In vitro study on device-induced damage to blood cellular components and degradation of von Willebrand factor in a CentriMag pump-assisted circulation.

BACKGROUND: High mechanical shear stress (HMSS) generated by blood pumps during mechanical circulatory support induces blood damage (or function alteration) not only of blood cell components but also of plasma proteins. METHODS: In the present study, fresh, healthy human blood was used to prime a blood circuit assisted by a CentriMag centrifugal pump at a flow rate of 4.5 L/min under three pump pressure heads (75, 150, and 350 mm Hg) for 4 h. Blood samples were collected for analyses of plasma-free hemoglobin (PFH), von Willebrand factor (VWF) degradation and platelet glycoprotein (GP) IIb/IIIa receptor shedding. RESULTS: The extent of all investigated aspects of blood damage increased with increasing cross-pump pressure and duration. Loss of high-molecular-weight multimers (HMWM)-VWF in Loop 2 and Loop 3 significantly increased after 2 h. PFH, loss of HMWM-VWF, and platelet GPIIb/IIIa receptor shedding showed a good linear correlation with mean shear stress corresponding to the three pump pressure heads. CONCLUSIONS: HMSS could damage red blood cells, cause pathological VWF degradation, and induce platelet activation and platelet receptor shedding. Different blood components can be damaged to different degrees by HMSS; VWF and VWF-enhanced platelet activation may be more susceptible to HMSS.

Linking Computational Fluid Dynamics Modeling to Device-Induced Platelet Defects in Mechanically Assisted Circulation.

Thrombotic and bleeding events are the most common hematologic complications in patients with mechanically assisted circulation and are closely related to device-induced platelet dysfunction. In this study, we sought to link computational fluid dynamics (CFD) modeling of blood pumps with device-induced platelet defects. Fresh human blood was circulated in circulatory loops with four pumps (CentriMag, HVAD, HeartMate II, and CH-VAD) operated under a total of six clinically representative conditions. Blood samples were collected and analyzed for glycoprotein (GP) IIb/IIIa activation and receptor shedding of GPIbα and GPVI. In parallel, CFD modeling was performed to characterize the blood flow in these pumps. Numerical indices of platelet defects were derived from CFD modeling incorporating previously derived power-law models under constant shear conditions. Numerical results were correlated with experimental results by regression analysis. The results suggested that a scalar shear stress of less than 75 Pa may have limited contribution to platelet damage. The platelet defect indices predicted by the CFD power-law models after excluding shear stress <75 Pa correlated excellently with experimentally measured indices. Although numerical prediction based on the power-law model cannot directly reproduce the experimental data. The power-law model has proven its effectiveness, especially for quantitative comparisons.

In-Vivo Evaluation of a Novel Integrated Pediatric Pump Lung in a 30 Day Ovine Animal Model.

Recently there has been increased use of mechanical circulatory support in pediatric patients as a bridge to cardiopulmonary recovery or transplantation. However, there are few devices that are optimized and approved for use in pediatric patients. We designed and prototyped a novel integrated pediatric pump lung (PPL) that underwent 30 day in-vivo testing in seven juvenile Dorset Hybrid sheep. Devices were implanted in a right atrial to pulmonary artery configuration. Six of seven sheep survived with a device functioning for 25-35 days. The device flow rate was maintained at 2.08 ± 0.34 to 2.54 ± 0.16 L/min with oxygen transfer of 109.8 ± 24.8 to 151.2 ± 26.2 ml/min over the study duration. Aside from a postoperative drop in hematocrit, all hematologic and blood chemistry test values returned to normal ranges after 1-2 weeks postoperatively. Similarly, lactate dehydrogenase increased postoperatively and returned to baseline. In two sheep, there were early device failures due to oxygenator thrombosis on postoperative days zero and five; they then had oxygenator exchanges with subsequent devices performing stably for 30 days. This study demonstrated that the integrated PPL device exhibited stable performance and acceptable biocompatibility in a 30 day ovine model.

Computational fluid dynamics-based design and in vitro characterization of a novel pediatric pump-lung.

