Current and Future Considerations in the Use of Mechanical Circulatory Support Devices: An Update, 2008-2018.

Our review in the 2008 volume of this journal detailed the use of mechanical circulatory support (MCS) for treatment of heart failure (HF). MCS initially utilized bladder-based blood pumps generating pulsatile flow; these pulsatile flow pumps have been supplanted by rotary blood pumps, in which cardiac support is generated via the high-speed rotation of computationally designed blading. Different rotary pump designs have been evaluated for their safety, performance, and efficacy in clinical trials both in the United States and internationally. The reduced size of the rotary pump designs has prompted research and development toward the design of MCS suitable for infants and children. The past decade has witnessed efforts focused on tissue engineering-based therapies for the treatment of HF. This review explores the current state and future opportunities of cardiac support therapies within our larger understanding of the treatment options for HF.

Platelet activation in ovines undergoing sham surgery or implant of the second generation PediaFlow pediatric ventricular assist device.

The PediaFlow pediatric ventricular assist device (VAD) is a magnetically levitated turbodynamic pump under development for circulatory support of small children with a targeted flow rate range of 0.3-1.5 L/min. As the design of this device is refined, ensuring high levels of blood biocompatibility is essential. In this study, we characterized platelet activation during the implantation and operation of a second generation prototype of the PediaFlow VAD (PF2) and also performed a series of surgical sham studies to examine purely surgical effects on platelet activation. In addition, a newly available monoclonal antibody was characterized and shown to be capable of quantifying ovine platelet activation. The PF2 was implanted in three chronic ovine experiments of 17, 30, and 70 days, while surgical sham procedures were performed in five ovines with 30-day monitoring. Blood biocompatibility in terms of circulating activated platelets was measured by flow cytometric assays with and without exogenous agonist stimulation. Platelet activation following sham surgery returned to baseline in approximately 2 weeks. Platelets in PF2-implanted ovines returned to baseline activation levels in all three animals and showed an ability to respond to agonist stimulation. Late-term platelet activation was observed in one animal corresponding with unexpected pump stoppages related to a manufacturing defect in the percutaneous cable. The results demonstrated encouraging platelet biocompatibility for the PF2 in that basal platelet activation was achieved early in the pump implant period. Furthermore, this first characterization of the effect of a major cardiothoracic procedure on temporal ovine platelet activation provides comparative data for future cardiovascular device evaluation in the ovine model.

Biocompatibility assessment of the first generation PediaFlow pediatric ventricular assist device.

The PediaFlow pediatric ventricular assist device is a miniature magnetically levitated mixed flow pump under development for circulatory support of newborns and infants (3-15 kg) with a targeted flow range of 0.3-1.5 L/min. The first generation design of the PediaFlow (PF1) was manufactured with a weight of approximately 100 g, priming volume less than 2 mL, length of 51 mm, outer diameter of 28 mm, and with 5-mm blood ports. PF1 was evaluated in an in vitro flow loop for 6 h and implanted in ovines for three chronic experiments of 6, 17, and 10 days. In the in vitro test, normalized index of hemolysis was 0.0087 ± 0.0024 g/100L. Hemodynamic performance and blood biocompatibility of PF1 were characterized in vivo by measurements of plasma free hemoglobin, plasma fibrinogen, total plasma protein, and with novel flow cytometric assays to quantify circulating activated ovine platelets. The mean plasma free hemoglobin values for the three chronic studies were 4.6 ± 2.7, 13.3 ± 7.9, and 8.8 ± 3.3 mg/dL, respectively. Platelet activation was low for portions of several studies but consistently rose along with observed animal and pump complications. The PF1 prototype generated promising results in terms of low hemolysis and platelet activation in the absence of complications. Hemodynamic results validated the magnetic bearing design and provided the platform for design iterations to meet the objective of providing circulatory support for young children with exceptional biocompatibility.

Computational fluid dynamics analysis of blade tip clearances on hemodynamic performance and blood damage in a centrifugal ventricular assist device.

