Study of cardiac regeneration activity using different minimally invasive introductory techniques with different regeneration methods

[eng] Scientific advances in recent decades have enabled the identification and classification of a wide variety of diseases, as well as the development of increasingly effective treatments. One of the most innovative and promising approaches is gene therapy, which aims to address diseases at their root: the cells. However, this strategy presents several challenges that must be addressed to ensure both efficacy and safety. First, it is essential to identify the cellular pathways involved in the disease in order to determine which molecular elements (such as mRNA or microRNA) may have therapeutic potential. Second, it is necessary to develop delivery systems that enable localized and minimally invasive application of the therapy, bringing it as close as possible to the affected area. Third, vectors are required to protect and facilitate the entry of genetic material into cells. Fourth, it is important that the therapy can be administered in a sustained manner over time, as most diseases cannot be resolved with a single dose. Finally, to ensure proper monitoring and control, the therapeutic systems used must be visible through clinical imaging techniques such as radiology or ultrasound. This thesis focuses on the application of gene therapies for the treatment of cardiovascular diseases, specifically myocardial infarction and heart failure. To address these conditions, a comprehensive literature review was conducted to identify the most therapeutically relevant microRNAs. Subsequently, a polymeric vector from the PBAE family was developed, designed to facilitate the intracellular delivery of microRNA and to co-deliver nitric oxide (NO), taking advantage of its beneficial vasodilatory properties. In parallel, a hydrogel microparticle system was designed and fabricated to allow for controlled release of the therapeutic agents and to be detectable through imaging techniques such as fluoroscopy and/or ultrasound. Furthermore, a minimally invasive macroscopic device was developed, capable of delivering the therapy directly to the target cardiac region for the treatment of heart failure. In the case of myocardial infarction, a different strategy was employed, integrating the microRNA into the coating of stents and balloons, leveraging existing delivery platforms (such as balloon catheters or expandable stents), which are highly effective in this clinical context. The results obtained demonstrated the efficacy of PBAE polymeric vectors in microRNA transfection, as well as their ability to release nitric oxide in a controlled manner. In addition, the developed hydrogel microparticles showed structural stability, sustained release capacity, and visibility via clinical imaging. Moreover, a collaborative study with Hospital Clínic of Barcelona was carried out to evaluate the efficacy of the hydrogel–vector system in a xenograft mouse model of liver cancer. Although this disease was not initially within the scope of the thesis, the results revealed an observable therapeutic response and tumor size reduction. Finally, coatings for stents and balloons were successfully developed, along with a functional steerable catheter for local treatment of heart failure. However, the final validation phase remains pending to confirm the specific efficacy of the selected therapies in each case. This work presents an integrated therapeutic strategy based on genetic vectors, controlled release platforms, and minimally invasive delivery systems tailored to cardiovascular pathologies.