BACKGROUND: Although extracorporeal membrane oxygenation (ECMO) has been used to provide temporary support for pediatric patients suffering severe respiratory or cardiac failure since 1970, ECMO systems specifically designed for pediatric patients, particularly for long-term use, remain an unmet clinical need. We sought to develop a new pediatric ECMO system, that is, pediatric pump-lung (PPL), consisting of a unique cylinder oxygenator with an outside-in radial flow path and a centrifugal pump. METHODS: Computational fluid dynamics was used to analyze the blood fluid field for optimized biocompatible and gas exchange performances in terms of flow characteristics, hemolysis, and gas transfer efficiency. Ovine blood was used for in vitro hemolysis and gas transfer testing. RESULTS: Both the computational and experimental data showed that the pressure drop through the PPL's oxygenator is significantly low, even at a flow rate of more than 3.5 L/min. The PPL showed better hemolysis performance than a commercial ECMO circuit consisting of the Quadrox-iD pediatric oxygenator and the Rotaflow pump at a 3.5 L/min flow rate and 250 mm Hg afterload pressure. The oxygen transfer rate of the PPL can reach over 200 mL/min at a flow rate of 3.5 L/min. CONCLUSIONS: The PPL has the potential to provide adequate blood pumping and excellent respiratory support with minimal risk of hemolysis for a wide range of pediatric patients.

Investigation of the role of von Willebrand factor in shear-induced platelet activation and functional alteration under high non-physiological shear stress.

BACKGROUND: von Willebrand factor (vWF) plays a crucial role in physiological hemostasis through platelet and subendothelial collagen adhesion. However, its role in shear-induced platelet activation and functional alteration under non-physiological conditions common to blood-contacting medical devices (BCMDs) is not well investigated. METHODS: Fresh healthy human blood was treated with an anti-vWF antibody to block vWF-GPIbα interaction. Untreated blood was used as a control. They were exposed to three levels of non-physiological shear stress (NPSS) (75, 125, and 175 Pa) through a shearing device with an exposure time of 0.5 s to mimic typical shear conditions in BCMDs. Flow cytometric assays were used to measure the expression levels of PAC-1 and P-Selectin and platelet aggregates for platelet activation and the expression levels of GPIbα, GPIIb/IIIa, and GPVI for receptor shedding. Collagen/ristocetin-induced platelet aggregation capacity was characterized by aggregometry. RESULTS: The levels of platelet activation and aggregates increased with increasing NPSS in the untreated blood. More receptors were lost with increasing NPSS, resulting in a decreased capacity of collagen/ristocetin-induced platelet aggregation. In contrast, the increase in platelet activation and aggregates after exposure to NPSS, even at the highest level of NPSS, was significantly lower in treated blood. Nevertheless, there was no notable difference in receptor shedding, especially for GPIIb/IIIa and GPVI, between the two blood groups at the same level of NPSS. The block of vWF exacerbated the decreased capacity of collagen/ristocetin-induced platelet aggregation. CONCLUSIONS: High NPSS activates platelets mainly by enhancing the vWF-GPIbα interaction. Platelet activation and receptor shedding induced by high NPSS likely occur through different pathways.

Increased phagocytosis capacity of circulating neutrophils in patients on continuous flow ventricular assist device support.

BACKGROUND: Neutrophils take part in the innate immune response, phagocytosis, and pro-inflammatory cytokine release. The phagocytic capacity of circulating neutrophils in patients on continuous flow (CF) ventricular assist device (VAD) has not been well studied. METHODS: Blood samples from 14 patients undergoing CF-VAD implantation were collected and analyzed preoperatively (at baseline) and on postoperative days (POD) 3, 7, 14, and 28. Flow cytometry was used to assess the surface expression levels of CD62L, CD162, and macrophage antigen-1 (MAC-1) and neutrophil phagocytic capacity. Interleukin 1 (IL1), IL6, IL8, TNF-α, neutrophil elastase, and myeloperoxidase in plasma were measured using enzyme-linked immunosorbent assays. RESULTS: Among the 14 patients, seven patients had preoperative bridge device support. Relative to baseline, patients with no bridge device had elevated leukocyte count and neutrophil elastase by POD3 which normalized by POD7. Neutrophil activation level, IL6, IL8, and TNF-α increased by POD3 and sustained elevated levels for 7-14 days postoperatively. Elevated neutrophil phagocytic capacity persisted even until POD28. Similar patterns were observed in patients on a preoperative bridge device. CONCLUSIONS: Neutrophil activation and phagocytic capacity increased in response to VAD support, while inflammatory cytokines remain elevated for up to 2 weeks postoperatively. These findings may indicate that VAD implantation elicits circulating neutrophils to an abnormal preemptive phagocytotic phenotype.

