Nuestros investigadores

Elisa Garbayo Atienza

Facultad de Farmacia y Nutrición. Universidad de Navarra
Líneas de investigación
Sistemas de liberación controlada de fármacos aplicados a enfermedades neurodegenerativas y cardiovasculares . Biomateriales para la regeneración de cerebro y miocardio
Índice H
20, (Google Scholar, 06/04/2019)

Publicaciones científicas más recientes (desde 2010)

Autores: Hanafy, A. S. ; et al.
ISSN 0168-3659  Vol. 295  2019  págs. 201 - 213
Current therapies for Parkinson's disease are symptomatic and unable to regenerate the brain tissue. In recent years, the therapeutic potential of a wide variety of neuroprotective and neuroregenerative molecules such as neurotrophic factors, antioxidants and RNA-based therapeutics has been explored. However, drug delivery to the brain is still a challenge and the therapeutic efficacy of many drugs is limited. In the last decade, micro- and nanoparticles have proved to be powerful tools for the administration of these molecules to the brain, enabling the development of new strategies against Parkinson's disease. The list of encapsulated drugs and the nature of the particles used is long, and numerous studies have been carried out supporting their efficacy in treating this pathology. This review aims to give an overview of the latest advances and emerging frontiers in micro- and nanomedical approaches for repairing dopaminergic neurons. Special emphasis will be placed on offering a new perspective to link these advances with the most relevant clinical trials and with the real possibility of transferring micro- and nanoformulations to industrial scale-up processes. This review is intended as a contribution towards facing the challenges that still exist in the clinical translation of micro- and nanotechnologies to administer therapeutic agents in Parkinson's disease.
Autores: Garbayo, Elisa; Mazo, Manuel María; et al.
ISSN 0022-3565  Vol. 370  Nº 3  2019  págs. 761 - 771
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are a promising cell source for cardiac repair after myocardial infarction (MI) because they offer several advantages such as potential to remuscularize infarcted tissue, integration in the host myocardium, and paracrine therapeutic effects. However, cell delivery issues have limited their potential application in clinical practice, showing poor survival and engraftment after transplantation. In this work, we hypothesized that the combination of hiPSC-CMs with microparticles (MPs) could enhance long-term cell survival and retention in the heart and consequently improve cardiac repair. CMs were obtained by differentiation of hiPSCs by small-molecule manipulation of the Wnt pathway and adhered to biomimetic poly(lactic-co-glycolic acid) MPs covered with collagen and poly(D-lysine). The potential of the system to support cell survival was analyzed in vitro, demonstrating a 1.70-fold and 1.99-fold increase in cell survival after 1 and 4 days, respectively. The efficacy of the system was tested in a mouse MI model. Interestingly, 2 months after administration, transplanted hiPSC-CMs could be detected in the peri-infarct area. These cells not only maintained the cardiac phenotype but also showed in vivo maturation and signs of electrical coupling. Importantly, cardiac function was significantly improved, which could be attributed to a paracrine effect of cells. These findings suggest that MPs represent an excellent platform for cell delivery in the field of cardiac repair, which could also be translated into an enhancement of the potential of cell-based therapies in other medical applications.
Autores: Del Rey, N. L. G.; Quiroga-Varela, Ana; Garbayo, Elisa; et al.
ISSN 1662-5129  Vol. 12  Nº 113  2018 
When James Parkinson described the classical symptoms of the disease he could hardly foresee the evolution of our understanding over the next two hundred years. Nowadays, Parkinson's disease is considered a complex multifactorial disease in which genetic factors, either causative or susceptibility variants, unknown environmental cues, and the potential interaction of both could ultimately trigger the pathology. Noteworthy advances have been made in different fields from the clinical phenotype to the decoding of some potential neuropathological features, among which are the fields of genetics, drug discovery or biomaterials for drug delivery, which, though recent in origin, have evolved swiftly to become the basis of research into the disease today. In this review, we highlight some of the key advances in the field over the past two centuries and discuss the current challenges focusing on exciting new research developments likely to come in the next few years. Also, the importance of pre-motor symptoms and early diagnosis in the search for more effective therapeutic options is discussed.
Autores: Pascual, Simón; Roli, F.; et al.
