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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2005.04.032 Byline: Zhongjun J. Wu (a), Mark Gartner (b), Kenneth N. Litwak (c), Bartley P. Griffith (a) Abstract: Currently available therapies for acute and chronic lung diseases have not been effective and have various problems associated with the technologies used. We present a novel active mixing pump-lung with the goal of providing total respiratory support to ambulatory patients. Author Affiliation: (a) Department of Surgery, University of Maryland, Baltimore, Md (b) Ension, Inc, Pittsburgh, Pa (c) Department of Surgery, University of Louisville, Louisville, Ky Article History: Received 17 February 2005; Revised 13 April 2005; Accepted 22 April 2005 Article Note: (footnote) This study was partially supported by a National Institutes of Health grant (R01HL 65740) and carried out while the authors were with the University of Pittsburgh.

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.

Left ventricular assist devices are routinely used to treat patients with advanced heart failure as a bridge to transplant or a destination therapy. However, non-physiological shear stress generated by left ventricular assist devices damages blood cells. The continued development of novel left ventricular assist devices is essential to improve the left ventricular assist device therapy for heart failure patients. The CH-VAD is a new maglev centrifugal left ventricular assist device. In this study, the CH-VAD pump was numerically analyzed and compared with the HVAD and HeartMate II pumps under two clinically relevant conditions (flow: 4.5 L/min, pressure head: normal ~80 and hypertension ~120 mmHg). The velocity and shear stress fields, washout, and hemolysis index of the three pumps were assessed with computational fluid dynamics analysis. Under the same condition, the CH-VAD hemolysis index was two times lower than the HVAD and HeartMate II pumps; the CH-VAD had the least percentage volume with shear stress larger than 100 Pa (i.e. normal condition: 0.4% vs HVAD 1.0%, and HeartMate II 2.9%). Under the normal condition, more than 98% was washed out of the three pumps within 0.4 s. The washout times were slightly shorter under the hypertension condition for the three pumps. No regions inside the CH-VAD or HVAD had extremely long residential time, while areas near the straightener of the HeartMate II pump had long residential time (>4 s) indicating elevated risks of thrombosis. The computational fluid dynamics results suggested that the CH-VAD pump has a better hemolytic biocompatibility than the HVAD and HeartMate II pumps under the normal and hypertension conditions.

In order to explore the role of a disintegrin and metalloproteinase (ADAM) proteolysis and direct mechanical damage in non-physiologic shear stress (NPSS)-caused platelet receptor shedding, the healthy donor blood treated with/without ADAM inhibitor was exposed to NPSS (150 Pa). The expression of the platelet surface receptors glycoprotein (GP) Ibα and glycoprotein (GP) VI (GPVI) in NPSS-damaged blood was quantified with flow cytometry. The impact of ADAM inhibition on adhesion of NPSS-damaged platelets on von Willibrand factor (VWF) and collagen was explored with fluorescence microscopy. The impact of ADAM inhibition on ristocetin- and collagen-caused aggregation of NPSS-damaged platelets was examined by aggregometry. The results showed that ADAM inhibition could lessen the NPSS-induced loss of platelet surface receptor GPIbα (12%) and GPVI (9%), moderately preserve adhesion of platelets on VWF (7.4%) and collagen (8.4%), and partially restore the aggregation of NPSS-sheared platelets induced by ristocetin (18.6 AU*min) and collagen (48.2 AU*min). These results indicated that ADAM proteolysis played a role in NPSS-induced receptor shedding. However, the ADAM inhibition couldn’t completely suppress the NPSS-caused loss of the platelet surface receptors (GPIbα and GPVI), only partially prevented the NPSS-induced reduction of platelet adhesion to VWF and collagen, and the agonist (ristocetin and collagen)-caused platelet aggregation. These results suggested that the direct mechanical damage is partially responsible for NPSS-induced receptor shedding in addition to the ADAM proteolysis. In conclusion, NPSS relevant to blood contacting medical devices can induce ADAM proteolysis and direct mechanical damage on the platelet receptor GPIbα and GPVI, leading to comprised hemostasis.