Neutrophil Structural and Functional Alterations After High Mechanical Shear Stress Exposure.

Patients on mechanical circulatory support are prone to infections, increasing morbidity and mortality. These circulatory support devices generate high mechanical shear stress (HMSS) that can causes trauma to blood. When leukocytes become damaged, their immune response function may be impaired or weakened, leading to increased infection vulnerability. This study examined neutrophil structural and functional alterations after exposure to 75, 125, and 175 Pa HMSS for 1 second. Human blood was exposed to three levels of HMSS using a blood shearing device. Neutrophil morphological alteration was characterized by examining blood smears. Flow cytometry assays were used to analyze expression levels of CD62L and CD162 receptors, activation level (CD11b), and aggregation (platelet-neutrophil aggregates). Neutrophil phagocytosis and rolling were examined via functional assays. The results show neutrophil structure (morphology and surface receptors) and function (activation, aggregation, phagocytosis, rolling) were significantly altered after HMSS exposure. These alterations include cell membrane damage, loss of surface receptors (CD62L and CD162), initiation of activation and aggregation, upregulation of phagocytic ability and increased rolling speed. The alterations were the most severe after 175 Pa exposure. HMSS caused damage and activation of neutrophils, potentially impairing normal neutrophil function, leading to weakened immune defense and increasing a patient's vulnerability to infections.

Spinal Cord Infarction With Prolonged Femoral Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVES: There have been sporadic reports of ischemic spinal cord injury (SCI) during venoarterial extracorporeal membrane oxygenation (VA-ECMO) support. The authors observed a troubling pattern of this catastrophic complication and evaluated the potential mechanisms of SCI related to ECMO. DESIGN: This study was a case series. SETTING: This study was performed at a single institution in a University setting. PARTICIPANTS: Patients requiring prolonged VA-ECMO were included. INTERVENTIONS: No interventions were done. This was an observational study. MEASUREMENTS AND MAIN RESULTS: Four hypotheses of etiology were considered: (1) hypercoagulable state/thromboembolism, (2) regional hypoxia/hypocarbia, (3) hyperperfusion and spinal cord edema, and (4) mechanical coverage of spinal arteries. The SCI involved the lower thoracic (T7-T12 level) spinal cord to the cauda equina in all patients. Seven out of 132 (5.3%) patients with prolonged VA-ECMO support developed SCI. The median time from ECMO cannulation to SCI was 7 (range: 6-17) days.There was no evidence of embolic SCI or extended regional hypoxia or hypocarbia. A unilateral, internal iliac artery was covered by the arterial cannula in 6/7 86%) patients, but flow into the internal iliac was demonstrated on imaging in all available patients. The median total flow (ECMO + intrinsic cardiac output) was 8.5 L/min (LPM), and indexed flow was 4.1 LPM/m2. The median central venous oxygen saturation was 88%, and intracranial pressure was measured at 30 mmHg in one patient, suggestive of hyperperfusion and spinal cord edema. CONCLUSIONS: An SCI is a serious complication of extended peripheral VA-ECMO support. Its etiology remains uncertain, but the authors' preliminary data suggested that spinal cord edema from hyperperfusion or venous congestion could contribute.

Computational fluid dynamics analysis and experimental hemolytic performance of three clinical centrifugal blood pumps: Revolution, Rotaflow and CentriMag.

