[Published in the University of Minnesota Medical Bulletin, Winter 1992. Copyright ©1992, Minnesota Medical Foundation]

by Michael P. Moore

Minnesota is home to more than 500 medical companies and health care organizations, most of them located in a geographic swath--the Medical Alley--that starts in Duluth and cuts through the Twin Cities area down to Rochester. This $7 billion industry is Minnesota's leading employer and is still growing faster than any other. What started this Minnesota version of Silicon Valley, and what is fueling its growth?

In the view of C. Walton Lillehei, Ph.D., M.D., the University of Minnesota's "Father of Open-Heart Surgery," the seminal event took place in 1957. He had just finished dismissing a graduate student who was making no progress on a critical new medical device when a young electronics repairman happened to pass by his office. Lillehei was familiar with the young man's skill in repairing the electrocardiograph machine in the University of Minnesota Hospital operating room, so he took a chance that he might have the ingenuity to succeed where the Ph.D. student had failed. "Hey Earl, I've got a problem for you," Lillehei called out as the young man passed by.

The problem Lillehei had in mind was to figure out how to build a battery-powered device small enough to be worn on a patient's belt yet able to deliver a regularly paced current through a wire to the surface of the patient's heart. Surgeons were desperate for the device to treat usually fatal heart block that was occurring in patients following open-heart surgery, which Lillehei pioneered in the early and mid-1950s with surgeons F. John Lewis, Mansur Taufic, and Richard Varco. No effective treatment existed, only temporary measures such as giving epinephrine or isoproternol to try to speed up the heart in hopes that the block would revert spontaneously within the first week or two.

As it had many times during the development of open-heart surgery techniques, the dog lab led to a solution. "We were able to reproduce heart block very simply by clamping the inferior vena cava and emptying the heart of blood and then putting a stitch around where we knew the conduction system was," Lillehei says. "One of the ways that had been advocated to treat heart block was direct shock to the chest. We tried that in dogs--and in a few of our patients because we were desperate--but it took 60 to 75 volts to stimulate the heart and we needed to give 60 shocks per minute, which was intolerable. In some of the infants we were able to keep them alive for two to three days, but blisters would form under the electrodes and the blisters would break...it was totally unsatisfactory. But, that led to the thought of putting a wire right on the heart, and when we tried this in dogs all you needed was 1-2 volts, which was imperceptible to the animal and obviously would be to the patient."

So in January 1957 Lillehei's surgical team used direct heart stimulation to successfully treat heart block in a young girl operated on for closure of a ventricular septal defect. "We used a Grass Physiological Stimulator borrowed from the Physiology Department, and it was successful in 38 patients over about the next year." The team even developed a method of attaching the device without opening the chest, by feeding the wire through a hollow needle to the heart, enabling them to save patients who experienced sudden heart block in the days following surgery. Still, the solution was unsatisfactory, because the device had to be plugged into an electrical source, limiting patients' mobility and leaving them at risk of a power failure or accidental electrocution.

Lillehei thought that since only a small current was required, it ought to be possible to make a battery-powered pacemaker. "I talked to a student who was working on his Ph.D. in the electrical division and said I needed a gadget that patients could wear on their belt, that would be battery powered and be able to supply a low voltage current at an adjustable rate of 50 to 110 pulses per minute. He said he could do it, but after six months of hearing vague assurances that he was making progress I finally pinned him down, and he didn't have anything."

That was when Earl Bakken happened by on his way to fix the EKG. "The hospital electricians wouldn't go into the operating room, so we found a young man with an electronics repair business and gave him a part-time contract to repair our devices. I remember Earl Bakken always wore a plaid workshirt and always got the job done right away," Lillehei says. "So I described the problem to him and he said sure, he thought he could do it. So I arranged for him to see the heart block procedure in the dog lab with one of my residents, Vincent Gott. Six weeks later he was back with a box 4 inches square by 2 inches high, and it worked great in the dog laboratory. We were soon equipping all our heart-block patients with the device, which they wore in a holster."

