February 2010 | VOL. 9, NO. 2 | www.McGowan.pitt.edu
Development of Heart Assist Device Gets $5.6 Million Boost
McGowan Institute for Regenerative Medicine faculty members Harvey Borovetz, PhD and Peter Wearden, MD, PhD, and researchers at the University of Pittsburgh and their collaborators have been awarded a $5.6 million federal contract to pursue the continued development of an implantable ventricular assist heart pump for infants and small children with congenital or acquired heart disease. The project aims to provide much-needed access to the sophisticated technologies that have saved the lives of older heart failure patients. Harvey Borovetz, PhD, distinguished professor and chair of the Department of Bioengineering and the deputy director of Artificial Organs and Medical Devices at the McGowan Institute, is the principal investigator of one of four projects that comprise the “Pumps for Kids, Infants and Neonates” (PumpKIN) Preclinical Program, a $23.6 million effort sponsored by the National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLBI). Dr. Borovetz and his colleagues at Pitt, Children’s Hospital of Pittsburgh of UPMC, Carnegie Mellon University, Goleta, California-based LaunchPoint Technologies, and Salt Lake City-based WorldHeart Inc., began designing and building their device, called PediaFlow™, more than 5 years ago.
“We now have the opportunity to put PediaFlow through the necessary development and testing needed to proceed to clinical trials,” Dr. Borovetz explained. “The aim is to begin human studies in 3 to 4 years.”
According to the NHLBI, nearly 1,800 American infants die annually due to congenital heart defects. Another 350 develop severe cardiomyopathy leading to heart failure. Each year, approximately 60 children younger than age 5 waiting on the heart transplant list may die before a donor organ becomes available.
PediaFlow, which is made of a titanium alloy and is about the size of an AA battery, incorporates innovative mag-lev technology. Blood is drawn through it by means of a high-speed rotor that essentially floats within its housing due to magnetic levitating forces. The rotor geometry, which is designed using state-of-the-art computer models and analyses, pulls oxygenated blood from the left ventricle through the device, returning the blood to the aorta and patient circulation. The flow rate of the PediaFlow can be varied between 0.5 to 1.5 liters per minute, suitable for the very smallest infants to toddlers.
“We believe the PediaFlow will be capable of replacing the heart function of our smallest patients,” explained Peter Wearden, MD, PhD, a cardiothoracic surgeon at Children’s Hospital who leads the clinical work of the project. “Left ventricular assist devices (LVADs) have been very successful in supporting older children and adults as a bridge to eventual heart transplantation, or, in some cases, as a temporary measure that allows the heart to rest and recover. But there currently are no FDA-approved LVADs for babies and toddlers.”
The other PumpKIN contractors are Mark Gartner, PhD, of Ension Inc., Pittsburgh, Pa.; Bartley P. Griffith, MD, University of Maryland, Baltimore; and Robert Jarvik, MD, Jarvik Heart Inc., New York, N.Y.Read More…
According to McGowan Institute for Regenerative Medicine faculty member Constance Chu, MD, a UPMC orthopaedic surgeon and director of the University of Pittsburgh Cartilage Restoration Laboratory, osteoarthritis is being diagnosed in people as young as age 20. Though most common in older adults, osteoarthritis – degeneration of the cartilage in the knee triggered by a breakdown of cartilage in a joint – may be caused by a widespread death of cartilage cells in the joint after an injury. In a study recently published, Dr. Chu, the Ferguson Endowed Chair in Orthopaedic Surgery at the University of Pittsburgh School of Medicine, found that trauma to a joint’s surface causes some of its cartilage cells to die instantly and others to deteriorate within hours or days after the impact.
As noted in The New York Times Well Blog, human knees are remarkable instruments, able to bear large loads and pivot in multiple directions. But they also damage easily, as evidenced by the approximately 175,000 anterior-cruciate-ligament (ACL)-reconstruction operations performed in the United States every year, a number that, by all estimates, has risen steeply in the past decade or so. Many of these operations are being done now on teenagers, who rip an ACL during a soccer or basketball game. (ACL operations were relatively uncommon in young people before youth sports grew so popular.) Others are in men and women in their 20s and 30s who fall on the ski slopes, for instance.
What has been less remarked upon is the concomitant growth, Dr. Chu says, in cases of exceptionally early-onset arthritis. Once a disease associated primarily with people past retirement age (and still most prevalent in that age group), osteoarthritis has been showing up in much younger people lately. “It’s not only in my practice,” Dr. Chu said. “Most orthopaedic surgeons are seeing very young people with very old knees.”
