by Sally Pobojewski

In a bionic world, people would be more like automobiles. When original equipment started to wear out, your doctor could just pull a new part off the shelf and plug it in. Getting a new heart would be as easy as getting a new fuel pump. And no one would have to die waiting for an organ transplant.

Plug-and-play replacement organs may seem far-fetched, but they could be closer than you think. Bionics — a merger of medicine and engineering where metal and plastic are just as important to the functioning of the human body as blood and tissue — has made major advances in the last 50 years.

Prosthetic implants for hips, knees and other damaged joints are helping people with arthritis maintain active, healthy lifestyles. Cochlear implants are making it possible for children with profound hearing loss to be educated in a regular classroom. Mechanical heart-assist pumps are helping people with end-stage heart disease stay alive until a transplant heart is available. With the widespread use of contact lenses, breast implants, cardiac pacemakers and heart valves, there aren’t many of us departing this world today with the same equipment we had coming in.

The University of Michigan Medical School has been a major player in the fast-moving field of bionics. Technology developed by U-M scientists has saved the lives of thousands of desperately ill people and improved the quality of life for many more. The Medical School is best known for its pioneering work in life support technology known as ECLS or ECMO, which is used worldwide in intensive care units to treat patients with acute lung or heart failure.

Today, scientists in the Medical School are testing the world’s first bionic lung in research animals. A bioartificial kidney and artificial liver support system are in human clinical trials. Scientists at the U-M’s Kresge Hearing Research Institute are studying how the brain perceives sound and the effect of drugs on the inner ear — research that could lead to a new generation of bionic devices for people with hearing loss. Others in the Medical School are implanting heart-assist pumps, inserting tiny telescopes inside the eye, building better bionic joints and developing gene therapy to heal broken bones.

Who knows what the future will bring? Maybe that heart-on-the-shelf idea isn’t so crazy, after all.

Preserving Life Outside the Body

Bob Bartlett Photo: D.C. Goings

Watching a patient die is the hardest part of being a doctor, but sometimes all that anger and frustration gets channeled in positive directions. Much of the lifesaving medical technology we take for granted today was invented by physicians who were tired of standing by helplessly as their patients died and decided to do something about it.

This was the case for a group of surgeons at Children’s Hospital in Boston in the mid-1960s. Frustrated by their inability to help children who were dying from acute heart or lung failure, they created a new kind of technology, which they called extracorporeal, or outside-the-body, membrane oxygenation or ECMO. One of those surgeons was a young resident named Robert H. Bartlett (M.D. 1963), who is now a professor of surgery in the Medical School and director of surgical intensive care for the U-M Health System.

The idea was to create a modified version of a heart-lung bypass machine — a new device that could take over temporarily for hearts or lungs damaged by infection, trauma or shock — giving them time to rest and recover until they regained their ability to function. In essence, the machine would breathe for the patient. Blood would be pumped out of the body, through a filtering device to remove carbon dioxide and add oxygen, and then would be returned to the patient.

At first, the researchers were optimistic. After all, they used heart-lung bypass machines during surgery all the time. How hard could it be to use the same basic procedure for several days, instead of several hours? Unfortunately, it turned out to be very hard. The longer research animals used in early experiments remained on the device, the more lethal complications they developed. As soon as the scientists solved one technical problem, there was another one to take its place.

“During the late 1960s and 70s, most people thought artificial lung technology was unnecessary, crazy or just wouldn’t work,” says Bartlett — a self-effacing man who chooses his words carefully and would much rather talk about the accomplishments of his colleagues or former students, instead of his own. “Today it’s a well-established and accepted technology, especially for infants and children with lethal pulmonary or cardiac failure where the lung or heart is expected to recover.”

In 1975, when the National Institutes of Health sponsored the first clinical trial of the new technology, the survival rate in adults with severe respiratory failure was only 10 percent. When Bartlett brought his research program to the U-M Medical School in 1980, he had used the technology successfully only with a handful of critically ill newborns and very young children with acute respiratory failure.