Bakken's success with the battery powered pacemaker was partly due to his training in transistor technology in the Department of Electrical Engineering at the University of Minnesota Institute of Technology (class of 1948), and partly due to the skill with medical devices he had developed in the garage-based electronics repair business he ran with his brother-in-law, Palmer Hermundslie. The two were soon able to move their company, Medtronic, Inc., to a larger building thanks to referrals from Lillehei. "As I went around the country describing the low mortality rate we had established in our open-heart surgery program, everyone wanted to know what we were doing for heart block. I'd tell them, 'Call Earl Bakken, he'll help you'."

With that start in the heart pacemaker business, Medtronic went on to develop an improved electrode and obtained the rights to an implantable pulse generator. Combined, the two devices became an implantable pacemaker, and Medtronic began production and sales of the devices in 1960. Soon, the market expanded dramatically as Lillehei and others recognized that many sudden cardiac deaths were the result of heart block and could be treated with a pacemaker. Today, the company is a diversified developer and manufacturer of devices for improving cardiovascular and neurological health, with annual sales of $1.021 billion in 1991 and 8,200 employees.

"There couldn't be a better example of technology transfer and economic development than the University of Minnesota-Medtronic story," Lillehei says. "It turned out to be the beginning of Medical Alley, with all the medical companies (35) that were started later by former Medtronic employees. Earl used to get upset that he was constantly losing good people, and I'd kid him that he was running 'Medtronic University'."

The cardiac pacemaker turned out to be the most economically lucrative of Lillehei's technology transfer projects, but it was neither the first nor the last. He cites the development of open-heart surgery and the disposable bubble oxygenator that made the operations widely available as a classic case of a medical advance that has stimulated tremendous economic activity, especially in the region where it began. "There are now 2,000 open-heart operations done every 24 hours worldwide," and a much larger proportion are still done in Minnesota because of the many heart surgeons trained at the University or drawn to the state by its medical reputation, Lillehei says.

That reputation was built in the field of surgery through the leadership of Owen H. Wangensteen, Chief of the Department of Surgery from 1939 to 1967. The surgical training program under Wangensteen involved rigorous preparation in surgical techniques and post-operative care, but most of all he stressed the importance of innovation based on basic and applied research. "He felt research gave a young surgeon the confidence to question traditional and accepted beliefs, to say 'Hey, wait a minute, this doesn't look right according to our research,'" Lillehei says. "One of his sayings was 'Tradition is great for the Notre Dame football team or the Cold Stream Guards, but it's a disaster in science,' because it so often represents inherited errors that are taught and passed down to generations of students without question or experimentation."

Wangensteen's own research on the physiology of intestinal obstruction led him to question accepted ideas about its cause, especially post-operatively. He responded by inventing the Wangensteen Suction Tube, a simple device that syphoned off gas and fluid that often caused fatal obstructions following abdominal surgery. During World War II the device was used extensively for soldiers who had surgery for abdominal wounds and were grouped together in wards called "Wangensteen Alleys." (The Wangensteen Suction Tube was featured on an episode of the television series M*A*S*H.)

"Many of us spent time in the Department of Physiology, which was very strong under Maurice Visscher, but you could explore any field, biochemistry, microbiology, even electrical engineering. There was no limit on the field of research; if you had an interest in something Dr. Wangensteen would pick up the phone and arrange for a sojourn in that department. The Surgery Department took care of the salaries for the residents, so the other departments usually were very happy to cooperate," Lillehei says.

Lillehei had his heart set on surgical training with Wangensteen when he left the Army in 1945. The technology of surgery was well established, with good anesthesia and knowledge of blood circulation. But he was struck by the fact that "people were dying of little holes in the heart." As a resident in 1951 he was following a 17-year-old girl with severe cardiac insufficiency, and when she died he remembers being shocked that the cause was a hole between the atria about the size of a 50 cent piece. "It was so easy to repair, if only there could be found a way to empty the heart of blood long enough to do the surgery."

