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Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Editor-in-Chief’s Review

Artificial Organs 2014: A Year in Review Paul S. Malchesky Artificial Organs Editorial Office, Painesville, OH, USA

Abstract: In this Editor’s Review, articles published in 2014 are organized by category and briefly summarized. We aim to provide a brief reflection of the currently available worldwide knowledge that is intended to advance and better human life while providing insight for continued application of technologies and methods of organ Replacement, Recovery, and Regeneration. As the official journal of the International Federation for Artificial Organs, the International Faculty for Artificial Organs, the International Society for Rotary Blood Pumps, the International Society for Pediatric Mechanical Cardiopulmonary Support, and the Vienna International Workshop on Functional Electrical Stimulation, Artificial Organs continues in the original mission of its founders “to foster communications in the field of artificial organs on an international level.” Artificial Organs continues to publish developments and clinical applications of artificial organ technologies in this broad and expanding field of organ Replacement, Recovery, and Regeneration from all over the world. We take this time also to express our gratitude to our authors

for offering their work to this journal. We offer our very special thanks to our reviewers who give so generously of time and expertise to review, critique, and especially provide meaningful suggestions to the author’s work whether eventually accepted or rejected. Without these excellent and dedicated reviewers, the quality expected from such a journal could not be possible. We also express our special thanks to our Publisher, John Wiley & Sons, for their expert attention and support in the production and marketing of Artificial Organs. We look forward to reporting further advances in the coming years. Key Words: Apheresis—Artificial oxygen carriers—Auditory support— Biocompatibility—Bioengineering—Biomaterials—Blood substitutes—Blood pumps—Cardiac support—Cardiopulmonary—Dermal—Dialysis—Functional electrical stimulation—Liver—Lung—Membrane oxygenation— Organ preservation—Orthopedic—Pancreas—Pulmonary —Renal—Surgery—Tissue engineering—Transplantation —Valves—Vascular—Vision.

APHERESIS

to a reduced number of cardiovascular events in hyperlipoproteinemia(a). Huijuan Yin et al. (2) of the Chinese Academy of Medical Sciences, Tianjin, China, reported on safety evaluations of photodynamic therapy (PDT) for blood purification in a rabbit study. There were no significant differences in white blood cells, red blood cells, or destroying platelets after PDT compared with the control group, and no significant damage in the heart, liver, spleen, lungs, kidneys, or other organs after PDT. These findings suggest that photodynamic blood purification is safe in vivo and has potential as a new therapy for inactivating bloodborne microorganisms.

Adrian Rosada et al. (1) of Charité BerlinInterdisziplinäres Stoffwechsel-Centrum, Berlin, Germany, evaluated the effect of regular lipid apheresis on cardiovascular events in 37 patients treated regularly with lipid apheresis at the time periods of preinitiation of apheresis and during apheresis treatment. Apheresis led to a significant reduction of lipid levels. The event-free survival rate after 1 year in the preapheresis period was 38% versus 75% in the during-apheresis period with a statistically significant difference. Apheresis seems to lower the progression of atherosclerosis leading

doi:10.1111/aor.12495 Received December 2014. Address correspondence and reprint requests to Dr. Paul S. Malchesky, Artificial Organs Editorial Office, 10 West Erie Street, Suite 200, Painesville, OH 44077 USA. E-mail: [email protected] Artificial Organs 2015, 39(3):260–287

ARTIFICIAL OXYGEN CARRIERS Mitsuhiro Fujihara et al. (3) of the Hokkaido Block Blood Center, Sapporo, Japan, assessed the effects of hemoglobin vesicle (HbV) infusion on the

2014 YEAR IN REVIEW systemic immune response using primary and secondary responses to keyhole limpet hemocyanin (KLH) in rats. The generation of primary anti-KLH IgM antibody in HbV-infused rats was not suppressed but was instead higher than those in salineinfused rats. HbV infusion did not suppress the increase of immunoglobulin G subclass of KLH antibody in secondary response. The T-cell response to KLH of bulk spleen cells was unaffected by infusion of HbV, suggesting that HbV loading has no suppressive effect on homeostatic survival of memory T-cells against KLH. Vivek R. Yadav et al. (4) of the University of Oklahoma Health Science Center, Oklahoma City, OK, USA, reported on a new composition of liposome-encapsulated hemoglobin (LEH) based on the use of polyethylene glycol (PEG2K) conjugated with nonphospholipid hexadecylcarbamoylmethylhexadecanoate (HDAS) to modify the surface of LEH particles (HDAS-PEG2K-LEH) developed as an artificial oxygen carrier to address posthemorrhage oxygen and volume deficit. They investigated the potential immune response to HDAS-PEG2K-LEH in a mice model with repeated HDAS-PEG2K-LEH injections over 4 weeks. The HDAS-PEG2K modification substantially reduced the circulating levels of anaphylatoxins C3a and C5a as well as the plasma levels of thromboxane B2. The repeated injections did not alter its clearance profile after 4 weeks of treatment. No antibody response against human hemoglobin (Hb) or PEG was detected. Histological observations of lung, liver, spleen, and kidney were not significantly different from saline-treated rats. Haruka Takeichi et al. (5) of the Tokai University School of Medicine, Isehara, Kanagawa, Japan, evaluated LEH in bronchial anastomotic healing after radiation and pneumonectomy. SpragueDawley rats received preoperative radiation (20 Gy) to the chest and underwent left pneumonectomy with bronchial stump closure using the Sweet method 4 days later, when they were randomized to receive intravenous infusion of LEH with high O2 affinity (n = 32) or saline (n = 29). Additional rats (n = 18) were treated in the same way without preoperative radiation. Bronchial bursting pressure was elevated in the rats receiving LEH both in the unirradiated group and in rats with preoperative radiation. There were no morphological differences except for macrophage infiltration to the anastomotic area, which was significantly prominent in the LEH-treated rats regardless of the presence or absence of preoperative irradiation (IR). The results suggest that LEH with high O2 affinity may improve mechanical strength

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and morphological findings in bronchial anastomosis in rats regardless of the presence or absence of preoperative IR. The irradiated rats later treated with LEH had equivalent or better bronchial healing than that of saline-treated naïve animals undergoing pneumonectomy alone. Akira Kawaguchi et al. (6) of the Tokai University School of Medicine, Isehara, Kanagawa, Japan, evaluated the effect of LEH on the microcirculation and oxygen metabolism at a surgical wound to accelerate its healing. Ten mL/kg of LEH with high (h-LEH) or low oxygen affinity (l-LEH), homologous red blood cells (RBCs), and empty liposome or saline as a control was infused before a 10-mm incision and interrupted suture closure of the gastric wall. Bursting pressure of the surgical wound was significantly higher 2 days after surgery only in the h-LEH-treated rats, but not at 4 days after surgery, when other rats showed increased bursting pressure to a nonsignificant level. Histological examination revealed less granulocyte infiltration, better granulation, and more macrophage infiltration in h-LEHtreated rats at 2 days, but no longer at 4 days postsurgery. Dose-response study revealed that 0.4 mL/kg of h-LEH (Hb 24 mg/kg) was effective for elevating bursting pressure at 2 days. h-LEH-treated rats had significantly suppressed HIF-1α accumulation in the wound 6, 24, and 48 h after surgery as compared with control animals treated with homologous RBC or saline. The results suggest that h-LEH, but not l-LEH or homologous transfusion, may accelerate wound healing early after gastric incision and anastomosis in the rat. Shinichi Kaneda et al. (7) of the Terumo Corporation, Nakai, Kanagawa, Japan, investigated the therapeutic time window of LEH in a rat model of cerebral ischemia by transient and permanent middle cerebral artery occlusion (MCAO). LEH was intravenously administered at 0.5 h after the onset of ischemia in the transient MCAO model and at 0.5, 2, 4, or 6 h in the permanent MCAO model. LEH treatment dose-dependently reduced the cerebral infarct volume, which was especially significant in the cortical region at doses of over 60 mg Hb/kg. In rats with permanent MCAO, LEH administration at a dose of 300 mg Hb/kg at 0.5 and 2 h after the onset of cerebral ischemia significantly reduced cerebral infarct volume. Immunohistochemical staining with pimonidazole showed that the areas of cerebral tissue that were hypoxic and had abnormal histological structure were reduced after LEH treatment, suggesting that LEH is efficacious in the treatment of cerebral infarction secondary to MCAO and that oxygen delivery to ischemic cerebral tissues by LEH Artif Organs, Vol. 39, No. 3, 2015

