Malferrari, Sara; (2021) Direct Ink Writing 3D Printing Technology for Bone Tissue Regeneration. Doctoral thesis (Ph.D), UCL (University College London.

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Abstract

Over two million bone grafts are performed every year worldwide to treat bone loss due to trauma or diseases (Campana et al., 2014). Synthetic grafts became interesting as a treatment for bone loss due to the variety of biomaterials available which can be selected and tuned according to the surgical requirements (Fernandez de Grado et al., 2018). The ideal bone graft should be biocompatible, easily osteointegrated in nearby bone, it should be osteoconductive, osteoinductive, resorbable and provide adequate structural support (Fillingham and Jacobs, 2016). 3D printing allows the layer-by-layer deposition of biomaterials with or without cells (bioink) to achieve structural complexity of native tissues in addition to desired porosity and shape of grafts. This thesis, aims to explore the use of Direct Ink Writing (DIW) 3D printing to provide solutions for bone substitutes by exploring cellular and acellular printing. Cellular printing (bioprinting) allows to print cells and biomaterials together. Selection of appropriate bioink is crucial to create tissues. Eight novel hydrogels, PGDa1 and PGDa2 (peptidic), GPBA, GPBAD and FBA (nucleic acid based), GGDBA1 and GGDBA2 (polysaccharide based) and GLLG (nucleic acid-ammino acid based) were tested for their biocompatibility, biodegradability, diffusion and printability. Only two hydrogels GGDBA1 and GPBA were selected for further studies. Although GGDBA1 was not able to promote osteogenic differentiation of mesenchymal stem cells on its own, it was seen to significantly (p<0.05) increase osteogenic differentiation indicators (alkaline phosphatase activity, type I collagen, total collagen and calcium deposition) compared to cells seeded on 2D well plates, when osteogenic media was added over a 28 days period. Due to its fast degradation at 37°C, GPBA was successfully used as sacrificial ink to create channels and hollow cylinders in Alginate scaffolds. In the acellular method, hydroxyapatite (HA) ink was developed and characterized. Results indicated that HA scaffold compressive strength depended on the chosen infill density and sintering parameters, adjustable to meet clinical requirements and could be sterilised (autoclave). A pilot study was conducted to validate HA ink to reproduce bone grafts of pre-defined shapes and sizes for corrective osteotomy of distal radius malunion. However HA ink optimisation is not the only parameter to take into account to obtain accurate bespoke grafts. Imaging segmentation and design are also crucial. Image processing software Simpleware was selected based on its accuracy and reproducibility to develop a workflow for design of bespoke alveolar bone HA grafts on an ex-vivo pig jaw model. When comparing the bespoke grafts with gold standard autografting, results showed that 3D printed HA grafts not only significantly (p<0.05) reduced surgical time, but allowed for higher fitting to bone anatomy and to achieve a total bone augmentation of 8mm as per clinical requirement oppositely to autografts. Scalability of bone grafts is a challenge when using DIW 3D printing. Freeform Reversible Embedding of Suspended Hydrogels technique was successfully implemented to print complex anatomical shapes with HA ink. Finally, this thesis provides groundwork for future investigations in the field of 3D printing bone tissue for clinical application.

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