A Volume-Adjustable Artificial Womb for Extremely Preterm Infants.

More than 13 million children are born preterm annually. Prematurity-related mortality accounts for 0.9 million deaths worldwide. The majority of those affected are Extremely Preterm Infants (gestational age less than 28 weeks). Immaturity causes organ failure and specific morbidities like germinal matrix hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis. Artificial womb and placenta technologies address these issues. As a bridge-to-life technology, they provide a liquid environment to allow organ maturation under more physiological conditions. The proposed artificial womb can adapt to fetal growth. Volume adjustment is achieved by removing fluid from the interspace between an inner and outer chamber. Results of the in vitro tests showed a temperature constancy of 36.8°C ± 0.3°C without pressure loss over 7 days. The volume of the inner sac was variable between 3.6 and 7.0 L. We designed a filtration and disinfection system for this particular purpose. This system has proven strong disinfection capabilities, effective filtering of metabolic waste, and the ability to avoid phospholipid washout. The presented artificial womb has sufficient volume variability to adapt to the physiologic growth of an extremely preterm neonate over a 4-week period. We regard this as an important step in the development of this bridge-to-life technology.

Ghost cells as a two-phase blood analog fluid-high-volume and high-concentration production.

BACKGROUND: Hemolysis in mechanical circulatory support systems is currently determined quantitatively. To also locally resolve hemolysis, we are developing a fluorescent hemolysis detection method. This requires a translucent two-phase blood analog fluid combined with particle image velocimetry, an optical flow field measurement. The blood analog fluid is composed of red blood cell surrogates. However, producing surrogates in sufficient volume is a challenge. We therefore present a high-volume and high-concentration production for our surrogates: ghost cells, hemoglobin-depleted erythrocytes. METHODS: In the ghost cell production, the hemoglobin is removed by a repeated controlled osmolar lysis. We have varied the solution mixture, centrifugation time, and centrifugation force in order to increase production efficiency. The production is characterized by measurements of output volume, hematocrit, transparency, and rheology of the blood analog fluid. RESULTS: The volume of produced ghost cells was significantly increased, and reproducibility was improved. An average production of 389 mL of ghost cells were achieved per day. Those ghost cells diluted in plasma have a rheology similar to blood while being permeable to light. CONCLUSION: The volume of ghost cells produced is sufficient for optical measurements as particle image velocimetry in mechanical circulatory support systems. This makes further work on experimental measurements for a locally resolved hemolysis detection possible.

Both moderate- and high-intensity exercise training increase intramyocellular lipid droplet abundance and modify myocellular distribution in adults with obesity.

Exercise training modifies lipid metabolism in skeletal muscle, but the effect of exercise training on intramyocellular lipid droplet (LD) abundance, size, and intracellular distribution in adults with obesity remains elusive. This study compared high-intensity interval training (HIIT) with more conventional moderate-intensity continuous training (MICT) on intramyocellular lipid content, as well as LD characteristics (size and number) and abundance within the intramyofibrillar (IMF) and subsarcolemmal (SS) regions of type I and type II skeletal muscle fibers in adults with obesity. Thirty-six adults with obesity [body mass index (BMI) = 33 ± 3 kg/m2] completed 12 wk (4 days/wk) of either HIIT (10 × 1 min, 90% HRmax + 1-min active recovery; n = 19) or MICT (45-min steady-state exercise, 70% HRmax; n = 17), while on a weight-maintaining diet throughout training. Skeletal muscle biopsies were collected from the vastus lateralis before and after training, and intramyocellular lipid content and intracellular LD distribution were measured by immunofluorescence microscopy. Both MICT and HIIT increased total intramyocellular lipid content by more than 50% (P < 0.01), which was attributed to a greater LD number per µm2 in the IMF region of both type I and type II muscle fibers (P < 0.01). Our findings also suggest that LD lipophagy (autophagy-mediated LD degradation) may be transiently upregulated the day after the last exercise training session (P < 0.02 for both MICT and HIIT). In summary, exercise programs for adults with obesity involving either MICT or HIIT increased skeletal muscle LD abundance via a greater number of LDs in the IMF region of the myocyte, thereby providing more lipid in close proximity to the site of energy production during exercise.NEW & NOTEWORTHY In this study, 12 wk of either moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) enhanced skeletal muscle lipid abundance by increasing lipid droplet number within the intramyofibrillar (IMF) region of muscle. Because the IMF associates with high energy production during muscle contraction, this adaptation may enhance lipid oxidation during exercise. Despite differences in training intensity and energy expenditure between MICT and HIIT, their effects on muscle lipid abundance and metabolism were remarkably similar.

