Tesis doctoral de Fabio Rocha Formiga
Myocardial infarction (mi) is a major health concern worldwide. Over the years extensive research has been conducted to find new treatments. Growth factor (gf)-based therapy has emerged as a promising strategy to treat patients with mi. However, the therapeutic value of gf has important limitations in vivo, related to their short-lived effect and high instability after systemic administration. In this work, we evaluated the therapeutic potential of gf encapsulated in poly(lactic-co-glycolic acid) (plga) microparticles (mp) to repair the myocardium after a mi. First, we developed plga-mp by total recirculation one-machine system (troms). Mp with a diameter of 5 µm were found to be compatible for intramyocardial administration in terms of injectability and tissue response. Next, we prepared vascular endothelial growth factor (vegf)-loaded plga-mp, which released bioactive vegf in a sustained manner in vitro. In a rat model of ischemia-reperfusion, an increase in vascularization was observed in animals treated with vegf-mp (p<0.05), but not in the non-loaded mp (nl-mp) or free vegf groups at 30 days follow-up. Correlating with this data, a positive remodeling of the heart was also detected in the vegf-mp group with a significantly greater left ventricle wall thickness (p<0.01). Next, we sought to explore further mechanisms of cardiac repair that could be therapeutically induced by gf. For that, we prepared plga-mp loaded with acidic fibroblast growth factor (fgf-1) and neuregulin-1 (nrg-1), two factors involved in distinct mechanisms of cardiac repair after mi. Fgf-1 and nrg-1 were successfully encapsulated into plga-mp, which released the bioactive factors in a controlled manner for up to 28 days in vitro. Also, we have demonstrated that plga-mp remained in the heart tissue for up to 90 days. The ability of fgf-1 and/or nrg-1 mp to promote cardiac regeneration was evaluated in a rat model of mi (permanent ligation). Three months after treatment, a cardiac function improvement was detected in the rats treated with fgf1-mp (16.7 ± 4.9%, p<0.05), nrg1-mp (18.0 ± 5.7%, p<0.05) or fgf1/nrg1-mp (13.0 ± 1.9%, p<0.05) in comparison with the nl-mp control group (1.1 ± 3.6%). In addition, a positive cardiac remodeling with a smaller infarct size and a significant tissue revascularization were detected. Also, recruitment of c-kit+ progenitor cells towards the ischemic myocardium under stimulation of fgf-1 and nrg-1 delivered from the mp was identified. Taken together, these findings support the feasibility of plga-mp to enhance the efficacy of vegf, fgf-1 and nrg-1 by triggering various mechanisms of cardiac repair, paving the way for therapeutic application of these factors in the setting of mi.
Datos académicos de la tesis doctoral «Growth factor loaded-microparticles as a tool for cardiac repair«
- Título de la tesis: Growth factor loaded-microparticles as a tool for cardiac repair
- Autor: Fabio Rocha Formiga
- Universidad: Navarra
- Fecha de lectura de la tesis: 15/12/2011
Dirección y tribunal
- Director de la tesis
- María Jose Blanco Prieto
- Tribunal
- Presidente del tribunal: José Antonio Paramo fernandez
- fermín Sánchez guijo (vocal)
- Ana isabel Torres suarez (vocal)
- Manuel Doblaré castellano (vocal)