Not everyone who suffers an ACL tear or other serious knee injury develops early arthritis, of course. “Right now, a good guess is that about 50 percent” will have clinical arthritis “within 5 to 10 years” after the injury, Dr. Chu said (meaning, for a 15-year-old, by the time he or she is 20 or 25, and for a 30-year-old, probably before he or she turns 40). “That’s quite a large number.”
Dr. Chu and many other researchers across the country are trying to develop methods to determine which people will develop arthritis after a knee injury and why. “Many labs are interested in this question,” she said. But for the moment, no one has had much success.
Without sufficient, healthy cartilage within a joint, the bone surfaces will rub against each other, possibly leading years later to painful and debilitating arthritis. To address this issue, Dr. Chu is working to develop diagnostic techniques to identify patients who might develop arthritis after an injury, and to provide treatments that will preserve as much cartilage as possible.
Dr. Chu is one of only a handful of board certified orthopaedic surgeons conducting research funded by the National Institutes of Health. Her cartilage research program is recognized for innovative research integrating cellular and molecular biology along with advanced and novel imaging technologies to study cartilage degeneration, repair, and regeneration.
On February 5, McGowan Institute for Regenerative Medicine faculty member W. P. Andrew Lee, MD, chief of the Division of Plastic and Reconstructive Surgery at the University of Pittsburgh Medical Center (UPMC) and leader of the hand transplant surgical team, treated Chris Pollock at the UPMC with the “Pittsburgh Protocol,” an immune modulation therapy that aims to reduce the risk associated with toxic anti-rejection drugs. Chris—a 41-year-old Harrisburg, Pennsylvania, man who lost both hands in a farming accident—is the second person in the nation to receive a bilateral hand transplant and the first to have his entire forearm replaced.
“Chris is the third patient to receive a hand transplant at UPMC since March 2009. The goal of our program has always been to make hand transplants safer as a viable alternative to prosthetics. With each successful surgery, we are closer to that goal,” said Dr. Lee.
A team of surgeons, critical care specialists, transplant nurses, and therapists has cared for Mr. Pollock since the 11-hour surgery. He received a total forearm transplant, including the elbow joint, on his right side and was transplanted slightly above the wrist on his left. He will soon begin daily occupational therapy at the UPMC Institute for Rehabilitation and Research as his physicians monitor him closely for signs of rejection.
“Both of our previous hand transplant recipients have been maintained on a low-dose of a single anti-rejection drug and have regained significant function and sensation in their transplanted hands. Thus far, Chris is recovering well from surgery,” said Dr. Lee.
UPMC, the U.S. Army Institute of Surgical Research, and the Armed Forces Institute of Regenerative Medicine (AFIRM) are funding the hand transplant study. Dr. Lee and surgeons performed the first unilateral hand transplant at UPMC on March 14, 2009, and the first bilateral hand transplant in the U.S. on May 4, 2009.
Six months ago, a parovirus destroyed his heart and put him in cardiac arrest. Today, after resuscitation, a heart-lung machine, respirators, an experimental heart, and a heart transplant, 2-year-old Harold “TJ” Wilson has returned home to Adams, Butler County, where he again plays with Thomas the Tank Engine and watches "Elmo" DVDs. McGowan Institute for Regenerative Medicine faculty member Peter Wearden, MD, PhD, Assistant Professor of Cardiothoracic Surgery, and Director of Pediatric Mechanical Cardiopulmonary Support at Children’s Hospital of Pittsburgh of UPMC, and one of the transplant team’s surgeons, said TJ "went through the wringer."
Children's, one of the busiest transplant centers in the nation, does 20 pediatric lung, heart, and heart-lung transplants a year. It's also a leading center for heart-assist devices. TJ was fortunate to be in the ideal place during his recovery’s most critical junctures.
The critical heart/lung medical devices—the Extra Corporeal Membrane Oxygenation (ECMO) machine and the Berlin Heart—were both utilized in TJ’s care. Each of these devices supported TJ when his body could not. They served as two significant bridges to a successful heart transplant.
TJ’s case marked the first time ECMO was used in Children's emergency room; placing tubes in his neck while he was undergoing chest compressions added to the challenge. Because the Food and Drug Administration has yet to approve its use in the United States, Children's Hospital had to seek a "compassionate use" permit before implanting the Berlin Heart. The FDA gave its approval—the fifth one Children's has received—and a Berlin Heart was shipped in from Germany.
