It has been recognized that microbes as well as microbial constituents can result in an overwhelming systemic inflammatory response and procoagulant state leading to sepsis, septic shock and death. The treatment of sepsis has remained extremely challenging and costly, with no success at targeting the downstream events of inflammation. Extracorporeal technologies such as chronic renal replacement therapy have indicated promising potential but offer no specificity. Therefore, finding new strategies would benefit public health. The current proposal addresses the removal of bacterial toxins from human plasma or whole blood to be applied to the extracorporeal treatment of septic patients. The technology relies on affinity binding of bacterial components from both Gram- and Gram+ sepsis, endotoxin, peptidoglycan and bacterial DNA present in blood or plasma flowing through a cartridge filled with agarose beads modified to bind these upstream players in the initiation and the propagation of inflammation and coagulopathy in sepsis. This is realized with high efficiency and good hemocompatibility. This phase I project deals with the prerequisite characterization of the resin and device, before a device prototype would be tested for its beneficial effect in a pig model of septic shock in Phase II. The specific goals of Phase I are: 1- To study the resin biocompatibility and toxicology requirements for a Class III medical device 2- To assess microparticle leaching for the resin that would otherwise be released in the patient's blood. 3- To demonstrate that the flow of blood or plasma has no effect on critical molecules in sepsis, Protein C or activated protein C (FDA-approved drug for the treatment of sepsis). In the long term, the achievement of removal of bacterial toxins from plasma and whole blood allows to anticipate a final extracorporeal device for sepsis treatment either by removal from plasma in a plasmapheresis setting or by removal from whole blood in combination with CRRT machines already existing in the intensive care units. The patients would benefit early in the development of the disease to decrease the inflammation, vascular damage and disseminated intravascular coagulation, as well as later where they experience immuno-paralysis due to an exhausted immune system. Removing the unwanted bacterial toxins is likely to be more advantageous than an anti-inflammatory approach, which may even be detrimental to the patient in some cases.
Thesaurus Terms: bacterial protein, biomaterial development /preparation, extracorporeal circulation, plasmapheresis, septicemia, therapy design /development activation product, biomaterial compatibility, blood coagulation, blood toxicology, carbon, inflammation, protein C, resin blood test, clinical research, human subject, patient oriented research
