Inflammation in Cardiovascular Tissue Engineering: The Challenge to a Promise: A Minireview

Tissue engineering employs scaffolds, cells, and stimuli brought together in such a way as to mimic the functional architecture of the target tissue or organ. Exhilarating advances in tissue engineering and regenerative medicine allow us to envision in vitro creation or in vivo regeneration of cardiovascular tissues. Such accomplishments have the potential to revolutionize medicine and greatly improve our standard of life. However, enthusiasm has been hampered in recent years because of abnormal reactions at the implant-host interface, including cell proliferation, fibrosis, calcification and degeneration, as compared to the highly desired healing and remodeling. Animal and clinical studies have highlighted uncontrolled chronic inflammation as the main cause of these processes. In this minireview, we present three case studies highlighting the importance of inflammation in tissue engineering heart valves, vascular grafts, and myocardium and propose to focus on the endothelial barrier, the “final frontier” endowed with the natural potential and ability to regulate inflammatory signals

BIOLOGICAL SCAFFOLDS FOR PERIPHERAL VASCULAR SURGERY

The gold standards for small diameter peripheral vascular graft replacement are autologous arteries or veins; however, one-third of patients lack such vessels due to previous vessel harvesting or advanced vascular disease. A promising approach for patients in this category is tissue engineering with off-the-shelf biological vascular grafts. Three small diameter acellular scaffolds were developed and evaluated as vascular grafts. Porcine renal arteries (2-3 mm diameter, 20 mm length) were decellularized by immersion and stabilized with penta-galloyl glucose (PGG) with and without subsequent heparinization via carbodiimide chemistry. Bovine mammary (4-6 mm ID, 250 mm length) and femoral arteries (6-8 mm ID, 250 mm length) were decellularized in a purpose-designed, pressurized detergent perfusion system and stabilized with PGG. Decellularization completeness was confirmed by histology, DNA analysis and absence of xenoreactive galactose-(alpha 1,3)-galactose antigen. Histology suggested good preservation of native collagen, elastin and basement membrane components collagen type IV, laminin, and fibronectin. Renal artery scaffolds stabilized with PGG showed increased resistance to elastase and heparinization increased resistance to collagenase. All scaffolds exhibited adequate values of burst pressure and diametrical compliance. Acellular scaffolds were tested for biocompatibility, patency, thrombogenicity and host cell infiltration by intra-circulatory implantation in rats as abdominal aorta interposition grafts (renal artery scaffolds) and as femoral interposition grafts in minipigs (mammary artery scaffolds). Renal artery scaffolds exhibited 100% patency upon explantation at 4 and 8 weeks and demonstrated revitalization with host cells staining positive for factor VIII and alpha-smooth muscle actin. Heparinized / PGG treated renal scaffolds exhibited the most promising short-term results in rats due to reduced thrombogenicity and intimal hyperplasia. Mammary artery scaffolds thrombosed within 1 week of implantation in the femoral position, but supported cellular infiltration. Preliminary studies also showed that cells could be seeded into specific tunics of the acellular scaffolds, thus generating revitalized grafts ready for implantation. These results suggest that acellular scaffolds derived from arterial segments are good candidates for development of vascular grafts and that the combination of targeted matrix stabilization, heparinization and tunic-specific cell seeding might exhibit significant clinical potential for treatment of peripheral vascular diseases