An important challenge facing the design of turbodynamic ventricular assist devices (VADs) intended for long-term support is the optimization of the flow path geometry to maximize hydraulic performance while minimizing shear-stress-induced hemolysis and thrombosis. For unshrouded centrifugal, mixed-flow and axial-flow blood pumps, the complex flow patterns within the blade tip clearance between the lengthwise upper surface of the rotating impeller blades and the stationary pump housing have a dramatic effect on both the hydrodynamic performance and the blood damage production. Detailed computational fluid dynamics (CFD) analyses were performed in this study to investigate such flow behavior in blade tip clearance region for a centrifugal blood pump representing a scaled-up version of a prototype pediatric VAD. Nominal flow conditions were analyzed at a flow rate of 2.5 L/min and rotor speed of 3000 rpm with three blade tip clearances of 50, 100, and 200 microm. CFD simulations predicted a decrease in the averaged tip leakage flow rate and an increase in pump head and axial thrust with decreasing blade tip clearances from 200 to 50 microm. The predicted hemolysis, however, exhibited a unimodal relationship, having a minimum at 100 microm compared to 50 microm and 200 microm. Experimental data corroborate these predictions. Detailed flow patterns observed in this study revealed interesting fluid dynamic features associated with the blade tip clearances, such as the generation and dissipation of tip leakage vortex and its interaction with the primary flow in the blade-blade passages. Quantitative calculations suggested the existence of an optimal blade tip clearance by which hydraulic efficiency can be maximized and hemolysis minimized.

Preclinical performance of a pediatric mechanical circulatory support device: The PediaFlow ventricular assist device.

OBJECTIVES: The PediaFlow (HeartWare International, Inc, Framingham, Mass) is a miniature, implantable, rotodynamic, fully magnetically levitated, continuous-flow pediatric ventricular assist device. The fourth-generation PediaFlow was evaluated in vitro and in vivo to characterize performance and biocompatibility. METHODS: Supported by 2 National Heart, Lung, and Blood Institute contract initiatives to address the limited options available for pediatric patients with congenital or acquired cardiac disease, the PediaFlow was developed with the intent to provide chronic cardiac support for infants as small as 3 kg. The University of Pittsburgh-led Consortium evaluated fourth-generation PediaFlow prototypes both in vitro and within a preclinical ovine model (n = 11). The latter experiments led to multiple redesigns of the inflow cannula and outflow graft, resulting in the implantable design represented in the most recent implants (n = 2). RESULTS: With more than a decade of extensive computational and experimental efforts spanning 4 device iterations, the AA battery-sized fourth-generation PediaFlow has an operating range of 0.5 to 1.5 L/min with minimal hemolysis in vitro and excellent hemocompatibility (eg, minimal hemolysis and platelet activation) in vivo. The pump and finalized accompanying implantable components demonstrated preclinical hemodynamics suitable for the intended pediatric application for up to 60 days. CONCLUSIONS: Designated a Humanitarian Use Device for "mechanical circulatory support in neonates, infants, and toddlers weighing up to 20 kg as a bridge to transplant, a bridge to other therapeutic intervention such as surgery, or as a bridge to recovery" by the Food and Drug Administration, these initial results document the biocompatibility and potential of the fourth-generation PediaFlow design to provide chronic pediatric cardiac support.

The National Heart, Lung, and Blood Institute Pediatric Circulatory Support Program.

Options for the circulatory support of pediatric patients under the age of 5 years are currently limited to short-term extracorporeal devices, the use of which is often complicated by infection, bleeding, and thromboembolism. Recognizing this void, the National Heart, Lung, and Blood Institute solicited proposals for the development of novel circulatory support systems for infants and children from 2 to 25 kg with congenital or acquired cardiovascular disease. Five contracts were awarded to develop a family of devices that includes (1) an implantable mixed-flow ventricular assist device designed specifically for patients up to 2 years of age, (2) another mixed-flow ventricular assist device that can be implanted intravascularly or extravascularly depending on patient size, (3) compact integrated pediatric cardiopulmonary assist systems, (4) apically implanted axial-flow ventricular assist devices, and (5) pulsatile-flow ventricular assist devices. The common objective for these devices is to reliably provide circulatory support for infants and children while minimizing risks related to infection, bleeding, and thromboembolism. The devices are expected to be ready for clinical studies at the conclusion of the awards in 2009.

