Despite the prevailing use of the continuous flow left ventricular assist devices (cf-LVADs), acquired von Willebrand syndrome (AvWS) associated with cf-LVADs still remains a major complication. As AvWS is known to be dependent on shear stress ( ) and exposure time (t exp ), this study examined the degradation of high molecular weight multimers (HMWM) of von Willebrand factor (vWF) in terms of τ and t exp . Two custom apparatus, i.e., capillary-tubing-type degrader (CTD) and Taylor-Couettetype degrader (TCD) were developed for short-term (0.033 sec ≤ t exp ≤ 1.05 s) and long-term (10 s ≤ t exp ≤ 10 min) shear exposures of vWF, respectively. Flow conditions indexed by Reynolds number (Re) for CTD were 14 ≤ Re ≤ 288 with corresponding laminar stress level of 52 ≤ CTD ≤ 1042 dyne/ cm 2 . Flow conditions for TCD were 100 ≤ Re ≤ 2500 with corresponding rotor speed of 180 ≤ ω o ≤ 4000 RPM and laminar stress level of 50 ≤ TCD ≤ 1114 dyne/cm 2 . Due to transitional and turbulent flows in TCD at Re > 1117, total stress (i.e., total = laminar + turbulent) was also calculated using a computational fluid dynamics (CFD) solver, Converge CFD. Inhibition of ADAMTS13 with different concentrations of EDTA (5 mM and 10 mM) was also performed to investigate the mechanism of cleavage in terms of mechanical and enzymatic aspects. Degradation of HMWM with CTD was negligible at all given testing conditions. Although no degradation of HMWM was observed with TCD at Re < 1117 ( total = 1012 dyne/cm 2 ), an increase in degradation of HMWM was observed beyond Re of 1117 for all given exposure times. At Re ~ 2500 ( total = 3070 dyne/ cm 2 ) with t exp = 60 s, a severe degradation of HMWM (90.7 ± 3.8%, abnormal) was observed, and almost complete degradation of HMWM (96.1 ± 1.9%, abnormal) was observed with t exp = 600 s. The inhibition studies with 5 mM EDTA at Re ~ 2500 showed that loss of HMWM was negligible (<10%, normal) for all given exposure times except for t exp = 10 min (39.5 ± 22.3%, borderline-abnormal).
Despite recent breakthroughs in targeted- and immune-based therapies, rapid development of drug resistance remains a hurdle for the long-term treatment of patients with melanoma. Targeting metastatically spreading circulating tumor cells (CTCs) may provide an additional approach to manage melanoma. This study investigates whether targeting cholesterol transport in melanoma CTCs can retard metastasis development. Nanolipolee-007, the liposomal form of leelamine, reduced melanoma metastasis in both a novel in vitro flow system mimicking the circulating system and in experimental as well as spontaneous animal metastasis models, irrespective of the BRAF mutational status of the CTCs. Leelamine led to cholesterol trapping in lysosomes, which subsequently shut down receptor-mediated endocytosis, endosome trafficking, and inhibited the major oncogenic signaling cascades important for survival such as the AKT pathway. As pAKT is important in CTC survival, inhibition by targeting cholesterol metabolism led to apoptosis, suggesting this approach might be particularly effective for those CTCs having high levels of pAKT to aid survival in the circulation system.
The design and initial test results of a new passively suspended Tesla type LAVD blood pump are described. CFD analysis was used in the design of the pump. Overall size of the prototype device is 50 mm in diameter and 75 mm in length. The pump rotor has a density lower than that of blood and when spinning inside the stator in blood it creates a buoyant centering force that suspends the rotor in the radial direction. The axial magnetic force between the rotor and stator restrain the rotor in the axial direction. The pump is capable of pumping up to 10 liters/min at a 70 mmHg head rise at 8000 RPM. The pump has demonstrated a normalized index of hemolysis level below .02 mg/dL for flows between 2 and 9.7 L/min. An inlet pressure sensor has also been incorporated into the inlet cannula wall and will be used for control purposes. One initial in vivo study showed an encouraging result. Further CFD modeling refinements are planned as well as endurance testing of the device.
Reynolds shear stress (RSS) has served as a metric for the effect of turbulence on hemolysis. Forstrom (1969) and Sallam and Hwang (1984) determined the RSS threshold for hemolysis to be 50,000 and 4,000 dyne/cm, respectively, using a turbulent jet. Despite the order of magnitude discrepancy, the threshold by Sallam and Hwang has been frequently cited for hemolytic potential in blood pumps. We recreated a Sallam apparatus (SA) to resolve this discrepancy and provide additional data to be used in developing a more accurate hemolysis model. Hemolysis was measured over a large range of Reynolds numbers (Re) (Re = 1,000-80,000). Washed bovine red blood cells (RBCs) were injected into the free jet of phosphate buffered saline, and hemolysis was quantified using a percent hemolysis, Hp = h (100 - hematocrit [HCT])/Hb, where h (mg/dl) is free hemoglobin and Hb (mg/dl) is total hemoglobin. Reynolds shear stress was calculated using two-dimensional laser Doppler velocimetry. Reynolds shear stress of ≥30,000 dyne/cm corresponding to Re of ≥60,000 appeared to cause hemolysis (p < 0.05). This RSS is an order of magnitude greater than the RSS threshold that Sallam and Hwang suggested, and it is similar to Forstrom's RSS threshold. This study resolved a long-standing uncertainty regarding the critical values of RSS for hemolysis and may provide a foundation for a more accurate hemolysis model.
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