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administered early after the onset of cerebral ischemia contributes to this effect. Chieko Murayama et al. (8) of the Tokai University School of Medicine, Isehara, Japan, evaluated the effect of liposome-encapsulated Hb with high O2 affinity (P50 O2 = 10 mm Hg, h-LEH) on enhancing tumor radiosensitivity. Doxorubicin (DXR; 0.5 or 2 mg/kg i.p.) or S-1 (4 or 8 mg/kg orally) alone or in combination with h-LEH (5 mL/kg i.v.) was administered for 2 weeks to C57BL/6N mice inoculated with Lewis lung carcinoma (LLC) in the leg. Combined use of h-LEH and chemotherapeutic agents (DXR or S-1) showed no additional enhancement on suppression of the tumor growth over the chemotherapeutic agent alone. However, the combination use of h-LEH significantly suppressed the number and total area of metastatic colonies in the lung compared with each chemotherapeutic agent alone. The addition of h-LEH to either agent showed further enhancement of oxygen-mediated degradation of hypoxia-inducible factor-1α (HIF-1α) and matrix metallopoteinase-2 (MMP-2) activity. Tatsuya Fukuta et al. (9) of the University of Shizuoka, Shizuoka, Japan, investigated the realtime cerebral distribution of polyethylene glycol (PEG)-modified liposomes (PEG-liposomes) labeled with 1-[18F]fluoro-3,6-dioxatetracosane in p-MCAO rats by positron emission tomography (PET). [18F]Labeled PEG liposomes were intravenously injected into p-MCAO rats 1 h after the onset of occlusion, and then a PET scan was performed for 2 h. The PET scan showed that the signal intensity of [18F] gradually increased in the ischemic region despite the drastic reduction in cerebral perfusion, suggesting that PEG-liposomes had accumulated in and around the ischemic region. Therefore, drug delivery to the ischemic region by use of liposomes would be possible under ischemic conditions, and a liposomal drug delivery system could be a promising strategy for protecting the ischemic brain from damage before recovery from ischemia. Akira Kawaguchi et al. (10) of the Tokai University School of Medicine, Isehara, Kanagawa, Japan, evaluated liposome-encapsulated Hb with l-LEH in transient whole brain ischemia in the Tokai highavoider rat (THA). Young/naïve (before Sidman Avoidance Test [SAT]) and adult/parent (after SAT) THA rats underwent acute and complete four-vessel occlusion in the chest for 3 or 5 min, administration of 2 mL/kg of l-LEH, saline, or homologous washed RBCs, reperfusion, and resuscitation. Young/naïve rats treated with l-LEH retained a rapid and consistent learning curve as in nonischemic controls, THA rats treated with RBCs, or saline had retarded learnArtif Organs, Vol. 39, No. 3, 2015

ing response on SAT as well as reduced cellularity in the amygdala. Adult/parent rats with established memory on SAT maintained perfect achievement even after ischemia and reperfusion. In contrast, l-LEH-treated rats showed no better performance on Morris water maze (function) or cellularity of the CA1 sector of the hippocampus (morphology) compared with the rats treated with RBCs. The data suggested that l-LEH was protective only for the amygdala on SAT tasks, but not for the CA1 sector of the hippocampus on spatial orientation. Vivek R. Yadav et al. (11) of the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA investigated whether treatment with diphenyldifluoroketone EF24, an inhibitor of nuclear factor kappa-B, would have salutary effects in hemorrhagic shock. They studied the effect of EF24 on the expression of the interleukin-1 receptor (IL-1R) superfamily in a rat model of hypovolemic shock. Hypovolemia was induced by gradually withdrawing approximately 50% of circulating blood, and EF24 was administered intraperitoneally (0.2 mg/kg) in 50 μL of saline. They observed a reduction in immunoreactive Toll-like receptor 4 and IL-1R1 in lung tissue of rats treated with EF24. Simultaneously, the pulmonary expression of suppression of tumorigencity 2 and single immunoglobin IL-1Rrelated (the putative down-regulators of the proinflammatory IL-1R pathway) was increased in EF24-treated hemorrhaged rats. The concentration of hemorrhage-induced tumor necrosis factor alpha (TNF-α) and IL-6 in lung tissue homogenates was also reduced by EF24 treatment. These results confirmed the previous in vitro observations in lipopolysaccharide-stimulated dendritic cells that EF24 beneficially modulates the IL-1R pathway and suggest that it could be investigated as an adjunct therapeutic in managing inflammation associated with hemorrhagic shock. Jan Simoni et al. (12) of the Texas HemoBioTherapeutics & BioInnovation Center, Lubbock, TX, USA, reported on their development of the Hb-based oxygen carrier, HemoTech, which utilizes the concept of pharmacologic cross-linking. It consists of purified bovine Hb cross-linked intramolecularly with open ring adenosine-5′triphosphate (ATP) and intermolecularly with open ring adenosine, and conjugated with reduced glutathione (GSH). The ATP prevents Hb dimerization, and adenosine promotes formation of Hb polymers as well as counteracts the vasoconstrictive and pro-inflammatory properties of Hb via stimulation of adenosine receptors. ATP also serves as a regulator of vascular tone through

2014 YEAR IN REVIEW activation of purinergic receptors. GSH blocks Hb’s extravasation and glomerular filtration by lowering the isoelectric point, as well as shields heme from nitric oxide (NO) and reactive oxygen species. HemoTech and its manufacturing technology have been broadly tested, including viral and prion clearance validation studies and various nonclinical pharmacology, toxicology, genotoxicity, and efficacy tests. The clinical proof-of-concept was carried out in sickle cell anemia subjects. The preclinical and clinical studies indicate that HemoTech works as a physiologic oxygen carrier and has efficacy in treating: (i) acute blood loss anemia by providing a temporary oxygen bridge while stimulating an endogenous erythropoietic response; (ii) sickle cell disease by counteracting vaso-occlusive/inflammatory episodes and anemia; and (iii) ischemic vascular diseases particularly thrombotic and restenotic events. Vanessa Mallet et al. (13) of the Institut National de la Santé et de la Recherche Médicale U1082, Morlaix, France, evaluated the natural oxygen carrier HEMO2Life at various dose levels in University of Wisconsin (UW) solution both in vitro with endothelial cells and in vivo in a pig kidney autotransplantation preclinical model. They showed in vitro that cells were significantly better preserved with HEMO2Life in a dose-dependent manner, with benefits in terms of survival, metabolic activity, and cellular integrity. In vivo, serum creatinine measurements at reperfusion confirmed the important benefits of HEMO2Life treatment on function recovery at the dose levels of 1, 2, and 5 g/L. Likewise, histological analysis of kidney parenchyma biopsies from day 7 confirmed the superiority of HEMO2Lifesupplemented UW over UW alone, and there was no difference between the doses. Three months’ follow-up confirmed the trend of the first 2 weeks, with creatinine and fibrosis levels similar to those in pretransplant kidneys. Hemant Misra et al. (14) of Prolong Pharmaceuticals LLC, South Plainfield, NJ, USA, reported on the use of PEGylated carboxyhemoglobin bovine (SANGUINATE) as a dual action carbon monoxide releasing (CO)/oxygen (O2) transfer agent for the treatment of hypoxia. Its components inhibit vasoconstriction, decrease extravasation, limit reactive oxygen species production, enhance blood rheology, and deliver oxygen to the tissues. Animal models of cerebral ischemia, peripheral ischemia, and myocardial ischemia demonstrated SANGUINATE’s efficacy in reducing myocardial infarct size, limiting necrosis from cerebral ischemia, and promoting more rapid recovery from hind limb ischemia. In a Phase I trial, three cohorts of eight healthy volunteers