Towards the development of a pediatric ventricular assist device.

The very limited options available to treat ventricular failure in children with congenital and acquired heart diseases have motivated the development of a pediatric ventricular assist device at the University of Pittsburgh (UoP) and University of Pittsburgh Medical Center (UPMC). Our effort involves a consortium consisting of UoP, Children's Hospital of Pittsburgh (CHP), Carnegie Mellon University, World Heart Corporation, and LaunchPoint Technologies, Inc. The overall aim of our program is to develop a highly reliable, biocompatible ventricular assist device (VAD) for chronic support (6 months) of the unique and high-risk population of children between 3 and 15 kg (patients from birth to 2 years of age). The innovative pediatric ventricular assist device we are developing is based on a miniature mixed flow turbodynamic pump featuring magnetic levitation, to assure minimal blood trauma and risk of thrombosis. This review article discusses the limitations of current pediatric cardiac assist treatment options and the work to date by our consortium toward the development of a pediatric VAD.

The PediaFlow pediatric ventricular assist device.

The very limited options available to treat ventricular failure in patients with congenital and acquired heart diseases have motivated the development of a pediatric ventricular assist device (VAD). Our effort involves a consortium consisting of the University of Pittsburgh, Carnegie Mellon University, Children's Hospital of Pittsburgh, World Heart Corporation, and LaunchPoint Technologies, LLC. The overall aim of our program is to develop a highly reliable, biocompatible VAD for chronic support (6 months) of the unique and high-risk population of children between 3 kg and 15 kg (patients from birth to 2 years of age). The innovative pediatric VAD we are developing (PediaFlow) is based on a miniature mixed-flow turbodynamic pump featuring magnetic levitation, with the design goal being to assure minimal blood trauma and risk of thrombosis. This article discusses the limitations of current pediatric cardiac assist treatment options and the work to date by our consortium toward the development of a pediatric VAD.

Elimination of adverse leakage flow in a miniature pediatric centrifugal blood pump by computational fluid dynamics-based design optimization.

We investigated a miniature magnetically levitated centrifugal blood pump intended to deliver 0.3-1.5 l/min of support to neonates and infants. The back clearance gap between the housing and large volume of the rotor, where the suspension and motor bearings are located, forms a continuous leakage flow path. Within the gap, flow demonstrates a very complex three-dimensional structure: the fluid adjacent to the rotating disk tends to accelerate by centrifugal force to flow radially outwards toward the outlet of the impeller against an unfavorable pressure gradient, which in turn forces blood to return along the stationary housing surfaces. Consequently, one or multiple vortices may be generated in the gap to block blood flow and cause the formation of a retrograde and antegrade leakage flow phenomenon at the gap outlet using an optimization process including extensive computational fluid dynamics (CFD) analysis of impeller refinements, we found that secondary blades located along the back or extended to the side surfaces of the rotor have the capacity to reduce and eliminate the retrograde flow in the back clearance gap. Flow visualization confirmed the CFD-predicted flow patterns. This work demonstrates the utility of CFD-based design optimization to optimize the fluid path of a miniature centrifugal pump.

Controller for an Axial Flow Blood Pump.

