MRNA-ACTIVATED REPROGRAMMING MATRICES FOR CARTILAGO TISSUE ENGINEERING (Q3144200)
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Project Q3144200 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | MRNA-ACTIVATED REPROGRAMMING MATRICES FOR CARTILAGO TISSUE ENGINEERING |
Project Q3144200 in Spain |
Statements
96,800.0 Euro
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121,000.0 Euro
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80.0 percent
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1 January 2018
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31 December 2021
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UNIVERSIDAD DE SANTIAGO DE COMPOSTELA
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42°52'49.51"N, 8°32'45.10"W
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15078
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EL CARTILAGO ARTICULAR ES UN TEJIDO POBREMENTE IRRIGADO Y CON LIMITADA CAPACIDAD PARA LA AUTO-REPARACION; ACTUALMENTE NO HAY UN TRATAMIENTO EFICAZ PARA SU CURACION. LA TECNOLOGIA DE VANGUARDIA PARA ESTE FIN UTILIZA CONDROCITOS AUTOLOGOS, SIN EMBARGO, EL METODO PRESENTA PROBLEMAS RELACIONADOS CON LA DESDIFERENCIACION CELULAR Y LA MORBILIDAD EN EL SITIO DONANTE. EL PRINCIPAL PROBLEMA DE LA REGENERACION DEL CARTILAGO ARTICULAR ES LA FALTA DE TECNOLOGIAS PARA IMPULSAR Y MANTENER UNA DIFERENCIACION CELULAR ADECUADA. LOS CIENTIFICOS HAN TRATADO DE RESOLVER ESTE PROBLEMA MEDIANTE LA GENERACION DE ANDAMIAJES DONDE LAS CELULAS ESTAN EXPUESTAS A COMPLEJAS COMBINACIONES DE FACTORES DE CRECIMIENTO. SIN EMBARGO, LOS RESULTADOS HAN SIDO DECEPCIONANTES Y LA COMPLEJIDAD DE LOS DISPOSITIVOS PODRIA COMPLICAR SU TRADUCCION CLINICA. UNA POSIBLE FORMA DE EVITAR ESTE PROBLEMA ES EL DISEÑO DE ANDAMIAJES ACTIVADOS CON GENES QUE CODIFICAN FACTORES DE TRANSCRIPCION, YA QUE ESTOS ACTUAN COMO REGULADORES MAESTROS DE LA DIFERENCIACION CELULAR. SIN EMBARGO, LAS MATRICES ACTIVADAS CON FACTORES DE TRANSCRIPCION PRESENTAN UNA BAJA TRANSFECCION, LO QUE COMPROMETE SU FUNCIONALIDAD._x000D_ EN 2016, NUESTRO GRUPO DE INVESTIGACION PRESENTO UNA PATENTE DE ANDAMIAJES ACTIVADOS CON ARNM QUE CODIFICAN SECUENCIAS DE FACTORES DE TRANSCRIPCION. ESTA TECNOLOGIA, MRMATRIX, PRESENTA CLARAS VENTAJAS EN COMPARACION CON LAS TECNOLOGIAS COMPETIDORAS. ENTRE ELLOS, UNA EXCELENTE CAPACIDAD PARA GENERAR LA EXPRESION FORZADA DEL FACTOR DE TRANSCRIPCION, Y PARA ACTIVAR LOS MARCADORES DE DIFERENCIACION EN CULTIVOS CELULARES IN VITRO DE CARTILAGO Y MUSCULO._x000D_ SIN EMBARGO, A PESAR DEL INTERES FUNDAMENTAL DE LA TECNOLOGIA MRMATRIX, EL MATERIAL UTILIZADO, EL GEL DE FIBRINA, RESULTA