In vivo and in vitro remodeling of a small intestinal submucosa extracellular matrix cardiac patch in an ovine model and splashing bioreactor

摘要

Previous studies have demonstrated that surgical patches comprised of small intestinal submucosa (SIS)-derived extracellular matrix (ECM) have biological remodeling potential in various tissues. In this series of experiments, the remodeling potential of a commercially available cardiac SIS-ECM patch was examined in both in vivo and in vitro models. This thesis begins by introducing the clinical need for a tissue-engineered cardiovascular scaffold that can grow with the patient and avoid the morbidity associated with currently available synthetic and biological materials. Such a patch would transform the surgical repair of congenital heart disease, in particular of patients with tetralogy of Fallot and in the repair of mitral regurgitation. The in vivo study investigated histological, mechanical, and bioelectrical properties of an SIS-ECM patch implanted in the ovine right-ventricular outflow tract (RVOT), and the histological and mechanical properties of the same patch implanted in the descending aorta and main pulmonary artery of a juvenile ovine. We found the juvenile ovine model to be a suitable model for evaluation of SIS-ECM patch remodeling, as seen by in vivo echocardiography, electrical mapping, and ex vivo optical mapping for the RVOT patch and mechanical testing, histology and immunohistochemistry for patches placed in all three positions. The in vitro study looked at an SIS-ECM patch pretreated with pepsin, seeded with mitral valve interstitial cells (MVICs), and exposed to mechanical stimulation in a splashing bioreactor for one week. Greater cell integration and proliferation and greater tissue cohesion was seen in the pepsin-treated SIS-ECM, while groups without mechanical stimulation demonstrated a stiffening effect for the bioreactor. In sheep, the SIS-ECM patch appears capable of remodeling to resemble native, functional ventricular tissue, but further validation of this patch material is required. Bioreactors can play an important role in validation of this promising scaffold material. Tissue-engineered scaffolds are unique in their complete ontological metamorphosis (from scaffold material to part of the patient's own tissue) and pose distinctive ethical challenges that must be responsibly managed. Contract studies, such as the research presented in chapters 3-5, that are funded by the medical device industry require close scrutiny and precautions to avoid conflicts of interest.