A rotary blood pump inherently provides only one noninvasive "observable'" parameter (motor current) and allows for only one "controllable" parameter (pump speed). To maintain the systemic circulation properly, the pump speed must be controlled to sustain appropriate outlet Hows and perfusion pressure while preventing pulmonary damage caused by extremes in preload. Steady-state data were collected at repeated intervals during chronic trials of the Nimbus AxiPump (Nimbus, Inc., Rancho Cordova, California, U.S.A.) in sheep (n = 7) and calves (n = 12). For each data set, the pump speed was increased at increments of 500 rpm until left ventricular and left atrial emptying was observed by left atrial pressure diminishing to zero. The effect of decreasing preload was evaluated perioperatively by inferior vena cava occlusion at a constant pump speed. Fourier analysis established a relationship between changes in the pump preload and the power spectra of the pump current waveform. Based on these results, a control method was devised to avoid ventricular collapse and maintain the preload within a physiologic range. The objective of this controller is the minimization of the second and third harmonic of the periodic current waveform. This method is intended to provide a noninvasive regulation of the pump by eliminating the need for extraneous transducers.

High-Resolution Fluorescent Particle-Tracking Flow Visualization within an Intraventricular Axial Flow Left Ventricular Assist Device.

Flow visualization is typically applied in blood pump development to both confirm the design expectations and identify regions that may be predisposed to blood element deposition and trauma. Rotary pumps, in particular, place high demands on the technique chosen to visualize the flow given the limited visual accessibility of the flow path and the high impeller speeds. Fluorescent image-tracking velocimetry currently is used at the University of Pittsburgh Medical Center to visualize flow accurately inside of these pumps both qualitatively and quantitatively. Flow patterns under steady conditions within an intraventricular axial flow, left ventricular assist pump (prototype No. 7, SUN Medical Technology Research Corporation, Nagano, Japan) were investigated using this technique. The flow fields at the impeller-stator interface and at the pump outlet were given specific attention. This allowed the assessment of the fluid dynamics throughout the hydrodynamic design limits of the pump.

Rheologic dissimilarities in female and male blood: potential link to development of cardiovascular diseases.

Oxygen Delivery Index (ODI) was introduced as the ratio of red blood cell concentration (hematocrit) to blood viscosity. The ODI can be considered an indirect characterization of oxygen transport to organs and tissues. ODI was obtained for 98 healthy donors (47 pre-menopausal women and 51 age-matched men). In this population ODI levels were found to be significantly lower (p < 0.001) in male blood (7.7 +/- 0.3 vs. 8.4 +/- 0.5 in female blood). Average ODI obtained for 15 cardiac patients (all males) was found to be significantly lower than that for healthy men. In red blood cell suspensions with the same hematocrit, ODI was found to decrease when plasma viscosity was increased via an increase in protein concentration. Additionally, it was found that ODI measured for samples of blood over a wide hematocrit range, obtained by dilution with autologous plasma, possessed the highest values at the hematocrit levels 30 to 40%. The decreased oxygen transport might contribute to the significantly higher morbidity and mortality from cardiovascular diseases for men compared to pre-menopausal women. ODI may be a useful parameter for evaluation of risk of development of cardiovascular disorders.

Polyethylene glycol additives reduce hemolysis in red blood cell suspensions exposed to mechanical stress.

Mechanical damage to blood cells is of considerable concern in the development and use of circulatory assist devices and other blood contacting systems. Furthermore, hemodilution with saline, dextran, and other plasma expanders applied during extracorporeal circulation and dialysis increases red blood cell (RBC) susceptibility to the high shear stresses associated with these procedures. In this paper, we present polyethylene glycol (PEG) as a potential erythrocyte protective agent against mechanically induced cellular trauma. Bovine RBCs were subjected to mechanical stress induced by rolling stainless steel shots through RBC suspensions for a constant exposure time. The suspensions were prepared at a hematocrit of 30% in various media: PEG (20,000 molecular weight), autologous bovine plasma, Dextran 40 solution, and phosphate buffered saline (PBS). RBC suspensions in Dextran 40 were prepared at a viscosity similar to the PEG suspensions. We found the hemolysis level of RBCs suspended in plasma and in PEG solutions to be several times lower (p < 0.001) than in the Dextran and PBS solutions. No statistically significant difference was found between the hemolysis that occurred in suspensions of RBCs in autologous plasma and in 2.0% PEG solutions. Even PEG concentration as low as 0.1% reduced hemolysis by more than 40% compared with PBS or the same concentration of Dextran in suspension medium. Our data demonstrate the efficacy of PEG molecules in reducing mechanical trauma to erythrocytes and suggest the potential for using PEG in assisted circulation, dialysis, and other procedures where RBCs are subjected to extensive mechanical stress.