The structural integrity of platelet receptors is essential for platelets to play the normal hemostatic function. The high non-physiologic shear stress (NPSS) commonly exists in blood-contacting medical devices and has been shown to cause platelet receptor shedding. The loss of platelet receptors may impair the normal hemostatic function of platelets. The aim of this study was to quantify NPSS-induced shedding of three key receptors on the platelet surface. Human blood was subjected to the matrix of well-defined shear stresses and exposure times, generated by using a custom-designed blood-shearing device. The expression of three key platelet receptors, glycoprotein (GP) Ibα, GPVI, and GPIIb/IIIa, in sheared blood was quantified using flow cytometry. The quantitative relationship between the loss of each of the three receptors on the platelet surface and shear condition (shear stress level and exposure time) was explored. It was found that these relationships followed well the power law functional form. The coefficients of the power law models for the shear-induced shedding of these platelet receptors were derived with coefficients of determination (R2) of 0.77, 0.73, and 0.78, respectively. The power law models with these coefficients may be potentially used to predict the shear-induced platelet receptor shedding of human blood.

Nonsurgical bleeding (NSB) in heart failure (HF) patients with continuous-flow left ventricular assist device (CF-LVAD) support is the most common clinical complication. The aim of this study was to investigate the association between oxidative stress and platelet glycoproteins GPIbα and GPVI shedding on the incidence of NSB in CF-LVAD patients. Fifty-one HF patients undergoing CF-LVAD implantation and 11 healthy volunteers were recruited. Fourteen patients developed NSB (bleeder group) during 1 month follow-up duration, while others were considered nonbleeder group (n = 37). Several biomarkers of oxidative stress were quantified at baseline and weekly intervals in all patients. Surface expression and plasma elements of platelet receptor glycoproteins GPIbα and GPVI were measured. Oxidative stress biomarkers and platelet GPIbα and GPVI receptor-shedding (decreased surface expression and higher plasma levels) were found to be preexisting conditions in baseline samples of both groups of HF patients when compared with healthy volunteers. Significantly elevated oxidative stress biomarkers and platelet glycoprotein receptor shedding were observed in postimplant bleeder group temporarily when compared with nonbleeder group. Strong significant associations between biomarkers of oxidative stress and platelet glycoprotein receptor shedding were observed, suggesting a possible role of oxidative stress in platelet integrin shedding leading to NSB in CF-LVAD patients. Receiver operating characteristic analyses of GPIbα and GPVI indicated that the likelihood of NSB had a predictive power of bleeding complication in CF-LVAD patients. In conclusion, elevated oxidative stress may play a role in GPIbα and GPVI shedding in the event of NSB. Thus, oxidative stress and GPIbα and GPVI shedding may be used as potential biomarkers for bleeding risk stratification in those patients.

Counterpulsation devices (CPDs) require an accurate, reliable electrocardiogram (ECG) waveform for triggering inflation and deflation. Surface electrodes are for short-term use, and transvenous/epicardial leads require invasive implant procedure. A subcutaneous ECG lead configuration was developed as an alternative approach for long-term use with timing mechanical circulatory support (MCS) devices. In this study, efficacy testing was completed by simultaneously recording ECG waveforms from clinical-grade epicardial (control) and subcutaneous (test) leads in chronic ischemic heart failure calves implanted with CPD for up to 30 days. Sensitivity and specificity of CPD triggering by R-wave detection was quantified for each lead configuration. The subcutaneous leads provided 98.9% positive predictive value and 98.9% sensitivity compared to the epicardial ECG leads. Lead migration (n = 1) and fracture (n = 1) were observed in only 2 of 40 implanted leads, without adversely impacting triggering efficacy due to lead redundancy. These findings demonstrate the efficacy of subcutaneous ECG leads for long-term CPD timing and potential use as an alternative method for MCS device timing.

The objective of this study was to investigate the changes in oxidative stress (OS) and circulating regulatory T cells (Tregs) of the immune system in patients supported by continuous-flow ventricular assist device (CF-VAD) with or without infection. We recruited 16 CF-VAD patients (5 with infection and 11 without infection) and 7 healthy volunteers. Generation of reactive oxygen species (ROS) from lymphocytes, superoxide dismutase (SOD) in erythrocyte, total antioxidant capacity (TAC), and oxidized low-density lipoprotein (oxLDL) in plasma were measured. Circulating Tregs were evaluated by flow cytometry. Heart failure (HF) patients had elevated OS than healthy volunteers as evident from higher lymphocyte ROS, elevated oxLDL, as well as depleted SOD and TAC levels. At baseline, HF patients had decreased percentage of Tregs (5.12 ± 1.5% vs. 8.14 ± 3.01%, p< 0.01) when compared with healthy volunteers. Postimplant patients with infection illustrated 35% and 44% rise in ROS and oxLDL, respectively, 31% decrease in TAC, and marked rise in percentage of Tregs (14.27 ± 3.17% vs. 9.38 ± 3.41%, p< 0.01) when compared with the patients without infection. Elevated OS and rise in Tregs were more prominent in CF-VAD patients with infection. In conclusion, OS and compromised immune system may be important indicators of systemic response of the body to CF-VAD among HF patients with infection.