Centrifugal blood pumps have become popular for adult extracorporeal membrane oxygenation (ECMO) due to their superior blood handling and reduced thrombosis risk featured by their secondary flow paths that avoid stagnant areas. However, the high rotational speed within a centrifugal blood pump can introduce high shear stress, causing a significant shear-induced hemolysis rate. The Revolution pump, the Rotaflow pump, and the CentriMag pump are three of the leading centrifugal blood pumps on the market. Although many experimental and computational studies have focused on evaluating the hydraulic and hemolytic performances of the Rotaflow and CentriMag pumps, there are few on the Revolution pump. Furthermore, a thorough direct comparison of these three pumps' flow characteristics and hemolysis is not available. In this study, we conducted a computational and experimental analysis to compare the hemolytic performances of the Revolution, Rotaflow, and CentriMag pumps operating under a clinically relevant condition, i.e., the blood flow rate of 5 L/min and pump pressure head of 350 mmHg, for adult ECMO support. In silico simulations were used to characterize the shear stress distributions and predict the hemolysis index, while in vitro blood loop studies experimentally determined hemolysis performance. Comparative simulation results and experimental data demonstrated that the CentriMag pump caused the lowest hemolysis while the Revolution pump generated the highest hemolysis.

Role of thrombin to non-physiological shear stress induced platelet activation and function alternation.

OBJECTIVE: Non-physiological shear stress (NPSS) and thrombin have two distinct mechanisms for activating platelets. NPSS in mechanically assisted circulation (MAC) devices can cause platelet dysfunction, e.g., by shedding its key receptors. In addition, patients with heart failure have increased levels of thrombin generation, which may further affect the NPSS-induced platelet dysfunction, resulting in device-associated complications. This study aimed to assess the combined effect of NPSS and thrombin in platelet activation, expression of adhesion receptors on the platelet surface, and alterations of platelet aggregation. METHODS: Fresh human blood from healthy donors was divided into two groups; one group was treated by adding 0.01 U/mL thrombin, and another group not treated with thrombin served as a control comparison. They were then pumped through a novel blood shearing device which produces similar shear stress conditions to those in the MAC devices. Three levels of NPSS (i.e., 75, 125, and 175 Pa) with a 1.0 s exposure time were selected for the shearing conditions. Expression of platelet activation markers (PAC-1, activated GPIIb/IIIa and CD62P, platelet surface P-selectin) were investigated along with the shedding of platelet receptors (GPIb, GPIIb/IIIa, and GPVI), generation of platelet microparticles, and Phosphatidylserine (PS)-positive platelets detected by flow cytometry. Platelet aggregation (induced by collagen/ristocetin) was measured by Lumi-aggregometry. RESULTS: Platelet receptors were shed after exposure to NPSS showing a positive correlation with the level of shear stress. The generation of platelet microparticles and PS-positive platelets also increased with greater NPSS. Elevated NPSS decreased the platelet aggregation capacity. Platelet activation level increased with greater NPSS. Being treated by thrombin can further exacerbate these characteristics under same level of NPSS, except that platelet activation level drastically dropped after the exposure to 175 Pa NPSS in the thrombin-treated blood. CONCLUSION: After being treated by thrombin, platelets became more susceptible to NPSS, resulting in more receptor shedding, platelet microparticles, and PS-positive platelets, thus limiting platelet aggregation capacity after exposure to NPSS. Platelet activation, in terms of PAC-1 and P-selectin, is an interim status competing between the expression and shedding of these makers/receptors. When platelets have reached a saturation level of activation, exposure to excessive NPSS can potentially impair activation.

Acquired platelet defects are responsible for nonsurgical bleeding in left ventricular assist device recipients.

BACKGROUND: Left ventricular assist devices (LVADs) have been used as a standard treatment option for patients with advanced heart failure. However, these devices are prone to adverse events. Nonsurgical bleeding (NSB) is the most common complication in patients with continuous flow (CF) LVADs. The development of acquired von Willebrand syndrome (AVWS) in CF-LVAD recipients is thought to be a key factor. However, AVWS is seen across a majority of LVAD patients, not just those with NSB. The purpose of this study was to examine the link between acquired platelet defects and NSB in CF-LVAD patients. METHODS: Blood samples were collected from 62 CF-LVAD patients at pre- and 4 post-implantation timepoints. Reduced adhesion receptor expression (GPIbα and GPVI) and activation of platelets (GPIIb/IIIa activation) were used as markers for acquired platelet defects. RESULTS: Twenty-three patients experienced at least one NSB episode. Significantly higher levels of platelet activation and receptor reduction were seen in the postimplantation blood samples from bleeders compared with non-bleeders. All patients experienced the loss of high molecular weight monomers (HMWM) of von Willebrand Factor (vWF), but no difference was seen between the two groups. Multivariable logistic regression showed that biomarkers for reduced platelet receptor expression (GPIbα and GPVI) and activation (GPIIb/IIIa) have more predictive power for NSB, with the area under curve (AUC) values of 0.72, 0.68, and 0.62, respectively, than the loss of HMWM of vWF (AUC: 0.57). CONCLUSION: The data from this study indicated that the severity of acquired platelet defects has a direct link to NSB in CF-LVAD recipients.

