Mohmad Saberi, Salfarina Ezrina; (2020) Development of 3D Printed Biodegradable Polyurethane Nanohybrid Scaffold for Heart Valve Regeneration. Doctoral thesis (Ph.D), UCL.

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Abstract

The currently available mechanical and bio-prosthetic heart valve (HV) have still not the rigorous clinical needs for HV replacement and multiple resizing operations are necessary for growing paediatric patients. Biodegradable elastomer scaffold has been the focus in this study as a cell delivery system for HV regeneration, where the polymer degrades after the development of cellular and matrix structure in the scaffold and ultimately leaving only functional tissue without foreign material. This study aims to develop scaffolds for HV regeneration, fabricated using 3D printing techniques in combination with thermally induced phase separation (3D-TIPS), from a biodegradable polymer. The polymer employed is a novel polyurethane, namely polyhedral oligomeric silsesquioxane – terminated poly(ethylene-diethylene glycol succinate-sebacate) urea-urethane (P(EDSS)UU-POSS), a biodegradable polyester-based polyurethane urea with nanocage POSS termination. The structure and physicochemical properties of 3D scaffolds manufactured under different processing conditions (TIPS at -20 °C and 0 °C; cast at 60 °C) and geometrical pore patterns (orthogonal, rectangular, honeycomb, triangular and circular) were characterised. Following the establishment of effective sterilisation techniques for biodegradable P(EDSS)UU-POSS using 8h-UV and 8h-UV + different components (phosphate buffer saline, PBS; ethanol, EtOH; polyhexamethylene biguanide, PHMB; and hydrogen peroxide, H2O2 solution), an in vitro study on cell responses to the elastomer was systematically investigated using different types of cells under different environments (endothelial cells on 2D and 3D scaffolds; fibroblasts on 3D scaffolds with different printed patterns; adipose-derived stem cells (ADSCs) on different types of protein-coated 3D scaffolds), and their differentiation into HV interstitial cells was assessed. The cell ingrowth, matrix deposition, vascularisation, and inflammatory reaction generated by the scaffolds in vivo were examined by subcutaneous implantation in rats for 12 weeks. Lastly, a degradation study of the 3D-TIPS scaffolds was carried out for 10 weeks in vitro, under oxidative, enzymatic, and hydrolytic conditions. The findings from the characterisation study has provided an understanding regarding the influence of manufacturing parameters (porosity percentage, pore size, pore pattern) on the scaffolds’ physicochemical (biomechanical properties, wettability) properties, which can be controlled favourably at the micro- and macropores level using a combination of 3D printing with TIPS process respectively. The sterilisation of the porous scaffolds was achieved by exposed the scaffolds to 8h-UV + 1h-H2O2 solution. The in vitro study revealed that the cells highly proliferated on scaffolds with higher stiffness and hydrophilic properties (3D-TIPS), sharper curvature of pore pattern (triangular), and protein-functionalised scaffolds. The differentiation study of ADSCs towards HV cells showed encouraging outcomes, with phenotypic expressions and functional features of HVs. In vivo immunohistochemistry results exhibited positive cellular activity and minimal inflammatory response, with decreased mechanical strength and increased stiffness from week 4 to week 12 of the subcutaneous implantation. The degradation profile study confirmed degradation of 3D-TIPS as high as 4 % of mass loss in oxidative degradation buffer, followed by the enzymatic and hydrolytic. By taking the advantages of the optimised processing conditions and properties, a preliminary prototype of HV scaffolds has demonstrated that the biodegradable 3D-TIPS P(EDSS)UU-POSS scaffold holds great potential for the creation of viable and long-lasting valve substitutes with hyperelasticity and slow-degradability while promoting tissue regeneration, simultaneously decrease or minimise many undesirable characteristics that possessed by currently available replacement valves.

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