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received single ascending doses of 80, 120, or 160 mg/kg of SANGUINATE. Two volunteers within each cohort served as a saline control. There were no serious adverse events. Serum haptoglobin decreased, but did not appear to be dose related. The T1/2 was dose dependent and ranged from 7.9 to 13.8 h. In addition to the Phase I trial, SANGUINATE was used under an expanded access emergency Investigational New Drug. SANGUINATE was found to be safe and well tolerated in a Phase I clinical trial, and therefore it will advance into further clinical trials in patients. Hans Bäumler et al. (15) of the CharitéUniversitätsmedizin Berlin, Berlin, Germany, reported that until now hemoglobin-based oxygen carriers (HBOCs) show serious side effects which resulted in failure of clinical trials and Food and Drug Administration disapproval. The main problem consists in vasoconstriction triggered by NO scavenging or/and oxygen oversupply in the precapillary arterioles and that HBOCs with a size between 100 nm and 1 μm and high oxygen affinity are needed. They showed their simple fabrication procedure, which can provide Hb particles (HbPs) with a narrow size distribution of around 700 nm, nearly uniform morphology, high oxygen affinity, and low immunogenicity. Isolated mouse glomeruli were successfully perfused with concentrated HbP suspensions without any observable vasoconstriction of the afferent arterioles. The results suggested no oxygen oversupply and limited NO scavenging by these particles, featuring them as a highly promising blood substitute. Saburo Neya et al. (16) of Chiba University, Chiba, Japan, investigated the structure and reactivity of cobalt-replaced myoglobin (Mb) as a possible application as an artificial oxygen carrier. Ligand binding analysis with relaxation kinetics revealed that various ligands bind to Co(III) Mb, contrary to the earlier thoughts. The equilibration process, however, was so slow that it proceeded over 90 min. These characteristic profiles of oxidized Co(III) Mb were ascribed to the electronic structure of Co(III) ion which is one electron larger than Fe(III) ion. The oxygen affinity of reduced Co(II) Mb was much smaller than that of Fe(II) Mb, indicating that Co(II) Mb has excellent oxygen transport ability. The latter observation, together with the lack of carbon monoxide binding in Co(II) Mb, suggests utility of Co(II) Mb as Mb-based oxygen carriers. AUDITORY SUPPORT Jun Chang Lee et al. (17) of Hanyang University, Seoul, Korea, reported on a modified binaural diagoArtif Organs, Vol. 39, No. 3, 2015

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nal beam-steering technique for reducing the focusing-direction deviations at high input frequencies up to 4000 Hz for binaural hearing support devices. In simulation tests, the focusing effect of the proposed algorithm was more consistent than conventional algorithms. The deviations between the target and the focusing directions were reduced 27% in the left device and 6% in the right device with 45° steering at a 4000 Hz input signal, and were reduced 3% in the left device and 25% in the right device with 135° steering. They believe that the proposed algorithm has the potential to help hearing-impaired people in various listening situations. BIOENGINEERING Pioyr Foltynski et al. (18) of the Polish Academy of Sciences, Warsaw, Poland, reported on a new smartphone-based method for wound area assessment that is based on the automatic recognition of the wound contour. The accuracy and precision of this method was assessed and compared with the accuracy and precision of commercial devices: Visitrak and SilhouetteMobile. The statistical analysis showed that the new method was more accurate and more precise than the Visitrak device, but less accurate and less precise than the SilhouetteMobile device. The new method also stores the data for future use by the physician. Shumin Wang et al. (19) of the Northern Hospital, Shenyang, China, reported on a case of resection of a retrosternal goiter through a novel combined cervical and robot-assisted approach. This approach was safe and provides an alternative option to the more invasive traditional approaches. Alois Pfenniger et al. (20) of the University of Bern, Bern, Switzerland, reported on performance analysis of a miniature hydrodynamic turbine generator for intracorporeal energy harvesting of 1 mW electric power powered by about 1% of the cardiac output flow in a peripheral artery. A numerical modeling of the fluid mechanics and experimental verification of the overall performance of a 1:1 scale friction turbine were performed in vitro. The model was validated for a range of turbine configurations and flow conditions (up to 250 mL/min) in terms of hydromechanic efficiency; up to 15% could be achieved with the nonoptimized configurations of the study. The model provided first estimates of the mechanical shear forces relevant to blood trauma and platelet activation. The time-integrated shear stress exposure is significantly lower than in cardiac assist devices due to lower flow velocities and predominantly laminar flow. Artif Organs, Vol. 39, No. 3, 2015

BIOMATERIALS AND BIOCOMPATIBILITY Jia Shen and Zhi Wei Xu (21) of Shanghai Children’s Medical Center, Shanghai, China, evaluated acellular bovine pericardium (ABP) patches in pericardial cavity reconstruction and the effect of sodium hyaluronic acid (NaHA) on inflammatory reaction in the prevention of pericardial adhesions. In rabbits, various groups were evaluated: Group A (n = 5), the control group, the pericardium was directly closed; Group B (n = 5), 0.15% glutaraldehyde-treated ABP (low cross-link degree); Group C, 0.3% glutaraldehyde-treated ABP (middle cross-link degree); Group D, 0.15% glutaraldehydetreated ABP + NaHA solution. In Group D, the serum concentration of TNF-α was significantly lower in the early postoperative period, and the mean adhesion score was significantly lower compared with the control group. Kwangwoo Nam et al. (22) of the Tokyo Medical and Dental University, Tokyo, Japan, reported on the development for making percutaneous devices that have high biocompatibility and do not induce downgrowth of epidermal cells. They prepared a porcine partial decellularized dermis (DD)/poly(methyl methacrylate) (PMMA) complex (PDPC) with a PMMA rod firmly stabilized inside. MMA was used because it would adhere firmly to a polymer such as a catheter. The MMA filled the cavities in the dermis and polymerized, anchoring to the collagenous fibrils inside the porcine DD. The PDPC was cemented to the PMMA rod tightly and it was integrated with the surrounding tissue within 12 weeks of implantation. No downgrowth of the epidermis was observed. Michael A. Navitsky et al. (23) of the Pennsylvania State University, University Park, PA, USA, studied the properties of platelet adhesion to the polyurethane urea surface as a function of time-varying shear exposure. A rotating disk system was used to study the influence of steady and pulsatile flow conditions. The disk was rotated in platelet-rich bovine plasma for 2 h, with adhesion quantified by confocal microscopy measurements of immunofluorescently labeled bovine platelets. Platelet adhesion under pulsating flow was found to decay exponentially with increasing shear rate. Adhesion levels were found to depend upon peak platelet flux and shear rate, regardless of rotational waveform. Yasuko Tomizawa (24) of the Tokyo Women’s Medical University, Tokyo, Japan, notes that spontaneous nonanastomotic transgraft hemorrhage occurring several years after grafting may be a new late complication of biological material-impregnated

