Montana State University

Mountains and Minds

We Can Heal That November 27, 2007 by Tracy Ellig • Published 11/27/07

MSU's biofilm research helps a Texas physician revolutionize the treatment of chronic wounds
Landmine

Dr. Randy Wolcott (Photo: Jodi Miller)
Dr. Randy Wolcott


Dr. Randy Wolcott walks into a small exam room. Seated before him is an elderly, balding man with an open wound on his right foot.

"Please don't cut anything off," the man says the moment Wolcott enters, fear and desperation in his voice.

The patient's right foot is chapped to flaking. Near the little toe, is a vivid red wound. He winces as Wolcott examines it. Like most of the patients who visit the Southwest Regional Wound Care Center in Lubbock, Texas, the man is diabetic.

"I hear that plea once or twice a day," Wolcott says later of the patient. Poor circulation and a lack of feeling in the legs and feet due to nerve damage are common with diabetes. A small cut or bruise can go unnoticed, become infected and flare into a limb- or life-threatening condition in three days. These wounds are so difficult to heal that most of medicine considers them a lost cause and treats them with amputation.

"They come to us because they've been told by another physician that the only solution is to cut off their foot or leg. They're terrified. If they have diabetes in their family, they may know that an amputation is the beginning of the end. They've seen loved ones leave this world a piece at a time and they're afraid."

Nationally, an estimated 82,000 people with diabetes had lower-limb amputations in 2002, according to the Centers for Disease Control. The numbers are expected to grow with America's soaring rate of obesity -- a leading cause of diabetes.

In Wolcott's experience, the man's foot should heal and be made whole again.

Just five years ago, he thought differently. But research from Montana State University's Center for Biofilm Engineering changed his outlook and treatment. Today, Wolcott is working with the Center to seek new ways to heal chronic wounds. Their aim: to keep tens of thousands of people in the United States, and hundreds of thousands worldwide, from becoming amputees.

Sixty to 80 patients visit Wolcott's clinic daily. The patients are young and old, men and women. Some shuffle in with walkers, others ease themselves along with canes; a few roll by in wheelchairs having lost a leg or a foot. The most fortunate among them walk. Inside their shoes or under their pant legs -- or sometimes in plain sight -- are infected wounds fit for a medical textbook.

"There are fragments of tissue, soupy-wet slough, pus and liquefied tissue, exposed bone -- we see something like that at least once a week," Wolcott said. "I tell people it's like stepping on a land mine."

It's not just feet and legs either. Out-of-control bedsores on a man with quadriplegic paralysis have led to a red gully along his spine more than 6 inches long. The bone of one of his hip joints is exposed by a wound that would take four hands to cover.

Wolcott is unflappable in his assessment: "We can heal that."

The biofilm revolution


(Photo: Kelly Gorham)

At the center of Wolcott's confidence is the theory that biofilms are the principal obstacle in the healing of chronic wounds.

Biofilms are bacteria that latch onto surfaces -- teeth, the inside of water pipelines, heart valves, catheters, human tissues and countless other surfaces -- and then form complex colonies that secrete a goo-like armor that makes them highly tolerant of antibiotics and disinfectants. Biofilms are considered a multi-billion dollar industrial and medical problem.

The word "biofilm" was coined in 1978 by Bill Costerton, former director of MSU's Center for Biofilm Engineering, in a paper published in Scientific American. Thirteen years later, MSU founded the Center for Biofilm Engineering, which has become the oldest, largest and best known biofilm research center in the world. It has research and testing partnerships with 22 companies, with medical biofilms being the fastest-growing sector of corporate interest.

Research at MSU's center has found that biofilm colonies are complex: There is evidence the bacteria may communicate with each other, as well as with the living tissue to which they are attached. Additionally, there is evidence the colony divides the labor: Some bacteria latch onto surfaces, others secrete protective goo and others harvest nutrients.

The biofilm model represents a big change in the way science and medicine have traditionally thought about bacteria.

"If you study a single ant, you can count its legs, see what it feeds on and where it goes. That's been the history of our understanding of bacteria. We've studied them individually," said Phil Stewart, director of the Center for Biofilm Engineering.

"But think how much you miss about what ants do when you just put one under the magnifying glass. You miss all the socially coordinated labor and the structures that are far bigger than any one ant could build. Bacteria working together may not be as visible as ants, but we are already seeing that they may be as complex," Stewart said.

