McGowan Institute for Regenerative Medicine Has a Strong Presence at ASAIO Annual Conference

McGowan Institute for Regenerative Medicine Has a Strong Presence at ASAIO Annual Conference

The American Society for Artificial Internal Organs (ASAIO) hosted the 59th Annual 2b asaio Conference in Chicago June 12 – 15, 2013. The Conference attracted over 600 attendees with a broad range of interests. This Conference included presentations from up to 350 speakers from more than a dozen countries. McGowan Institute for Regenerative Medicine affiliated faculty members and their representative PhD candidates presented many technical papers. Faculty members represented included (in alphabetical order):

James Antaki, PhD, associate professor in biomedical engineering, Carnegie Mellon University
Christian Bermudez, MD, associate director cardiothoracic transplant division of cardiac surgery, University of Pittsburgh Medical Center
Harvey Borovetz, PhD, distinguished professor and chair in the Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh
William Federspiel, PhD, William Kepler Whiteford professor of chemical engineering, surgery and bioengineering, University of Pittsburgh
Marina Kameneva, PhD, research professor of surgery, University of Pittsburgh School of Medicine
Ergin Kocyildirim, PhD, assistant professor, Department of Cardiothoracic Surgery, University of Pittsburgh
Mauricio Rojas, MD, assistant professor, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh
William Wagner, PhD, director, McGowan Institute for Regenerative Medicine
Peter Wearden, MD, PhD, assistant professor of cardiothoracic surgery, Children’s Hospital of Pittsburgh

The Conference is truly unique in that it provides a forum for individual researchers to present not only to fellow investigators, but also to members of industry and to government representatives who will be involved in regulatory affairs as the projects are developed into the production of clinical devices. The ASAIO Annual Conference provides continuing education for accreditation for physicians, nurses, and perfusionists.

The ASAIO 60^th Anniversary Conference will be held in Washington, DC, June 18-21, 2014. Dr. Wearden is the program chair.

Abstracts from this year’s conference follow:

INFLOW CANNULA ENHANCEMENTS AND BIOCOMPATIBILITY RESULTS FOR

THE PEDIAFLOW® PEDIATRIC VAD

Salim E Olia,1,2 Timothy M Maul,1,2,3 Shaun T Snyder,4 Dave B Paden,4 Peter D Wearden,1,2,3 Dennis R Trumble,5 James F Antaki,2,5 Harvey S Borovetz,1,2

Marina V Kameneva.1,2

1Bioengineering, University of Pittsburgh, Pittsburgh, PA;

2McGowan Institute for Regenerative Medicine, Pittsburgh, PA;

3Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA;

4LaunchPoint Technologies, Goleta, CA;

5Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA.

Preliminary ovine biocompatibility results of the frozen‐design PediaFlow® pediatric VAD (PF4) were promising with mean free hemoglobin below 8.0 mg/dL despite suboptimal pump performance due to inflow cannula kinking. With a fixed depth and shallow bend, achieving adequate drainage required extensive manipulation of the heart leading to excessive strain and eventual kinking of the inflow cannula at the connector. Addressing these limitations, the second generation utilized a stainless steel coiling instead of Nitinol, a larger bend radius, and a reinforced connection junction. This inflow cannula was kink resistant and enabled the PF4 to achieve a flow rate >2.0 L/min for the study duration while maintaining superb biocompatibility.

Acknowledging the varying anatomical configurations of pediatric patients and the challenges faced during implantation, a 3rd iteration has been designed for the final series of pre‐clinical studies. A new U‐type parabolic tip lowers the likelihood of a full occlusion during potential suction events while minimizing the pressure losses caused by fenestrated‐type cannulae. The metal reinforced tip assists insertion while serving as a radiopaque marker during imaging. A detachable sewing ring will ease placement while enabling variable insertion depths using a tool‐less spring clamp mechanism to optimize ventricle offloading.