Thanks to research advances and improved technology, the picture is much brighter today. A survey of Health System patients treated between 1980 and 1998 with what is now called ECLS, or extracorporeal life support technology, showed that 56 percent of adults with acute respiratory failure recovered and were discharged from the hospital. The success rate in newborn infants and young children was even better. Eighty-eight percent of newborns with neonatal respiratory failure survived, as did 70 percent of children treated during the same time period. Lungs of newborns and children recover faster, so ECLS is more effective and produces fewer complications in children than in adults.

“The U-M Health System has the largest and most diverse experience with ECLS technology in the world,” Bartlett says. “The technology has expanded from Michigan to 120 centers worldwide. It’s standard care in every children’s hospital, but still isn’t used often or soon enough with adults in intensive care units.”

Unfortunately, ECLS offers no hope to millions of people in the U.S. with chronic, rather than acute, organ failure. These are people with cystic fibrosis, emphysema, hepatitis, and end-stage heart or kidney disease whose condition will deteriorate gradually over time. Some wait years for transplant organs, often dying before a suitable organ is found. Others live with the debilitating side effects of long-term kidney dialysis or progressive heart or liver failure.

To help patients with chronic lung disease, Bartlett and U-M colleague Ronald Hirschl (M.D. 1983, Residencies 1989, 1991), an associate professor of surgery, have developed an artificial lung which is now being tested in sheep. Called the MC3 BioLung, it was designed and is produced by MC3 — Michigan Critical Care Consultants, Inc. — an Ann Arbor research and development firm started 12 years ago by Bartlett and two of his graduate students. Bartlett recently received a $4.8 million, five-year grant from the National Institutes of Health to complete animal studies and develop the artificial lung to the point where it can be tested in people.

Using the pumping power of the sheep’s heart, the BioLung attaches to the pulmonary artery and replaces 100 percent of normal lung function. The one-pound device can be used outside the body or implanted inside the chest wall. Blood passes through one side of a cartridge divided by a thin, permeable membrane. Oxygen flows through the other side. As blood flows through the device, carbon dioxide and oxygen diffuse through the membrane. Reoxygenated blood is then returned to the animal.

“We are now at the point where we can use the lung for a week at a time in healthy sheep,” Bartlett says. “When we can extend that time to about a month, we will start preparing for a clinical trial in seriously ill patients who are candidates for a lung transplant. Our hope is that the device will sustain them long enough to find a donor.”

Progress with the artificial lung encouraged Bartlett and his research team to start work on an artificial liver life support system, which could buy time for the approximately 18,000 people in the United States with end-stage liver disease who are waiting for a transplant. “Our hope was that it could be used to treat chronic liver failure, much as hemodialysis is used for chronic kidney failure,” Bartlett says.

The human liver is a complex, multi-function organ and replacing it, even for a few days or weeks, is a daunting challenge. Not only does the liver remove toxic substances from blood, it also produces important proteins that regulate metabolism, blood clotting and the immune response.

“The liver can regenerate itself, but it stops regenerating in the midst of severe liver failure,” Bartlett explains. “One of our research fellows, Sam Awad, demonstrated that if you remove all the toxic material from blood, the liver cells get better. So we developed a system, tested it in animals and started a clinical trial in 1998.”

Results of the first test of Bartlett’s artificial liver with 20 acutely ill patients were encouraging. The treatment helped six patients improve and remain healthy enough to receive a liver transplant. Three of those patients are still living today. Two patients recovered liver function and left the hospital without needing a transplant. “That was unexpected and very positive,” Bartlett says. “We actually had donors for those patients, but they were doing so well, we decided against a transplant.”

Eager to share news of their success, Bartlett’s research team presented preliminary results at a symposium in Germany where they met scientists from a German firm called Teraklin AG. Teraklin scientists were reporting encouraging results from their artificial liver support system, which was already being used to treat patients in Europe. The German system was called MARS for molecular albumin recycling system.

“The Teraklin device used the same principles and concepts, but a few of the technical details and materials used to remove toxic compounds from blood were different,” Bartlett says. “It was different enough that we knew the device would work better than our version.”

