________________________________________________________________Countless lives have been saved by implantable medical devices (e.g., total artificial hearts, ventricular assist devices, pacemakers, cardioverterdefibrillators, and central lines) and extracorporeal devices that flow whole human blood outside the body through indwelling catheters and external circuits, during cardiopulmonary bypass (CPB), hemodialysis, and extracorporeal membrane oxygenation (ECMO) 1,2 . However, the need to co-administer soluble anticoagulant drugs, such as heparin, with many of these procedures, significantly reduces their safety and hampers their effectiveness 3,4 . Without systemic anticoagulation, these extracorporeal and indwelling devices can rapidly occlude due to thrombosis because clots form when fibrin and platelets in the flowing blood adhere to the surfaces of these artificial materials 5 . Unfortunately, heparin causes significant morbidity and mortality including post-operative bleeding, thrombocytopenia, hypertriglyceridemia, hyperkalemia and hypersensitivity 6 , and its use is contraindicated in several patient populations 7 . In fact, the majority of drug-related deaths from adverse clinical events in the UnitedStates are due to systemic anticoagulation 8 .This need to prevent blood clotting while minimizing administration of anticoagulant drugs has led to the search for biomaterial surface coatings that can directly suppress blood clot formation. The most successful approach to date has been to chemically immobilize heparin on blood-contacting surfaces to reduce thrombosis and lower anticoagulant administration 9,10 . Although this approach has been widely adopted, major limitations persist because the surface-bound heparin leaches, resulting in a progressive loss of anticoagulation 24,25 . Importantly, the TP continues to retain the free LP as a thin mobile liquid layer even when the surface is challenged with a flowing immiscible fluid, such as blood (Fig. 1a). We refer to this unique anti-thrombogenic bilayer composed of the TP and LP coating as a Tethered-Liquid Perfluorocarbon (TLP) surface. RESULTS A generic blood repellent surface coatingTo test the anti-adhesive properties of the TLP coating method, we examined surface adhesion of fresh whole human blood on an acrylic surface sloped at an angle of 30 degrees, with or without a TLP coating composed of tethered perfluorohexane and liquid perfluorodecalin. Blood droplets immediately adhered to the control uncoated acrylic surface and left a trail of blood components over the course of 5 sec (Fig. 1b, top, Supplementary Fig. 1 and Supplementary Movie 1).In contrast, when the same surface was coated with TLP, the blood droplet almost immediately slid off the surface (< 0.3 sec), and remarkably, there was no evidence of any residual blood trail (Fig. 1b, Supplementary Fig. 1 and Supplementary Movie 2). We quantified blood adhesion to surfaces by measuring the minimum angle required to cause a droplet to slide ("sliding angle") ( Fig. 1c). Control uncoated s...

The high selectivity of the human blood-brain barrier (BBB) restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic organ-on-a-chip BBB model lined by induced pluripotent stem cellderived human brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins and functional efflux pumps, and it displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB.

Here we describe a blood-cleansing device for sepsis therapy inspired by the spleen, which can continuously remove pathogens and toxins from blood without first identifying the infectious agent. Blood flowing from an infected individual is mixed with magnetic nanobeads coated with an engineered human opsonin--mannose-binding lectin (MBL)--that captures a broad range of pathogens and toxins without activating complement factors or coagulation. Magnets pull the opsonin-bound pathogens and toxins from the blood; the cleansed blood is then returned back to the individual. The biospleen efficiently removes multiple Gram-negative and Gram-positive bacteria, fungi and endotoxins from whole human blood flowing through a single biospleen unit at up to 1.25 liters per h in vitro. In rats infected with Staphylococcus aureus or Escherichia coli, the biospleen cleared >90% of bacteria from blood, reduced pathogen and immune cell infiltration in multiple organs and decreased inflammatory cytokine levels. In a model of endotoxemic shock, the biospleen increased survival rates after a 5-h treatment.

To illuminate the evolutionary pressure acting on the folding free energy landscapes of naturally occurring proteins, we have systematically characterized the folding free energy landscape of Top7, a computationally designed protein lacking an evolutionary history. Stopped-flow kinetics, circular dichroism, and NMR experiments reveal that there are at least three distinct phases in the folding of Top7, that a nonnative conformation is stable at equilibrium, and that multiple fragments of Top7 are stable in isolation. These results indicate that the folding of Top7 is significantly less cooperative than the folding of similarly sized naturally occurring proteins, suggesting that the cooperative folding and smooth free energy landscapes observed for small naturally occurring proteins are not general properties of polypeptide chains that fold to unique stable structures but are instead a product of natural selection.