An ex vivo comparison of partial thromboplastin time and activated clotting time for heparin anticoagulation in an ovine model.

BACKGROUND: Sheep are a primary model of mechanical circulatory support (MCS) with heparin anticoagulation therapy frequently being monitored by activated clotting time (ACT) due to ease and cost. In patients undergoing long-term heparin therapy, other anticoagulation monitoring strategies, such as activated partial thromboplastin time (aPTT), have proven to be more reliable indicators for the adequacy of anticoagulation, frequently determined by heparin concentration. As there is a paucity of similar studies in sheep, we sought to investigate the correlation between heparin concentration and ACT and aPTT using whole sheep blood in an ex vivo model. METHODS: Fresh whole blood was serially drawn from an adult female Dorset-hybrid sheep and aliquots were placed into tubes containing heparin saline solutions with concentrations ranging from 0 to 7.81 U heparin per mL of whole blood. ACT and aPTT values were measured on each of the samples. The experiment was performed four times with the same animal. A simple linear regression was performed to determine correlation, and subgroup analysis was performed on low versus high heparin concentrations typically seen in human patients on long-term MCS, such as extracorporeal membrane oxygenation (ECMO), versus cardiopulmonary bypass, respectively. RESULTS: aPTT measurements versus the heparin concentration had an R2  = 0.7295. ACT measurements versus the heparin concentration had a R2  = 0.4628. aPTT measurements versus the ACT measurements had a R2  = 0.2974. The strength of the correlation between aPTT and heparin concentration increased at low heparin concentrations (R2  = 0.8392). CONCLUSION: aPTT had a more reliable correlation to heparin concentration and thus anticoagulation level than ACT. This was particularly true at lower heparin concentrations, similar to ranges seen for patients on ECMO. The correlation between aPTT and ACT values was poor. Further in vivo studies should be performed to confirm our results.

Models of Shear-Induced Platelet Activation and Numerical Implementation With Computational Fluid Dynamics Approaches.

Shear-induced platelet activation is one of the critical outcomes when blood is exposed to elevated shear stress. Excessively activated platelets in the circulation can lead to thrombus formation and platelet consumption, resulting in serious adverse events such as thromboembolism and bleeding. While experimental observations reveal that it is related to the shear stress level and exposure time, the underlying mechanism of shear-induced platelet activation is not fully understood. Various models have been proposed to relate shear stress levels to platelet activation, yet most are modified from the empirically calibrated power-law model. Newly developed multiscale platelet models are tested as a promising approach to capture a single platelet's dynamic shape during activation, but it would be computationally expensive to employ it for a large-scale analysis. This paper summarizes the current numerical models used to study the shear-induced platelet activation and their computational applications in the risk assessment of a particular flow pattern and clot formation prediction.

Neutrophil dysfunction due to continuous mechanical shear exposure in mechanically assisted circulation in vitro.

OBJECTIVE: Leukocytes play an important role in the body's immune system. The aim of this study was to assess alterations in neutrophil phenotype and function in pump-assisted circulation in vitro. METHODS: Human blood was circulated for four hours in three circulatory flow loops with a CentriMag blood pump operated at a flow of 4.5 L/min at three rotational speeds (2100, 2800, and 4000 rpm), against three pressure heads (75, 150, and 350 mm Hg), respectively. Blood samples were collected hourly for analyses of neutrophil activation state (Mac-1, CD62L, CD162), neutrophil reactive oxygen species (ROS) production, apoptosis, and neutrophil phagocytosis. RESULTS: Activated neutrophils indicated by both Mac-1 expression and decreased surface expression of CD62L and CD162 receptors increased with time in three loops. The highest level of neutrophil activation was observed in the loop with the highest rotational speed. Platelet-neutrophil aggregates (PNAs) progressively increased in two loops with lower rotational speeds. PNAs peaked at one hour after circulation and decreased subsequently in the loop with the highest rotational speed. Neutrophil ROS production dramatically increased at one hour after circulation and decreased subsequently in all three loops with similar levels and trends. Apoptotic neutrophils increased with time in all three loops. Neutrophil phagocytosis capacity in three loops initially elevated at one hour after circulation and decreased subsequently. Apoptosis and altered phagocytosis were dependent on rotational speed. CONCLUSIONS: Our study revealed that the pump-assisted circulation induced neutrophil activation, apoptosis, and functional impairment. The alterations were strongly associated with pump operating condition and duration.