In vitro evaluation of hemolysis and sublethal blood trauma in a novel subcutaneous vascular access system for hemodialysis.

Hemodialysis requires reliable frequent access to the patients' vasculature, with blood flow rates of > 300 ml/min. Currently in the U.S. market, there are three types of hemodialysis access systems: the native arteriovenous fistula, generally using 15G needles; the synthetic arteriovenous (AV) graft, also generally using 15G needles; and the percutaneous catheter. Some of the problems with current vascular access technologies include insufficient blood flow, blood trauma, thrombosis, infection, cardiac load, and venous stenosis. The LifeSite System (Vasca, Inc.) represents an alternative for vascular access, and consists of a subcutaneous valve and 12F cannula accessed by a standard 14G needle. The LifeSite valve is implanted in the upper torso with the cannula generally entering the right internal jugular vein. The purpose of this study was to compare the LifeSite System with two known vascular access systems: the 10F dialysis catheter (Tesio-Cath, MedComp) and the 15G A.V. Fistula Needle Set (JMS Co., Ltd.) with regard to blood damage produced by these devices in use. Mechanical hemolysis and sublethal blood trauma were evaluated by means of in vitro blood pumping through a circulating loop incorporating a hemodialysis vascular access system. Sublethal blood damage was examined by using a hemorheologic assay that included parameters such as erythrocyte mechanical fragility, plasma total protein and fibrinogen concentrations, and blood viscosity. The tests demonstrated that, at both studied flow rates of 300 ml/min and 450 ml/min, the LifeSite produced lower hemolysis and less sublethal damage to blood than either the Tesio-Cath catheter or the A.V. Fistula Needle Set.

Blood soluble drag-reducing polymers prevent lethality from hemorrhagic shock in acute animal experiments.

Over the past several decades, blood-soluble drag reducing polymers (DRPs) have been shown to significantly enhance hemodynamics in various animal models when added to blood at nanomolar concentrations. In the present study, the effects of the DRPs on blood circulation were tested in anesthetized rats exposed to acute hemorrhagic shock. The animals were acutely resuscitated either with a 2.5% dextran solution (Control) or using the same solution containing 0.0005% or 5 parts per million (ppm) concentration of one of two blood soluble DRPs: high molecular weight (MW=3500 kDa) polyethylene glycol (PEG-3500) or a DRP extracted from Aloe vera (AVP). An additional group of animals was resuscitated with 0.0075% (75 ppm) polyethylene glycol of molecular weight of 200 kDa (PEG-200), which possesses no drag-reducing ability. All of the animals were observed for two hours following the initiation of fluid resuscitation or until they expired. We found that infusion of the DRP solutions significantly improved tissue perfusion, tissue oxygenation, and two-hour survival rate, the latter from 19% (Control) and 14% (PEG-200) to 100% (AVP) and 100% (PEG-3500). Furthermore, the Control and PEG-200 animals that survived required three times more fluid to maintain their blood pressure than the AVP and PEG-3500 animals. Several hypotheses regarding the mechanisms underlying these observed beneficial hemodynamic effects of DRPs are discussed. Our findings suggest that the drag-reducing polymers warrant further investigation as a potential clinical treatment for hemorrhagic shock and possibly other microcirculatory disorders.

How to teach artificial organs.

Artificial organs education is often an overlooked field for many bioengineering and biomedical engineering students. The purpose of this article is to describe three different approaches to teaching artificial organs. This article can serve as a reference for those who wish to offer a similar course at their own institutions or incorporate these ideas into existing courses. Artificial organ classes typically fulfill several ABET (Accreditation Board for Engineering and Technology) criteria, including those specific to bioengineering and biomedical engineering programs.

