Todd, Lucy; (2025) A Voronoi Journey: 3D Nature-Inspired Scaffolds to Improve Cancer Immunotherapy and Model Biological Environments. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

There are very few people today who have not been affected by a cancer diagnosis, either personally or through a loved one. Cancer can often appear as a growing, undefeatable threat. However, the portfolio of life-saving treatments continues to expand, with ever-increasing success rates. One of the most promising cancer immunotherapies is Chimeric Antigen Receptor (CAR) T-cell Adoptive Cell Transfer (ACT). This treatment involves extracting a patient’s own T-cells from the lymph node, proliferating and activating them ex vivo, genetically engineering them to target specific tumour antigens, and reinfusing them into the patient. One of the major challenges with this therapy is the cost associated with the large number of T-cells required. Current 2D culturing methods neglect to facilitate 3D mechanical and physical interactions required for effective T-cell activation and expansion. Applying the Nature-Inspired Solution (NIS) methodology developed at the UCL Centre for Nature-Inspired Engineering, this thesis presents a collection of accessible, open-access software for designing, building, analysing, optimising, and simulating 3D Voronoi scaffolds (porous structures defined by the proximity of neighbouring points) as T-cell culturing environments. Over 12,000 scaffolds are generated in silico using a parallelised design pipeline in Rhino (an architecture software), with parameters analysed through a novel data visualisation tool built for this research (LION Data). Correlations between Voronoi design features and four key structural parameters (eg., number of vertices and edges) are derived to improve scaffold predictability and reproducibility and are also successfully tested in a bone and tumour microenvironment. Among these scaffolds, eight are identified as topologically similar, although not identical, to the lymph node microenvironment and two are 3D printed and tested using a novel T-cell simulation code. These Voronoi scaffolds demonstrate greater T-cell motility than a previously published, physical lymph node model and less motility than a structurally equivalent lattice scaffold. Additionally, LION Data has been successfully tested in two universities and three research groups (including battery safety and skin permeability data) and was launched into a company (LION Software). Together, this collection of innovative software offers a powerful, nature-inspired platform with the potential to significantly increase ex vivo T-cell expansion and reduce the cost of CAR T-cell therapy for patients worldwide.

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