RESUMEN
Cardiovascular diseases are the leading cause of death in the United States. Treatment often requires surgical interventions to re-open occluded vessels, bypass severe occlusions, or stabilize aneurysms. Despite the short-term success of such interventions, many ultimately fail due to thrombosis or restenosis (following stent placement), or incomplete healing (such as after aneurysm coil placement). Bioactive molecules capable of modulating host tissue responses and preventing these complications have been identified, but systemic delivery is often harmful or ineffective. This review discusses the use of localized bioactive molecule delivery methods to enhance the long-term success of vascular interventions, such as drug-eluting stents and aneurysm coils, as well as nanoparticles for targeted molecule delivery. Vascular grafts in particular have poor patency in small diameter, high flow applications, such as coronary artery bypass grafting (CABG). Grafts fabricated from a variety of approaches may benefit from bioactive molecule incorporation to improve patency. Tissue engineering is an especially promising approach for vascular graft fabrication that may be conducive to incorporation of drugs or growth factors. Overall, localized and targeted delivery of bioactive molecules has shown promise for improving the outcomes of vascular interventions, with technologies such as drug-eluting stents showing excellent clinical success. However, many targeted vascular drug delivery systems have yet to reach the clinic. There is still a need to better optimize bioactive molecule release kinetics and identify synergistic biomolecule combinations before the clinical impact of these technologies can be realized.
RESUMEN
Here we describe development of an extracorporeal hemoadsorption device for sepsis therapy that employs commercially available polysulfone or polyethersulfone hollow fiber filters similar to those used clinically for hemodialysis, covalently coated with a genetically engineered form of the human opsonin Mannose Binding Lectin linked to an Fc domain (FcMBL) that can cleanse a broad range of pathogens and endotoxin from flowing blood without having to first determine their identity. When tested with human whole blood in vitro, the FcMBL hemoadsorption filter (FcMBL-HF) produced efficient (90-99%) removal of Gram negative (Escherichia coli) and positive (Staphylococcus aureus) bacteria, fungi (Candida albicans) and lipopolysaccharide (LPS)-endotoxin. When tested in rats, extracorporeal therapy with the FcMBL-HF device reduced circulating pathogen and endotoxin levels by more than 99%, and prevented pathogen engraftment and inflammatory cell recruitment in the spleen, lung, liver and kidney when compared to controls. Studies in rats revealed that treatment with bacteriocidal antibiotics resulted in a major increase in the release of microbial fragments or 'pathogen-associated molecular patterns' (PAMPs) in vivo, and that these PAMPs were efficiently removed from blood within 2 h using the FcMBL-HF; in contrast, they remained at high levels in animals treated with antibiotics alone. Importantly, cleansing of PAMPs from the blood of antibiotic-treated animals with the FcMBL-hemoadsorbent device resulted in reduced organ pathogen and endotoxin loads, suppressed inflammatory responses, and resulted in more stable vital signs compared to treatment with antibiotics alone. As PAMPs trigger the cytokine cascades that lead to development of systemic inflammatory response syndrome and contribute to septic shock and death, co-administration of FcMBL-hemoadsorption with antibiotics could offer a more effective approach to sepsis therapy.