So Bartlett made it his business to help Teraklin AG obtain approval from the U.S. Food & Drug Administration to use the MARS system in the United States. As part of that process, the U-M Health System is currently participating, with four other medical centers, in a phase III clinical trial to compare the effectiveness of the MARS artificial liver system against standard medical treatment. The trial will enroll 75 patients with chronic liver failure who are so sick they are in what doctors call a hepatic coma. U-M physician Robert Fontana (M.D. 1988), an assistant professor of internal medicine, is directing the clinical trial.

“We are anxious to have MARS technology approved by the FDA,” Bartlett says. “Then we will go to work trying to improve it, which the people in Germany are working on, too. We have become good friends and we’re working on all these projects together. We’re not in the business of competing. We’re in the business of doing what’s best for the patient.”

Bartlett has treated patients in intensive care whose heart, lungs, liver and kidneys were all being supported simultaneously by different extracorporeal devices. “Interlocking the devices is not much of a problem, because they all come in standard sizes,” he says. Eventually Bartlett expects to see a universal blood-processing device with plug-in modules or cartridges for different applications. Implantable devices will never be one-size-fits-all, however, because human anatomy varies too much from person to person.

No matter how advanced the technology, all ECLS devices have the same fatal flaw: Whenever blood is exposed to anything other than endothelial cells lining the inside of blood vessels, it tends to clot. And even tiny blood clots developing in a piece of plastic tubing or on a pump’s metal surface can kill the patient.

“It’s necessary to use medications like heparin, which cause bleeding in the patient, to prevent clotting,” Bartlett says. “Balancing the risk of clotting with the risk of bleeding is the biggest problem in any type of artificial organ implantation. Clotting starts with blood platelets, so if we could stop platelets from sticking to surfaces, we could prevent clots from forming.”

For seven years, Bartlett has been working with Mark Meyerhoff, U-M professor of chemistry, to develop the ideal prosthetic surface — a polymer on which blood won’t clot. Meyerhoff’s polymers contain tiny silica particles that release low levels of nitric oxide gas — the same gas produced by human endothelial cells to relax blood vessels and inhibit coagulation. Research in Bartlett’s lab showed that the new polymer eliminated the need for heparin in research animals during ECLS procedures.

“Once we have plastic surfaces that prevent platelets from sticking, the entire field of artificial organs will change dramatically, because the clotting problem is the major limiting factor,” Bartlett says. “This is where the research focus is directed now. We still have some technical obstacles to overcome, but I think we are very close to solving the problem.”

Building a Bioartificial Kidney with Living Cells

David Humes with renal-assist technology Photo: Martin Vloet

More than 300,000 Americans with kidney disease are alive today because they spend several hours every week connected to a renal dialysis machine. During dialysis, the patient’s blood flows through hollow fibers, which remove toxic waste products normally filtered out by healthy kidneys.

But long-term use of dialysis creates its own set of problems — heart attacks, strokes, blood clots, infection — that kill patients just as surely as kidney disease does, says H. David Humes, M.D., a professor of internal medicine in the Medical School.

“If you are a 59-year-old man and go on dialysis, your average predicted mortality is four years,” Humes says. “Your chances of living longer are better if you are diagnosed with prostate or colon cancer, as opposed to end-stage renal disease on dialysis.”

Humes thought there must be a better way to help patients with serious kidney disease other than filtering their blood through what he calls “a dead synthetic membrane.” He developed a new device made of hollow fibers lined with a type of kidney cell called renal proximal tubule cells. These cells reclaim vital electrolytes, salt, glucose and water, as well as control production of immune system molecules called cytokines, which the body needs to fight infection. Conventional kidney dialysis machines remove these important components of blood plasma, along with toxic waste products, and cannot provide the cytokine regulation function of living cells.

In 1995, Humes started a company called Nephros Therapeutics, Inc., to develop and market his new technology. Today, instead of animal cells, Nephros scientists use cells from human kidneys donated for transplant — kidneys that cannot be used because they have anatomical defects or scarring. The kidneys are processed to remove progenitor cells, similar to adult stem cells, which are capable of forming millions of proximal tubule cells when grown under the right conditions in a special blend of growth factors, nutrients and proteins. The cells grow to cover the inside of hollow fibers — 4,000 of which are packed in cartridges and used in conjunction with a conventional hemodialysis filter to create what Humes calls a bioartificial kidney.