Detection of physiological control inputs preload and afterload from intrinsic pump parameters in total artificial heart.

BACKGROUND: In the total artificial heart (TAH), the inputs to the physiological control unit, preload, and afterload, are detected from intrinsic pump parameters (e.g., motor current). Within this study, their detection techniques are developed, and their reliability in pre- and afterload prediction is mapped for a broad range of cardiovascular system states. METHODS: We used ReinHeart TAH which is a fully implantable TAH with a plunger coil drive that is alternately emptying the left and right chambers. From the coil currents we first derived a force generated by the piston with respect to its position and then analyzed its pattern to detect (1) preload-chamber filling, found as piston position at begin ejection and (2) afterload-mean outflow pressures, determined as linearly calibrated average piston force during ejection. TAH is then integrated into a mock loop circulation (MLC) which is set to 135 different steady operating points varying in chamber filling (0%-100%, five steps), mean outflow pressures (system circulation: 60-90-120 mm Hg, pulmonary circulation: 15-30-45 mm Hg), and heart cycle duration (171-600 ms in seven non-equidistant steps). The detected preload and afterload are compared to MLC set values, and the errors are mapped. RESULTS: Respectively for the left and right chambers, the preload was detectable in 134 and 118 operating points and the mean error was ±3% and ±2%. The afterload was detectable in 135 and 87 operating points and the mean error was 37% and 30% respectively for left and right circulation. The operational points that are further away from homeostatic equilibrium values generally yielded larger errors. The largest errors were observed for right circulation at long cycle duration, low afterload, and low filling. CONCLUSIONS: The study yields reliable preload estimation in a broad range of physiological states, particularly for left circulation. Detection of afterload needs further improvements. The study revealed a need for piston movement optimization within the ReinHeart TAH during the early phase of systole.

Development and evaluation of a variable, miniaturized oxygenator for various test methods.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) became an accepted therapy for the treatment of severe acute respiratory distress syndrome and chronic obstructive pulmonary disease. However, ECMO systems are still prone to thrombus formation and decrease of gas exchange over time. Therefore, it is necessary to conduct qualified studies to identify parameters for optimization of ECMO systems, and especially the oxygenator. However, commercially marketed oxygenators are not always appropriate and available for certain research use cases. Therefore, we aimed to design an oxygenator, which is suitable for various test conditions such as blood tests, numerical simulation, and membrane studies, and can be modified in membrane area size and manufactured in laboratory. METHODS: Main design criteria are a homogeneous blood flow without stagnation zones, low pressure drop, manufacturability in the lab, size variability with one set of housing parts and cost-efficiency. Our newly designed oxygenator was tested comparatively regarding blood cell damage, gas transfer performance and pressure drop to prove the validity of the design in accordance with a commercial device. RESULTS: No statistically significant difference between the tested oxygenators was detected and our new oxygenator demonstrated sufficient hemocompatibility. Furthermore, our variable oxygenator has proven that it can be easily manufactured in the laboratory, allows to use various membrane fiber configurations and can be reopened easily and non-destructively for analysis after use, and the original geometry is available for numerical simulations. CONCLUSION: Therefore, we consider this newly developed device as a valuable tool for basic experimental and numerical research on the optimization of oxygenators.

Exercise training remodels subcutaneous adipose tissue in adults with obesity even without weight loss.

