De Gregorio, Maria (2017) Polymer bioactivation: a versatile tool to guide angiogenesis and tissue regeneration. [Tesi di dottorato]

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This PhD thesis stems from a research project conducted at the Center for Advanced Biomaterials for Health Care/CRIB Istituto Italiano di Tecnologia in Naples (Italy). The partial or total loss of organs and tissues is a major cause of hospitalization in the world. The transplant is a possible therapeutic option for various degenerative diseases for which it is not always possible a replacement therapy. However, transplantation still suffers from a number of limitations that reduce its success. Among them there are the need for lifelong immunosuppressive therapy, the risk of infection at the site of transplantation and the shortage of organ donation. In this context, a new science has emerged; it is tissue engineering (TE), which has quickly become a key research area in the field of regenerative medicine. TE is a multidisciplinary science that includes the principles of chemistry, biochemistry, medicine, engineering and physics, in order to provide engineered tissues to restore the lost function of damaged tissues and organs. This discipline combines scaffolds, biologically active molecules and cells to build functional tissues. During regeneration it is crucial for a tissue to receive the right amount of O2 and nutrients. For this reason, one of the main goals of TE is to induce the formation of a functional vascular network. The aim of this project is to enhance the ability of bioactive polymeric matrices to guide regeneration through the spatial and temporal control of the angiogenesis process. In this perspective, I have been involved in different activities including scaffold design and fabrication but particularly the study of its performance from a biological standpoint. Aiming to guide angiogenesis in a space and time controlled fashion we produced scaffolds with controlled porosity and suitable to be loaded with vascular growth factors in order to generate a biochemical gradient. To this purpose scaffolds were fabricated using two different techniques: random assembly, which implies an uncontrolled porosity, and ordered assembly, which includes a controlled porosity. Afterwards, I moved to the comprehension and the validation of the interplay between the scaffold and the cells as well as between the scaffold and the host tissue after implantation. Besides biochemical signals, or rather gradients of these signals, several studies show that endothelial cells are particularly influenced by topographic cues coming from the extracellular matrix. In view of this, I decided to investigate if these signals are able to guide sprouting angiogenesis in a space and time controlled manner without the use of growth factors. To this aim, to resemble physiological signals which are intrinsically dynamic, we used a photoswitches-based strategy to modify the surface of a s specific biomaterial, through a reversible photochemical technique. Finally, since in the past I was involved in studies focused on the use of Carbon Monoxide (CO) to restore the organ function after ischemia/reperfusion injury, I hypothesized that the advantages related to the use of polymer nanocarriers may contribute to solve the open challenges related to the use of this gas in the clinical practice. Several studies, actually, revealed the positive effects of CO in the restoration of the organ function after injury (liver, kidney, heart and others), however this molecule is still considered mostly a toxic gas. In addition, its therapeutic use is hampered by the difficulty to modulate its administration. CO, indeed, is slightly soluble in water so that to reach therapeutic concentrations it should be inhaled at high doses becoming, therefore, dangerous. These issues have been partially overcome through the introduction of the so-called CO-releasing molecules (CORMs). These compounds are able to release CO in the blood, nevertheless, the release is still too fast. In this context is the hypothesis to test, in a model of liver damage, the effect of CORMs encapsulated in polymer nanoparticles able to vehiculate and release them in a controlled manner in order to encourage liver regeneration.

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