Development of the PSU Child Pump.

The Pennsylvania State University (PSU) Child Pump, a centrifugal continuous-flow ventricular assist device (cf-VAD), is being developed as a suitable long-term implantable device for pediatric heart failure patients between 10 and 35 kg, body surface area (BSA) of 0.5-1.2 m2, 1-11 years of age, and requiring a mean cardiac output of 1.0-3.5 L/min. In-vitro hydraulic and hemodynamic performances were evaluated on a custom mock circulatory loop with ovine blood. Normalized index of hemolysis (NIH) was evaluated under four conditions: 1) 8,300 rpm, 3.5 L/min, ΔP = 60 mm Hg, 2) 8,150 rpm, 5.1 L/min, ΔP = 20 mm Hg, 3) 8,400 rpm, 3.2 L/min, ΔP = 70 mm Hg, and 4) 9,850 rpm, 5.0 L/min, ΔP = 80 mm Hg, resulting in normalized index of hemolysis = 0.027 ± 0.013, 0.015 ± 0.006, 0.016 ± 0.008, and 0.026 ± 0.011 mg/dl, respectively. A mock fit study was conducted using a three-dimensional printed model of a 19 kg patient's thoracic cavity to compare the size of the PSU Child Pump to the HeartMate3 and the HVAD. Results indicate the PSU Child Pump will be a safer, appropriately sized device capable of providing the given patient cohort proper support while minimizing the risks of blood trauma as they wait for a transplant.

Chronic Ovine Studies Demonstrate Low Thromboembolic Risk in the Penn State Infant Ventricular Assist Device.

Mechanical circulatory support for children under 6 years of age remains a challenge. This article describes the preclinical status and the results of recent animal testing with the Penn State Infant Left Ventricular Assist Device (VAD). The objectives have been to 1) demonstrate acceptably low thromboembolic risk to support Food and Drug Administration approval, 2) challenge the device by using minimal to no anticoagulation in order to identify any design or manufacturing weaknesses, and 3) improve our understanding of device thrombogenicity in the ovine animal model, using multicomponent measurements of the coagulation system and renal ischemia quantification, in order to better correlate animal results with human results.The Infant VAD was implanted as a left VAD (LVAD) in 18-29 kg lambs. Twelve LVAD and five surgical sham animals were electively terminated after approximately 30 or 60 days. Anticoagulation was by unfractionated heparin targeting thromboelastography R times of 2x normal (n = 6) or 1x normal (n = 6) resulting in negligible heparin activity as measured by anti-Xa assay (<0.1 IU/ml). Platelet inhibitors were not used.There were no clinically evident strokes or evidence of end organ dysfunction in any of the 12 electively terminated LVAD studies. The degree of renal ischemic lesions in device animals was not significantly different than that found in five surgical sham studies, demonstrating minimal device thromboembolism.In summary, these results in a challenging animal test protocol support the conclusion that the Penn State Infant VAD has a low thromboembolic risk and may allow lower levels of anticoagulation.

Targeting cholesterol transport in circulating melanoma cells to inhibit metastasis.

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.