In addition to the superior medical team and devices, doctors said it helped that TJ was strong-willed, intelligent, and cooperative. He also benefited from having parents who are good caregivers.
"I have a special fondness for TJ. He has incredible spirit," Dr. Wearden said. "There's something about him, and maybe that's because he went through so much with us."
It was in April 2004 when surgeons from the University of Pittsburgh Medical Center (UPMC) led by McGowan Institute faculty member Robert Kormos, MD (pictured left), Director Artificial Heart Program, Co-Director Heart Transplantation at UPMC, and Medical Director of Vital Engineering, implanted the HeartMate II--at that time a new left ventricular assist system (LVAS)--in a 22-year-old woman. The implant was the third in the United States as part of a pilot trial sponsored by Thoratec Corporation to test the safety and potential effectiveness of the HeartMate II.
The device is a miniature rotary pump with axial flow bearings and is intended for patients with end-stage heart failure. A key feature of the design is a sophisticated control system developed by researchers at the McGowan Institute for Regenerative Medicine that senses when to increase or decrease the rate of blood flow. Other approved and experimental devices require manual adjustments. The control system developed by the researchers involves a patented algorithm that permits the LVAS to respond to the needs of the patient based on the level of activity, generating up to 10 liters of blood flow per minute, a rate that would be required to climb stairs, for example. The controller was the brainchild of McGowan Institute faculty member James Antaki, PhD (pictured right), associate professor in Biomedical Engineering at Carnegie Mellon University and adjunct professor in the University of Pittsburgh’s Departments of Surgery and Bioengineering. UPMC was one of four centers that tested the device in seven patients who are candidates for heart transplantation. The device was evaluated initially for use as a bridge to heart transplantation, but its developers saw its eventual use for long-term support.
On January 20, 2010, Thoratec Corporation announced that it received FDA approval of its Pre-Market Approval (PMA) supplement, allowing the use of its HeartMate II LVAS for destination therapy (DT). With this approval, the HeartMate II can be used to provide long-term cardiac support for patients suffering from advanced-stage heart failure who are not eligible for transplantation. Thoratec said it will begin the rollout of the device for the DT indication immediately and has sufficient inventory to address the expected increase in demand. The device was approved for bridge-to-transplantation (BTT) in the U.S. under the original PMA in April 2008.
A continuous flow device, the HeartMate II is an implantable LVAS powered by a rotary pumping mechanism and is designed to have a much longer functional life than pulsatile devices and to operate more simply and quietly. The device provides blood flow through the circulatory system on a continuous basis with only one moving part. It is also smaller and easier to implant than previously approved pulsatile devices.
McGowan Institute for Regenerative Medicine faculty member Michael R. Pinsky, MD, professor and vice chair for academic affairs, Department of Critical Care Medicine, is the senior author of a study paper finding intensive care unit patients are not the only ones likely to be severely depressed in the aftermath of hospitalization. Family and friends who care for them often suffer emotional and social hardship, too. The prospective study from the University of Pittsburgh School of Medicine is the first to monitor patients and caregivers during a 1-year period for predictors of depression and lifestyle disruption.
The findings, published in Chest, indicate that the informal caregivers of ICU survivors endure even more stress than those caring for Alzheimer’s disease patients, noted Dr. Pinsky.
“Caregiver depression is the collateral damage of these stressful ICU admissions,” he noted. “This research reveals that loved ones of critically ill patients have profound and unmet needs for assistance even after hospital discharge. The emotional and economic burden is enormous, and these issues must be addressed.”
Part of a larger project examining ICU outcomes, this study focused on the survivors of critical illness requiring breathing assistance with a ventilator for at least 48 hours as well as their informal caregivers, meaning family and friends. Caregivers were evaluated for depression symptoms 2, 6, and 12 months after mechanical ventilation was initiated in the patient. At the 2 month mark, more than 40 percent of the patients had died.
Of the 48 caregivers who were interviewed at all three time points, the majority were female and nearly half were wives of the patients. A predictor of depression symptoms at both 2 and 12 months was looking after a male patient. At 12 months, patient tracheostomy, in which a hole is made through the neck directly into the airway to assist breathing, also was a predictor of caregiver symptoms. If patients had at least a high school education, caregivers were more likely to report lifestyle disruption at the 2-month mark. Tracheostomy, functional dependency, and male patient gender were predictive of lifestyle disruption at 12 months.
