Speeding Up Recovery

Scraped knees are a routine part of childhood, and youthful skin will repair itself in a matter of days. But the ability to heal ourselves ebbs as we age, and people with diabetes and some other conditions can take months or even years to recover from what starts out as a minor cut.

Patients with chronic wounds, some of which never heal, are prone to infection and at risk for amputation. And because these painful ulcers require frequent and intensive medical treatments, they also cost the U.S. health-care system an estimated $12 billion annually, according to a 2007 study published in the journal Ostomy Wound Management, a number that’s likely to rise along with an aging population and the increasing prevalence of diabetes.

Now Tufts researchers may have come up with a way to help those who suffer from the physical and emotional stress caused by acute and chronic wounds. Ira Herman, director of the cellular and molecular physiology program at the School of Medicine, and his colleagues are developing a new class of wound-healing agents designed to speed blood vessel growth—a key step in the healing process.

If these newly-created wound-healing agents work in humans, it could mean a faster, better healing process, customized to patients’ individual needs. That’s good news for the estimated 6.5 million diabetic Americans with chronic, non-healing ulcers, among many others.

“We and our colleagues want to advance and revolutionize what we’re doing for those suffering with chronic wounds,” says Herman, who is also director of the Tufts Center for Innovations in Wound Healing Research.

Herman, who has been investigating how cells and tissues respond to injury for more than two decades, used the natural healing process as a template for his new approach. In a typical wound that heals well—a 10 year old’s skinned knee, for example—new blood vessel growth at the injury site, a process called angiogenesis, is a crucial first step. Those new capillaries and vessels bring in the oxygen and nutrients necessary to build new tissues. “At the center of wound healing is the vasculature,” says Herman. “If you don’t have functional circulation, you can’t get a wound out of the starting blocks.”

But for angiogenesis to occur, those cells that give rise to the new vasculature must be able to migrate to and around the injury site. By the early 1990s, Herman discovered that collagenase, an enzyme produced by the bacterium Clostridium histolyticum, accelerated wound healing by allowing cells to migrate many times faster in tissue culture.

The enzyme’s main purpose is to digest, or break down, collagen—a key component of skin and other connective tissues—in the wound, like scarifying a road before re-paving it. Collagenase, which humans also produce, chops collagen molecules up into the shorter protein fragments called peptides. The bacterial and human versions, though, snip the collagen in slightly different ways, leading to divergent peptides. Herman reasoned that the bacterial collagenase might give rise to peptides that could offer an edge in promoting healing; he and his colleagues set out to test that hypothesis.

Customized Healing

To test that idea, Herman and his colleagues began treating cellular and animal tissue models with enzymes, control substances or the peptides produced by the bacterial collagenase’s action. Working with him were Kathleen Riley, V10, Tatiana Demidova-Rice, then a doctoral degree candidate in the cellular, molecular and developmental biology program and now a postdoctoral associate at the Sackler School, and Anita Geevarghese, A12, an undergraduate majoring in biochemistry.

While some protein fragments were produced by both the bacterial and human collagenases, the scientists isolated more than 10 different peptides that were unique to bacterial enzymatic activity. The team then sequenced the bacteria-specific peptides to determine their chemical structures, the first research team to do so.

Armed with that new knowledge, the team was able to combine specific peptide components produced by the bacterial enzyme to make synthetic peptides capable of stimulating blood-vessel growth and wound healing even better than the naturally-occurring ones. “We created our own new class of wound-healing molecules with special features that the individual peptides didn’t have by themselves,” says Herman.

To demonstrate these experimental peptides’ healing prowess, the scientists created wound models by sandwiching layers of animal cells and tissue components—some features representing skin, other cells standing in for vasculature—and “wounding” them with a blunt needle. (Herman likens this 3D wound-healing model to a peanut butter and jelly sandwich—with a hole punched out of it with an apple corer.) When they added the synthetic peptides to simulate wound healing, the peptides indeed enhanced the speed of key wound-healing responses in the models, including angiogenesis.

This new breed of customized synthetic peptides could one day become an integral part of emergency medicine or combat casualty care, Herman hopes. Sprinkled into wounds, the man-made peptides might even be engineered to enhance specific stages of the healing process. A diabetic with a chronic wound, for example, could receive peptides designed to stimulate blood vessel growth, while an accident victim or soldier suffering from acute wounds might receive peptides engineered to reduce scarring. Immediate treatment could shorten healing time as well as minimize pain and suffering, Herman anticipates.

“Everyone’s wound is a little different,” he adds.

Herman wants to bring novel wound-care solutions like these—tools that he calls “smart devices”—out of the lab and into the ER or battlefield hospital. In addition to the engineered peptides, those smart devices could include engineered replacement organs, like the silk scaffolding David Kaplan, a professor of biomedical engineering at Tufts, uses in novel ways.

The Tufts Center for Innovations in Wound Healing Research that Herman directs brings together experts from Tufts’ medical, dental, veterinary and engineering schools, as well as Tufts Medical Center and other local research institutes, including the Draper Laboratory. It’s all part of Herman’s mission to cross-pollinate the wound-healing research initiative. “By joining together the insight and expertise of colleagues in engineering, materials science, vascular biology and wound repair science,” says Herman, “we are now designing and producing smart devices that will, we hope, accelerate healing, regardless of wound type.”

Jacqueline Mitchell can be reached at jacqueline.mitchell@tufts.edu.