Nanosistemas avanzados para aplicaciones dermatológicas

La llegada de la nanotecnología a las ciencias de la salud ha generado muchas expectativas debido a las importantes aplicaciones diagnósticas, terapéuticas y cosméticas. Uno de los grandes retos en este proceso reside en el desarrollo de «nanoterapias», dirigidas específicamente a los tejidos y órganos diana, evitando los efectos secundarios de los tratamientos actuales. Debido a su biocompatibilidad, las nanopartículas de oro (AuNPs) son unas de las nanopartículas metálicas más utilizadas en la investigación biomédica de nuevos productos. Las AuNPs tienen una superficie reactiva que permite la unión de moléculas orgánicas, así como interesantes propiedades ópticas como la resonancia de plasmon superficial adquirida por el oro coloidal a tamaño nanométrico, facilitando el diseño de sistemas avanzados con múltiples aplicaciones. Existen varios estudios que demuestran que las nanopartículas de oro conjugadas a moléculas estabilizantes (como por ejemplo el polietilenglicol), presentan patrones de toxicidad muy bajos, inferiores a la propia toxicidad de las sales de oro precursoras. Por otra parte, el ácido hialurónico (HA) es ampliamente utilizado en medicina, sobre todo con aplicaciones dermatológicas. Destaca su función estructural y de mantenimiento de la homeostasis, jugando un papel importante en determinados tejidos como la piel, el cartílago o en las articulaciones. Además, el HA interactúa a nivel celular a través de diferentes receptores celulares como son el CD44, Rhamm, LYVE1 y HARE. Su principal virtud es su capacidad de absorber agua hasta aumentar 50 veces su peso en seco. Dicha capacidad para retener agua lo convierte en un excelente aliado para hidratar la piel, protegerla de los radicales libres y favorecer la regeneración de la piel, convirtiéndose en un ingrediente indispensable para las marcas cosméticas. No obstante, tiene como limitación que su gran peso molecular que dificulta su penetración a capas profundas de la piel. Durante esta tesis, hemos desarrollado un avanzado nanosistema llamado Golden Hyaluronan (GH), conjugando moléculas de HA de pequeño tamaño a nanopartículas de oro de manera estable, facilitando de este modo la penetración en capas profundas de la piel. Hemos estudiado tanto los efectos producidos a nivel estructural como celular superando con éxito las pruebas de toxicidad, genotoxicidad y eficacia in vitro, así como los ensayos de seguridad y eficacia in vivo. El principal receptor de este nanosistema ha sido el CD44, a través del cual, el HA está implicado en procesos de migración, proliferación celular, supervivencia y diferenciación. Nuestros estudios demuestran que el GH ha estimulado la síntesis de diferentes moléculas implicadas en procesos de regeneración, especialmente moléculas con interés cosmético, como son el HA, el colágeno o la elastina, confirmando así nuestra hipótesis. De esta manera, con los resultados de esta tesis, Endor ha desarrollado un producto pionero en el mercado con aplicaciones dermocosméticas, concretamente en el ámbito de la regeneración de la piel para el rejuvenecimiento facial llamado Y.en Effect (http://www.yen-effect.com/index.html).The emergence of nanotechnology in life sciences has generated high expectations due to its promising diagnostic, therapeutic and cosmetic applications. One of the major challenges of this process lies in the development of "nanotherapies", that are specifically targeted to destined tissues and organs avoiding the systemic adverse effects of current treatments. Because of their biocompatibility, gold nanoparticles (AuNPs) are among the most widely used metal nanoparticles on the research of new biomedical products. AuNPs possess a reactive surface that allows the attachment of organic molecules and exhibit interesting optical properties, such as the surface plasmon resonance, which facilitate the design of advanced systems with multiple applications. Several studies have shown that AuNPs conjugated to stabilizing molecules (such as polyethylene glycol) express very low levels of toxicity, lower than precursor gold salts. On the other hand, hyaluronic acid (HA) is broadly used in medicine, especially in dermatology. HA has structural functions and it is involved in the maintenance of homeostasis, playing an important role in certain tissues such as skin, cartilage and joints. In addition, HA acts on cellular level through binding to different receptors such as CD44, Rhamm, LYVE1 and HARE. Through its main receptor CD44, HA has been shown to be involved in migration, cell proliferation, survival and differentiation processes. HA is an essential ingredient of cosmetic products and its use has been proven to promote skin regeneration despite being a large molecule that can not penetrate the deep layers of the skin. During this project, we have developed an advanced nanosystem called Golden Hyaluronan (GH), consisting of a spherical core of gold nanoparticle conjugated to modified small size HA molecules in a stable manner; thus, facilitating deep skin layer penetration. We have also studied both structural and cellular effects produced by GH, showing that it successfully passes in vitro toxicity, genotoxicity, and efficacy tests as well as in vivo toxicity and efficacy trials. Our studies with GH have shown a safety health profiling as well as better effects on efficacy compared to HA. We have shown that GH has stimulated the synthesis of different molecules involved in regeneration processes especially the synthesis of molecules with cosmetic interest, such as HA, collagen, and elastin, confirming our hypothesis. Thereby, utilizing the results of this thesis, Endor has developed a pioneering product with dermocosmetic applications in the field of skin regeneration and rejuvenation, called Y.en Effect