SEVEN‐DAY IN VIVO EVALUATION OF A LOW‐FLOW ACTIVE‐MIXING

EXTRACORPOREAL CARBON DIOXIDE REMOVAL SYSTEM (ECCO2R) FOR

PEDIATRIC RESPIRATORY SUPPORT

R Garrett Jeffries,1,2 Yerbol Mussin,3 Denis S Bulanin,3 Laura W Lund,4 William J

Federspiel,1,2,5,6 Ergin Kocyildirim,2 Peter D Wearden.2,7

1Bioengineering, University of Pittsburgh, Pittsburgh, PA;

2McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA;

3Center for Life Sciences, Nazarbayev University, Astana, Kazakhstan;

4ALung Technologies Inc., Pittsburgh, PA;

5Chemical Engineering, University of Pittsburgh, Pittsburgh, PA;

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA;

7Cardiothoracic Surgery, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA.

Adult ECCO2R devices and pediatric oxygenators share the common objectives of low blood flow and low priming volume while safely maintaining sufficient respiratory support. The objective of this work was to conduct initial feasibility studies to determine if a highly efficient active mixing adult ECCO2R system can safely be translated directly to the pediatric population. Methods: Eight healthy juvenile sheep (22‐33 kg) were connected to the Hemolung Respiratory Assist System (ALung Technologies) via independent 8‐10Fr perfusion/drainage cannulae in the right external jugular (REJ) for up to seven days. Circuit flow was maintained by the Hemolung integrated pump. Anticoagulation was maintained with heparin to target an aPTT of 1.5‐2.3X baseline. Summary of Results: All eight animals were successfully connected to the circuit, five of which were treated for the full seven‐day period. None of the three studies ending prematurely were related to device functionality. The mean of the seven‐day average flow rates was 290 ± 10 ml/min excluding one animal, where flow was increased up to 480 ml/min to reduce cranial swelling.

Average CO2 removal rates were 59 ± 5 ml/min and returned blood O2 saturation remained at 100%. Conclusions: The Hemolung provided clinically relevant levels of CO2 removal and fully oxygenated the blood, at appropriate pediatric flow ranges in each animal receiving treatment for seven days. These study outcomes suggest that the potential exists for use of the Hemolung in a venovenous pediatric configuration to safely provide respiratory support utilizing a significantly less complex system than traditional ECMO.

ON THE MECHANISMS OF THROMBOSIS IN ASSISTED BLOOD CIRCULATION:

TRAFFICKING OF RED BLOOD CELLS AND PLATELETS IN MICROFLUIDIC

SYSTEMS

Amanda Daly,1,2 Samuel J Hund,3 James F Antaki,3 Marina V Kameneva.1,2,4

1Bioengineering, University of Pittsburgh, Pittsburgh, PA;

2McGowan Institute for Regenerative Medicine, Pittsburgh, PA;

3Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA;

4Surgery, University of Pittsburgh, Pittsburgh, PA.

Platelet deposition on artificial surfaces is strongly influenced by the advection of platelets towards the wall – in which red blood cells (RBCs) play an important role. The objective of this study is to investigate the trafficking of RBCs and platelets in three representative micro‐channels that mimic irregularities commonly found in artificial organs: (A) a sudden expansion having a backward step and sharp constriction, (B) a straight channel with an obstruction, and (C) a serpentine channel with multiple bends. A suspension of platelets, RBCs and transparent, hemoglobin depleted RBC ghosts are visualized using a high‐speed camera and inverted microscope. Image analysis is performed to characterize the pathlines of representative RBCs and platelets as well as their steady‐state distribution (concentration fields). The studies revealed regions of elevated platelet concentration, believed to be caused by their interaction (collisions) with RBCs, as a function of flow rate and hematocrit. On‐going studies will provide insight into the interaction force field between RBCs and platelets that in turn can be translated to a multi‐phase rheological model. The ultimate objective is to improve the mathematical prediction of thrombus deposition in gaps, steps and bends in blood‐wetted devices.