2014 YEAR IN REVIEW fabric vascular grafts (BMIFVs). He hypothesized that autologous connective tissue detachment may be caused by the high porosity of the fabric graft and high blood pressure (BP). Bleeding around the fiber is the first sign of development. Fabric grafts with optimal porosity and biocompatibility should be used for manufacturing BMIFVs. Huan Li et al. (25) of Zhejiang University, China, developed a model for predicting shear-induced hemolysis. The proposed model takes into account the known empirical formula, the threshold equation, by setting a nonzero initial condition of the blood. By comparing the estimated results with the published experimental data, it showed that the accuracy of the proposed model was notably improved. Furthermore, the analysis in frequency domain indicated that the damage contribution of the timevarying shear stress decreased with the increase of frequency. CARDIAC SUPPORT AND BLOOD PUMPS Jing-Jing Ye et al. (26) of The Children’s Hospital of Zhejiang University and Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou, China, assessed the noninvasive perioperative evaluation of right ventricular (RV) function in children with tetralogy of Fallot (TOF). Tissue Doppler imaging, strain rate, and strain analysis revealed that RV systolic and diastolic function indices were lower preoperatively in the TOF group compared with the control group, and did not improve after TOF repair. Plasma N-terminal probrain natriuretic peptide (NT-proBNP) concentrations were significantly higher in the TOF group preand postoperatively compared with the control group. In the preoperative TOF group, NT-proBNP concentration was significantly correlated with peak systolic strain rate and systolic strain in the mid segments of the RV free wall. Plasma MMP-9 concentrations were significantly increased in the preoperative TOF group compared with the control group, and significantly correlated with plasma NT-proBNP and log NT-proBNP concentrations. RV function correlated with plasma NT-proBNP concentrations in children with TOF. Robert A. Niebler et al. (27) of The Medical College of Wisconsin, Milwaukee, WI, USA, assessed the incidence and outcome of pediatric patients with intracranial hemorrhage (ICH) while supported on ventricular assist devices (VADs). Five of 30 patients supported on a VAD over nearly 13 years were diagnosed with an ICH. Four patients had an identified cerebral thromboembolic injury prior to

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the ICH. Four patients required interruption in their anticoagulation regimen due to other bleeding concerns prior to ICH. Neurosurgical intervention consisted of evacuation of hemorrhage in one, whereas two others required management of hydrocephalus with external ventricular drainage. Three of the five patients died on VAD support. Two deaths were directly related to ICH. Two patients were successfully transplanted; one remains with a significant neurological impairment, and the other has recovered with minimal residual impairment following neurosurgical evacuation of a large subdural hematoma. ICH is a devastating complication of VAD support. Prior ischemic infarcts and interruptions to anticoagulation may put a patient at risk for ICH. Prompt neurosurgical evaluation/intervention can result in positive outcomes. Ashish P. Saini et al. (28) of the Penn State Hershey College of Medicine, Hershey, PA, USA, carried out quantitative assessment of fetal heart function with tissue Doppler velocity (TDI) imagingreference values for color tissue Doppler (CTDI) velocities and compared with pulsed wave (PW) tissue Doppler velocities. They included 91 fetuses seen for routine prenatal ultrasound. Bland–Altman analysis was used for comparisons. PW and CTDI S′ velocities correlated strongly in all three cardiac segments evaluated. PW TDI and CTDI velocity measurements are feasible in the fetus and correlate well. However, PW TDI velocities are higher than CTDI velocities with significant regional variation. Giuseppe Scrascia et al. (29) of the University of Bari “Aldo Moro,” Bari, Italy, reported on a metaanalysis of randomized controlled trials on antiinflammatory strategies to reduce acute kidney injury (AKI) in cardiac surgery patients. Only leukocyte filters effectively reduced worsening renal function incidences. Not all cardiopulmonary bypass (CPB)related anti-inflammatory strategies analyzed reduced renal damage after cardiac operations. In adult patients, probably other factors are predominant on inflammation in determining AKI. Christof Karmonik et al. (30) of The Methodist Hospital, Houston, TX, USA, investigated differences in hemodynamic conditions in the thoracic aorta for pulsatile and continuous-flow left ventricular assist devices (CF-LVADs) using computational fluid dynamics (CFD). Patient-specific models were reconstructed from three patients with CF-LVAD (HeartMate II [HMII]) and three patients with biventricular assist devices (Excor) where only the aortic part was included in the simulations. Retrograde flow patterns were observed in all cases proximal to the location of the outflow cannula Artif Organs, Vol. 39, No. 3, 2015

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anastomosis site. On average, dynamic pressures derived from the retrograde flow velocities were higher in the continuous-flow group with large variations dependent on the angle of the cannula anastomosis relative to the ascending aorta. Elevated wall shear stress (WSS) contralaterally to the anastomosis site was observed in three of the six models with higher values for the continuous cases. Lower WSS and reduced pressure in the ascending aorta, both favorable hemodynamic conditions, were found in pulsatile versus CF-LVADs by means of CFD. These findings indicate, along with clinical observations reported by others, the superior performance of pulsatile LVADs. Frank Nestler et al. (31) of the University of Queensland, Brisbane, Queensland, Australia, modeled and characterized a rotary total artificial heart (rTAH) in steady flow over a wide operational range for pump and hydraulic parameters. A support vector machine (SVM) model with a radial basis function kernel was the best performer. Francesco Moscato et al. (32) of the Medical University of Vienna, Vienna, Austria, investigated cardiac rhythms using available pump data only. Datasets (n = 141) obtained in the normal ward, in the intensive care unit (ICU), and during bicycle ergometry were analyzed in 11 recipients of a CF-LVAD. A very good agreement of cardiac rhythm parameters from the pump flow compared with electrocardiogram (ECG) was found. Tachycardia, atrial fibrillation, and extra systoles could be accurately identified from the tachograms derived from the pump flow. Continuous monitoring of cardiac rhythms from available pump data is possible and has the potential to reduce the out-of-hospital diagnostic burden and to permit a more efficient adjustment of the level of mechanical support. John Valdovinos et al. (33) of UCLA, Los Angeles, CA, USA, evaluated the use of an external compression device (C-Pulse Heart Assist System) as a Fontan assist device. A mock circulation was used to mimic the hemodynamics of a hypertensive Fontan circulation in a pediatric patient. The effect of the number, one or two, and placement of valves, before or after the compression cuff, on inferior vena cava pressure (IVCP) was studied, as was the effect of device inflation volume and compression rate on maintaining low IVCP. With two valves, the C-Pulse was able to maintain IVCP as low as 8.5 mm Hg. The application of an external compression device combined with two valves has potential for use as an artificial right ventricle by maintaining low IVCP and providing pulsatile flow through the lungs. Artif Organs, Vol. 39, No. 3, 2015