Nanosistemas avanzados para aplicaciones dermatológicas /

La llegada de la nanotecnología a las ciencias de la salud ha generado muchas expectativas debido a las importantes aplicaciones diagnósticas, terapéuticas y cosméticas. Uno de los grandes retos en este proceso reside en el desarrollo de «nanoterapias», dirigidas específicamente a los tejidos y órganos diana, evitando los efectos secundarios de los tratamientos actuales. Debido a su biocompatibilidad, las nanopartículas de oro (AuNPs) son unas de las nanopartículas metálicas más utilizadas en la investigación biomédica de nuevos productos. Las AuNPs tienen una superficie reactiva que permite la unión de moléculas orgánicas, así como interesantes propiedades ópticas como la resonancia de plasmon superficial adquirida por el oro coloidal a tamaño nanométrico, facilitando el diseño de sistemas avanzados con múltiples aplicaciones. Existen varios estudios que demuestran que las nanopartículas de oro conjugadas a moléculas estabilizantes (como por ejemplo el polietilenglicol), presentan patrones de toxicidad muy bajos, inferiores a la propia toxicidad de las sales de oro precursoras. Por otra parte, el ácido hialurónico (HA) es ampliamente utilizado en medicina, sobre todo con aplicaciones dermatológicas. Destaca su función estructural y de mantenimiento de la homeostasis, jugando un papel importante en determinados tejidos como la piel, el cartílago o en las articulaciones. Además, el HA interactúa a nivel celular a través de diferentes receptores celulares como son el CD44, Rhamm, LYVE1 y HARE. Su principal virtud es su capacidad de absorber agua hasta aumentar 50 veces su peso en seco. Dicha capacidad para retener agua lo convierte en un excelente aliado para hidratar la piel, protegerla de los radicales libres y favorecer la regeneración de la piel, convirtiéndose en un ingrediente indispensable para las marcas cosméticas. No obstante, tiene como limitación que su gran peso molecular que dificulta su penetración a capas profundas de la piel. Durante esta tesis, hemos desarrollado un avanzado nanosistema llamado Golden Hyaluronan (GH), conjugando moléculas de HA de pequeño tamaño a nanopartículas de oro de manera estable, facilitando de este modo la penetración en capas profundas de la piel. Hemos estudiado tanto los efectos producidos a nivel estructural como celular superando con éxito las pruebas de toxicidad, genotoxicidad y eficacia in vitro, así como los ensayos de seguridad y eficacia in vivo. El principal receptor de este nanosistema ha sido el CD44, a través del cual, el HA está implicado en procesos de migración, proliferación celular, supervivencia y diferenciación. Nuestros estudios demuestran que el GH ha estimulado la síntesis de diferentes moléculas implicadas en procesos de regeneración, especialmente moléculas con interés cosmético, como son el HA, el colágeno o la elastina, confirmando así nuestra hipótesis. De esta manera, con los resultados de esta tesis, Endor ha desarrollado un producto pionero en el mercado con aplicaciones dermocosméticas, concretamente en el ámbito de la regeneración de la piel para el rejuvenecimiento facial llamado Y.en Effect (http://www.yen-effect.com/index.html).The emergence of nanotechnology in life sciences has generated high expectations due to its promising diagnostic, therapeutic and cosmetic applications. One of the major challenges of this process lies in the development of "nanotherapies", that are specifically targeted to destined tissues and organs avoiding the systemic adverse effects of current treatments. Because of their biocompatibility, gold nanoparticles (AuNPs) are among the most widely used metal nanoparticles on the research of new biomedical products. AuNPs possess a reactive surface that allows the attachment of organic molecules and exhibit interesting optical properties, such as the surface plasmon resonance, which facilitate the design of advanced systems with multiple applications. Several studies have shown that AuNPs conjugated to stabilizing molecules (such as polyethylene glycol) express very low levels of toxicity, lower than precursor gold salts. On the other hand, hyaluronic acid (HA) is broadly used in medicine, especially in dermatology. HA has structural functions and it is involved in the maintenance of homeostasis, playing an important role in certain tissues such as skin, cartilage and joints. In addition, HA acts on cellular level through binding to different receptors such as CD44, Rhamm, LYVE1 and HARE. Through its main receptor CD44, HA has been shown to be involved in migration, cell proliferation, survival and differentiation processes. HA is an essential ingredient of cosmetic products and its use has been proven to promote skin regeneration despite being a large molecule that can not penetrate the deep layers of the skin. During this project, we have developed an advanced nanosystem called Golden Hyaluronan (GH), consisting of a spherical core of gold nanoparticle conjugated to modified small size HA molecules in a stable manner; thus, facilitating deep skin layer penetration. We have also studied both structural and cellular effects produced by GH, showing that it successfully passes in vitro toxicity, genotoxicity, and efficacy tests as well as in vivo toxicity and efficacy trials. Our studies with GH have shown a safety health profiling as well as better effects on efficacy compared to HA. We have shown that GH has stimulated the synthesis of different molecules involved in regeneration processes especially the synthesis of molecules with cosmetic interest, such as HA, collagen, and elastin, confirming our hypothesis. Thereby, utilizing the results of this thesis, Endor has developed a pioneering product with dermocosmetic applications in the field of skin regeneration and rejuvenation, called Y.en Effect

