Tissue-Engineered Vascular Grafts: Recellularisation and Surface Functionalisation with Hybrid Magnetic Nanomedicine Developed with Theranostic Potential

Abstract

Cardiovascular Disease is the number one cause of death in the world, with a mortality rate, globally of 35.1% representing 17.6 million lives lost annually. The majority of these deaths are related to vascular diseases, such as atherosclerotic plaques, which can obstruct blood flow perfusion of organs and tissue causing serious injuries or even death. In the heart, in order to prevent heart failure, blood flow to the tissue must be restored as quickly as possible, ideally via minimally invasive interventions such as stenting or other types of angioplasty as the gold standard. However, this is not always suitable, thus, blood vessel bypass grafts may be required. Tissue-engineered vascular grafts has being aimed as a product that has the capacity to be repopulated with the patient’s own cells to reduce immunogenicity and increase graft patency. A particular importance of tissue-engineered vascular grafts using degradable biopolymers is for clinical paediatric cardiothoracic surgeries. This thesis uses porcine carotid decellularized arteries as degradable biopolymer scaffolds. Currently, although significant progress has occurred, recellularisation process is not optimised due to the complex structure of the artery wall or for issues related to the biochemical and physicochemical cues from the arterial vessel surface that can lead to thrombus and stenosis formation. Tissue engineering is a highly multidisciplinary field that combines a number of areas of science and engineering to study new possibilities for repairing and regenerating tissues and organs. This thesis is focused on current essential requirements as well as some strategies for future developments of tissue-engineered blood vessels, involving tissue engineering and nanomedicine. Chapter 2 is devoted exclusively to tissue engineering. The studies were performed to overcome the barrier posed by the dense/layered architecture of porcine carotid decellularized arteries thus improving tunica media repopulation, using a cost effective microneedle-based device developed to modify the physical structure in a minimally invasive manner. This was achieved by creating radial microchannels, which enhanced the radial cellular repopulation while preserving the biomechanical properties and the extracellular matrix integrity. Moreover, repopulation by assessing two different seeding methods, injection technique and cell seeding bioreactor were carried out and presented successful radial tunica media repopulation. Chapter 3 relates to nanotechnology, where a thermal stimulus-responsive hybrid magnetic-nanomedicine with theranostic potential for biomedical applications from cancer therapy to tissue engineering were developed, by synthesising and engineering superparamagnetic iron oxide nanoparticles, magnetic mesoporous silica nanoparticles and thermosensitive phospholipid bilayers. Chapter 4 merged nanomedicines and tissue engineering, encompassing the modification of the surface of the decellularized arteries with nanomedicines of modular design and with theranostic potential developed in chapter 3, thus initiating a new generation of tissue-engineered vascular grafts, that could potentially be studied to enrich the grafts balancing of microenvironmental cues to promote optimal immunomodulation, wound healing and tissue formation/remodelling with the delivery of chemical and biological agents. In summary, this PhD thesis has led to the development of new strategies to aid progress in tissue engineering and regenerative medicine, such as 3D ECM-derived scaffolds with potential controlled and triggerable release of cargos and theranostics.