Ambulatory home wearable lung: progress and future directions.

Extracorporeal life support (ECLS) was first implemented as an extension of cardiopulmonary bypass technology. The early use of ECLS in patients with acute respiratory distress syndrome (ARDS) was discouraging, likely due to limitations of technology and understanding of the disease process. However, over the last decade, there has been a rapid expansion in ECLS use. This "rebirth" in 2009 was largely driven by the need for ECLS during the Influenza A subtype H1N1 pandemic and the results of the conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR) trial showing improved outcomes in patients with ARDS on ECLS compared to traditional management. Along with the increase in overall use of ECLS, there has been an increase in the number of patients with lung failure who are on long-term support, either awaiting lung recovery or transplantation. Many of these patients are awake, participating in physical rehabilitation, and even ambulating while supported with ECLS. Given the recent advances in patient care, and improvements in ECLS technology, the movement towards home for stable patients supported with ECLS may be on the horizon. Patients supported with ventricular assist devices (VAD) underwent a similar transition towards home in the 1990s, before which they were hospital bound. The road to an ambulatory home wearable lung will likely mirror that pathway. This review will give a brief overview of the transition of VAD patients out of the hospital, the history of ECLS, the current state of ECLS for lung failure, new and upcoming ECLS technology, and hurdles on the road home for ECLS patients.

Flow characteristics and hemolytic performance of the new Breethe centrifugal blood pump in comparison with the CentriMag and Rotaflow pumps.

Blood pumps have been increasingly used in mechanically assisted circulation for ventricular assistance and extracorporeal membrane oxygenation support or during cardiopulmonary bypass for cardiac surgery. However, there have always been common complications such as thrombosis, hemolysis, bleeding, and infection associated with current blood pumps in patients. The development of more biocompatible blood pumps still prevails during the past decades. As one of those newly developed pumps, the Breethe pump is a novel extracorporeal centrifugal blood pump with a hybrid magnetic and mechanical bearing with attempt to reduce device-induced blood trauma. To characterize the hydrodynamic and hemolytic performances of this novel pump and demonstrate its superior biocompatibility, we use a combined computational and experimental approach to compare the Breethe pump with the CentriMag and Rotaflow pumps in terms of flow features and hemolysis under an operating condition relevant to ECMO support (flow: 5 L/min, pressure head: ~350 mmHg). The computational results showed that the Breethe pump has a smaller area-averaged wall shear stress (WSS), a smaller volume with a scalar shear stress (SSS) level greater than 100 Pa and a lower device-generated hemolysis index compared to the CentriMag and Rotaflow pumps. The comparison of the calculated residence times among the three pumps indicated that the Breethe pump might have better washout. The experimental data from the in vitro hemolysis testing demonstrated that the Breethe pump has the lowest normalized hemolysis index (NIH) than the CentriMag and Rotaflow pumps. It can be concluded based on both the computational and experimental data that the Breethe pump is a viable pump for clinical use and it has better biocompatibility compared to the clinically accepted pumps.

Device-Induced Hemostatic Disorders in Mechanically Assisted Circulation.