Excessive adipose tissue mass underlies much of the metabolic health complications in obesity. Although exercise training is known to improve metabolic health in individuals with obesity, the effects of exercise training without weight loss on adipose tissue structure and metabolic function remain unclear. Thirty-six adults with obesity (body mass index = 33 ± 3 kg · m-2 ) were assigned to 12 weeks (4 days week-1 ) of either moderate-intensity continuous training (MICT; 70% maximal heart rate, 45 min; n = 17) or high-intensity interval training (HIIT; 90% maximal heart rate, 10 × 1 min; n = 19), maintaining their body weight throughout. Abdominal subcutaneous adipose tissue (aSAT) biopsy samples were collected once before and twice after training (1 day after last exercise and again 4 days later). Exercise training modified aSAT morphology (i.e. reduced fat cell size, increased collagen type 5a3, both P ≤ 0.05, increased capillary density, P = 0.05) and altered protein abundance of factors that regulate aSAT remodelling (i.e. reduced matrix metallopeptidase 9; P = 0.02; increased angiopoietin-2; P < 0.01). Exercise training also increased protein abundance of factors that regulate lipid metabolism (e.g. hormone sensitive lipase and fatty acid translocase; P ≤ 0.03) and key proteins involved in the mitogen-activated protein kinase pathway when measured the day after the last exercise session. However, most of these exercise-mediated changes were no longer significant 4 days after exercise. Importantly, MICT and HIIT induced remarkably similar adaptations in aSAT. Collectively, even in the absence of weight loss, 12 weeks of exercise training induced changes in aSAT structure, as well as factors that regulate metabolism and the inflammatory signal pathway in adults with obesity. KEY POINTS: Exercise training is well-known to improve metabolic health in obesity, although how exercise modifies the structure and metabolic function of adipose tissue, in the absence of weight loss, remains unclear. We report that both 12 weeks of moderate-intensity continuous training (MICT) and 12 weeks of high-intensity interval training (HIIT) induced modifications in adipose tissue structure and factors that regulate adipose tissue remodelling, metabolism and the inflammatory signal pathway in adults with obesity, even without weight loss (with no meaningful differences between MICT and HIIT). The modest modifications in adipose tissue structure in response to 12 weeks of MICT or HIIT did not lead to changes in the rate of fatty acid release from adipose tissue. These results expand our understanding about the effects of two commonly used exercise training prescriptions (MICT and HIIT) on adipose tissue remodelling that may lead to advanced strategies for improving metabolic health outcomes in adults with obesity.

Three-dimensional membranes for artificial lungs: Comparison of flow-induced hemolysis.

BACKGROUND: Membranes based on triply periodic minimal surfaces (TPMS) have proven a superior gas transfer compared to the contemporary hollow fiber membrane (HFM) design in artificial lungs. The improved oxygen transfer is attributed to disrupting the laminar boundary layer adjacent to the membrane surface known as main limiting factor to mass transport. However, it requires experimental proof that this improvement is not at the expense of greater damage to the blood. Hence, the aim of this work is a valid statement regarding the structure-dependent hemolytic behavior of TPMS structures compared to the current HFM design. METHODS: Hemolysis tests were performed on structure samples of three different kind of TPMS-based designs (Schwarz-P, Schwarz-D and Schoen's Gyroid) in direct comparison to a hollow fiber structure as reference. RESULTS: The results of this study suggest that the difference in hemolysis between TPMS membranes compared to HFMs is small although slightly increased for the TPMS membranes. There is no significant difference between the TPMS structures and the hollow fiber design. Nevertheless, the ratio between the achieved additional oxygen transfer and the additional hemolysis favors the TPMS-based membrane shapes. CONCLUSION: TPMS-shaped membranes offer a safe way to improve gas transfer in artificial lungs.

Controlling the flow balance: In vitro characterization of a pulsatile total artificial heart in preload and afterload sensitivity.