ISSN 0378-5122  Vol. 110  2018  págs. 1 - 9
The capacity of the heart to heal after a myocardial infarction is not enough to restore normal cardiac function. Fortunately, delivery of therapeutics such as stem cells, growth factors, exosomes and small interfering ribonucleic acid (siRNA), among other bioactive molecules, has been shown to enhance heart repair and improve cardiac function. Furthermore, new delivery systems for these therapeutic agents have enhanced their regenerative and cardioprotective potential. In particular, nano- and microparticles (NPs and MPs) are promising. These systems may be administered directly in the infarcted myocardium or reach the heart after intravenous injection due to the enhanced permeability and retention effect or active targeting. Thus, NPs and MPs have made it possible to administer a wide range of potential drugs, including therapeutic molecules and/or stem cells, and evidence in favor of their use has been reported in several preclinical studies. Here, we review the studies done over the last 5 years using NPs and MPs loaded with therapeutics for repairing cardiac tissue after a myocardial infarction, and discuss some of the advances, challenges and future prospects in this field. In addition, we address the application of NPs and MPs for cardioprotective purposes.
Autores: Pascual, Simón; Abizanda, Gloria María; et al.
ISSN 1061-186X  Vol. 27  Nº 5 - 6  2018  págs. 573 - 581
Neuregulin-1 loaded poly(lactic-co-glycolic acid) (PLGA) microparticles hold great promise for treating acute myocardial infarction, as they have been proved to recover heart function and induce positive heart remodelling in preclinical studies. More recently, the inflammatory response of the heart after acute myocardial infarction (AMI) has been identified as one of the major mechanisms in cardiac tissue remodelling and repair. However, the connection between neuregulin-1 PLGA microparticles and inflammation is still not well characterised. In the present study we assessed this relationship in a mouse AMI model. First, in vitro evidence indicated that neuregulin-1 PLGA microparticles induced a macrophage polarisation toward a regenerative phenotype (CD206+ cells), preventing macrophages from evolving toward the inflammatory phenotype (B7-2+ cells). This correlated with in vivo experiments, where neuregulin-1 PLGA microparticles locally improved the CD206+/B7-2+ ratio. Moreover, neuregulin-1 PLGA microparticles were administered at different time points (15¿min, 24, 72 and 168¿h) after infarction induction without causing secondary inflammatory issues. The time of treatment administration did not alter the inflammatory response. Taken together, these results suggest that neuregulin-1 PLGA microparticles can be administered depending on the therapeutic window of the encapsulated drug and that they enhance the heart's reparative inflammatory response after acute myocardial infarction, helping cardiac tissue repair.
Autores: Blanco, María José; Garbayo, Elisa;
ISSN 0378-5173  Vol. 523  Nº 2  2017  págs. 439 - 440
Autores: Díaz, Paula; Saludas, L.; Pascual, Simón; et al.
ISSN 0168-3659  Vol. 249  2017  págs. 23 - 31
Tissue engineering is a promising strategy to promote heart regeneration after a myocardial infarction (MI). In this study, we investigated the reparative potential of a system that combines adipose-derived stem cells (ADSCs) with microparticles (MPs) loaded with neuregulin (NRG), named ADSC-NRG-MPs, on a rat MI model. First, cells were attached to the surface of MPs encapsulating NRG and coated with a 1:1 mixture of collagen and poly-D-lysine. One week after in vivo administration, the system favored the shift of macrophage expression from a pro-inflammatory to a regenerative phenotype. At long-term, the adhesion of ADSCs to MPs resulted in an increased cell engraftment, with cells being detectable in the tissue up to three months. In consonance, better tissue repair was observed in the animals treated with cells attached to MPs, which presented thicker left ventricles than the animals treated with ADSCs alone. Moreover, the presence of NRG in the system promoted a more complete regeneration, reducing the infarct size and stimulating cardiomyocyte proliferation. Regarding vasculogenesis, the presence of ADSCs and NRG-MPs alone stimulated vessel formation when compared to the control group, but the combination of both induced the largest vasculogenic effect, promoting the formation of both arterioles and capillaries. Importantly, only when ADSCs were administered adhered to MPs, they were incorporated into newly formed vessels. Collectively, these findings demonstrate that the combination of ADSCs, MPs and NRG favored a synergy for inducing a greater and more complete improvement in heart regeneration and provided strong evidence to move forward with preclinical studies with this strategy. (C) 2017 Elsevier B.V. All rights reserved.
Autores: Saludas, L.; Pascual, Simón; prosper f; et al.
ISSN 0378-5173  Vol. 523  Nº 2  2017  págs. 454 - 475
Heart failure still represents the leading cause of death worldwide. Novel strategies using stem cells and growth factors have been investigated for effective cardiac tissue regeneration and heart function recovery. However, some major challenges limit their translation to the clinic. Recently, biomaterials have emerged as a promising approach to improve delivery and viability of therapeutic cells and proteins for the regeneration of the damaged heart. In particular, hydrogels are considered one of the most promising vehicles. They can be administered through minimally invasive techniques while maintaining all the desirable characteristics of drug delivery systems. This review discusses recent advances made in the field of hydrogels for cardiac tissue regeneration in detail, focusing on the type of hydrogel (conventional, injectable, smart or nano-and micro-gel), the biomaterials used for its manufacture (natural, synthetic or hybrid) and the therapeutic agent encapsulated (stem cells or proteins). We expect that these novel hydrogel-based approaches will open up new possibilities in drug delivery and cell therapies. (C) 2016 Elsevier B.V. All rights reserved.