Differences in device design may have an effect on platelet damage and associated clinical complications. We aimed to compare device-specific platelet functionality in 26 heart failure patients supported with three continuous-flow left ventricular assist devices: HeartMate II (n = 8), Jarvik 2000 (n = 9), and HeartWare (n = 9). Intraplatelet reactive oxygen species (ROS) generation, mitochondrial damage, and platelet apoptosis were compared between device types before and after the implantation at every week up to 1 month. Overall, the baseline characteristics, demographics, routine laboratory values were comparable between the three device groups. Intraplatelet ROS, mitochondrial damage, and platelet apoptosis significantly elevated in the HeartWare group in comparison with the other two device groups after implantation. The major bleeding, infections, systemic inflammatory response syndrome, and right ventricular failure were found to be more common among the HeartWare group than others. Intraplatelet ROS and platelet damage levels were returned to baseline in both the HeartMate II and the Jarvik groups, whereas in HeartWare group they remained elevated. The patients with the Jarvik and the HeartMate II experienced less clinical complications and the platelet functionality is not compromised by these devices. Data from this study suggests that the continuous-flow left ventricular assist devices design may exert different effects on platelet function.

Despite the significant contribution of the Fontan procedure to the therapy of complex congenital heart diseases, many patients progress to failure of their Fontan circulation. The use of ventricular assist devices to provide circulatory support to these patients remains challenging. In the current study, a continuous axial-flow pump was used to support a univentricularFontan circulation. A modified Fontan circulation (atrio-pulmonary connection) was constructed in six Yorkshire piglets (8–14 kg). A Dacron conduit (12 mm) with two branches was constructed to serve as a complete atrio-pulmonary connection without the use of cardiopulmonary bypass. The Impella pump was inserted into the conduit through an additional Polytetrafluoroethylene (PTFE) graft in five animals. Hemodynamic data were collected for 6 hours under the supported Fontan circulation. The control animal died after initiating the Fontan circulation independent of resuscitation. Four pump supported animals remained hemodynamically stable for 6 hours with pump speeds between 18,000 rpm and 22,000 rpm (P1–P3). Oxygen saturation was maintained between 95 and 100. Normal organ perfusion was illustrated by blood gas analysis and biochemical assays. A continuous axial-flow pump can be used for temporal circulatory support to the failing Fontan circulation as “bridge” to heart transplantation or recovery.

There is a scarcity of source material available in animal models appropriate to test pediatric-size blood pump design for assisting the left ventricle. A juvenile ovine animal model was developed to evaluate two pediatric ventricular assist devices (VADs). The child-size Jarvik 2000 and CircuLite VADs were tested with this model. The 33 in vivoexperiments were retrospectively studied to evaluate the reliability of the animal model. Dorset hybrid juvenile sheep (20~36 kg) were used to evaluate the small pediatric VADs. Under general anesthesia, a left lateral thoracotomy was performed through the fifth intercostal space. The devices were implanted between the left ventricle apex and the descending aorta without cardiopulmonary bypass. Heparin was infused continuously for anticoagulation therapy. Support duration averaged 26.7 ± 19.6 days. Completion of 75.7 (2533) experiments was done as intended. The animals were docile and did not require sitters beyond the immediate operative period. Complication includes leg injury, graft infection, gastrointestinal bleeding, intravenous line disconnection, weight loss, renal failure, red urine, (one for each) and pulmonary failure in two. Activated clotting time was adjusted viacontinuous intravenous heparin to 150–200 seconds. Reliable hemodynamics and biocompatibility data were collected for evaluate pediatric intracorporeal VADs in the animal model. The juvenile sheep model is reliable, reproducible, and translatable for testing pediatric VADs. These experiments provided vital information for improvement of the devices and for clinical application in the future.