The objective of this study is to identify the preload and afterload sensitivity of the ReinHeart TAH 2.0. For adequate left-right flow balance, the concept of a reduced right stroke volume (by about 10%) and active adaption of the right diastole duration are evaluated concerning the controllability of the flow balance. This study used an active mock circulation loop to test a wide range of preload and afterload conditions. Preload sensitivity was tested at atrial pressures (APs) between 4 and 20 mm Hg. Left afterload was varied in a range of 60-140 mm Hg mean aortic pressure (MAP), right afterload was simulated between 15 and 40 mm Hg. Four scenarios were developed to verify that the flow difference fully covers the defined target range of 0-1.5 L/min. Although a positive correlation between inlet pressure and flow is identified for the right pump chamber, the left pump chamber already fills completely at an inlet pressure of 8-10 mm Hg. With increasing afterload, both the left and right flow decrease. A positive flow balance (left flow exceeds right flow) is achieved over the full range of tested afterloads. At high APs, the flow difference is limited to a maximum of 0.7 L/min. The controllability of flow balance was successfully evaluated in four scenarios, revealing that a positive flow difference can be achieved over the full range of MAPs. Under physiological test conditions, the linear relationship between flow and heart rate was confirmed, ensuring good controllability of the TAH.

In-vitro performance of a single-chambered total artificial heart in a Fontan circulation.

An in-vitro study was conducted to investigate the general feasibility of using only one pumping chamber of the SynCardia total artificial heart (TAH) as a replacement of the single ventricle palliated by Fontan circulation. A mock circulation loop was used to mimic a Fontan circulation. The combination of both ventricle sizes (50 and 70 cc) and driver (Freedom Driver and Companion C2 Driver) was investigated. Two clinical relevant scenarios (early Fontan; late Fontan) as derived from literature data were set up in the mock loop. The impact of increased transpulmonary pressure gradient, low atrial pressure, and raised central venous pressure on cardiac output was studied. From a hemodynamic point, the single-chambered TAH performed sufficiently in the setting of the Fontan circulation. Increased transpulmonary pressure gradient, from ideal to pulmonary hypertension, decreased the blood flow in combinations by almost 2 L/min. In the early Fontan scenario, a cardiac output of 3-3.5 L/min was achieved using the 50 cc ventricle, driven by the Companion C2 Driver. Even under pulmonary hypertension, cardiac outputs greater than 4 L/min could be obtained with the 70 cc pump chamber in the late Fontan scenario. In the clinically relevant Fontan scenarios, implementation of the single chambered TAH performed successfully from a hemodynamic point of view. The replacement of the failing univentricular heart by a single chamber of the SynCardia TAH may provide an alternative to a complex biventricular repair procedure or ventricular support in Fontan patients.

An accelerometer-based guidance device for CT-guided procedures: an improved wireless prototype.

INTRODUCTION: The aim of the study was to demonstrate the feasibility of a prototype for accelerometer-based guidance for percutaneous CT-guided punctures and compare it with free-hand punctures. MATERIAL AND METHODS: The prototype enabled alignment with the CT coordinate system and a wireless connectivity. Its feasibility was tested in a swine cadaver model: 20 out-of-plane device-assisted punctures performed without intermittent control scans (one-step punctures) were evaluated regarding deviation to target and difference between planned and obtained angle. Thereafter, 22 device-assisted punctures were compared with 20 free-hand punctures regarding distance to target, deviation from the planned angle, number of control scans and procedure time. Differences were compared with the Mann-Whitney U-test (p < .05). RESULTS: The one-step punctures revealed a deviation to target of 0.26 ± 0.37 cm (axial plane) and 0.21 ± 0.19 cm (sagittal plane) and differences between planned and performed puncture angles of 0.9 ± 1.09° (axial plane) and 1.15 ± 0.91° (sagittal planes). In the comparative study, device-assisted punctures showed a significantly higher accuracy, 0.20 ± 0.17 cm vs. 0.30 ± 0.21 cm (p < .05) and lower number of required control scans, 1.3 ± 1.1 vs. 3.7 ± 0.9 (p < .05) compared with free-hand punctures. CONCLUSION: The accelerometer-based device proved to be feasible and demonstrated significantly higher accuracy and required significantly less control scans compared to free-hand puncture.

Hemolysis at low blood flow rates: in-vitro and in-silico evaluation of a centrifugal blood pump.