Many engineers and surgeons had attempted to design and build a machine to take over the function of the heart and lungs long enough for a surgeon to make intracardiac repairs. Among them was Charles Dennis, associate professor of surgery, who in 1945 was asked by Wangensteen to attempt to develop a heart-lung machine. For the next six years he worked in the dog laboratory to try to solve problems such as achieving sufficient oxygenation without blood foaming, and minimizing damage to red blood cells. In 1951, having achieved relatively high survival in dogs, Dennis used his cumbersome device to try to save two young patients, but both died. Later that year he left for the State University of New York Downstate Medical Center, taking his heart-lung machines with him. For relinquishing its rights to the Dennis devices, the University of Minnesota received $16,000, which was used to establish a fund to support heart research by Lillehei and others.

Because of the difficulties Dennis and others were having developing a satisfactory heart-lung machine, surgeons began trying other strategies. One strategy was to cool the patient enough to double the time the brain normally could go without blood, providing surgeons with about seven or eight minutes of operating time in the clamped off heart. The University of Minnesota team of F. John Lewis, Mausur Taufic, and Richard Varco, with Lillehei assisting, used the hypothermia technique to perform the world's first successful open-heart operation on September 2, 1952, saving the life of a five-year old girl. Over the next two years they used the technique in 11 patients, but they found that it was not suited to children, and that adults ran a high risk of ventricular fibrillation due to the cooling.

Lillehei and his residents had a research lab right next to Dennis's, and he remembers being as puzzled as Dennis about why the heart-lung device wasn't working. "The pump was no problem, it was when you tried to artificially oxygenate the blood that all kinds of difficulties arose," Lillehei says. "Even when Dennis and others achieved good survival in dogs, the techniques failed in humans. This led to a general pessimism regarding the prospects for open-heart surgery, because it seemed that you could only perform the rigorous bypass techniques on a healthy heart--as in the dog research--but that the sick human heart would never be able to withstand it."

That led Lillehei and residents Morley Cohen and Herbert Warden to conceive the idea of using one dog to perform the oxygenating function for another dog undergoing open-heart surgery. "It was just an experiment, we never thought we would be able to use it in humans, but we were able to obtain 30 minutes of operating time--considered a long time in those days--and the dogs recovered very easily. After we had performed the cross-circulation procedure in several hundred dogs with overwhelming success, we presented the findings to Dr. Wangensteen and got approval to try it in children who could not withstand the hypothermia treatment, with a parent providing cross circulation for the child," Lillehei says.

Their first cross-circulation case in March 1954 was cancelled because of fear expressed by some in the medical school that Lillehei's team was about to achieve 200 percent mortality in one operation. Wangensteen intervened, however, citing the overwhelming success in the dog laboratory as justification for going ahead. The procedure went well in the first patient, a one-year old boy, but he died of pneumonia 11 days later. The second patient, a four-year-old boy, also developed pneumonia but recovered and went home cured of his ventricular septal defect. Over the next year they performed a total of 45 such operations (with 32 survivors), including nine (with five survivors) for repair of the complex group of disorders presented by tetralogy of Fallot. None of the patient deaths were attributable to the cross-circulation technique, and there was no donor mortality, but it was still felt that a heart-lung machine would be the eventual answer to oxygenation during open-heart surgery. "Infants were especially difficult to save, because at that time there were no respirators, no blood gas pH monitors, and no intensive care," Lillehei says.

The solution would come from another fateful meeting. Richard De Wall, a recent graduate of the Medical School who was practicing medicine in Anoka, Minn., came to see Lillehei one day in 1954 to inquire about a position as a medical researcher. "I didn't really have anything for him to do, but he was very persistent and came back several times just to help out around the lab," Lillehei remembers. "One day we were all scrubbed and ready to do a cross circulation-supported operation but we had no one to run the pump, so I signed up De Wall as a resident, and he ran the pump for us."

Needing an assignment for his new resident, Lillehei presented the problem of designing an effective heart-lung machine. "I didn't tell him about all of the failures, especially the fact that most experts said you couldn't bubble oxygen into the blood because of the danger of undetectable air bubbles getting to the brain. I just told Dick to try to figure out a way to get the bubbles out, and then I gave him suggestions as he built the various models of the device."