REAL TIME CHARACTERIZATION OF FLOW INDUCED PLATELET DEPOSITION

ONTO CLINICALLY‐RELEVANT OPAQUE SURFACES

Megan A Jamiolkowski,1,2 Joshua R Woolley,1,2 Sang‐Ho Ye,1,2 Salim E Olia,1,2

Marina V Kameneva,1,2 James F Antaki,2,3 William R Wagner.1,2

1McGowan Institute for Regenerative Medicine, Pittsburgh, PA;

2University of Pittsburgh, Pittsburgh, PA;

3Carnegie Mellon University, Pittsburgh, PA.

Purpose: Many ventricular assist devices (VAD) utilize a highly polished titanium alloy, TiAl6V4, as a blood contacting surface. However, few studies have examined platelet deposition onto alternative opaque surfaces in real time. Using hemoglobin depleted red blood cells (RBC ghosts) and long working distance optics to visualize platelet deposition, we sought to perform such an evaluation.

Methods: Fluorescently labeled platelets were mixed with human RBC ghosts and perfused across 6 opaque materials (TiAl6V4, silicon carbide (SiC), alumina (Al2O3), 2‐methacryloyloxyethyl phosphorylcholine polymer (MPC) coated TiAl6V4, yttria partially stabilized zirconia (YZTP), zirconia toughened alumina (ZTA)) for 5 minutes at a wall shear rate of 400s‐1. Fluorescent microscopy was used to visualize platelet deposition.

Results: The images acquired were evaluated for platelet surface coverage using a customized MatLab (Mathworks) program and statistically analyzed by a repeated measure ANOVA. Al2O3, MPC, YZTP, and ZTA were found to be significantly less thrombogenic than TiAl6V4 (P <0.01). Platelet images were validated by electron microscopy.

Conclusion: The videos of TiAl6V4 show the formation of thrombi covering approximately 5% of the surface area after one minute blood perfusion. These thrombi grew in the direction of flow over time, resulting in a maximum surface coverage of 15%. Al2O3, MPC, YZTP, and ZTA had significantly less platelet deposition than TiAl6V4, with a maximum surface coverage of less than 5 %. This study indicates that Al2O3, MPC, YZTP, and ZTA are promising alternatives to TiAl6V4 and may improve the thromboresistance of blood‐wetted devices, such as VADs.

THE USE OF GMP‐PRODUCED MULTISTEM® CELLS IN COMBINATION OF

EXTRA CORPOREAL MEMBRANE OXYGENATION IN ARDS

Ergin Kocyildirim,1 Nayra Cardenes,2 Mauricio Rojas,2 John R Tedrow,2 Christian

Bermudez.1

1Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA;

2Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.

Acute Respiratory Distress syndrome (ARDS) is a common clinical entity and a major cause of morbidity and mortality. Despite advances in intensive care management and ventilator support techniques, mortality rates have remained high. Extracorporeal membrane oxygenation (ECMO) may provide an alternative support therapy to minimize the trauma caused by mechanical ventilation when the conventional ventilator support has failed. However, trials evaluating ECMO in ARDS didn’t demonstrate benefit because of the limited nature of the oxygenation, CO2 removal and high rate of bleeding complications. A novel potential therapy for ARDS is the use of bone marrow derived mesenchymal stem cells (B‐MSC) which effects not only by modulating inflammation but also by protecting local endothelium and epithelium. We designed an animal model to assess the effect of stem cells in combination with ECMO treatment in ARDS. 11 sheep received 2.5‐3.5μg/kg E. coli endotoxin to create ARDS. 5 animals who received endotoxin only were considered as control group. 3 sheep received veno‐venous ECMO support that was established between superior vena cava and main pulmonary artery

1 hour after the end of the endotoxin infusion. 3 sheep received a dose of 40 million of clinical grade gmp‐produced MultiStem® cells (Athersys, Inc.) intratracheally one half‐hour after the end of the infusion endotoxin, followed by ECMO treatment. PO2 and plasma neutrophil levels, BAL, and postmortem histopathology were studied.

The results of this pilot experiment showed that combination of stem cells with ECMO treatment may be useful in future studies investigating the diagnosis, treatment and the prevention of ARDS.