Medical devices for the minimally invasive delivery of therapeutic cargo for the prevention of heart failure
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2020-11-10Author
Monahan, David
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Abstract
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.