Hans D. Theiss et al. (34) of the Klinikum Grosshadern, Munich, Germany, in a retrospective study, investigated the impact of preconditioning of the right ventricle with the calcium sensitizer levosimendan immediately before LVAD implantation on outcome and survival. Nine consecutive LVAD patients with echocardiographic and invasive evidence of right heart insufficiency received levosimendan with 0.1 μg/kg body weight/min for 24 h before implantation of the assist device. The administration of levosimendan was safe and no relevant side effects were observed. Twelve-month survival after implantation of the LVAD was 89%, representing a superior outcome compared with the fifth Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry data with 75% survival. Five patients were successfully transplanted. Nicholas R. Gaddum et al. (35) of King’s College London, London, UK, investigated an adaptive controller which maintains a linear relationship between mean flow and flow pulsatility to imitate native Starling-like flow regulation which requires only the measurement of the rotary LVAD flow. The Starling-like controller’s flow sensitivity to preload was measured as 0.39 L/min/mm Hg, 10 times greater than constant speed control (0.04 L/min/mm Hg), and the Starling-like control reduced mean flow from 4.14 to 3.58 L/min, maintaining safe support. From simulated sleep to wake, Starling-like control increased flow from 2.93 to 4.11 L/min as a response to the increased residual LV pulsatility. Prashant Mohite et al. (36) of the Royal Brompton & Harefield NHS Foundation Trust, London, UK, reviewed the status of refractory heart failure dependent on short-term mechanical circulatory support (MCS) and its future. The outcome of heart transplant and long-term VAD in such patients is poor. Although some patients with acute heart failure experience recovery of myocardial function with short-term MCS, others become dependent. The authors discussed the advantages and disadvantages of heart transplant and long-term VAD in such patients. Po-Lin Hsu et al. (37) of the RWTH Aachen University, Aachen, Germany, investigated the design of a foldable VAD for minimally invasive insertion percutaneously. They reported on a simplified twodimensional analytical method to estimate the mechanical stress and deformation of memory alloy skeletons and applied the method in design examples. The results confirmed the feasibility of such a simplified analytical approach to reveal priorities for structural optimization before

2014 YEAR IN REVIEW time-consuming finite element method simulations, providing an effective tool in the initial structural design stage of foldable minimally invasive VADs. Choon-Sik Jhun and Joshua P. Cysyk (38) of The Pennsylvania State University, College of Medicine, Hershey, PA, USA, assessed in vitro, ventricular contractility and compliance measured during axial flow LVAD support. The effective compliance for both control and heart failure was independent of the LVAD speed. When examining the time course of cardiac recovery induced by the LVAD support, LV performance should be measured immediately before and after LVAD support while keeping LVAD speed consistent to avoid potential overestimation of long-term cardiac recovery. Silje E. Jahren et al. (39) of the University of Bern, Bern, Switzerland, carried out an analysis of pressure head-flow (HQ) loops of pulsatile rotodynamic blood pumps. The simulated ventriculo-aortic cannulation showed that the level of (un)loading and the shape of the HQ loops strongly depend on the phase shift. Increased contribution of native contraction (increased ventricular stroke work [WS]) resulted in a broadening of the loops. It was found that the previously described linear relationship between WS and the area of the HQ loop for constant pump speeds becomes a family of linear relationships, whose slope depends on the phase shift. Marina Pieri et al. (40) of the San Raffaele Scientific Institute, Milan, Italy, investigated the use of bivalirudin as the primary anticoagulant for patients with implantable VADs. In 12 consecutive patients, no thromboembolic complications occurred. Anticoagulation was monitored by the activated partial thromboplastin time (aPTT). Bivalirudin should no longer be regarded as a second-line therapy for anticoagulation in patients with VAD. Leonida Compostella et al. (41) of the Istituto Codivilla Putti, Cortina d’Ampezzo, Italy, evaluated the exercise performance of 26 chronic heart failure (CHF) patients within 2 months after initiation of support by an axial-flow LVAD as destination therapy. As a reference group, 30 patients with CHF not supported by LVAD were evaluated after an episode of acute heart failure. The axial-flow LVAD patients are able to sustain a low-intensity workload; though some cardiopulmonary exercise test parameters suggest persistence of a marked physical deconditioning, their cardiorespiratory performance was similar to that of less compromised CHF patients, possibly due to positive hemodynamic effects beginning to be produced by the assist device. Hideyuki Fumoto et al. (42) of the Cleveland Clinic, Cleveland, OH, USA, reported on the short-

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term performance of their PediPump LVAD. Their pump was implanted in six healthy lambs to evaluate in vivo performance for up to 30 days. Three animals were euthanized prematurely. The three lambs were electively sacrificed 30 days after implantation; all had stable hemodynamics and minimal hemolysis. Mean 30-day pump flow was 1.8 ± 0.1 L/min at a pump speed of 12 200 ± 400 rpm. At necropsy, depositions were observed at the front (n = 1) and rear rotor axial positioning stops (n = 4); improved polishing techniques on the stationary stop surface, and the addition of a hard-carbon, thin-film coating on the rotating stop of the pumps used for the last two experiments addressed the deposition. Angelo M. Dell’Aquila et al. (43) of the University of Muenster, Muenster, Germany, reported on this center’s survival results after implantation of intrapericardial third-generation centrifugal assist devices compared with previous left ventricular systems (VAD), taking into account the different preoperative INTERMACS levels. No significant survival improvement was observed among all patients who underwent VAD implantation in INTERMACS Levels 1–2. Among patients who underwent elective VAD implantation (INTERMACS 3–5), the HeartWare (HW) group had a significantly better outcome compared with the other INTERMACS-matched groups (previous continuous-flow devices and pulsatile systems), with a survival rate of 88.8% in group A versus 34.2% in group B, and 45.6% in group C at 24 months. Elective system implantation shows improved survival benefit over the other INTERMACSmatched devices. Moreover, preoperative unstable hemodynamics resulted in a poor prognosis independently from the pump generation. Massimo A. Padalino et al. (44) of the University of Padova Medical School, Padova, Italy, described their success with the use of HW VADs in three patients 0.2 μg/ cm2). Under in vivo conditions using a newborn piglet model, heart rate and mean arterial BP remained stable for extracorporeal flow rates of up to 61 mL/kg/min. The LAD was connected to umbilical vessels (maximum flow rate of 24 mL/min [10.4 mL/ kg/min]), and O2 gas exchange was 3.0 μL/min/cm2. Hiromu Kehara et al. (97) of the Shinshu University School of Medicine, Matsumoto, Japan, studied platelet function during CPB with centrifugal (CP) and roller pumps (RP) using multiple electrode aggregometry (MEA). Ten swine underwent CPB for 3 h, with five weaned off using CP and five using RP. In the CP and RP groups, aggregation was significantly reduced 30 min and 3 h after starting CPB. Platelet function, evaluated with MEA, was lowest 30 min after CPB was started, but did not decrease over time in either group. As assessed by MEA, platelet function using CP and RP did not differ significantly. Platelet dysfunction was caused mainly by initial contact with foreign materials and may not be dependent on type of pump. Prashant N. Mohite et al. (98) of Harefield Hospital, London, UK, studied distal limb perfusion in 45 patients undergoing peripheral VA-ECMO. A peripheral VA-ECMO circuit was implanted via groin. Distal limb perfusion was achieved with an introducer sheath (6–8 Fr) in 13 cases and with a distal-perfusion cannula (10–12 Fr) in 32 cases. Four patients developed signs of ischemia requiring surgical intervention; one patient required a below-knee amputation. The incidences of limb ischemia and limb ischemia requiring surgical intervention were significantly higher for the introducer sheath compared with the cannula (30.6 vs. 15.6% and 15.4 vs. 6.25%, respectively). The patients supported on ECMO with a distal-perfusion cannula spent a significantly longer time on ECMO compared with the ones in whom an introducer sheath was used. Use of a distal-perfusion cannula is a most reliable method of limb perfusion in peripheral VA-ECMO. Tim A.S. Kaufmann et al. (99) of RWTH Aachen University, Aachen, Germany, applied their model of analysis of flow conditions during CPB as dependent on cannulation and support modalities to develop a novel CPB outflow cannula to reduce the jet effect and increase cerebral blood flow. The multimodule cannula (MMC) is based on a generic elbow cannula. It features an inner wall to smoothly guide the blood as well as an elliptically shaped outlet diffuser. During standard CPB conditions of 5 L/min, the pressure drop over the MMC is 61 mm Hg, comArtif Organs, Vol. 39, No. 3, 2015

