Portolés, Universidad Complutense de Madrid (Spain)

- Dr. María del Puerto Morales y Dr. Sabino Veintemillas, Instituto de Ciencia de Materiales de Madrid (Spain)

- Prof. Paula Marques, Universidade de Aveiro (Portugal)

- Prof. Guillermo Ameer, Northwestern University, Chicago (USA)

- Prof. Melchor Álvarez de Mon, Universidad de Alcalá de Henares, Madrid (Spain)

- Dr. Diego Clemente, Hospital Nacional de Parapléjicos, Toledo (Spain)

- Dr. Juan de los Reyes Aguilar and Dr. Juliana R. Martins, Hospital Nacional de Parapléjicos, Toledo (Spain)

- Dr. Anne des Rieux, Universitécatholique de Louvain, Brussels (Belgium)

- Prof. Lino Ferreira, Biocant, University of Coimbra, Cantanhede (Portugal)

- Prof. Julio Camarero and Dr. Teresa González, IMDEA-Nanociencia, Madrid (Spain)

- Prof. José Luis Polo Sanz and Raúl Martín, Universidad de Castilla-La Mancha, Toledo (Spain)

 

 

 

PhD Thesis in the group

 

- Juan Miguel Talavera Mosquera, “Modelos de atención sanitaria en la lesión medular espinal pediátrica y del adolescente”, 20/07/2021, Sobresaliente cum laude.

 

- Ana Domínguez Bajo, “Design and development of biomaterials for spinal cord injury repair”, 21/12/2020, International Mention, Sobresaliente, cum laude.

 

- Enrique Hernández Balaguera, "Characterisation of the passive electrical behaviour of excitable and non-excitable rodent tissues using the current interruption method and impedance measurements", 18/06/2019, Sobresaliente, cum laude.

 

 

 

Formermembers of the group

 

- Dr. Ana Domínguez Bajo, Universitécatholique de Louvain, Brussels (Belgium)

 

- Ankor González Mayorga, Complejo Hospitalario de Navarra (Spain)

 

- André Girão, PhD student visitor (University of Aveiro, Portugal)