Preclinical testing of an upscaled tissue engineered stem cell patch towards use in translational studies

Abstract

Heart failure is an epidemic which is increasing in prevalence and is associated with an enormous healthcare burden, accounting for 1-2% of the entire NHS healthcare budget. Existing treatment options are primarily focussed on preventing or retarding the progression of disease rather than reversing the disease process. The survival rate has been stubbornly slow to improve with a 5 year mortality rate of 50%. Therefore, at present there is an unmet need for novel treatment strategies. Pluripotent stem cell derived cardiomyocytes (SC-CM) are an exciting and potentially revolutionary treatment option for repairing the damaged heart. Encouraging preclinical experiments have reported that it is possible SC-CMs to survive, electrically couple, and improve contractile function of the host heart, but an increase in arrhythmia has been observed. It has also been shown that the existing delivery methods (intracoronary and intramyocardial) used in human clinical trials of bone marrow mononuclear cells are inadequate to enable long term retention of cells in the heart and therefore newer strategies are needed. Biomaterials are promising, for example, engineered heart tissue has been shown in small animal studies to enable long term cell retention; however, to date the creation of engineered heart tissue suitable for the first in man clinical trials is lacking. The aims of this PhD project were to explore the use of biomaterials including engineered heart tissue and conductive polymers in stem cell grafting experiments. Firstly, upscaled engineered heart tissue was characterised in-vitro and feasibility and efficacy tested in a preclinical intermediate model of myocardial infarction. A rabbit model was chosen and set up for these experiments due to the numerous 6 similarities with human myocardium and it being a suitable next step from small animal models. Cell retention was tested at various time points up to one month and efficacy was tested using changes in left ventricular function as determined by echocardiography. Potentially harmful side effects of arrhythmia burden were tested in-vivo and ex-vivo using telemetry and arrhythmia provocation protocols.The experiments in this PhD described the successful in-vitro characterisation of upscaled engineered heart tissue and preclinical testing in a rabbit model of myocardial infarction. The patches were not associated with an increase in arrhythmia burden and improvements in ventricular function were observed when compared to infarcted hearts. We were also able to show that conductive polymers were able to alter the conductive properties of the epicardial surface of the heart and did not appear pro-arrhythmic in nature.