A couple months later De Wall and Lillehei had assembled a surprisingly simple blood oxygenator. It relied on a helix of sterilizable plastic tubing that allowed oxygenated blood to release air bubbles and become heavier, settling to the bottom of the helix where bubble-free blood was collected in a reservoir and routed back to the patient. A minimal amount of blood was used, based on unexpected findings in dogs that only about one tenth as much blood as was commonly used was needed to keep patients alive during surgery. De Wall tested the device in about 70 dogs, gradually perfecting it until in May 1955, it was ready to be used in humans.

During construction of the helix design, De Wall told Lillehei that he needed to use tubing that could be bent without breaking or requiring many connections, and could be sterilized between patients. Plastic was the logical answer, but it was scarce in those days of mostly glass and rubber containers. Lillehei found the $10 of plastic tubing needed for each oxygenator through a high school classmate, Ray Johnson. A 1939 graduate of the University of Minnesota's chemical engineering program, Johnson had started a company, Mayon Plastics, which produced plastic tubing for the dairy industry and for production of mayonnaise.

Ironically, the company's success was partly due to its use of a substance called Antifoam A to coat its tubing and prevent foaming of the liquids being transported. Lillehei recognized that this characteristic would be helpful in preventing foaming of blood, but he was unaware that Antifoam A had originally been developed by a group working on a bubble oxygenator at Antioch College in Ohio. Mayon Plastics, in Hopkins, Minn., still supplies medical companies, thanks to the requests for tubing it began receiving in the 1950s as the De Wall-Lillehei blood oxygenator caught on. Johnson also recently endowed a research professorship in the Department of Chemical Engineering.

Two years after its introduction, the De Wall-Lillehei Bubble Oxygenator had been used in 350 open-heart operations at the University of Minnesota Hospital. De Wall steadily improved the device through three models, but it remained a very simple sterilizable device that could be built to accomodate only the amount of blood required for each patient. This was completely different than the other heart-lung machines, which were complex and expensive. For example, the Mayo Clinic in Rochester, Minn., began an open-heart surgery program in 1955, using a $500,000 machine built in collaboration with John Gibbon, a pioneer in the field who started with a device designed by IBM engineers. "As heart surgeons came to us and to the Mayo Clinic for training in open-heart techniques, they sure were confused by the simple versus the complex oxygenator designs," Lillehei laughs. "I always emphasized the need to worship at the altar of simplicity."

In 1957 another one of Lillehei's residents, Vincent Gott, invented a bubble oxygenator in which De Wall's helix design was flattened and enclosed between two heat-sealed plastic sheets. This sheet bubble oxygenator proved to be the key to widespread acceptance of open-heart surgery, because it could be easily manufactured and distributed in a sterile package, and it was cheap enough to be disposable. With it and the techniques developed by Lillehei and his colleagues, the University of Minnesota became world famous for making open-heart surgery possible and relatively safe.

In 1958, Lillehei introduced another revolution to open-heart surgery by performing the world's first replacement of a heart valve with an artificial substitute. This success set in motion another area of research and invention with his residents, seeking to design and test new mechanical heart valves. They succeeded not only in introducing three of the most effective, durable, and safe valves, but in further establishing Minnesota as a provider of medical devices to the world.

Washington Scientific Industries, Orono, Minn., commercialized a torroidal disc valve design invented in 1966 by Lillehei and Ahmad Nakib, a surgical resident from Lebanon. It added central flow to the peripheral flow offered by other discoid valves. Approximately 500 were implanted, mostly to replace the mitral valve, between 1967 and 1970, and there have been no structural failures reported to the manufacturer.

Another Medical Alley company, Medical Inc., Inver Grove Heights, Minn., was started to commercialize a valve designed in 1967 by Lillehei and Robert L. Kaster, a 1962 electrical engineering graduate of the Institute of Technology. The Lillehei-Kaster pivoting disc valve introduced a free-floating carbon disc that opened to 80 degrees. More than 65,000 of the valves have been implanted since 1970, again with no reported structural failures or dysfunction due to wear.

