A polymethylpentene (PMP) fiber gas exchange device was evaluated in healthy sheep (35-42 kg) to characterize its performance and potential use in clinical extracorporeal life support (ECLS). Five PMP devices (1.3 m2) were compared with five silicone rubber membrane lung (SRML) devices (1.5 m2) that were supported on venovenous ECLS for 72 hours. The two device groups were compared for differences in gas exchange, device pressure gradient, hematology, blood biochemistry, and pathology. The results showed superiority in the PMP devices in both oxygen and CO2 exchange when compared at similar blood flow rates. Platelet consumption and the device pressure gradient were significantly less when using the PMP device. The device pressure gradient across the PMP devices was < 20 mm Hg as compared with > 150 mm Hg for the SRML devices at all blood flow rates. Changes in plasma hemoglobin levels, leukocyte counts, blood chemistry results, and pathologic findings were not significantly different between the two device groups. Plasma leakage or device failure did not occur in any of the test devices. These data support the use of the PMP device for extended circulatory support. Patients may fare better because of improved preservation of platelets, and the low resistance may allow for wider use of centrifugal-style pumps or the use of the device in a pumpless arteriovenous mode.

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BACKGROUND Desmosomes and adherens junctions provide mechanical continuity between cardiac cells, whereas gap junctions allow for cell-cell electrical/metabolic coupling. These structures reside at the cardiac intercalated disc (ID). Also at the ID is the voltage-gated sodium channel (VGSC) complex. Functional interactions between desmosomes, gap junctions, and VGSC have been demonstrated. Separate studies show, under various conditions, reduced presence of gap junctions at the ID and redistribution of connexin43 (Cx43) to plaques oriented parallel to fiber direction (gap junction “lateralization”). OBJECTIVE To determine the mechanisms of Cx43 lateralization, and the fate of desmosomal and sodium channel molecules in the setting of Cx43 remodeling. METHODS Adult sheep were subjected to right ventricular pressure overload (pulmonary hypertension). Tissue was analyzed by quantitative confocal microscopy and by transmission electron microscopy. Ionic currents were measured using conventional patch clamp. RESULT Quantitative confocal microscopy demonstrated lateralization of immunoreactive junctional molecules. Desmosomes and gap junctions in lateral membranes were demonstrable by electron microscopy. Cx43/desmosomal remodeling was accompanied by lateralization of 2 microtubule-associated proteins relevant for Cx43 trafficking: EB1 and kinesin protein Kif5b. In contrast, molecules of the VGSC failed to reorganize in plaques discernable by confocal microscopy. Patch-clamp studies demonstrated change in amplitude and kinetics of sodium current and a small reduction in electrical coupling between cells. CONCLUSIONS Cx43 lateralization is part of a complex remodeling that includes mechanical and gap junctions but may exclude components of the VGSC. We speculate that lateralization results from redirectionality of microtubule-mediated forward trafficking. Remodeling of junctional complexes may preserve electrical synchrony under conditions that disrupt ID integrity.

The purpose of this study was to describe the hemolytic effects of both negative pressure and an air-blood interface independently and in combination in an in-vitro static blood model. Samples of fresh ovine or human blood (5 mL) were subjected to a bubbling air interface (0–100 mL/min) or negative pressure (0–600 mmHg) separately, or in combination, for controlled periods of time, and analyzed for hemolysis. Neither negative pressure nor an air interface alone increased hemolysis. However, when air and negative pressure were combined, hemolysis increased as a function of negative pressure, the air interface, and time. Moreover, when blood samples were exposed to air prior to initiating the test, hemolysis was 4–5 times greater than samples not pre-exposed to air. When these experiments were repeated using freshly drawn human blood the same phenomena were observed, but the hemolysis was significantly higher than that observed in sheep blood. In this model, hemolysis is caused by combined air and negative pressure and is unrelated to either factor alone.

Current artificial lungs fail in 1-4 weeks due to surface-induced thrombosis. Biomaterial coatings may be applied to anticoagulate artificial surfaces, but none have shown marked long-term effectiveness. Poly-carboxybetaine (pCB) coatings have shown promising results in reducing protein and platelet-fouling in vitro. However, in vivo hemocompatibility remains to be investigated. Thus, three different pCB-grafting approaches to artificial lung surfaces were first investigated: 1) graft-to approach using 3,4-dihydroxyphenylalanine (DOPA) conjugated with pCB (DOPA-pCB); 2) graft-from approach using the Activators ReGenerated by Electron Transfer method of atom transfer radical polymerization (ARGET-ATRP); and 3) graft-to approach using pCB randomly copolymerized with hydrophobic moieties. One device coated with each of these methods and one uncoated device were attached in parallel within a veno-venous sheep extracorporeal circuit with no continuous anticoagulation (N=5 circuits). The DOPA-pCB approach showed the least increase in blood flow resistance and the lowest incidence of device failure over 36-hours. Next, we further investigated the impact of tip-to-tip DOPA-pCB coating in a 4-hour rabbit study with veno-venous micro-artificial lung circuit at a higher activated clotting time of 220-300s (N≥5). Here, DOPA-pCB reduced fibrin formation (p=0.06) and gross thrombus formation by 59% (p<0.05). Therefore, DOPA-pCB is a promising material for improving the anticoagulation of artificial lungs.