Medical devices for the minimally invasive delivery of therapeutic cargo for the prevention of heart failure
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Therapeutic advances are increasing the number of patients that survive cardiac disease such as a myocardial infarction, however, current treatments do not fully stop the development of heart failure. Advanced therapeutic strategies such as stem cell therapies have not proved effective in phase III trials likely due to poor retention and survival of transplanted cells in the infarcted myocardium. This has led to the use of biomaterials which can deliver cells to the myocardium increasing retention rates up to 80% while also mechanically supporting the weakened ventricle. Although biomaterials may be an option for clinical translation, they currently lack effective delivery strategies to the heart and are limited by the traumatic injection into the myocardium. In this thesis it is shown that delivering therapeutics to the epicardium using minimally invasive medical device approaches may be an effective alternative to this problem. Firstly, the SPREADs device is used as a novel bioresorbable biomaterial carrier that can be delivered to the heart using a minimally invasive subxiphoid approach. SPREADs could mechanically support the infarcted ventricle while simultaneously delivering cells in a chronic porcine model of myocardial infarction. Secondly, the TherEpi device is presented that allows for the minimally invasive multidose delivery of therapeutics to the epicardium. This thesis shows that multidose delivery of follastatin like protein 1 (FSTL-1) with TherEpi significantly improves cardiac function, reduces scar size, prevents ventricular thinning, and improves angiogenesis in a rodent model of MI in comparison to both single dose epicardial delivery of FSTL-1 and MI controls. Next, the STAR device is presented which allows active delivery of therapeutics even with the formation of a fibrous capsule. STAR can be loaded with a mechanoresponsive tough gel and a bioresponsive ascorbyl palmitate gel to allow on demand release of drugs in response to mechanical and biological stimuli. Lastly, a model of chemotherapy induced cardiotoxicity using a h9c2 cell is presented and tested with promising prophylactic cardioprotectants. It is shown that resveratrol significantly reduced cell death in comparison to clinically approved dexrazoxane and carvedilol in the h9c2 model of doxorubicin induced cardiotoxicity. Resveratrol could be used in systems such as TherEpi and STAR for prophylactic localised delivery for prevention of doxorubicin induced cardiotoxicity. In summary this thesis prevents novel minimally invasive medical devices for therapeutic delivery.
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