BACKGROUND: Treating severe forms of the acute respiratory distress syndrome and cardiac failure, extracorporeal membrane oxygenation (ECMO) has become an established therapeutic option. Neonatal or pediatric patients receiving ECMO, and patients undergoing extracorporeal CO2 removal (ECCO2R) represent low-flow applications of the technology, requiring lower blood flow than conventional ECMO. Centrifugal blood pumps as a core element of modern ECMO therapy present favorable operating characteristics in the high blood flow range (4 L/min-8 L/min). However, during low-flow applications in the range of 0.5 L/min-2 L/min, adverse events such as increased hemolysis, platelet activation and bleeding complications are reported frequently. METHODS: In this study, the hemolysis of the centrifugal pump DP3 is evaluated both in vitro and in silico, comparing the low-flow operation at 1 L/min to the high-flow operation at 4 L/min. RESULTS: Increased hemolysis occurs at low-flow, both in vitro and in silico. The in-vitro experiments present a sixfold higher relative increased hemolysis at low-flow. Compared to high-flow operation, a more than 3.5-fold increase in blood recirculation within the pump head can be observed in the low-flow range in silico. CONCLUSIONS: This study highlights the underappreciated hemolysis in centrifugal pumps within the low-flow range, i.e. during pediatric ECMO or ECCO2R treatment. The in-vitro results of hemolysis and the in-silico computational fluid dynamic simulations of flow paths within the pumps raise awareness about blood damage that occurs when using centrifugal pumps at low-flow operating points. These findings underline the urgent need for a specific pump optimized for low-flow treatment. Due to the inherent problems of available centrifugal pumps in the low-flow range, clinicians should use the current centrifugal pumps with caution, alternatively other pumping principles such as positive displacement pumps may be discussed in the future.

Hemodynamics inside the neo- and native sinus after TAVR: Effects of implant depth and cardiac output on flow field and coronary flow.

Transcatheter aortic valve replacement (TAVR) has emerged as a widely used therapy for aortic valve diseases. With TAVR, flow hemodynamics may change leading to areas of flow stagnation prone to thrombosis risk. The neo-sinus, created by introducing a prosthesis inside the diseased native valve, may prompt leaflet thrombosis due to areas of flow stasis. This study attempted to understand the effect of different prosthesis implant depths on the flow field within the neo- and native sinus and on the coronary perfusion. Experiments were performed inside an in vitro pulse duplicator producing physiological conditions according to ISO 5840-1:2015 standard. Flow fields were obtained for two cardiac outputs (CO) using particle image velocimetry (PIV). Washout was calculated as a measure of flow stasis. The two main results are: a lower implant position and a lower CO/frequency led to better native sinus washout, but worsened neo-sinus washout. In contrast, a higher implant position led to higher coronary flow (for higher CO/frequency). No significant effect of implant depth on coronary flow was observed for lower CO/frequency. In summary, a higher implant position using this self-expanding prosthesis is associated with reduced neo-sinus flow stasis. Hereby, washout of the native sinus, as well as coronary flow, are dependent on cardiac output.

In vitro thrombogenicity testing of pulsatile mechanical circulatory support systems: Design and proof-of-concept.

Thrombogenic complications are a main issue in mechanical circulatory support (MCS). There is no validated in vitro method available to quantitatively assess the thrombogenic performance of pulsatile MCS devices under realistic hemodynamic conditions. The aim of this study is to propose a method to evaluate the thrombogenic potential of new designs without the use of complex in-vivo trials. This study presents a novel in vitro method for reproducible thrombogenicity testing of pulsatile MCS systems using low molecular weight heparinized porcine blood. Blood parameters are continuously measured with full blood thromboelastometry (ROTEM; EXTEM, FIBTEM and a custom-made analysis HEPNATEM). Thrombus formation is optically observed after four hours of testing. The results of three experiments are presented each with two parallel loops. The area of thrombus formation inside the MCS device was reproducible. The implantation of a filter inside the loop catches embolizing thrombi without a measurable increase of platelet activation, allowing conclusions of the place of origin of thrombi inside the device. EXTEM and FIBTEM parameters such as clotting velocity (α) and maximum clot firmness (MCF) show a total decrease by around 6% with a characteristic kink after 180 minutes. HEPNATEM α and MCF rise within the first 180 minutes indicate a continuously increasing activation level of coagulation. After 180 minutes, the consumption of clotting factors prevails, resulting in a decrease of α and MCF. With the designed mock loop and the presented protocol we are able to identify thrombogenic hot spots inside a pulsatile pump and characterize their thrombogenic potential.