"The biofilm concept bumps bacteria up the tree of life from super-primitive organisms to something a little smarter than we previously gave them credit for," Stewart added. "Thinking about them as multi-cellular creatures is a pretty radical change. I think it's revolutionary."

It was revolutionary for Wolcott.

Epiphany

In the late 1990s, Wolcott was a demoralized specialist in treating chronic wounds. He repeatedly watched infections defeat his efforts to heal and was left with no recourse but to have a patient's foot or leg amputated.

He did so knowing that 70 percent of diabetics who undergo an amputation die within five years due to the stress placed on their heart from their altered circulatory system. During those five years they are likely to have more amputations and to rate their quality of life worse than cancer patients, according to some studies.

"All I could do was watch these people die a piece at a time," Wolcott said.

Desperate to find a solution to the chronic-wounds part of the diabetes problem, Wolcott attended a wound-care conference in 2002. A last-minute replacement speaker made a hasty presentation that included an illustration of biofilms by Peg Dirckx of MSU's Center for Biofilm Engineering.

Wolcott now refers to Dirckx's illustration as "the epiphany slide."

"I knew the failure of these wounds to heal had something to do with the bacteria, but I was still groping for an answer," Wolcott said. "When I saw that slide, it explained everything. Biofilms are fundamentally, radically different. When you embrace the biofilm model it explains everything with chronic wounds, from why the wounds won't heal to why some treatments work better than others."

Wolcott contacted Garth James, director of medical projects at the MSU center, and a partnership was born. In 2006, the National Institutes of Health awarded MSU a $2.9 million grant to expand its research into the biofilm-chronic wound connection. That grant will be used in partnership with Wolcott and the division of dermatology at the University of Washington's Department of Medicine.

MSU is doing basic research on biofilms using specimens provided by Wolcott, who eventually may provide a venue for clinical trials.

But even now, Wolcott's understanding of the biofilm model has led him to experiment with new treatments that are helping his patients.

"We used to have -- literally -- 10 to 15 patients a month in for amputations. Now we've gone months without any. It's huge," Wolcott said. "I can confidently look patients in the eye and say I'm 80 percent certain that their wound is going to heal."

Treatment


(Photo: Jodi Miller)

The successful treatment of a chronic wound requires long-term, intensive management on a number of different fronts, according to Wolcott.

When Wolcott says long term, he means it. Biofilms are so tenacious, it can take four months to a year to heal a chronic wound, sometimes longer.

A common first step to treating a wound is debridement, or scraping the biofilm -- a yellow-greenish sludge -- along with dead tissue off the top of the wound with a metal scalpel. For some patients, this can be painful even with anesthetic. Others feel nothing as diabetes has destroyed the nerve endings in their feet and legs.

Wolcott has six hyperbaric chambers where patients spend hours in a super-oxygenated environment that's good for healthy tissue and bad for biofilms. On willing patients, he uses sterilized maggots that feed on the biofilms and dead tissue, but leave healthy tissue alone.

Wolcott also uses lactoferrin and xylitol to treat biofilms. Lactoferrin occurs naturally in tears, mucus and breast milk and appears to prevent bacteria from clumping together. It is used commercially in meat packing plants to prevent biofilms from growing on hides.

Xylitol occurs in fruits, vegetables and other plants. It is also produced as part of normal human metabolism. It is used in toothpaste and chewing gum for its anti-biofilm properties.

An arsenal of antibiotics also plays a major role in Wolcott's treatments.

"Antibiotics are not worthless, but they have to be used in conjunction with other things," he said.

Wolcott's center treated and tracked 190 patients with critically poor blood circulation in the lower limbs and who had wounds deemed unhealable under the current standard of care. These wounds were considered the "worst of the worst," according to Wolcott, and typically would have resulted in a major limb amputation. Of those patients, the center was able to heal 146 -- a healing rate of 77 percent.

Beyond the treatments, Wolcott and Stewart both see education of physicians, scientists and patients as one of the best short-term tools for battling biofilm-infected chronic wounds.

"The medical community is slow to change," Wolcott said. "This is not something physicians have been trained in. Their training tells them the most expedient treatment is amputation."

Medical schools are missing the problem too, Wolcott said.

"The National Institutes of Health says that nearly 80 percent of all human infections are suspected to be biofilm related, yet only 10 percent of the study of infection is about biofilms," he said.

"The majority of medical textbooks barely even mention biofilms," Stewart said. "The concept is not part of the curriculum in any way."