Autores: Pascual, Simón; Simon-Yarza, T; Garbayo, Elisa; et al.
ISSN 0378-5173  Vol. 523  Nº 2  2017  págs. 531 - 533
Neuregulin (NRG1) and fibroblast growth factor (FGF1) are well known growth factors implicated in cardiomyocyte proliferation and survival, as well as in angiogenesis, the development of adult heart and the maintenance of cardiac function. NRG1 and FGF1 have become promising therapeutic agents to treat myocardial infarction (MI) disorder. Unfortunately, clinical trials performed so far reported negative efficacy results, because growth factors are rapidly degraded and eliminated from the biological tissues once administered. In order to increase their bioavailability and favour their therapeutic effects, they have been combined with poly(lactic-co-glycolic acid) and polyethylene glycol microparticles (PLGA MPs and PEG-PLGA MPs). Here we compare both types of microparticles loaded with NRG1 or FGF1 in terms of efficacy in a rat MI model. Our results showed that intramyocardial injection of NRG1 or FGF1-loaded PLGA and PEG-PLGA MPs brought about similar improvements in the ejection fraction, angiogenesis and arteriogenesis after administration into the infarcted hearts. PEG coating did not add any effect regarding MP efficacy. Both PLGA and PEG-PLGA MPs were equally phagocyted in the heart. To our knowledge, this is the first study analysing the opsonisation process in heart tissue. The results allow us to conclude that the opsonisation process is different in heart tissue compared to blood. (C) 2016 Elsevier B.V. All rights reserved.
Autores: Garbayo, Elisa; Gavira, Juan José; García de Yébenes, Manuel; et al.
ISSN 2045-2322  Vol. 6  2016  págs. 25932
Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials.
Autores: Garbayo, Elisa; Ansorena, Eduardo; et al.
ISSN 0142-9612  Vol. 110  2016  págs. 11-23
Glial cell line-derived neurotrophic factor (GDNF) remains the most potent neurotrophic factor for dopamine neurons. Despite its potential as treatment for Parkinson's disease (PD), its clinical application has been hampered by safety and efficacy concerns associated with GDNF's short in vivo half-life and with significant brain delivery obstacles. Drug formulation systems such as microparticles (MPs) may overcome these issues providing protein protection from degradation and sustained drug release over time. We therefore sought to evaluate the efficacy and safety of GDNF delivered via injectable biodegradable MPs in a clinically relevant model of PD and to investigate the mechanism contributing to their beneficial effects. MPs were injected unilaterally into the putamen of parkinsonian monkeys with severe nigrostriatal degeneration. Notably, a single administration of the microencapsulated neurotrophic factor achieved sustained GDNF levels in the brain, providing motor improvement and dopaminergic function restoration. This was reflected by a bilateral increase in the density of striatal dopaminergic neurons 9 months after treatment. Moreover, GDNF was retrogradely transported to the substantia nigra increasing bilaterally the number of dopaminergic and total neurons, regardless of the severe degeneration. GDNF-MP injection within the putamen elicited no adverse effects such as immunogenicity, cerebellar degeneration or weight loss. MPs are therefore a safe, efficient vehicle for sustained protein delivery to the brain, supporting the therapeutic benefit of GDNF when encapsulated within MPs for brain repair. Overall, these findings constitute important groundwork for GDNF-MP clinical development.
Autores: Pascual-Gil, S.; Garbayo, Elisa; Díaz, Paula; et al.
ISSN 0168-3659  Vol. 203  2015  págs. 23 - 38
Myocardial infarction causes almost 7.3 million deaths each year worldwide. However, current treatments are more palliative than curative. Presently, cell and protein therapies are considered the most promising alternative treatments. Clinical trials performed until now have demonstrated that these therapies are limited by protein short half¿life and by low transplanted cell survival rate, prompting the development of novel cell and protein delivery systems able to overcome such limitations. In this review we discuss the advances made in the last 10 years in the emerging field of cardiac repair using biomaterial¿based delivery systems with focus on the progress made on preclinical in vivo studies. Then, we focus in cardiac tissue engineering approaches, and how the incorporation of both cells and proteins together into biomaterials has opened new horizons in the myocardial infarction treatment. Finally, the ongoing challenges and the perspectives for future work in cardiac tissue engineering will also be discussed.
Autores: Pascual, Simón; Simon-Yarza, T.; Garbayo, Elisa; et al.