pared with 68 mm Hg with a standard cannula. The maximum velocities are decreased from 3.7 to 3.3 m/s. In the cannula jet of the MMC, the velocities are reduced further, down to 1.6 m/s. The cerebral blood flow is typically reduced during CPB. Using the MMC, however, it reaches almost physiological values at 715 mL/min. Satoshi Kohira et al. (100) of the Kitasato University School of Medicine, Sagamihara, Japan, studied the effects of administration of the neutrophil elastase inhibitor sivelestat on inflammatory response before and at initiation of CPB in patients undergoing pediatric open-heart surgery. Twenty consecutive patients were divided into pre-CPB (n = 10) and control (n = 10) groups. Patients in the pre-CPB group received a 24-h continuous intravenous infusion of 0.2 mg/kg/h sivelestat starting at the induction of anesthesia and an additional 0.1 mg/ 100 mL during CPB priming. Patients in the control group received a 24-h continuous intravenous infusion of 0.2 mg/kg/h sivelestat starting at the commencement of CPB. White blood cell count and neutrophil count and C-reactive protein levels were significantly lower in the pre-CPB group whereas platelet count was significantly higher. During CPB, mixed venous oxygen saturation remained significantly higher and lactate levels lower in the pre-CPB group. Administration of sivelestat before CPB initiation is more effective than administration at initiation for the suppression of inflammatory responses due to CPB. FUNCTIONAL ELECTRICAL STIMULATION Antonio Padilha Lanari Bó et al. (101) of the Laboratory of Computer Science, Robotics, and Microelectronics, Montpellier, France, reported on the use of fixed-intensity functional electrical stimulation (FES) for attenuating essential tremor (ET). They studied the strategy that FES-induced constant muscle contraction may provide functional benefit for tremor patients. Experiments were conducted in which stimulation was intermittently turned on and off while the subjects performed a static motor task. The results indicated that tremor attenuation is feasible, as consistent tremor attenuation levels were obtained in 8 out of 10 ET patients. Nonetheless, tremor reduction was not instantaneous for all successful trials, indicating that prior training with FES may improve the overall response. Further studies are necessary. Sebastian Springer et al. (102) of the Ariel University, Ariel, Israel, investigated whether introducing an interphase interval (IPI) to biphasic pulses during

2014 YEAR IN REVIEW stimulation of the dorsiflexor muscles would affect force production and determine whether the IPI effect is dependent on electrode position. Twelve healthy volunteers participated in the study. The introduction of a 100 μs-long IPI may enhance force production when one electrode is located over the common peroneal nerve. However, increasing the duration of the IPI beyond 100 μs did not result in further increase in force production. In contrast, the introduction of an IPI did not increase force production when both electrodes were located over the dorsiflexor muscles. These findings may help to optimize stimulation settings during functional electrical stimulation to prevent foot drop. LIVER SUPPORT Gabriele Donati et al. (103) of the University of Bologna, Bologna, Italy, reported on the molecular adsorbent recirculating system (MARS) for hepatic failure. Sixty-four patients with life-threatening liver failure were selected, and 269 MARS treatments were carried out as a bridge for orthotopic liver transplantation (OLT) or for liver function recovery. All patients were grouped according to the aim of the therapy. Group A consisted of 47 patients treated for liver function recovery. Group B consisted of 11 patients on the waiting list who underwent OLT. Group C consisted of six patients on the waiting list who did not undergo OLT. MARS was clinically well tolerated by all patients and significantly reduced hepatic toxins. Better survival rates were linked to an OLT program, but patients’ clinical characteristics on starting therapy were the main factors predicting survival. The role of hepatocyte growth factor should be evaluated in larger clinical trials. Bastian Lüer et al. (104) of the University Clinic of Surgery, Bonn, Germany, reported on the effect of adding pulsatility to gaseous oxygen persufflation during liver preservation. Livers from rats were retrieved 30 min after cardiac arrest and subjected to 18 h of cold storage with either nonpulsatile or pulsatile gaseous oxygen persufflation. Pulsatile persufflation significantly improved parenchymal integrity (enzyme release, bile flow) upon reperfusion, with respect to nonpulsatile persufflation or cold storage as evaluated with release of alanine aminotransferase. The effect was associated with the prevention of the ischemic decline in gene and protein expression of the vasoprotective Krüppellike factor 2, increased perfusate levels of the endogenous vasodilator NO, and reduced portal vascular resistance upon reperfusion. Pulsatile mechanostimulation of the hepatovasculature seems a

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genuine protective mechanism, affecting early graft recovery upon reperfusion. Roberto Marangoni et al. (105) of Azienda Ospedaliera Sant’Anna, Como, Italy, reported on the development of a high-efficiency MARS for liver support. They modified the MARS albumin circuit with the insertion of double adsorption units in parallel. Four patients were treated with this modified method (high-efficiency MARS, HE MARS). After a single MARS session, bilirubin was reduced more with HE MARS than standard MARS and bile acid reduction was increased. Weiping Ding et al. (106) of the University of Science and Technology of China, Hefei, China, studied the preconcentration method (PCM) to increase the adsorption of protein-bound toxins onto adsorbents in an artificial liver support systems. In the PCM, a concentrator is installed before the inlet of the adsorbent cartridge. They studied activated carbon to remove albumin-bound bilirubin. Their results showed that when the PCM is used, the mass transfer rate of bilirubin from solution to activated carbon is enhanced, the adsorbed bilirubin amount per unit mass of activated carbon is greatly increased, and more albumin-bound bilirubin molecules are quickly removed from the albumin solution. By adjusting the concentration ratio, the adsorption of albumin-bound bilirubin onto activated carbon can be further increased. ORTHOPEDIC SUPPORT Jae Hyup Lee et al. (107) of Seoul National University, Seoul, Korea, investigated the effects of recombinant human bone morphogenetic protein2 (rhBMP-2) loaded beta-tricalcium phosphate (β-TCP) microsphere-hydrogel composite on the osseointegration of dental implants in minipigs after 8 weeks. Animals treated with the rhBMP-2-loaded carrier composite showed a significantly higher percentage bone volume and a greater trabecular thickness for the newly formed bone in the tooth defect areas when compared to the group treated with the carrier alone (β-TCP microsphere-hydrogel carrier). The rhBMP-2 group had a significantly higher osseointegration, a larger percentage bone volume, greater trabecular thickness in the newly formed bone in tooth defect areas, a larger newly formed bone fraction in the fixture pitch, and a greater number of newly formed trabecular bones. The rhBMP-2-loaded carrier composite promotes new bone formation after tooth extraction and strengthens osseointegration of dental fixtures by improving the degree of osseointegration around the dental implant fixture. Artif Organs, Vol. 39, No. 3, 2015