In moments of candor, Wolcott can barely conceal his outrage.

"The mainstream approach to biofilms is so frustrating to me. Right now, what is done is to neglect the biofilm until it needs to be treated with antibiotics. If there is a serious flare-up, the body part is cut off," Wolcott said. "It would be ridiculous if it weren't so barbaric."

MSU's findings


(Photo: Kelly Gorham)

Researchers at MSU are working hard to provide the evidence needed to convince scientists and physicians of the biofilm-chronic wound connection.

"Randy's successes indicate that at least we're having an important impact for some patients," MSU's Garth James said. "But it's anecdotal. To find convincing evidence in a scientific manner is slower and more frustrating."

Some of that work is carried out in a windowless lab on the third floor of MSU's Engineering and Physical Sciences Building where doctoral candidate Pat Secor snaps on a pair of latex gloves and handles four bullet-shaped vials. Into each vial he puts an exact amount of fluid using a needle-nosed pipette. On the counter is a slightly battered black notebook.

"That's pretty much my whole life right there," said Secor, a Bozeman native whose cellular biology thesis is on the biofilm-chronic wound connection.

The book contains months of handwritten notes Secor has made as he has investigated what bacteria live in wound tissue samples from Wolcott's patients. The evidence is compelling for a biofilm-chronic wound link: 60 percent of chronic wound tissue samples contain biofilms, compared to only 6 percent of acute wounds from the same patient group. An acute wound is one that heals in a normal time span, instead of the months or years it takes a chronic wound to heal.

Additionally, chronic wounds appear to harbor complex ecosystems of bacteria. To date, the center has found 34 aerobic bacteria (those that thrive with oxygen) living in chronic wounds and 11 anaerobic bacteria (those that thrive without oxygen).

"The number changes every week," James said. "The more we look, the more we find."

The anaerobic bacteria are of particular interest because they've been mostly overlooked.

"These are very hard bacteria to find," James said. "They're very hard to grow in a culture, and even when you're successful in growing them it can take weeks. Clinics order anaerobic cultures all the time and find nothing. But we find them when we use DNA analysis."

The center published its findings in the October issue of Wound Repair and Regeneration, an important step in convincing the science community of biofilms' importance in chronic wounds. But there is still much to be done.

"We know they're there," James said. "But the million-dollar question is how do these biofilms delay wound healing?"

Secor's work is methodical, repetitive, quiet and precise. But he's been to Wolcott's clinic. He's met patients with holes in their feet and legs, lurid red, bleeding and oozing wounds they endure for months, sometimes years.

"Getting to see the patients one-on-one gave me motivation," Secor said. "I see it as a problem with a person rather than just a plastic tube I mail off for DNA sequencing."

A whole man

The fruits of this science can be seen in the story of Jerry Montemayor, a 38-year-old school administrator in Lubbock, who stubbed his toe on the corner of his bed one morning in December 2005 and nearly lost his foot.

Initially, Montemayor ignored the bruise. A diabetic, Montemayor has poor blood circulation in his lower legs and feet. Three days later, his toe was discolored and he limped with discomfort. He went to an emergency room.

Emergency room physicians told Montemayor his foot was severely infected and he must be admitted. He spent the next 12 days in the hospital. When his infection didn't respond to treatment, Montemayor's physicians told him his foot should be amputated, or he risked losing his entire leg and possibly his life.

"First they said it would be the top of my foot, then half of my foot, then my whole foot," Montemayor said. "They kept telling me I needed to set a date and time for my amputation. Believe me, if it wasn't for the power of prayer I don't think I'd have gotten through this."

Montemayor sought a second opinion. The next day, two staff members from Wolcott's center visited.

"I'll never forget that visit," Montemayor said. "One of the girls said 'We've seen worse. We suggest you do not get this amputated. We can treat this.'"

It was Christmas Eve.

Montemayor took their advice and began nearly a year's worth of treatments at Wolcott's clinic on Christmas Day. Today, he walks on both feet.

"The clinic staff said they were going to do their best and they did," Montemayor said. "I'm blessed to be walking."

"It's hard to relive that experience in the hospital," he said. "At the time I was thinking about my personal life. I was thinking how this would affect me meeting someone, or having a relationship with someone. Is she going to accept and support me? Is she going to be able ?to walk next to me and accept that I have a prosthetic limb?

"I was thinking 'If I have kids will I be able to run and play with them?'" Montemayor said. "I was thinking 'Am I going to be a whole man?'"