טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentBerdichevski Alexandra
SubjectTissue Engineering Based on Injectable Intra-Arterial
Micro-Carrier Delivery System for Cardiac Muscle
Regeneration
DepartmentDepartment of Biomedical Engineering
Supervisor Professor Dror Seliktar
Full Thesis textFull thesis text - English Version


Abstract

Cardiovascular disease is one of the leading causes for morbidity and mortality in the developed countries. Cardiac tissue engineering is a promising novel approach in the regenerative medicine field aimed to provide a reparative solution for the damaged myocardium and restore heart function. However, functional donor-to-host integration of the engineered tissue constructs remains a critical challenge. The overall objective of this work is to design an optimal delivery system for cells and growth factors for cardiac treatment, taking into account several parameters for better integration of the engineered construct within the host tissues, including a preferable mode of implantation, superior pro-angiogenic properties and reduced foreign body response. In this context, we developed MRI/fluorescence bi-modal imaging to document the integration of the hydrogel implants in vivo in a non-invasive and continuous manner. We focused on the characterization of the scaffold’s dissolution, resorption and host response as a function of the hydrogel’s chemical composition, 3D geometry and implantation strategy. We found that each type of implant configuration had very different dissolution kinetics and distinct bi-phasic release profile of degradation products into the surrounding tissues. Moreover, the stability, the host-implant response and the biodegradation mechanism were significantly modulated by the hydrogel composition. Next, we incorporated vascular endothelial growth factor (VEGF) within the hydrogel network and investigated the pro-angiogenic properties of the hydrogels. We demonstrated the controlled release of this growth factor from the hydrogel scaffolds, with subsequent pronounced pro-angiogenic effect in vivo when PEG-Fibrinogen micro-beads were used as a delivery platform. Finally, we adapted PEG-Fibrinogen micro-beads for injection into a myocardial infarction model in rats. Feasibility in vivo studies demonstrated that injected micro-beads remained localized and stable at the injection site, as was evident by the MRI and histology.

Overall, we demonstrated that using different hydrogel modalities can have a significant effect on the implant integration. As such, implantation strategy should be a major consideration when designing tissue engineered constructs and delivery systems, particularly for challenging applications in myocardial repair. The PEG-Fibrinogen micro-beads provide a preferred platform for the implantation in this regard, because of the controllable and reproducible preparation, injectable mode of implantation, as well as superior integration and pro-angiogenic properties.