Ironically, the valve design that has turned out to be the world leader was initially rejected by commercial manufacturers. A surgical resident from India, Bhagavant Kalke, in 1965 proposed to Lillehei a design based on two leaflets, hinged at the top and bottom to allow them to open and close with the flow of blood. Tests of this design in the laboratory showed the best hydrodynamic performance Lillehei had witnessed. However, the first and only patient to receive the Kalke-Lillehei valve died two days after surgery in 1968, although an autopsy was unable to determine the cause of death. Perhaps because of this unexplained death, the inventors were unable to find a commercial manufacturer for the valve.

Eight years later, the Kalke-Lillehei valve was resurrected by a "saint." It was chosen as the basis for a valve to be marketed by a new company called St. Jude Medical, started by another pioneer of Minnesota's Medical Alley, Manuel Villafana. A former Medtronic employee who introduced the Medtronic pacemaker to South America, Villafana recognized the value of a long-lasting lithium-powered pacemaker invented by Wilson Greatbatch, inventor of the original implantable pacemaker licensed by Medtronic. Despite the fact that lithium batteries would last 5 to 10 times as long as the standard mercury batteries, the lithium-powered pacemaker was rejected by Medtronic and others because lithium was potentially explosive. Convinced by Greatbatch that he had solved this problem, Villafana left Medtronic to start Cardiac Pacemakers, Inc. (CPI). With the help of Lillehei's brother Richard (deceased), also a pioneering surgeon at the University of Minnesota, the lithium pacemaker was tested and commercialized, and CPI quickly prospered.

Villafana sold CPI to Eli Lilly and Company in 1975 for $126 million. He then targeted the heart valve industry as being ripe for expansion, and he began working with Lillehei to improve and commercialize the bileaflet valve. "He named the company and the valve after St. Jude, because that's the saint you pray to for a miracle," Lillehei says. Plenty of miracles have occurred, beginning with the first implantation of the St. Jude Valve in 1977, performed by Dr. Demetre Nicoloff at the University of Minnesota Hospital. Through 1990, more than 320,000 have been implanted, more than any other heart valve. St. Jude Medical now has about 46 percent of the worldwide market for heart valves, and it has diversified into other products such as cardiac assist pumps and vascular grafts. Total sales topped $175 million in 1990.

Villafana continued his entrepreneurial path by leaving St. Jude in 1981 to found another medical company, Golden Valley Medical, and most recently Helix Biocore. Although originally started to provide biotechnology services for the pharmaceutical industry, Villafana in 1990 switched Helix Biocore's course to developing and commercializing an improvement on the St. Jude Valve.

Lillehei remains in a part-time position as director of medical affairs at St. Jude Medical. He also is a clinical professor of surgery at the University of Minnesota, where his most frequent contacts are with R. Morton "Chip" Bolman III, director of cardiothoracic surgery and first holder of the C. Walton and Richard C. Lillehei Endowed Chair in Thoracic and Cardiovascular Surgery. The chair was established through contributions from the two surgeons' students and friends, who also founded the Lillehei Surgical Society. C. Walton Lillehei trained 139 surgeons at the University of Minnesota from 1951 to 1967, and an additional 28 at Cornell Medical Center in New York City from 1968 to 1974.

As he looks back over the revolutionary years of the 1950s and 1960s, when both the University of Minnesota surgical program and Minnesota's medical industry achieved status as world leaders, Lillehei remembers a blizzard of activity, both academic and commercial. "There were so many things going on, and we developed so many relationships with local companies that were either introducing new products or supplying the needs of our program--it was good for us and good for them. For example, I remember a fellow named Lou Lehr, who had been hired to start a medical division at 3M. He came over with some samples of tape and we made suggestions about how it could be adapted for hospital use. Then they began making all the linen for the operating rooms and disposable plastic drapes for surgery. Today medical and surgical products are one of 3M's major divisions."

Lillehei and others, including Medtronic Chairman Emeritus Earl Bakken, see that kind of academic-industrial technology transfer link as ensuring that when a future C. Walton Lillehei has an idea for a medical device, there will be an Earl Bakken nearby to make sure the job is done right.

Michael P. Moore is director of research communication and technology marketing in the University's Office of Research and Technology Transfer Administration.