ISSN 0168-3659  Vol. 220  2015  págs. 388 - 396
The growth factor neuregulin (NRG) is one of the most promising candidates in protein therapy as potential treatment for myocardial infarction (MI). In the last few years, biomaterial based delivery systems, such as polymeric microparticles (MPs) made of poly(lactic co glycolic acid) and polyethylene glycol (PLGA and PEG-PLGA MPs), have improved the efficacy of protein therapy in preclinical studies. However, no cardiac treatment based on MPs has yet been commercialized since this is a relatively new field and total characterization of polymeric MPs remains mandatory before they reach the clinical arena. Therefore, the objective of this study was to characterize the in vivo release, bioactivity and biodegradation of PLGA and PEG-PLGA MPs loaded with biotinylated NRG in a rat model of MI. The effect of PEGylation in the clearance of the particles from the cardiac tissue was also evaluated. Interestingly, MPs were detected in the cardiac tissue for up to 12 weeks after administration. In vivo release analysis showed that bNRG was released in a controlled manner throughout the twelve week study. Moreover, the biological cardiomyocyte receptor (ErbB4) for NRG was detected in its activated form only in those animals treated with bNRG loaded MPs. On the other hand, the PEGylation strategy was effective in diminishing phagocytosis of these MPs compared to noncoated MPs in the long term(12 weeks after injection). Taking all this together, we report new evidence in favor of the use of polymeric PLGA and PEG-PLGA MPs as delivery systems for treating MI, which could be soon included in clinical trials. (C) 2015 Elsevier B.V. All rights reserved.
Autores: Daviaud, N.; Garbayo, Elisa; Lautram, N.; et al.
ISSN 0306-4522  Vol. 256  2014  págs. 10 - 22
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder afflicting 2% of the population older than 65 years worldwide. Recently, brain organotypic slices have been used to model neurodegenerative disorders, including PD. They conserve brain three-dimensional architecture, synaptic connectivity and its microenvironment. This model has allowed researchers a simple and rapid method to observe cellular interactions and mechanisms. In the present study, we developed an organotypic PD model from rat brains that includes all the areas involved in the nigrostriatal pathway in a single slice preparation, without using neurotoxins to induce the dopaminergic lesion. The mechanical transection of the nigrostriatal pathway obtained during slice preparation induced PD-like histopathology. Progressive nigrostriatal degeneration was monitored combining innovative approaches, such as diffusion tensor magnetic resonance imaging (DT-RMI) to follow fiber degeneration and mass spectrometry to quantify striatal dopamine content, together with bright-field and fluorescence microscopy imaging. A substantia nigra dopaminergic cell number decrease was observed by immunohistochemistry against rat tyrosine hydroxylase (TH) reaching 80% after 2 days in culture associated with a 30% decrease of striatal TH-positive fiber density, a 15% loss of striatal dopamine content quantified by mass spectrometry and a 70% reduction of nigrostriatal fiber fractional anisotropy quantified by DT-RMI. In addition, a significant decline of medium spiny neuron density was observed from days 7 to 16. These sagittal organotypic slices could be used to study the early stage of PD, namely dopaminergic degeneration, and the late stage of the pathology with dopaminergic and GABAergic neuron loss. This novel model might improve the understanding of PD and may represent a promising tool to refine the evaluation of new therapeutic approaches.
Autores: Garbayo, Elisa; Estella-Hermoso de Mendoza, Ander; Blanco, María José;
ISSN 0929-8673  Vol. 21  Nº 36  2014  págs. 4100 - 4131
Nanomedicine has recently emerged as an exciting tool able to improve the early diagnosis and treatment of a variety of intractable or age-related brain disorders. The most relevant properties of nanomaterials are that they can be engineered to cross the blood brain barrier, to target specific cells and molecules and to act as vehicles for drugs. Potentially beneficial properties of nanotherapeutics derived from its unique characteristics include improved efficacy, safety, sensitivity and personalization compared to conventional medicines. In this review, recent advances in available nanostructures and nanomaterials for brain applications will be described. Then, the latest applications of nanotechnology for the diagnosis and treatment of neurological disorders, in particular brain tumors and neurodegenerative diseases, will be reviewed. Recent investigations of the neurotoxicity of the nanomaterial both in vitro and in vivo will be summarized. Finally, the ongoing challenges that have to be meet if new nanomedical products are to be put on the market will be discussed and some future directions will be outlined.
Autores: Pelacho, Beatriz; Garbayo, Elisa; et al.
ISSN 0168-3659  Vol. 173  2014  págs. 132 - 139
Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment were detected. Our data support the therapeutic benefit ofNRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies. (C) 2013 Elsevier B.V. All rights reserved.