“Our previous studies indicate that caregivers often change their lives to care for recovering patients, including quitting work, taking lower-paying jobs, or leaving college in order to spend more time at home,” Dr. Pinsky said. “These are highly stressful choices, and it is imperative that we develop interventions to help families cope with the burden of critical illness even after they have left the hospital.”
Studies are now underway to assess approaches designed to mitigate these problems for both patients and caregivers.
McGowan Institute for Regenerative Medicine faculty member Douglas Kondziolka, MD, the Peter J. Jannetta Professor and vice chairman of education in Neurological Surgery, professor of Radiation Oncology, and director of the Center for Image-Guided Neurosurgery, and UPMC psychiatrist Robert Howland lead a team of scientists and clinicians who are part of an investigational study of the Reclaim™ Deep Brain Stimulation (DBS) System in people that have treatment-resistant depression. Dr. Kondziolka has done the DBS surgery on 4 patients, with a fifth scheduled soon, as part of a multicenter trial of the procedure in about 30 depressed patients. Half of them will have their devices turned on for 4 months while the other half will not have theirs turned on until after that period. UPMC is one of five hospitals involved in the study nationwide.
The trial is designed to test whether the procedure is safe and has a measurable benefit for those whose devices are activated. If the federal Food and Drug Administration approves, the experiment, using equipment manufactured by Medtronic, Inc., will be expanded to hundreds of patients nationally, Dr. Kondziolka said.
The experimental DBS surgery operates on the premise that a small, steady voltage applied to the electrodes can quiet the "sadness center" that is hyperactive in people with chronic depression. Participants implanted with the device systems will be monitored for 12 months following implant, with long-term follow-up until the device is approved or the study is stopped.
Candidates for the trial are adults who have major depressive disorder and have not responded to several treatments for depression. Participants in the study will continue to receive their current antidepressant medications while participating in the trial.
DBS therapy is currently approved for use in the United States, Europe, Canada, and Australia for the treatment of Essential Tremor and Parkinson's disease. Deep brain stimulation for the treatment of depression is investigational.
AWARDS AND RECOGNITIONS
McGowan Institute for Regenerative Medicine faculty member Mark S. Roberts, MD, MPP, has been recruited by the University of Pittsburgh Graduate School of Public Health (GSPH) to lead the school’s Department of Health Policy and Management.
Dr. Roberts’ areas of expertise are decision analyses and the mathematical modeling of diseases and their treatments. He uses a variety of methods from cost-effectiveness analysis to simulation modeling to examine costs and policies related to transplantation, vaccination, surgery, and the use of medications.
Most recently, Dr. Roberts served as Pitt professor of medicine, health policy and management, industrial engineering, and clinical and translational science, and as chief of the section of decision sciences and clinical systems modeling in the School of Medicine’s Division of General Internal Medicine.
“Throughout his career, Mark has blended clinical and research work in the decision sciences to advise health care providers and individuals,” said Arthur S. Levine, M.D., senior vice chancellor, health sciences, and dean of the University of Pittsburgh School of Medicine. “He has the academic credentials, scientific creativity, and the ‘reality testing’ of many years on the front lines as a clinical decision-maker to further bridge the study of medicine to the development of public policies at this potential turning point in history.”
“Health policy is more important than ever as we enter a new era of health care reform,” added Donald S. Burke, M.D., GSPH dean. “We anticipate that Mark will use his expertise in evidence-based decision-making to train tomorrow’s health care administrators and to advise the nation’s leaders on the best approaches to providing health care for Americans."
Dr. Roberts has published 115 manuscripts in peer-reviewed journals and is the immediate past president of the Society for Medical Decision Making. He received a medical degree from Tufts University and a master’s degree in public policy and health policy from Harvard University’s Kennedy School. He was raised in Carson City, Nevada, and is an avid hiker and skier. He and his wife, Eileen, live in O’Hara Township and have three adult children.
Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
Polk AA, Maul TM, McKeel DT, Snyder TA, Lehocky CA, Pitt B, Stolz DB, Federspiel WJ, Wagner WR
A biohybrid artificial lung prototype with active mixing of endothelialized microporous hollow fibers
Acute respiratory distress syndrome (ARDS) affects nearly 150,000 patients per year in the US, and is associated with high mortality ( approximately 40%) and suboptimal options for patient care. Mechanical ventilation and extracorporeal membrane oxygenation are limited to short-term use due to ventilator-induced lung injury and poor biocompatibility, respectively.
