Development of novel tissue-engineering scaffolds for preventing post-myocardial infarction ventricular remodelling (Doctoral thesis)

Μπάρκα, Ελεονώρα Γ.

Myocardial infarction constitutes an important health related problem worldwide. During the past decades, experimental studies, using cell-based therapies and growth factors administration integrated in biomaterial scaffolds, have demonstrated the potential to reduce the infarcted area and thus to improve regional and global left ventricular function. This study focuses on developing and characterizing novel alginate hydrogels, which can be used as efficient scaffolds in myocardial tissue engineering. In the present thesis, alginate hydrogels were synthesized according to the mechanisms of dialysis, or internal gelation. Divalent ions of alkaline earths, specifically Ca2+, Mg2+, Sr2+, and Ba2, were tested as gelling ions. The Ca-, Sr-, and Ba-alginate hydrogels were successfully synthesized; their dynamic viscosity was sufficiently high (compared to the low viscosity of the alginate solution). These hydrogels were lyophilized and their structural features were studied by FT-IR spectroscopy, while their morphology and texture was studied by scanning electron microscopy (SEM) observations and mercury porosimetry measurements. The results showed that the lyophilized hydrogels (assuming that they reflect their texture when they are in the liquid state in the form of hydrogels) have an ideal structure and porosity, in terms of very high porosity, pore size distribution (which ranges between 60-200 μm, with a peak at ~110 μm), and high pores interconnectivity, in order to host cell cultures into their porous matrix, as well as to be implanted in the myocardial tissue, since they displayed high similarity (lamellar microstructure) to the microstructure of lyophilized myocardial tissue (which was also examined in a similar manner). It is worthy to note that no hydrogels were obtained with Mg2+ cations. A main aim of this study was to optimize the hydrogel composition, which would be an ideal tissue engineering scaffold in myocardial ischemia – reperfusion application. Thus, the influence of Ca2+ ions (i.e. their concentration and the method for supplying them in the alginate acid solution) on the properties, the features, and the quality of the produced hydrogels (reflected in the stability and the molecular configuration of the produced hydrogels) were thoroughly investigated, both experimentally, with viscosity measurements and FT-IR spectroscopy, and theoretically, with DFT (density functional theory) calculations. There was a significant overall agreement between the experimental results and the theoretical calculations and modeling. the theoretical models predict an optimum Ca2+ concentration for achieving the best chelation in the alginate hydrogel, which was also found experimentally. Further addition of Ca2+ ions in the gel (beyond this concentration) results in the relaxation and the degradation of the dense (so called “egg-box”) structure of the hydrogel. This is an important result because reperfusion supplies a high amount of Ca2+ ions to the damaged area. Thus, it was proposed that it is better to implant a Ca-deficient alginate hydrogel in the myocardium, because this Ca-deficient alginate can spontaneously uptake the Ca2+ ions from the biological liquids and form in situ in the heart the well-dense Ca-alginate hydrogel. Τhe Ca-alginate hydrogel was chemically modified to produce complete tissue engineering scaffolds, which can bear growth factors and host cells and transfer and deliver them to the damaged area of the infarcted myocardium. Covalent bonding of different compounds (namely biotine, growth hormone, and the peptide GGGGRGDSP) with the alginate chain was successfully achieved by using carbodiimide conjugate chemistry. Earlier studies have demonstrated that the treatment with growth hormone (GH) is beneficial in preventing left ventricular remodeling. In this thesis, three delivery systems of GH from Ca-alginate hydrogel were developed. The produced Ca-alginate hydrogels were tested in vitro, with cell cultures, and in vivo, with implantations in Wistar rats, according to specific medical protocols.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Μηχανικών Επιστήμης Υλικών
Subject classification: Έμφραγμα μυοκαρδίου
Keywords: Έμφραγμα μυοκαρδίου,Αναδιαμόρφωση αριστερής κοιλίας,Ιστική Μηχανική,Ικριώματα,Υδροπηκτώματα,Αλγινικό οξύ,Myocardial Infarction,Ventricular remodelling,Tissue Engineering,Scaffolds,Hydrogels,Alginate
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