Bettini, Annalisa; (2022) Investigating a novel intramyocardial delivery method for induced pluripotent stem cell-derived cardiomyocytes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cell therapy is a potential novel treatment for cardiac regeneration and numerous studies have attempted to transplant cells to regenerate the myocardium lost during myocardial infarction. To date, only minimal improvements to cardiac function have been reported. This is likely to occur from low cell retention following delivery and high cell death after transplantation. The thesis aimed to improve the delivery and engraftment of viable cells by using an injectable biomaterial which provides an implantable, biodegradable substrate for attachment and growth of cardiomyocytes derived from induced pluripotent stem cells (iPSC). The thesis describes the fabrication and characterisation of Thermally Induced Phase Separation (TIPS) microspheres, and functionalisation of the microspheres to enable cell attachment in xeno-free conditions. The selected formulation resulted in iPSC attachment, expansion, and retention of pluripotent phenotype. Differentiation of iPSC into cardiomyocytes was investigated and characterised, comparing in vitro culture to microsphere culture using flow cytometry, immunocytochemistry and western blotting techniques. Microsphere culture was shown to be protective against anoikis and compatible for injectable delivery. The in vivo compatibility of the microspheres was assessed using pre-clinical murine models. The microspheres were rendered trackable, using the computed tomography contrast agent barium sulphate, to assess the distribution after ultra-sound guided intramyocardial injections for targeted delivery. The findings suggest that barium sulphate-loaded microspheres can be used as a novel tool for optimising delivery techniques and tracking persistence and distribution of implanted products. Once in vivo compatibility was established, a cellularised microsphere formulation was delivered to the myocardium of immunocompromised mice, to compare the efficacy of biomaterial assisted versus suspension cell therapy. This work demonstrates that TIPS microcarriers offer a supporting matrix for culturing iPSC and iPSC derived cardiomyocytes in vitro and when implanted in vivo have the potential to be developed into an injectable biomaterial for cardiac regeneration.

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