Autores: Daviaud, N.; Garbayo, Elisa; Schiller, P.; et al.
ISSN 0014-4886  Vol. 248  2013  págs. 429 - 440
Stem cell therapy is a promising treatment for neurological disorders such as cerebral ischemia, Parkinson's disease and Huntington's disease. In recent years, many clinical trials with various cell types have been performed often showing mixed results. Major problems with cell therapies are the limited cell availability and engraftment and the reduced integration of grafted cells into the host tissue. Stem cell-based therapies can provide a limitless source of cells but survival and differentiation remain a drawback. An improved understanding of the behaviour of stem cells and their interaction with the host tissue, upon implantation, is needed to maximize the therapeutic potential of stem cells in neurological disorders. Organotypic cultures made from brain slices from specific brain regions that can be kept in culture for several weeks after injecting molecules or cells represent a remarkable tool to address these issues. This model allows the researcher to monitor/assess the behaviour and responses of both the endogenous as well as the implanted cells and their interaction with the microenvironment leading to cell engraftment. Moreover, organotypic cultures could be useful to partially model the pathological state of a disease in the brain and to study graft-host interactions prior to testing such grafts for pre-clinical applications. Finally, they can be used to test the therapeutic potential of stem cells when combined with scaffolds, or other therapeutic enhancers, among other aspects, needed to develop novel successful therapeutic strategies or improve on existing ones.
Autores: Garbayo, Elisa; Ansorena, Eduardo; Blanco, María José;
ISSN 0378-5122  Vol. 76  Nº 3  2013  págs. 272 - 278
Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease. Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood-brain barrier and target a specific region are still needed. Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly targeted drugs. The advent of new molecular and cellular targets like ¿-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients.
Autores: Ansorena, Eduardo; et al.
ISSN 0378-5173  Vol. 440  Nº 1  2013  págs. 19-26
Human glial cell line-derived neurotrophic factor (hGDNF) is a very promising protein for the treatment of Parkinson's disease and other neurodegenerative disorders. The present work describes a quick and simple method to obtain a high amount of purified hGDNF using a mammalian cell-derived system. The method is based on the high expression level provided by a Semliki Forest virus vector and its ability to induce a strong shut-off of host-cell protein synthesis in mammalian cells. As a result, hGDNF is the only protein present in the supernatant and can be efficiently purified by a single chromatographic step. Using this system it was possible to eliminate other secreted proteins from the culture medium, like insulin-like growth factor-5, which are hard to remove using other hGDNF production methods. Purified hGDNF presents a complex glycosylation pattern typical of mammalian expression systems and is biologically active. This protocol could be extended to other secreted proteins and could be easily scaled up for industrial purposes. (C) 2012 Elsevier B.V. All rights reserved.
Autores: Díaz, Paula; Garbayo, Elisa; Simon-Yarza, T; et al.
ISSN 0939-6411  Vol. 85  Nº 1  2013  págs. 143 - 150
Myocardial infarction (MI) is the leading cause of death worldwide, and extensive research has therefore been performed to find a cure. Neuregulin-1 (NRG) is a growth factor involved in cardiac repair after MI. We previously described how biocompatible and biodegradable microparticles, which are able to release NRG in a sustained manner, represent a valuable approach to avoid problems related to the short half-life after systemic administration of proteins. The effectiveness of this strategy could be improved by combining NRG with several cytokines involved in cardiac regeneration. The present study investigates the potential feasibility of using NRG-releasing particle scaffold combined with adipose-derived stem cells (ADSC) as a multiple growth factor delivery-based tissue engineering strategy for implantation in the infarcted myocardium. NRG-releasing particle scaffolds with a suitable size for intramyocardial implantation were prepared by TROMS. Next, ADSC were adhered to particle scaffolds and their potential for heart administration was assessed in a MI rat model. NRG was successfully encapsulated reaching encapsulation efficiencies of 92.58±3.84%. NRG maintained its biological activity after the microencapsulation process. ADSCs adhered efficiently to particle scaffolds within a few hours. The ADSC-cytokine delivery system developed proved to be compatible with intramyocardial administration in terms of injectability through a 23-gauge needle and tissue response. Interestingly, ADSC-scaffolds were present in the peri-infarted tissue 2weeks after implantation. This proof of concept study provides important evidence required for future effectiveness studies and for the translation of this approach.
Autores: Garbayo, Elisa; Díaz, Paula; et al.