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Yuan-Ming Hsu et al. (108) of the Far Eastern Memorial Hospital, New Taipei City, Taiwan, investigated the bactericidal and mechanical properties of daptomycin-incorporated polymethylmethacrylate (PMMA) bone cement (DLABC) as an infection prophylaxis in arthroplasty. The compressive strength was higher than 100 MPa and sufficient according to ISO 5833 and was released for 2 weeks. All recipes of DLABC had a microbial inhibitory effect, but the bactericidal effect with the highest encapsulated amount (2 g per 40 g PMMA) of daptomycin was more significant. Ming Zhang et al. (109) of Sichuan University, Chengdu, China, investigated the repair of segmental long bone defects in a rabbit radius nonunion model by comparison of cylindrical porous titanium (Ti) and hydroxyapatite (HA) scaffolds. The difference in the results was not significant; both porous scaffolds showed excellent repairing ability. The porous Ti scaffold not only enhanced the bone repair process, similar to porous HA scaffolds, but also has superior biomechanical properties, suggesting that porous Ti scaffolds may have promise for use in the clinical setting. Mohd Yusof Baharuddin et al. (110) of the University of Malaya, Kuala Lumpur, Malaysia, investigated the designing of a cementless femoral stem 316L stainless steel using the investment casting technique for their specific population. Using finite element analysis, they showed that the maximum von Mises stress was 66.88 MPa proximally with a safety factor of 2.39 against endosteal fracture, and micromotion was 4.73 μm, which promotes osseointegration. This method offers a fabrication process with lower cost, subsequently helping patients, particularly those from nondeveloped countries. Yongwen Guo et al. (111) of Sichuan University, Chengdu, China, investigated a novel customdesigned high-density nano-hydroxyapatite/ polyamide (n-HA/PA) prosthesis with a polyvinyl alcohol (PVA) hydrogel humeral head surface for the repair of the shoulder joint head for hemiarthroplasty in 16 New Zealand white rabbits. The X-ray results showed that there was a clear space between the prosthesis head and the glenoid surface, and the joint capsules and surfaces of the glenoid and PVA were well preserved. Histological results showed significant osteogenesis surrounding the firmware part. The maximum tensile strength between the prosthesis and host bone reached 2.63 MPa at the 12th week postimplantation. Ki Hyoung Koo et al. (112) of Dongguk University Ilsan Hospital, Goyang, Korea, evaluated the effiArtif Organs, Vol. 39, No. 3, 2015

ciency of an apatite-coated collagen sponge for the long-term delivery of bone morphogenetic protein (BMP-2) in a rabbit model of lumbar posterolateral fusion. Fifteen rabbits, divided into three groups, underwent posterolateral lumbar fusion. The first group (control group) received uncoated collagen sponges without BMP-2. The second group (uncoated group) received uncoated collagen sponges with BMP-2 (40 μg each side). The third group (apatite-coated group) received apatite-coated collagen sponges with the same level of BMPs (40 μg each side). At 6 weeks of evaluation, fusion rates showed that the apatite-coated group had a significantly higher rate of fusion than the control group, while the uncoated group did not. Biomechanical study showed significantly higher tensile strength in the apatite-coated group than the uncoated group and denser trabeculations. PULMONARY SUPPORT Mark Schoberer et al. (113) of RWTH Aachen University, Aachen, Germany, reported on the miniaturization of a low-volume oxygenator for use as an artificial placenta. Miniaturization appears to be a key to clinical application. R. Garrett Jeffries et al. (114) of the University of Pittsburgh, Pittsburgh, PA, USA, reported on the effect of impeller design and spacing on gas exchange in a percutaneous respiratory assist catheter (IPRAC). The effects of the design and spacing were carried out using CFD and in vitro deionized water gas exchange testing. Six impeller blade geometries were designed and tested. The maximum CO2 removal efficiency (exchange per unit surface area) achieved was 573 ± 8 mL/min/m2 (40.1 mL/min absolute). The gas exchange rate increased significantly (5–10%) with reduced axial spacing allowing for additional shaft impellers (23 vs. 14). CFD gas exchange predictions were within 2–13% of experimental values. RENAL SUPPORT AND DIALYSIS Sonia Catalina Rivera-González et al. (115) of the National Institute of Cardiology Ignacio Chavez, Mexico, D.F., Mexico, evaluated the factors that prevent dry weight achievement in patients with endstage renal disease (ESRD) in renal replacement therapy through the change in their body weight after kidney transplant (KT) compared with 1 week before KT. Patients with body weight difference ≤2 kg were considered as being close to their dry weight (Group 1, N = 112), whereas patients with body

2014 YEAR IN REVIEW weight difference >2 kg were considered as being overhydrated (Group 2, N = 76). Multivariate regression analysis showed that male sex, peritoneal dialysis, and systolic BP before KT were independent risk factors for overhydration. Shou-liang Hu et al. (116) of Yangtze University, JingZhou, Hubei, China, reported on the effectiveness of sustained low-efficiency hemodialysis (SLED) plus hemoperfusion (HP) and continuous hemofiltration (CHF) plus hemoperfusion for acute severe organophosphate poisoning (ASOPP). Fifty-six patients with ASOPP were divided into CHF + HP group and SLED + HP group. The two groups showed no statistical differences in in-hospital duration, biochemical indicators, APACHE II score, hemodynamic parameters, survival rate, or the mortality rate. SLED plus HP was relatively more economical and convenient for patients with ASOPP in clinical practice. Yi-Lun Zhou et al. (117) of Capital Medical University, Beijing, China, investigated the impact of dry weight (DW) determined by calf bioimpedance ratio (CBR) on carotid stiffness and left ventricular hypertrophy in hemodialysis (HD) patients. One hundred fifteen HD patients were enrolled in a pilot trial divided into the bioimpedance group and control group. In the bioimpedance group, DW was routinely adjusted under the guidance of CBR every 3 months. In the control group, the assessment of DW remained a clinical judgment. Compared with the control group, the bioimpedance group had significantly lower values of annual averages of systolic home BP, carotid stiffness index β, left ventricular mass index, and the percentage of individuals with CBR over target range at month 12. Continued DW control achieved by periodical CBR measurement improved arterial stiffness and left ventricular hypertrophy with good tolerability in HD patients. Xujie Zhang et al. (118) of the Fourth Military Medical University, Xi’an, China, reported on a retrospective case-matched study of patients with severe acute pancreatitis (SAP) with early organ failure (EOF); 19 patients each either received continuous venovenous hemofiltration (CVVH) or not (control). The study failed to prove that early classic CVVH had any benefits on the outcomes of SAP patients with EOF. Unexpectedly, early classic CVVH worsened organ functional capacity. Marcela L. Mendes et al. (119) of the University of São Paulo State-Botucatu School of Medicine, São Paulo, Brazil, evaluated the use of cryopreserved solutions of the thrombolytic agent alteplase for occluded tunneled venous catheters (CVCs) in HD patients. Eighty-one patients accounting for 179

