Heart failure development post myocardial infarction is one of the greatest causes of morbidity and mortality worldwide. Induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) are a promising cell source to regenerate the heart post MI and prevent heart failure development. However, when delivered to the heart, very few cells will engraft and repair the heart. Innovations in bioengineering have led to biomaterials which can hold the cells in place and provide a structural platform to support new tissue formation. This thesis describes a pro-angiogenic, injectable self-assembling peptide hydrogel (SAPH) for the delivery of iPSC-CM to the heart. The most suitable SAPH was first assessed by looking at the different SAPHs compatibility with endothelial cells and iPSC-CM in vitro. To validate the novel SAPHs as a cardiac cell therapy delivery vehicle, SAPHs were delivered via intra-cardiac injection into the hearts of healthy mice. SAPHs were also investigated for their suitability to be used as a delivery vehicle for stem cells post MI. A range of parameters were then used to assess cardiac function and remodelling post gel injection. Alpha 4, a novel SAPH, was shown to support the 3D culture of HUVECs and therefore was used as the base peptide for the addition of different integrin binding motifs. A spheroid based sprouting assay showed the combined addition of GFOGER and RGD integrin binding domains increased sprouting and migration of endothelial cells into the SAPH. iPSC-CM showed good compatibility with encapsulation within SAPHs in vitro and migrated to form large clusters of spontaneously beating cells within the gel. Furthermore, Alpha 4 can be safely delivered to the hearts of mice and remain in situ with no negative effects on cardiac function. When Alpha 4 + RGD + GFOGER was used to deliver iPSC-CM to hearts post MI, it preserved diastolic function and reduced maladaptive remodelling in the heart. These findings suggest Alpha 4 with the addition of GFOGER and RGD is a promising biomaterial for the delivery of induced pluripotent stem cell derived cardiomyocytes to the heart post MI.
Self-assembling peptide hydrogel/ iPSC-CM composites for cardiac repair
King, K. (Author). 31 Dec 2023
Student thesis: Phd