ISSN 0939-6411  Vol. 85  Nº 3  2013  págs. 665 - 672
Poly-lactide-co-glycolide (PLGA) microparticles emerged as one of the most promising strategies to achieve site-specific drug delivery. Although these microparticles have been demonstrated to be effective in several wound healing models, their potential in cardiac regeneration has not yet been fully assessed. The present work sought to explore PLGA microparticles as cardiac drug delivery systems. PLGA microparticles were prepared by Total Recirculation One-Machine System (TROMS) after the formation of a multiple emulsion. Microparticles of different size were prepared and characterized to select the most suitable size for intramyocardial administration. Next, the potential of PLGA microparticles for administration in the heart was assessed in a MI rat model. Particle biodegradation over time and myocardial tissue reaction were studied by routine staining and confocal microscopy. Results showed that microparticles with a diameter of 5¿m were the most compatible with intramyocardial administration in terms of injectability through a 29-gauge needle and tissue response. Particles were present in the heart tissue for up to 3months post-implantation and no particle migration toward other solid organs was observed, demonstrating good myocardial retention. CD68 immunolabeling revealed 31%, 47% and below 4% microparticle uptake by macrophages 1week, 1month, and 3months after injection, respectively (P<0.001). Taken together, these findings support the feasibility of the developed PLGA microparticles as vehicles for delivering growth factors in the infarcted myocardium.
Autores: Garbayo, Elisa; Ansorena, Eduardo; Blanco, María José;
ISSN 1389-2010  Vol. 13  Nº 12  2012  págs. 2388 - 2402
Neurodegenerative disorders (NDs) are rapidly increasing as population ages. However, successful treatments for NDs have so far been limited and drug delivery to the brain remains one of the major challenges to overcome. There has recently been growing interest in the development of drug delivery systems (DDS) for local or systemic brain administration. DDS are able to improve the pharmacological and therapeutic properties of conventional drugs and reduce their side effects. The present review provides a concise overview of the recent advances made in the field of brain drug delivery for treating neurodegenerative disorders. Examples include polymeric micro and nanoparticles, lipidic nanoparticles, pegylated liposomes, microemulsions and nanogels that have been tested in experimental models of Parkinson's, Alzheimer's and Hungtinton's disease. Overall, the results reviewed here show that DDS have great potential for NDs treatment.
Autores: Delcroix, G. J. R.; Garbayo, Elisa; Sindji, L.; et al.
ISSN 0142-9612  Vol. 32  Nº 6  2011  págs. 1560 - 1573
Multipotent mesenchymal stromal cells (MSCs) raise great interest for brain cell therapy due to their ease of isolation from bone marrow, their immunomodulatory and tissue repair capacities, their ability to differentiate into neuronal-like cells and to secrete a variety of growth factors and chemokines. In this study, we assessed the effects of a subpopulation of human MSCs, the marrow-isolated adult multilineage inducible (MIAMI) cells, combined with pharmacologically active microcarriers (PAMs) in a rat model of Parkinson's disease (PD). PAMs are biodegradable and non-cytotoxic poly(lactic-co-glycolic acid) microspheres, coated by a biomimetic surface and releasing a therapeutic protein, which acts on the cells conveyed on their surface and on their microenvironment. In this study, PAMs were coated with laminin and designed to release neurotrophin 3 (NT3), which stimulate the neuronal-like differentiation of MIAMI cells and promote neuronal survival. After adhesion of dopaminergic-induced (DI)-MIAMI cells to PAMs in vitro, the complexes were grafted in the partially dopaminergic-deafferented striatum of rats which led to a strong reduction of the amphetamine-induced rotational behavior together with the protection/repair of the nigrostriatal pathway. These effects were correlated with the increased survival of DI-MIAMI cells that secreted a wide range of growth factors and chemokines. Moreover, the observed increased expression of tyrosine hydroxylase by cells transplanted with PAMs may contribute to this functional recovery.
Autores: Garbayo, Elisa; Raval, A. P.; Curtis, K. M.; et al.
ISSN 0022-3042  Vol. 119  Nº 5  2011  págs. 972 - 988
Cell-based therapies for global cerebral ischemia represent promising approaches for neuronal damage prevention and tissue repair promotion. We examined the potential of marrow-isolated adult multilineage-inducible (MIAMI) cells, a homogeneous subpopulation of immature human mesenchymal stromal cell, injected into the hippocampus to prevent neuronal damage induced by global ischemia using rat organotypic hippocampal slices exposed to oxygen-glucose deprivation and rats subjected to asphyxial cardiac arrest. We next examined the value of combining fibronectin-coated biomimetic microcarriers (FN-BMMs) with epidermal growth factor (EGF)/basic fibroblast growth factor (bFGF) pre-treated MIAMI compared to EGF/bFGF pre-treated MIAMI cells alone, for their in vitro and in vivo neuroprotective capacity. Naive and EGF/bFGF pre-treated MIAMI cells significantly protected the Cornu Ammonis layer 1 (CA1) against ischemic death in hippocampal slices and increased CA1 survival in rats. MIAMI cells therapeutic value was significantly increased when delivering the cells complexed with FN-BMMs, probably by increasing stem cell survival and paracrine secretion of pro-survival and/or anti-inflammatory molecules as concluded from survival, differentiation and gene expression analysis. Four days after oxygen and glucose deprivation and asphyxial cardiac arrest, few transplanted cells administered alone survived in the brain whereas stem cell survival improved when injected complexed with FN-BMMs. Interestingly, a large fraction of the transplanted cells administered alone or in complexes expressed beta III-tubulin suggesting that partial neuronal transdifferentiation may be a contributing factor to the neuroprotective mechanism of MIAMI cells.