Hemolysis caused by flow-induced mechanical damage to red blood cells is still a problem in medical devices such as ventricular assist devices (VADs), artificial lungs, and mechanical heart valves. A number of different models have been proposed by different research groups for calculating the hemolysis, and of these, the power law–based models (HI()=Ct) have proved the most popular because of their ease of use and applicability to a wide range of devices. However, within this power law category of models there are a number of different implementations. The aim of this work was to evaluate different power law–based models by calculating hemolysis in a specifically designed shearing device and a clinical VAD, and comparing the estimated results with experimental measurements of the hemolysis in these two devices. Both the Eulerian scalar transport and all the Lagrangian models had fairly large percentage of errors compared with the experiments (minimum Eulerian 91 and minimum Lagrangian 57) showing they could not accurately predict the magnitude of the hemolysis. However, the Eulerian approach had large correlation coefficients (>0.99) showing that this method can predict relative hemolysis, which would be useful in comparative analysis, for example, for ranking different devices or for design optimization studies.

Data from early in vivoexperiments demonstrated that the child-size Jarvik heart was capable of providing partial to nearly complete circulatory support with acceptable adverse effects on blood. However, bearing thrombosis was responsible for device malfunction in most cases. To overcome this problem, original pin bearings were replaced with novel conical bearings. This study evaluated chronic in vivoperformance of the modified child-size Jarvik heart in the pediatric setting. Six juvenile sheep were implanted with the modified child-size Jarvik heart. Cardiac and pump output were measured daily. Serial blood samples were drawn to evaluate hematology, biocompatibility, and end-organ function. End-organ damage and device thrombosis were examined at necropsy. No device malfunction occurred during animal experiments up to 70 days. Mean cardiac output of the animals was 3.4 L/min. The child-size Jarvik heart was able to deliver a blood flow ranging from 1.4 to 2.5 L/min at speed from 10,000 rpm to 14,000 rpm. Mean plasma-free hemoglobin was 9.8 ± 5.6 mg/dl, indicating no hemolysis. Acute elevation occurred in some organ function tests after the implant surgery but returned to normal range thereafter. These indices and necropsy showed no end-organ damage. No device thrombosis was observed. The current in vivoexperience shows that the modified child Jarvik 2000 heart retained its hemodynamic function and excellent biocompatibility, and the conical bearings permitted it to remain free of thrombus.

Cannulation is necessary when blood is removed from the body, for example in hemodialysis, cardiopulmonary bypass, blood oxygenators, and ventricular assist devices. Artificial blood contacting surfaces are prone to thrombosis, especially in the presence of stagnant or recirculating flow. In this work, computational fluid dynamics was used to investigate the blood flow fields in three clinically available cannulae (Medtronic DLP 12, 16, and 24 F), used as drainage for pediatric circulatory support and to calculate parameters that may be indicative of thrombosis potential. The results show that using the 24 F cannula below flow rates of about 0.75 L/min produces hemodynamic conditions, which may increase the risk of blood clotting within the cannula. No reasons are indicated for not using the 12 or 16 F cannulae with flow rates between 0.25 and 3.0 L/min.

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.

The heart-lung machine has commonly been used to replace the functions of both the heart and lungs during open heart surgeries or implemented as extracorporeal membrane oxygenation (ECMO) to provide cardiopulmonary support of the heart and lungs. The traditional heart-lung system consists of multiple components and is bulky. It can only be used for relatively short-term support. The concept of the wearable artificial pump-lung is to combine the functions of the blood pumping and gas transfer in a single, compact unit for cardiopulmonary or respiratory support for patients suffering from cardiac failure or respiratory failure, or both, and to allow patients to be ambulatory. To this end, a wearable artificial lung (APL) device is being developed by integrating a magnetically levitated centrifugal impeller with a hollow fiber membrane bundle. In this study, we utilized a computational fluid dynamics based performance optimization with a heuristic scheme to derive geometrical design parameters for the wearable APL device. The configuration and dimensions of the impeller and the diffuser, the required surface area of fiber membranes and the overall geometrical dimensions of the blood flow path of the APL device were considered. The design optimization was iterated based on the fluid dynamic objective parameters (pressure head, pressure distribution, axial force acting on the impeller, shear stress), blood damage potential (hemolysis and platelet activation), and mass transfer (oxygen partial pressure and saturation). Through the design optimization, an optimized APL device was computationally derived. A physical prototype of the designed APL device was fabricated and tested in vitro. The experimental data showed that the optimized APL can provide adequate blood pumping and oxygen transfer over the range of intended operating conditions.