Feng, Zhiping; (2025) Multimodal in vivo evaluation of experimental therapies for myocardial infarction. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Myocardial infarction (MI) remains a leading cause of mortality worldwide. Current clinical therapies alleviate symptoms and slow progression but cannot regenerate damage. Consequently, various regenerative therapies, including stem cell-based, biomaterial-based, and gene transfer—have been developed to promote cardiac regeneration. Here I established a mouse model of myocardial infarction and used advanced four-dimensional ultrasound and speckle tracking echocardiography to quantify dysfunction. The model was then used to evaluate cells, biomaterial and gene therapies for MI. To improve stem cell delivery, an alginate patch was developed which could be injected under ultrasound-guidance. Patches were radiolabeled with 111Indium allowing their location to be monitored using single-photon emission computed tomography (SPECT). Patches injected under ultrasound guidance did not remain on the epicardium, so iterative modifications to the patch formulation and delivery method were tested with SPECT used to determine delivery success. An adhesive chitosan-coated patch was developed which could be surgically attached to the epicardium and remained in location for over 7 days. Luciferase expressing epicardial cells were loaded onto 111Indium labeled patches and attached to the epicardium. SPECT and bioluminescence imaging demonstrated that the patch remained on-target and cells remained viable over 7 days, highlighting how multimodal imaging can be useful in optimizing delivery of therapeutic cells. To investigate the activation of cardiomyocyte cycling via adeno-associated virus (AAV)-gene therapy, I injected AAVs encoding an activator, and a luciferase reported of the YAP pathway. Bioluminescence imaging identified in vivo activation of the YAP pathway, whilst ultrasound and MRI identified focal hyperplasia and deterioration of cardiac function after YAP activation. This multimodal in vivo system can monitor gene expression and resultant changes in cardiac function, allowing optimization of gene therapies. This thesis shows how multimodal imaging can be used for minimally invasive delivery and direct monitoring of therapeutics in combination with accurate functional measurements, making an ideal platform for developing therapies.

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