Autores: Garbayo, Elisa; Ansorena, Eduardo; Lanciego, José Luis; et al.
ISSN 0885-3185  Vol. 26  Nº 10  2011  págs. 1943 - 1947
Background: Glial cell-derived neurotrophic factor is a survival factor for dopaminergic neurons and a promising candidate for the treatment of Parkinson's disease. However, the delivery issue of the protein to the brain still remains unsolved. Our aim was to investigate the effect of long-term delivery of encapsulated glial cell-derived neurotrophic factor within microspheres. Methods: A single dose of microspheres containing 2.5 mu g of glial cell-derived neurotrophic factor was implanted intrastriatally in animals 2 weeks after a 6-hydroxydopamine lesion. Results: The amphetamine test showed a complete behavioral recovery after 16 weeks of treatment, which was maintained until the end of the study (week 30). This effect was accompanied by an increase in dopaminergic striatal terminals and neuroprotection of dopaminergic neurons. Conclusions: The main achievement was the long-term neurorestoration in parkinsonian animals induced by encapsulated glial cell-derived neurotrophic factor, suggesting that microspheres may be considered as a means to deliver glial cell-derived neurotrophic factor for Parkinson's disease treatment.
Autores: Curtis, K.; Gómez, L. A.; Ríos, C.; et al.
ISSN 1471-2199  Vol. 11  Nº 61  2010  págs. 61
Background: RT-qPCR analysis is a widely used method for the analysis of mRNA expression throughout the field of mesenchymal stromal cell (MSC) research. Comparison between MSC studies, both in vitro and in vivo, are challenging due to the varied methods of RT-qPCR data normalization and analysis. Therefore, this study focuses on putative housekeeping genes for the normalization of RT-qPCR data between heterogeneous commercially available human MSC, compared with more homogeneous populations of MSC such as MIAMI and RS-1 cells. Results: Eight genes including; ACTB, B2M, EF1 alpha, GAPDH, RPL13a, YWHAZ, UBC and HPRT1 were tested as possible housekeeping genes based on their expression level and variability. EF1 alpha and RPL13a were validated for RT-qPCR analysis of MIAMI cells during expansion in varied oxygen tensions, endothelial differentiation, neural precursor enrichment, and during the comparison with RS-1 cells and commercially available MSC. RPL13a and YWHAZ were validated as normalization genes for the cross-species analysis of MIAMI cells in an animal model of focal ischemia. GAPDH, which is one of the most common housekeeping genes used for the normalization of RT-qPCR data in the field of MSC research, was found to have the highest variability and deemed not suitable for normalization of RT-qPCR data. Conclusions: In order to make comparisons between heterogeneous MSC populations, as well as adult stem cell like MSC which are used in different laboratories throughout the world, it is important to have a standardized, reproducible set of housekeeping genes for RT-qPCR analysis. In this study we demonstrate that EF1 alpha, RPL13a and YWHAZ are suitable genes for the RT-qPCR analysis and comparison of several sources of human MSC during in vitro characterization and differentiation as well as in an ex vivo animal model of global cerebral ischemia. This will allow for the comparative RT-qPCR analysis of multiple MSC populations with the goal of future use in animal models of disease as well as tissue repair.
Autores: Pelacho, Beatriz; Garbayo, Elisa; et al.
ISSN 0168-3659  Vol. 147  Nº 1  2010  págs. 30 - 37
The use of pro-angiogenic growth factors in ischemia models has been associated with limited success in the clinical setting, in part owing to the short lived effect of the injected cytokine. The use of a microparticle system could allow localized and sustained cytokine release and consequently a prolonged biological effect with induction of tissue revascularization. To assess the potential of VEGF(165) administered as continuous release in ischemic disease, we compared the effect of delivery of poly(lactic-co-glycolic acid) (PLGA) microparticles (MP) loaded with VEGF(165) with free-VEGF or control empty microparticles in a rat model of ischemia-reperfusion. VEGF165 loaded microparticles could be detected in the myocardium of the infarcted animals for more than a month after transplant and provided sustained delivery of active protein in vitro and in vivo. One month after treatment, an increase in angiogenesis (small caliber caveolin-1 positive vessels) and arteriogenesis (alpha-SMA-positive vessels) was observed in animals treated with VEGF microparticles (p < 0.05), but not in the empty microparticles or free-VEGF groups. Correlating with this data, a positive remodeling of the heart was also detected in the VEGF-microparticle group with a significantly greater LV wall thickness (p < 0.01). In conclusion, PICA microparticle is a feasible and promising cytokine delivery system for treatment of myocardial ischemia. This strategy could be scaled up and explored in pre-clinical and clinical studies. (C) 2010 Elsevier B.V. All rights reserved.