Mechanically assisted circulation (MAC) sustains the blood circulation in the body of a patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) or on ventricular assistance with a ventricular assist device (VAD) or on extracorporeal membrane oxygenation (ECMO) with a pump-oxygenator system. While MAC provides short-term (days to weeks) support and long-term (months to years) for the heart and/or lungs, the blood is inevitably exposed to non-physiological shear stress (NPSS) due to mechanical pumping action and in contact with artificial surfaces. NPSS is well known to cause blood damage and functional alterations of blood cells. In this review, we discussed shear-induced platelet adhesion, platelet aggregation, platelet receptor shedding, and platelet apoptosis, shear-induced acquired von Willebrand syndrome (AVWS), shear-induced hemolysis and microparticle formation during MAC. These alterations are associated with perioperative bleeding and thrombotic events, morbidity and mortality, and quality of life in MCS patients. Understanding the mechanism of shear-induce hemostatic disorders will help us develop low-shear-stress devices and select more effective treatments for better clinical outcomes.

Neutrophil injury and function alterations induced by high mechanical shear stress with short exposure time.

High mechanical shear stresses (HMSS) can cause damage to blood, which manifests as morphologic changes, shortened life span, biochemical alterations, and complete rupture of blood cells and proteins, leading to the alterations of normal blood function. The aim of this study is to determine the state of neutrophil activation and function alterations caused by HMSS with short exposure time relevant to ventricular assist devices. Blood from healthy donors was exposed to three levels of HMSS (75Pa, 125Pa, and 175Pa) for a short exposure time (0.5 s) using our Couette-type blood-shearing device. Neutrophil activation (Mac-1, platelet-neutrophil aggregates) and surface expression levels of two key functional receptors (CD62L and CD162) on neutrophils were evaluated by flow cytometry. Neutrophil phagocytosis and transmigration were also examined with functional assays. Results showed that the expression of Mac-1 on neutrophils and platelet-neutrophil aggregates increased significantly while the level of CD62L expression on neutrophils decreased significantly after the exposure to HMSS. The Mac-1 expression progressively increased while the CD62L expression progressively decreased with the increased level of HMSS. The level of CD162 expression on neutrophils slightly increased after the exposure to HMSS, but the increase was not significant. The phagocytosis assay data revealed that the ability of neutrophils to phagocytose latex beads coated with fluorescently labeled rabbit IgG increased significantly with the increased level of HMSS. The transmigration ability of neutrophils slightly increased after the exposure to HMSS, but did not reach a significant level. In summary, HMSS with a short exposure time of 0.5 seconds could induce neutrophil activation, platelet-neutrophil aggregation, shedding of CD62L receptor, and increased phagocytic ability. However, the exposure to the three levels of HMSS did not cause a significant change in neutrophil transmigration capacity and shedding of CD162 receptor on neutrophils.

Model-Based Design and Optimization of Blood Oxygenators.

Blood oxygenators, also known as artificial lungs, are widely used in cardiopulmonary bypass surgery to maintain physiologic oxygen (O2) and carbon dioxide (CO2) levels in blood, and also serve as respiratory assist devices to support patients with lung failure. The time- and cost-consuming method of trial and error is initially used to optimize the oxygenator design, and this method is followed by the introduction of the computational fluid dynamics (CFD) that is employed to reduce the number of prototypes that must be built as the design is optimized. The CFD modeling method, while having progress in recent years, still requires complex three-dimensional (3D) modeling and experimental data to identify the model parameters and validate the model. In this study, we sought to develop an easily implemented mathematical models to predict and optimize the performance (oxygen partial pressure/saturation, oxygen/carbon dioxide transfer rates, and pressure loss) of hollow fiber membrane-based oxygenators and this model can be then used in conjunction with CFD to reduce the number of 3D CFD iteration for further oxygenator design and optimization. The model parameters are first identified by fitting the model predictions to the experimental data obtained from a mock flow loop experimental test on a mini fiber bundle. The models are then validated through comparing the theoretical results with the experimental data of seven full-size oxygenators. The comparative analysis show that the model predictions and experimental results are in good agreement. Based on the verified models, the design curves showing the effects of parameters on the performance of oxygenators and the guidelines detailing the optimization process are established to determine the optimal design parameters (fiber bundle dimensions and its porosity) under specific system design requirements (blood pressure drop, oxygen pressure/saturation, oxygen/carbon dioxide transfer rates, and priming volume). The results show that the model-based optimization method is promising to derive the optimal parameters in an efficient way and to serve as an intermediate modeling approach prior to complex CFD modeling.