Experimental investigation of right-left flow balance concepts for a total artificial heart.

A total artificial heart (TAH) must be designed to autonomously balance the flows of the systemic and pulmonary circulation to prevent potentially lethal lung damage. The flow difference between the systemic and pulmonary circulation is mainly caused by the bronchial (arteries) shunt flow and can change dynamically. The ReinHeart TAH consists of only one actuator that ejects blood alternately from the right and left pump chamber. This design entails a coupling of the right and left stroke and thus, complicates the independent adaptation of the right and left flow. In this experimental study on the ReinHeart TAH, four concepts to keep the flows well balanced were investigated using an active mock circulation loop for data acquisition. Three concepts are based on mechanical design changes (variation of pusher plate shape, flexible right pump chamber housing, and reduced right stroke volume) to achieve a static flow difference. In combination with these static concepts, a concept influencing the ratio of systole and diastole duration to respond to dynamic changes was studied. In total, four measurement series, each with 270 operating points, to investigate the influence of circulatory filling volume, heart rate, bronchial shunt flow, and lung resistance were recorded. In the course of this study, we introduce a concept deviation indicator, providing information about the efficiency of the concepts to balance the flows based on changes in lung's blood pressures. Furthermore, the distribution of the measured data was evaluated based on bubble plot visualizations. The investigated variation of the right pusher plate shape results in high lung pressures which will cause lethal lung damage. In comparison, a flexible right pump chamber housing shows lower lung pressures, but it still has the potential to damage the lungs. Reducing the stroke volume of the right pump chamber results in proper lung pressures. The flow balance can dynamically be influenced with a positive effect on the lung pressures by choosing a suitable systole-diastole-ratio. The results of this study suggest that an adequate right-left flow balance can be achieved by combining the mechanical concept of a reduced right stroke volume with an active control of the systole-diastole-ratio.

Implementation of eHealth and AI integrated diagnostics with multidisciplinary digitized data: are we ready from an international perspective?

Digitization of medicine requires systematic handling of the increasing amount of health data to improve medical diagnosis. In this context, the integration of the versatile diagnostic information, e.g., from anamnesis, imaging, histopathology, and clinical chemistry, and its comprehensive analysis by artificial intelligence (AI)-based tools is expected to improve diagnostic precision and the therapeutic conduct. However, the complex medical environment poses a major obstacle to the translation of integrated diagnostics into clinical research and routine. There is a high need to address aspects like data privacy, data integration, interoperability standards, appropriate IT infrastructure, and education of staff. Besides this, a plethora of technical, political, and ethical challenges exists. This is complicated by the high diversity of approaches across Europe. Thus, we here provide insights into current international activities on the way to digital comprehensive diagnostics. This includes a technical view on challenges and solutions for comprehensive diagnostics in terms of data integration and analysis. Current data communications standards and common IT solutions that are in place in hospitals are reported. Furthermore, the international hospital digitalization scoring and the European funding situation were analyzed. In addition, the regional activities in radiomics and the related publication trends are discussed. Our findings show that prerequisites for comprehensive diagnostics have not yet been sufficiently established throughout Europe. The manifold activities are characterized by a heterogeneous digitization progress and they are driven by national efforts. This emphasizes the importance of clear governance, concerted investments, and cooperation at various levels in the health systems.Key Points• Europe is characterized by heterogeneity in its digitization progress with predominantly national efforts. Infrastructural prerequisites for comprehensive diagnostics are not given and not sufficiently funded throughout Europe, which is particularly true for data integration.• The clinical establishment of comprehensive diagnostics demands for a clear governance, significant investments, and cooperation at various levels in the healthcare systems.• While comprehensive diagnostics is on its way, concerted efforts should be taken in Europe to get consensus concerning interoperability and standards, security, and privacy as well as ethical and legal concerns.