In Vitro and In Vivo Performance Evaluation of the Second Developmental Version of the PediaFlow Pediatric Ventricular Assist Device.

Ventricular assist devices (VADs) have significantly impacted the treatment of adult cardiac failure, but few options exist for pediatric patients. This has motivated our group to develop an implantable magnetically levitated rotodynamic VAD (PediaFlow®) for 3-20 kg patients. The second prototype design of the PediaFlow (PF2) is 56% smaller than earlier prototypes, and achieves 0.5-1.5 L/min blood flow rates. In vitro hemodynamic performance and hemolysis testing were performed with analog blood and whole ovine blood, respectively. In vivo evaluation was performed in an ovine model to evaluate hemocompatibility and end-organ function. The in vitro normalized index of hemolysis was 0.05-0.14 g/L over the specified operating range. In vivo performance was satisfactory for two of the three implanted animals. A mechanical defect caused early termination at 17 days of the first in vivo study, but two subsequent implants proceeded without complication and electively terminated at 30 and 70 days. Serum chemistries and plasma free hemoglobin were within normal limits. Gross necropsy revealed small, subclinical infarctions in the kidneys of the 30 and 70 day animals (confirmed by histopathology). The results of these experiments, particularly the biocompatibility demonstrated in vivo encourage further development of a miniature magnetically levitated VAD for the pediatric population. Ongoing work including further reduction of size will lead to a design freeze in preparation for of clinical trials.

Platelet activation after implantation of the Levitronix PediVAS in the ovine model.

The Levitronix PediVAS is an extracorporeal magnetically levitated pediatric ventricular assist system with an optimal flow rate range of 0.3-1.5 L/min. The system is being tested in preclinical studies to assess hemodynamic performance and biocompatibility. The PediVAS was implanted in nine ovines for 30 days using either commercially available cannulae (n = 3) or customized Levitronix cannulae (n = 6). Blood biocompatibility in terms of circulating activated platelets was measured by flow cytometric assays to detect P-selectin. Platelet activation was further examined after exogenous agonist stimulation. Platelet activation increased after surgery and eventually returned to baseline in animal studies where minimal kidney infarcts were observed. Platelet activation remained elevated for the duration of the study in animals where a moderate number of kidney infarcts with or without thrombotic deposition in the cannulae were observed. When platelet activation did return to baseline, platelets appropriately responded to agonist stimulation, signifying conserved platelet function after PediVAS implant. Platelet activation returned to baseline in the majority of studies, representing a promising biocompatibility result for the Levitronix PediVAS.

Pre-clinical Implants of the Levitronix PediVAS® Pediatric Ventricular Assist Device - Strategy for Regulatory Approval.

The PediVAS blood pump is a magnetically levitated centrifugal pump designed for pediatric bridge-to-decision or bridge-to-recovery in pediatric patients from 3-20kg in weight. In preparation for submission of an investigational device exemption (IDE) application, we completed a final six-animal series of pre-clinical studies. The studies were conducted under controlled conditions as prescribed by the recently released FDA guidance document for animal studies for cardiovascular devices. Three 30-day chronic left ventricular support studies were completed in a juvenile lamb model to demonstrate the safety and hemocompatibility of the PediVAS pump. Three additional 8-hour acute biventricular support studies were performed to demonstrate the feasibility of this approach from a hemodynamic and systems standpoint. It is estimated that 50% of pediatric patients who require left ventricular support also require right ventricular support. All studies were successfully completed without complications, device malfunctions, or adverse events. End-organ function was normal for the chronic studies. We noted small surface lesions on one kidney from each chronic study as well as the presence of ring thrombus on connectors, as expected for these types of studies in animal models. The strategy and challenges imposed by performing a controlled cardiovascular device study in a juvenile lamb model are discussed. We believe that these successful implants demonstrate safety and performance for the PediVAS device for support of an IDE application to initiate human clinical trials and provide a roadmap for other researchers.