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attempted clearances were assessable for efficacy. One hundred forty-seven of the 179 catheter clearance attempts resulted in successful catheter clearance after one dose. Twenty-seven of all occluded CVCs were successful after two doses whereas five were not. No adverse events were reported. Cryopreserved 1-mg/mL aliquots of alteplase are safe and effective in the clearance of occluded CVC for hemodialysis patients. Yangrong Zhang et al. (120) of Northwestern University, Evanston, IL, USA, developed a receptor for advanced glycation end products (AGEs [RAGE])based bioadsorbent device that would be capable of removing endogenous AGEs from human blood. The extracellular domain of RAGE was immobilized onto agarose beads to generate the bioadsorbent. The bioadsorbent significantly reduced the concentration of total AGEs in serum isolated from endstage kidney disease patients by 57%. AGE removal resulted in a significant reduction of vascular cell adhesion molecule-1 expression in human endothelial cells and abolishment of osteoclast formation in osteoclast progenitor cells. This approach provides the foundation for further development of soluble RAGE-based extracorporeal therapies to selectively deplete serum AGEs from human blood and decrease inflammation in patients with diabetes and/or chronic kidney disease. Reindert Graaff et al. (121) of the University of Groningen, Groningen, The Netherlands, investigated skin autofluorescence (AF) changes after a single session in 35 HD patients, and if they might be related to changes in plasma AF. The HD patients had, on average, a 65% higher skin AF value than age-matched healthy persons. Plasma AF was reduced by 14%, whereas skin AF was not changed after a single HD treatment. No significant influence of the reduced plasma AF on skin AF levels was found, suggesting that the measurement of skin AF can be performed during the whole dialysis period and is not directly influenced by the changes in plasma AF during HD. Thabata Coaglio Lucas et al. (122) of the Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, compared the blood flow and analyzed the influence of shear stress and shear rate in fibrin deposition and thrombus formation in nontunneled HD catheters with unobstructed side holes (unobstructed device) or with some side holes obstructed by blood thrombi (obstructed device). CFD was performed to simulate realistic blood flow. These results were compared with the fibrin distribution and thrombus architecture data obtained from scanning electron microscopy (SEM) and two Artif Organs, Vol. 39, No. 3, 2015

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photons laser scanning microscopy (TPLSM) on human thrombus formed in catheters removed from patients. CFD showed that regions of flow eddies and separation were mainly found in the venous holes region. TPLSM characterization of thrombi and fibrin structure in patient samples showed fibrin formations in accordance with simulated flux dynamics. The findings were supported by SEM data documenting a preferential fibrin arrangement on side hole walls. Sayuri Tanaka et al. (123) of Shimane University Faculty of Medicine, Izumo, Japan, investigated the effect of p-cresol, a uremic toxin, on insulin resistance by assessing its effect on adipocytes and their precursors using 3T3-L1 cells, a mouse preadipocyte cell line. Compared with control, 3T3-L1 cells treated with 100 and 200 μM p-cresol were significantly decreased in number at days 3 and 7 of culture. The bromodeoxyuridine incorporation assay demonstrated similar inhibitory effects. Oil Red O staining showed that the number of mature adipocytes was decreased by treatment with 200 μM p-cresol and the number of apoptotic cells was increased by treatment with 100 and 200 μM p-cresol. Peroxisome proliferator-activated receptor γ (PPARγ) mRNA expression increased time-dependently during the differentiation process of 3T3-L1 cells. p-Cresol dose-dependently decreased differentiation-induced mRNA expression of PPARγ. Uptake of 3H-labeled 2-deoxyglucose was markedly decreased by 200 μM p-cresol in the presence or in the absence of insulin. High concentrations of p-cresol disturbed the cell cycle, induced apoptosis, inhibited the differentiation of preadipocytes into mature adipocytes, and decreased glucose uptake at baseline and after insulin stimulation. Accumulated p-cresol may induce reduction in adipose tissue, insulin resistance, and malnutrition, eventually leading to poor outcomes in chronic dialysis patients. Robert Ekart et al. (124) of the University Medical Center of Maribor, Maribor, Slovenia, evaluated the hypothesis that Hb levels in HD patients are associated with serum testosterone concentrations. Testosterone, Hb, and other biochemical parameters were measured in a representative sample of 98 chronic HD patients (50 male, 48 female). A statistically significant positive correlation between testosterone and Hb was found in all patients, men, but not in women. Multiple regression analysis for all patients has shown statistically significant association between Hb and testosterone, high-sensitivity C-reactive protein, lean body mass, post-HD systolic and diastolic BP. Multiple regression analysis in men showed an association between Hb and testosterone Artif Organs, Vol. 39, No. 3, 2015

and post-HD diastolic BP, and in women, association between Hb and testosterone, calcium, and post-HD diastolic BP. We found an association between serum testosterone concentration and Hb in male and female HD patients. Zaur M. Unarokov et al. (125) of the Academician E.N. Meshalkin Novosibirsk State Research Institute of Circulation Pathology, Novosibirsk, Russia, addressed the problem of maintenance of intradialytic hemodynamic safety in unstable patients with AKI and tested the hypothesis that “small” quantities of acetate in standard bicarbonate dialysate can cause pronounced acetatemia and exacerbate cardiovascular instability. In a prospective randomized study, a group of patients with AKI after cardiac surgery was treated with sustained lowefficiency dialysis with either acetate-containing bicarbonate dialysate or acetate-free dialysate. Application of acetate-containing bicarbonate dialysate resulted in blood acetate levels up to 12 times the normal level and was associated with a 3.8-fold increased risk of hemodynamic complications in comparison with acetate-free dialysate. The choice of acetate-free or acetate-containing bicarbonate dialysate does not influence adequacy of correction of the acid-base and electrolyte content of blood. Detlef H. Krieter et al. (126) of the University Hospital Würzburg, Würzburg, Germany, evaluated the clearance of drugs (bortezomib [BOR], dexamethasone [DEX], and thalidomide [THA]) for multiple myeloma therapy during in vitro high-cutoff (HCO) HD compared with high-flux (PFX) HD. Plasma clearance (K) values of HCO and PFX for THA, BOR, and DEX were about 40, 70, and 65%, respectively, lower compared with urea. K was highest for THA. K was negatively correlated with plasma albumin concentrations (CHSA). CHSA continually decreased over time only with HCO, resulting in lower calculated protein-bound drug fraction (PBF). Compared with BOR and DEX, the PBF of THA was significantly lower. A mathematical simulation based on the K values of urea and the drugs reliably estimated PBF. If the Kurea of a dialyzer and the PBF of any given drug are known, Kdrug can be reliably estimated by mathematical simulation. Zenib Aljadi et al. (127) of the Karolinska Institute, Stockholm, Sweden, studied the effect of blood-membrane interaction on human peripheral basophils and neutrophils in HD with high- and low-permeability polysulfone dialyzers. The surface expression of CD203c (basophil selection marker) and CD63 (activation marker) after activation by the bacterial peptide formyl-methionyl-leucyl-

2014 YEAR IN REVIEW phenylalanine (fMLP) or anti-Fcε receptor I (FcεRI) antibody and the absolute number of basophils were investigated before and after HD with each of the dialyzers, and the expression on neutrophils was analyzed. The expression of CD63 in basophils was significantly higher in the patient group compared with that in healthy controls, but no differences were observed after activation by anti-FcεRI. During HD, the low-flux membrane induced up-regulation of CD63 expression on basophils, while passage through the high-flux membrane did not significantly alter the responsiveness. They found no significant differences in the expression of the neutrophil activation markers (CD11b, the active epitope of CD11b, and CD88) comparing the two different dialyzers before and after dialysis and healthy controls. Together, these findings suggest that alterations in basophil activity may be a useful marker of membrane bioincompatibility in HD. Maarten Wester et al. (128) of the University Medical Center Utrecht, Utrecht, The Netherlands, assessed the removal of urea in a wearable dialysis device using electro-oxidation (EO). Platinum electrodes degraded more urea than ruthenium oxide or graphite electrodes. Chlorine generation was much higher with platinum electrodes. Platinum and ruthenium oxide electrodes released platinum. Activated carbon (AC) potently reduced dialysate chlorine levels to

Artificial organs 2014: a year in review.

In this Editor's Review, articles published in 2014 are organized by category and briefly summarized. We aim to provide a brief reflection of the curr...
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