Predictors of Occlusion of Hepatic Blood Vessels after Irreversible Electroporation of Liver Tumors.

PURPOSE: To examine predictors of midterm occlusion in portal and hepatic veins within or adjacent to the ablation zone after irreversible electroporation (IRE) of liver tumors. MATERIALS AND METHODS: This retrospective cohort analysis included 39 patients who underwent CT-guided IRE of liver tumors. Vessels within or adjacent to the ablation zone were identified on CT images acquired immediately after the procedure, and the positional relationships with the ablation zone (within/adjacent), locations (proximal/distal), and diameters (< 4 mm or ≥ 4 mm) were evaluated. Using contrast-enhanced follow-up scans, each vessel was classified as patent, stenosed, or occluded. Associations between vessel occlusion and each variable were investigated. RESULTS: Overall, 33 portal veins and 64 hepatic veins were analyzed. Follow-up scans showed occlusion in 12/33 (36.7%) portal veins and 17/64 (26.6%) hepatic veins. Vessels within the ablation zone were occluded significantly more frequently than vessels adjacent to the ablation zone (portal: 55.6% [10/18] vs 13.3% [2/15], P = .04; hepatic: 45.4% [15/33] vs 6.4% [2/31], P = .011). Vessels with a diameter < 4 mm were also occluded significantly more frequently than vessels with a diameter ≥ 4 mm (portal: 72.7% [8/11] vs 18.1% [4/22], P = .011; hepatic: 54.8% [17/31] vs 0% [0/33], P < .001). The respective positive and negative predictive values for occlusion of vessels categorized as both within and < 4 mm were 88% (7/8) and 82% (20/25) for portal veins and 79% (15/19) and 96% (43/45) for hepatic veins. CONCLUSIONS: Midterm vessel occlusion after liver IRE could be predicted with relatively high accuracy by assessing ablation location and vessel diameter.

EndOxy: Mid-term stability and shear stress resistance of endothelial cells on PDMS gas exchange membranes.

Endothelialized oxygenator devices (EndOxy) with a physiological, nonthrombogenic, and anti-inflammatory surface offer the potential to overcome current shortcomings of conventional extracorporeal membrane oxygenation such as complications like thromboembolism and bleeding that deteriorate adequate long-term hemocompatibility. The approach of endothelialization of gas exchange membranes, and thus the formation of a nonthrombogenic and anti-inflammatory surface, is promising. In this study, we investigated the mid-term shear stress resistance as well as gas transfer rates and cell densities of endothelial cells seeded on RGD-conjugated polydimethylsiloxane (RGD-PDMS) gas exchange membranes under dynamic conditions. Human umbilical vein endothelial cells were seeded on RGD-PDMS and exposed to defined shear stresses in a microfluidic bioreactor. Endothelial cell morphology was assessed by bright field microscopy and immunocytochemistry. Furthermore, gas transfer measurement of blank, RGD-conjugated, and endothelialized PDMS oxygenator membranes was performed. RGD-PDMS gas exchange membranes proved suitable for the dynamic culture of endothelial cells for up to 21 days at a wall shear stress of 2.9 dyn/cm2 . Furthermore, the cells resisted increased wall shear stresses up to 8.6 dyn/cm2 after a previous dynamic preculture of each one hour at 2.9 dyn/cm2 and 5.7 dyn/cm2 . Also, after a longer dynamic preculture of three days at 2.9 dyn/cm2 and one hour at 5.7 dyn/cm2 , increased wall shear stresses of 8.6 dyn/cm2 were tolerated by the cells and cell integrity could be remained. Gas transfer (GT) tests revealed that neither RGD conjugation nor endothelialization of RGD-PDMS significantly decrease the gas transfer rates of the membranes during short-term trials. Gas transfer rates are stable for at least 72 hours of dynamic cultivation of endothelial cells. Immunocytochemistry showed that the cell layer stained positive for typical endothelial cell markers CD31 and von Willebrand factor (VWF) after all trials. Cell density of EC on RGD-PDMS increased between 3 and 21 days of dynamic culture. In this study, we show the suitability of RGD-PDMS membranes for flow resistant endothelialization of gas-permeable membranes, demonstrating the feasibility of this approach for a biohybrid lung.