DEMASIADO INESTABLE PARA UNA REGENERACION OPTIMA EN LA MAYORIA DE LOS TEJIDOS. EL OBJETIVO DE ESTE PROYECTO ES DISEÑAR PROTOTIPOS ESPECIFICOS BASADOS EN EL CONCEPTO MRMATRIX CON MAYOR ESTABILIDAD Y BIOACTIVIADAD, Y CON UNA ORIENTACION CLARA: LA INGENIERIA DE TEJIDOS DEL CARTILAGO ARTICULAR._x000D_ LOS PROTOTIPOS ESPECIFICOS SUGERIDOS SE BASARAN EN DOS IDEAS: PRIMERO, EN UN HIDROGEL BIOMIMETICO QUE SE ACTIVARA CON UNA COMBINACION MEJORADA DE FACTORES DE TRANSCRIPCION CONDROGENICOS. LA SEGUNDA IDEA ES UNA MATRIZ DE LIBERACION SOSTENIDA EN LA QUE UN ARNM CONDROGENICO SE ADMINISTRARA CON UNA COMBINACION SINERGICA DE FACTORES DE CRECIMIENTO. EL PROYECTO COMPRENDE TAREAS ESPECIFICAS PARA DISEÑAR ESTOS DISPOSITIVOS Y PARA OPTIMIZAR SU EFICACIA DE TRANSFECCION Y BIOCOMPATIBILIDAD. A CONTINUACION, SE PROBARA LA CAPACIDAD DE UNA SELECCION DE PROTOTIPOS PARA INDUCIR LA FORMACION DE CARTILAGO EN CULTIVOS 3D DE CELULAS MADRE MESENQUIMALES. LA CALIDAD DEL CARTILAGO SE EVALUARA POR HISTOLOGIA, INMUNOHISTOQUIMICA Y POR MARCADORES ESPECIFICOS. UN FOCO IMPORTANTE DEL PROYECTO SERA MEDIR LOS INDICADORES DE HIPERTROFIA DEL CARTILAGO, YA QUE ESTE ES UN PROBLEMA CON LAS TECNOLOGIAS ACTUALES DE INGENIERIA DE TEJIDOS. FINALMENTE, LOS MEJORES PROTOTIPOS SERAN PROBADOS EN UN MODELO DE DEFECTO DE CARTILAGO ARTICULAR EN CONEJOS, DONDE QUEREMOS VALIDAR LA EFICACIA DE NUESTRA TECNOLOGIA EN UN ENTORNO TERAPEUTICAMENTE RELEVANTE._x000D_ EL PROYECTO TENDRA UN IMPACTO CRITICO AL PROPORCIONAR CRITERIOS CLAVE PARA LA GENERACION DE FUTUROS DISEÑOS DE MRMATRIX, Y RESULTARA EN LA PRIMERA IMPLEMENTACION EXITOSA DEL PRODUCTO EN UN AREA MEDICA DONDE EXISTE UNA NECESIDAD URGENTE DE MEJORES TECNOLOGIAS MEDICAS. (Spanish)
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ARTICULAR CARTILAGE IS A POORLY IRRIGATED TISSUE WITH LIMITED CAPACITY FOR SELF-REPAIR AFTER INJURY, AND CURRENTLY THERE IS NOT AN EFFECTIVE TREATMENT TO HEAL IT. STATE-OF-THE-ART TECHNOLOGY FOR ARTICULAR CARTILAGE REGENERATION USES AUTOLOGOUS CHONDROCYTES, HOWEVER, THE METHOD PRESENTS IMPORTANT PROBLEMS RELATED TO CELL DEDIFFERENTIATION AND DONOR SITE MORBIDITY. INDEED, THE MAJOR PROBLEM WITH ARTICULAR CARTILAGE REGENERATION IS THE LACK OF TECHNOLOGIES TO DRIVE AND MAINTAIN A CELL DIFFERENTIATION. SCIENTISTS HAVE TRIED TO SOLVE THIS PROBLEM BY GENERATING TISSUE SCAFFOLDS WHERE CELLS ARE EXPOSED TO COMPLEX COMBINATIONS OF GROWTH FACTORS. HOWEVER, THE RESULTS HAVE BEEN DISAPPOINTING AND THE COMPLEXITY OF THE DEVICES COULD COMPLICATE CLINICAL TRANSLATION. A POSSIBLE WAY AROUND THIS PROBLEM IS TO MOVE TOWARD SCAFFOLDS ACTIVATED WITH GENES CODING FOR TRANSCRIPTION FACTORS, SINCE