Implementation of Zebrafish Ontologies for Toxicology Screening.

Toxicological evaluation of chemicals using early-life stage zebrafish (Danio rerio) involves the observation and recording of altered phenotypes. Substantial variability has been observed among researchers in phenotypes reported from similar studies, as well as a lack of consistent data annotation, indicating a need for both terminological and data harmonization. When examined from a data science perspective, many of these apparent differences can be parsed into the same or similar endpoints whose measurements differ only in time, methodology, or nomenclature. Ontological knowledge structures can be leveraged to integrate diverse data sets across terminologies, scales, and modalities. Building on this premise, the National Toxicology Program's Systematic Evaluation of the Application of Zebrafish in Toxicology undertook a collaborative exercise to evaluate how the application of standardized phenotype terminology improved data consistency. To accomplish this, zebrafish researchers were asked to assess images of zebrafish larvae for morphological malformations in two surveys. In the first survey, researchers were asked to annotate observed malformations using their own terminology. In the second survey, researchers were asked to annotate the images from a list of terms and definitions from the Zebrafish Phenotype Ontology. Analysis of the results suggested that the use of ontology terms increased consistency and decreased ambiguity, but a larger study is needed to confirm. We conclude that utilizing a common data standard will not only reduce the heterogeneity of reported terms but increases agreement and repeatability between different laboratories. Thus, we advocate for the development of a zebrafish phenotype atlas to help laboratories create interoperable, computable data

Implementation of zebrafish ontologies for toxicology screening

Toxicological evaluation of chemicals using early-life stage zebrafish (Danio rerio) involves the observation and recording of altered phenotypes. Substantial variability has been observed among researchers in phenotypes reported from similar studies, as well as a lack of consistent data annotation, indicating a need for both terminological and data harmonization. When examined from a data science perspective, many of these apparent differences can be parsed into the same or similar endpoints whose measurements differ only in time, methodology, or nomenclature. Ontological knowledge structures can be leveraged to integrate diverse data sets across terminologies, scales, and modalities. Building on this premise, the National Toxicology Program’s Systematic Evaluation of the Application of Zebrafish in Toxicology undertook a collaborative exercise to evaluate how the application of standardized phenotype terminology improved data consistency. To accomplish this, zebrafish researchers were asked to assess images of zebrafish larvae for morphological malformations in two surveys. In the first survey, researchers were asked to annotate observed malformations using their own terminology. In the second survey, researchers were asked to annotate the images from a list of terms and definitions from the Zebrafish Phenotype Ontology. Analysis of the results suggested that the use of ontology terms increased consistency and decreased ambiguity, but a larger study is needed to confirm. We conclude that utilizing a common data standard will not only reduce the heterogeneity of reported terms but increases agreement and repeatability between different laboratories. Thus, we advocate for the development of a zebrafish phenotype atlas to help laboratories create interoperable, computable data