In vitro study on the hemocompatibility of plasma electrolytic oxidation coatings on titanium substrates.

Passively levitated ventricular assist devices (VADs) are vulnerable to impeller-housing contact and could benefit from surface coatings that improve wear resistance. Such coatings can be manufactured by plasma electrolytic oxidation (PEO), but their suitability for blood-contact applications needs further investigation. We therefore compared blood-surface interactions of polished titanium grade 5 (Ti Gr 5), as a general VAD reference material, uncoated ground titanium grade 4 (Ti Gr 4) and two commercially available PEO coatings on Ti Gr 4. In n = 4 static platelet adhesion tests, material samples were incubated with platelet-rich plasma (PRP) and consecutively analyzed for adhesive platelets by immunofluorescence microscopy. Additionally, PRP supernatant of incubated material samples was analyzed for changes in antithrombin III and fibrinogen concentrations by turbodimetry and enzyme-linked immunosorbent assay, respectively. We could not find any significant differences between the materials in the analyzed hemocompatibility markers (P > .05). Thus, we conclude that PEO coatings might offer a similar hemocompatibility to that of polished Ti Gr 5 and uncoated Ti Gr 4. Nevertheless, future studies should investigate blood-surface interactions of PEO coatings under realistic VAD-related flow conditions to better evaluate their potential for VAD applications.

Size-Tailored Biocompatible FePt Nanoparticles for Dual T1/T2 Magnetic Resonance Imaging Contrast Enhancement.

The development of new contrast agents (CAs) for magnetic resonance imaging (MRI) is of high interest, especially because of the increased concerns of patient safety and quick clearance of clinically used gadolinium and iron oxide-based CAs, respectively. Here, a two-step synthesis of superparamagnetic water-soluble iron platinum (FePt) nanoparticles (NPs) with core sizes between 2 and 8 nm for use as CAs in MRI is reported. First, wet-chemical organometallic NPs are synthesized by thermal decomposition in the presence of stabilizing oleic acid and oleylamine. Second, the hydrophobic NPs are coated with an amphiphilic polymer and transferred into aqueous media. Their magnetization values and relaxation rates exceed those published for CAs already used for clinical application. Their saturation magnetization increases with the core size to approximately 82 A·m2/kgFe. For 8 nm NPs, the T2 relaxivity of approximately 221 (mM·s)-1 is 5 times larger than that for the ferumoxides, and for 6 nm NPs, the T1 relaxivity of approximately 12 (mM·s)-1 is slightly higher than that of ultrasmall gadolinium oxide NPs. The 6 nm FePt NPs are identified as excellent CAs for both T1 and T2 imaging. Most importantly, because of their coating, significantly low cytotoxicity is achieved. FePt NPs prove to be a promising alternative to gadolinium and iron oxide NPs showing high-quality CA characteristics for both T1- and T2-weighted images.

Modeling of magnetoliposome uptake in human pancreatic tumor cells in vitro.

The internalization kinetics resulting from magnetic nanoparticle interactions with tumor cells play an important role in nanoparticle-based cancer treatment efficiency. Here, the uptake kinetics of magnetoliposomes (ML) into human pancreatic tumor cells (MiaPaCa-2 and BxPC-3) are quantified using magnetic particle spectrometry. A comparison to the uptake kinetics for healthy L929 cells is given. The experimental results are used for the development of an uptake kinetics model describing the three relevant internalization processes: ML adsorption to the cell membrane, endo- and exocytosis. By fitting of experimental data, the rate constant of each internalization process is determined enabling the prediction of internalized ML at any incubation time. After seven hours incubation time, MiaPaCa-2 internalized three times more ML than BxPC-3 and L929 cells even though their ML adsorption rate constants were nearly the same. As the interaction of the ML with the cell membrane is non-specific, the uptake kinetics mirror the individual cell response to ML internalization. With a new mathematical term to cover the exocytosis contribution to the overall internalization process, the extended uptake kinetics model offers new possibilities to analyze the specific internalization mechanism for other nanoparticle and cell types.