Cesarelli, Giuseppe (2020) Engineering novel scaffolds with in silico designed microarchitectures and potentially suitable for spatio-temporal drugs release. [Tesi di dottorato]

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Porous bioactive scaffolds are key components in several tissue engineering strategies. For their effective implementation, it is necessary bioactive scaffolds are capable to accurately deliver potent biological signals to control and guide the morphogenic and tissuegenic processes. This thesis describes the development of a novel bottom–up approach to design, engineer and fabricate modular scaffolds with a precise morphological structure and potentially capable of a controlled presentation over time and space of biological factors. Initially, an in silico study supported by the scientific literature was done to design modules (structural layers and drug delivery systems) features. Simultaneously, the same study focused on the selection of the better suited materials and manufacturing techniques to use during the fabrication stage. Secondly, layers with a 0°/45°/90° filaments orientation and different thickness and/or features (related to the function to fulfil) were fabricated using a magnetic embossing process; contextually, truncated round-shaped drug delivery systems were manufactured using a combination of soft lithography and drug loaded microparticles sintering methods. Finally, modules integration was described and scaffold assembled using a solution-based assembly process. The results show that modules architecture strongly resembles the designed virtual models and present a superficial topography in the submicron-scale. Drug loaded microparticles could be successfully sintered and sealed inside microfabricated shells as shown by microscopy observations. Scaffolds tomographic models present a satisfactory correspondence with virtual models. Compression tests show elastic moduli values of ≈30 MPa and an effective bonding between layers which could ensure scaffolds integrity for in vitro and in vivo tests. In silico and real porosities values are equal to ≈57%. In vitro biocompatibility tests on scaffolds demonstrate good endothelial cells adhesion (≈58% at 6h) and proliferation up to 7 days. Confocal microscopy shows cells successfully adhered and stretched on scaffold layers surfaces. Finally, a tomographic model has proved the effective integration of structural layers and drug delivery systems demonstrating the fabrication of a predesigned scaffold with vascular endothelial growth factor loaded drug delivery systems integrated in the scaffold centre. In conclusion, this thesis demonstrates the feasibility to fabricate modular scaffolds which could potentially demonstrate enhanced control strategies to support the presentation of biomacromolecular factors at the right time, with the right dose, and for the right time frame.

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