“These progenitor cells are real miracle cells,” Humes says. “With all the manipulation we put them through, they remain vigorous, robust and able to function as if they were still inside the body.”

Nephros Therapeutics recently completed a clinical trial to test the safety of the renal assist device in 10 critically ill patients with acute renal failure at the U-M Health System and the Cleveland Clinic. The company has applied for FDA approval for a follow-up study in six academic medical centers that began in August. Eventually, Humes hopes to test the effectiveness of his bioartificial kidney against dialysis in patients with chronic renal failure and to develop an implantable version that can be used inside the body.

“Nobody believed our renal assist device would work,” Humes says. “Until there’s a success story, people are very skeptical. But whenever I was discouraged, all I had to do was talk to patients. Knowing how badly these people suffer gives you sustaining power to move forward in what may appear to be unconventional therapy.”

Implanting a World of Sound

Cochlear implants are one of bionic technology’s greatest success stories. Today, thousands of people with significant hearing loss rely on cochlear implants — electronic devices that fit inside the cochlea of the inner ear and make it possible for even the profoundly deaf to hear.

“Results with today’s cochlear implants are exceeding any expectations we had when I started in the field 20 years ago,” says Teresa Zwolan, Ph.D., an associate professor of otolaryngology and director of the U-M’s Cochlear Implant Program. “Years ago you had to be profoundly deaf to be a candidate for an implant. But the technology has improved so much and patients are doing so well with them that even adults and children who receive minimal benefit from hearing aids are eligible for a cochlear implant.”

Bryan Pfingst, John Middlebrooks and Josef Miller with an oversized model of the external, middle and inner ear, photographed through the window of a sound-attenuating chamber. Photo: Martin Vloet

Back in the 1960s, Josef Miller, Ph.D., a scientist in the U-M Kresge Hearing Research Institute, first heard researchers from the House Ear Institute in Los Angeles describe their early prototypes of a cochlear implant. “Every scientist at that meeting — including me — threw up their hands and said ‘this will never work,’” says Miller, a professor of otolaryngology in the Medical School. “That was 40 years ago. And we were all wrong. We were dead wrong.

“The nervous system really outsmarted us,” Miller adds. “It was so good that even though we were only able to do a primitive job, the nervous system was clever enough to interpret our crude information and make use of it. Implants at that time were single-channel devices with poor quality information, but people could hear a car horn and other environmental sounds. It was a remarkable improvement in their quality of life.”
With current technology, people not only hear car horns, they can hear a conversation — often even over the telephone. More than 40,000 people around the world use cochlear implants, and nearly 1,000 of them received those implants at the U-M Health System. Established in 1984, the U-M’s Cochlear Implant Program has made the Health System one of the top four centers for cochlear implants in the U.S., participating in clinical trials for every commercially available device on the market today.

Teresa Zwolan and Steven Telian Photo: Martin Vloet

Recently the FDA approved the use of cochlear implants for infants as young as 12 months old. “The research is very strong that the younger children are when they receive an implant, the better they do,” Zwolan says. “With aggressive therapy, children who receive implants at 12 months probably will be fully mainstreamed with normal-hearing children by the time they start kindergarten. But the longer you wait, the poorer the prognosis.”

Zwolan adds that there is still some controversy associated with the use of cochlear implants. When the technology was first introduced, many members of the deaf community who use sign language to communicate were strongly opposed to the use of implants. Although opposition has lessened over the years, Zwolan says she is careful to make sure parents know the controversy exists.

“Ninety-five percent of children born deaf are born to parents with normal hearing,” she says. “If hearing parents have a deaf baby, they don’t know how to communicate with their child. The cochlear implant provides a means for letting them communicate without having to learn a completely new language. In our view, the decision [to get an implant] needs to be a parental choice that fits the family’s lifestyle.”