Autores: Ansorena, Eduardo; Garbayo, Elisa; Lanciego, José Luis; et al.
ISSN 0378-5173  Vol. 385  Nº 1-2  2010  págs. 6 - 11
The administration of glial cell line-derived neurotrophic factor (GDNF) has emerged as a promising strategy for the treatment of several diseases of the nervous system as Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury and nerve regeneration as well as ocular diseases and drug addictions. A procedure for the purification of human recombinant glycosylated GDNF using a mammalian expression system as the source of the protein is discussed in the present paper. The neurotrophic factor was purified using cation exchange chromatography and gel filtration. A human cell line was chosen as the source of therapeutic protein, since a recombinant protein with a structure and glycosylation pattern equivalent to the native form is desirable for its prospective therapeutic utilization. The activity of the highly pure protein obtained was confirmed with a cell-based bioassay. The purified protein is suitable for its in vivo evaluation in animals and for possible subsequent clinical application.
Autores: Garbayo, Elisa; Gil-Pascual S; prosper f; et al.
Libro:  Bioresorbable polymers for biomedical applications : from fundamentals to translational medicine
Vol. 120  2017  págs. 445-467
However, although cardiac tissue engineering approaches have been shown to improve heart recovery after MI, there is still no approved treatment available on the market. More research is needed on cardiac tissue engineering strategies to optimize these promising treatments.
Autores: Díaz, Paula; Pascual, Simón; Garbayo, Elisa; et al.
Libro:  Drug delivery: An integrated Clinical and Engineering Approach
2016  págs. 437 - 478
Emphasizing an integrated clinical and engineering approach, this book explores the FDA regulatory and bioethical challenges involved in advancing drug delivery. It examines special clinical states requiring innovative drug delivery modifications, such as hypercoagulability often seen in pregnancy, cancer, and autoimmune diseases. It discusses methods for improved drug delivery in clinical settings using clinical end points, clinical trials, simulations, and other venues. It also describes the latest drug delivery advances involving nanomaterials, NEMS and MEMS devices, hydrogels, microencapsulation, lipids, stem cells, patches, ultrasound, and more.
Autores: Zapata, Natalia María; Garbayo, Elisa; Blanco, María José; et al.
Libro:  Biointerfaces: where material meets biology
2015  págs. 74 - 104
Autores: Simon-Yarza, T; Garbayo, Elisa; et al.
Libro:  Nanostructured biomaterials for overcoming biological barriers
2012  págs. 501 - 526
Autores: Garbayo, Elisa; Delcroix, G. J. R.; Schiller, P.; et al.
Libro:  Tissue engineering for tissue and organ regeneration
2011  págs. 379 - 414
Autores: Ríos, C.; Garbayo, Elisa; Gómez, L. A.; et al.
Libro:  Stem cell and regenerative medicine
2010  págs. 9 - 22




- 43 peer-reviewed publications ( 30 Q1 publications, 1 editorial and 8 book chapters) in top-ranked journals including Biomaterials (2 papers) or Journal of Controlled Release (7 papers) - 4 publications as corresponding author and 31 as first/second author - Guest editor of the Special Issue ¿Biomaterials in Tissue Engineering¿ published in the International Journal of Pharmaceutics (2017) - 2 papers selected as cover in first decile journals (Journal of Controlled Release (2017) and Movement Disorders (2011)) and 1 paper highlighted in the Journal carousel (The Journal of Pharmacology and Experimental Therapeutics (2019). - 1342 citations (H-index 20) with 3 works cited more than 100 times. Average of 180 citations per year during the last 5 years - Ramón y Cajal Research Fellow 2018 (RYC2018-025897-I) - PI in one national project funded by MINECO (SAF2017-83734-R) and participation in 17 research projects (4 European/International: NANOHEART, LEADERA, INELPY, NPQ10, 9 national, 3 regional and 1 private) - 67 communications in conferences (2 invited speaker and 23 oral) - Expert in the Spanish State Research Agency - Reviewer of 31 journals of Delivery Science and Technology like Advanced Materials, Small, Biomaterials or Chemical Engineering Journal.