In this report, we describe the development of a biohybrid lung prototype, employing a rotating endothelialized microporous hollow fiber (MHF) bundle to improve blood biocompatibility while MHF mixing could contribute to gas transfer efficiency. MHFs were surface modified with radio frequency glow discharge (RFGD) and protein adsorption to promote endothelial cell (EC) attachment and growth. The MHF bundles were placed in the biohybrid lung prototype and rotated up to 1500 revolutions per minute (RPM) using speed ramping protocols to condition ECs to remain adherent on the fibers.
Oxygen transfer, thrombotic deposition, and EC p-selectin expression were evaluated as indicators of biohybrid lung functionality and biocompatibility. A fixed aliquot of blood in contact with MHF bundles rotated at either 250 or 750 RPM reached saturating pO(2) levels more quickly with increased RPM, supporting the concept that fiber rotation would positively contribute to oxygen transfer. The presence of ECs had no effect on the rate of oxygen transfer at lower fiber RPM, but did provide some resistance with increased RPM when the overall rate of mass transfer was higher due to active mixing. RFGD followed by fibronectin adsorption on MHFs facilitated near confluent EC coverage with minimal p-selectin expression under both normoxic and hyperoxic conditions. Indeed, even subconfluent EC coverage on MHFs significantly reduced thrombotic deposition adding further support that endothelialization enhances, blood biocompatibility.Overall these findings demonstrate a proof-of-concept that a rotating endothelialized MHF bundle enhances gas transfer and biocompatibility, potentially producing safer, more efficient artificial lungs.
Biotechnology and Bioengineering. 2010 Jan 20.
Pumps for Kids, Infants and Neonates (PumpKIN) Preclinical Program: The PediaFlow™ Pediatric VAD
|Co-Investigators||William Wagner, Marina Kameneva, Steve Webber, and Peter Wearden|
For the past five years our consortium, consisting of the University of Pittsburgh and the Children’s Hospital of Pittsburgh, Carnegie Mellon University, LaunchPoint Technologies and WorldHeart Inc., has undertaken an ambitious program to develop a pediatric blood pump, motivated by the critical need to treat infants and toddlers with congenital and acquired heart diseases. We have relied on first principles to develop, de-novo, a miniature blood pump specifically intended for this population. The first phase of this program has produced the PediaFlow™ PF3, believed to be the world’s smallest magnetically levitated (maglev) blood pump with the following outstanding features:
With a flow rate range between 0.3 -1.5 LPM and a footprint approximating a AA cell battery, the clinical PediaFlow VAD will provide circulatory support for neonates, infants, and children less than 20 kg who experience cardiac failure and circulatory collapse due to congenital and acquired cardiovascular disease. Our consortium is uniquely poised to carry this forward to clinical use, fulfilling the needs of the PumpKIN program. The individual and collective strengths of our individual organizations and our unique and close collaborations over decades have resulted in innovative implantable blood pumps introduced to clinical use and trials following regulatory approvals.
The overall objectives of our response to the PumpKIN RFP are to finalize device development and conduct pre-clinical qualification testing necessary to apply for an IDE for a US clinical trial within 2.5 years. Specifically:
I. Finalize the current PediaFlow (PF3) pediatric VAD, leading to the clinical PediaFlow VAD design;
II. Conduct all necessary pre-clinical in-vitro and in-vivo testing with the clinical PediaFlow VAD design;
III. Submit an application and obtain IDE approval for the PediaFlow VAD;
IV. Collaborate with the PumpKIN Data Coordinating Center (DCC) and the other PumpKIN pre-clinical contractors to develop the clinical protocol and monitoring procedures which will be used in the PumpKIN program clinical study; and
V. Provide regulatory, manufacturing, training, and technical support for the PediaFlow VAD while the clinical study is underway.Successful completion of these aims will produce a pediatric ventricular assist device that will provide new opportunities for pediatric cardiac therapy and especially for the very smallest patients. Our very successful work for the past five years under the NHLBI Pediatric Circulatory Support Program (N01-HV-48192) serves as the basis for our current PumpKIN RFP application.
National Heart, Lung and Blood Institute, NIH
Newsletter Comments or Questions: McGowan@pitt.edu