In a normal ear, vibrations from sound waves striking the eardrum are transferred to fluid inside a snail-shaped bony organ called the cochlea deep in the inner ear. When this fluid moves, it stimulates thousands of hair cells, which line the inside of the cochlea. When hair cells move, they create neural impulses, which are picked up by auditory nerve fibers and carried to a part of the brain called the auditory cortex. The auditory cortex sends these signals to other areas of the brain where they are processed and interpreted allowing us to “hear” the signals as sound.

If hair cells are damaged or missing, they cannot generate signals the brain needs to perceive sound. So implants with tiny stimulating electrodes, inserted inside the cochlea, substitute for damaged hair cells by producing electrical signals that travel through the auditory nerve to the brain. After a brief training period, most people — especially those who lost their hearing after they learned to talk — can recognize and understand what they hear.

Implanting the device is a delicate microsurgical procedure that takes an experienced surgeon from 90 minutes to three hours, according to Steven A. Telian, M.D., professor of otolaryngology and medical director of the U-M Cochlear Implant Program. “First, we make a recessed area in the mastoid bone behind the ear to hold the electronic receiver/ stimulator,” Telian says. “Then, we drill an opening into the cochlea and insert the electrode. To access the cochlea, we have to work right next to the facial nerve, so the surgeon has to compromise between being able to see well and making sure the nerve is not damaged.”

Cochlear implants can’t help people without an auditory nerve, which carries sound from the ear to the brain. For people without an auditory nerve, there’s a new type of technology called an auditory brainstem implant. “Instead of a string of electrodes placed in the cochlea, there’s a patch of electrodes placed on part of the brainstem called the cochlear nucleus,” says Telian. “The sound perception is much less reliable and clear than with a cochlear implant, but it does give people who otherwise would be completely deaf some degree of sound perception.”

Even though today’s cochlear implant technology is very good, Medical School researchers are trying to make it even better. David J. Anderson, Ph.D., a professor in the U-M College of Engineering and a professor of otolaryngology in the Medical School, is working with scientists at Cochlear Corporation — a major manufacturer of cochlear implants — to develop electrode arrays produced with advanced photolithography technology, instead of by hand. In addition to better quality control and lower production costs, which could help reduce the high costs of implants, Anderson says photolithography will make it possible to produce implants with more electrodes in closer proximity to auditory nerve cells.

Bryan E. Pfingst, Ph.D. and John C. Middlebrooks, Ph.D., both professors of otolaryngology and scientists at U-M’s Kresge Hearing Research Institute, are studying sound perception and how the brain’s auditory cortex processes signals it receives from the auditory nerve. By analyzing auditory signal processing, they hope to overcome one of the limitations of current implant technology — the inability to transmit changes in voice pitch or tone.

“Tone languages like Chinese use rising or falling intonation and high or low pitch to carry important syntactic information,” Middlebrooks says. “One-quarter of the world’s population speaks tonal languages, so if the implant cannot transmit pitch information, that is a serious concern.”

Pfingst and Middlebrooks study guinea pigs with cochlear implants that have tiny recording electrodes implanted near auditory neurons in their brains. Using food rewards, technicians train the guinea pigs to respond to sounds by pushing a button on the floor of their cage. “We study how the animals perceive sound by asking them to discriminate between different sounds or tones played on different channels in their implant,” Pfingst says.

In another study, Josef Miller and Richard A. Altschuler, Ph.D. — a professor of cell and developmental biology and professor of otolaryngology in the Medical School — found that inserting substances called growth factors into the inner ears of deafened guinea pigs can prevent auditory nerve cells from dying and stimulate the growth of healthy, functioning nerve fibers, which are vital to successful use of a cochlear implant.

Miller is scientific director of a $3 million European research program called BioEar. The goal is to develop the first drug delivery system for use with a cochlear implant. A human clinical trial is scheduled to begin late in 2004, which will be the first study testing the effects of delivering drugs continuously to the human inner ear.

“We want to induce the nerves of the inner ear to grow out to and make intimate contact with individual electrodes of this next-generation cochlear implant,” Miller explains. “It’s not just a better implant; it’s really tissue engineering the inner ear.”