THOSE ACT AS MASTER REGULATORS OF CELL DIFFERENTIATION. STILL, MATRICES ACTIVATED WITH TRANSCRIPTION FACTORS FACE THE PROBLEM OF INEFFICIENT DELIVERY OF THE GENE, WHICH CAN COMPROMISE THE FUNCTIONALITY OF THE SYSTEM. _x000D_ IN 2016, OUR RESEARCH GROUP FILED A PATENT FOR SCAFFOLDS ACTIVATED WITH MRNA ENCODING FOR TRANSCRIPTION FACTOR SEQUENCES. THIS TECHNOLOGY HAS BEEN DENOMINATED MRMATRIX, AND PRESENTS CLEAR ADVANTAGES AS COMPARED TO COMPETING TECHNOLOGIES. AMONG THEM, AN OUTSTANDING CAPACITY TO GENERATE FORCED TRANSCRIPTION FACTOR EXPRESSION, AND TO ACTIVATE DIFFERENTIATION MARKERS BOTH IN CARTILAGE AND MUSCLE IN VITRO CELL CULTURES._x000D_ HOWEVER, DESPITE THE FUNDAMENTAL INTEREST OF THE MRMATRIX TECHNOLOGY, THE MATERIAL USED, FIBRIN GEL, WAS TOO UNSTABLE FOR OPTIMAL REGENERATION IN MOST TISSUES, AND LACKED BIOMIMETISM. THE OBJECTIVE OF THIS PROJECT IS TO ENGINEER SPECIFIC PROTOTYPES BASED ON THE MRMATRIX CONCEPT WITH HIGHER STABILITY AND BIOACTIVITY, AND WITH A CLEAR TARGET: ARTICULAR CARTILAGE TISSUE ENGINEERING._x000D_ THE SPECIFIC PROTOTYPES SUGGESTED WILL BE BASED ON TWO IDEAS: FIRST, A BIOMIMETIC HYDROGEL THAT WILL BE ACTIVATED WITH AN IMPROVED COMBINATION OF CHONDROGENIC TRANSCRIPTION FACTORS. THE SECOND IDEA IS A CONTROLLED RELEASE MATRIX WHERE A MRNA CODING FOR A CHONDROGENIC TRANSCRIPTION FACTOR WILL BE DELIVERED SUSTAINABLY WITH A SYNERGISTIC GROWTH FACTOR COMBINATION. THE PROJECT COMPRISES SPECIFIC TASKS TO ENGINEER THESE DEVICES AND TO OPTIMIZE THEIR TRANSFECTION EFFICACY AND BIOCOMPATIBILITY. THEN, A SELECTION OF THESE PROTOTYPES WILL BE TESTED FOR THEIR CAPACITY TO INDUCE CARTILAGE FORMATION IN 3D CULTURES OF MESENCHYMAL STEM CELLS IN VITRO. THE QUALITY OF THE CARTILAGE FORMED WILL BE TESTED BY HISTOLOGY, IMMUNOSTOCHEMISTRY AND BY SPECIFIC EXPRESSION MARKERS. A PARTICULAR FOCUS OF THE PROJECT WOULD BE MEASURING INDICATORS OF CARTILAGE HYPERTROPHY, SINCE THIS IS A MAJOR PROBLEM WITH CURRENT TECHNOLOGIES IN CARTILAGE TISSUE ENGINEERING. FINALLY, THE BEST PROTOTYPES WILL BE TESTED IN AN ARTICULAR CARTILAGE DEFECT RABBIT MODEL WHERE WE WANT TO VALIDATE THE EFFICACY OF OUR TECHNOLOGY IN A THERAPEUTICALLY RELEVANT SETTING._x000D_ THE PROJECT WILL HAVE A CRITICAL IMPACT BY PROVIDING KEY CRITERIA FOR GENERATING FUTURE DESIGNS OF MRMATRIX, AND WILL RESULT IN THE FIRST SUCCESSFUL IMPLEMENTATION OF THE PRODUCT IN A MEDICAL AREA WHERE BETTER MEDICAL TECHNOLOGIES ARE DIRELY NEEDED. (English)
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Santiago de Compostela
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Identifiers
MAT2017-84361-R
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