Basic Research
Mitogenic Stimulus to Wound Healing
Wounds are increasing burden for our society due to our aging population and increasing rates of obesity and diabetes. Common wounds include diabetic foot ulcers, venous stasis ulcers, arterial insufficiency ulcers and pressure sores. In addition, because of the complexity of medical care given today, we more frequently see wounds that result from surgical intervention, radiation therapy, or drug therapy such as corticosteroids or chemotherapy agents for cancer. Common to all wounds is a loss of tissue.
Wound healing strategies must allow the cells within the wound to divide and proliferate to recreate the complex three-dimensional structure of intact tissue with an adequate blood supply. To do this, we must transition cells in a wound from the tendency to apoptose to stimulation to divide and proliferate. Our collaborator, Dr. Donald Ingber of Children’s Hospital has described the three mitogenic inputs for cell division: growth factors, mechanical forces and the extracellular matrix (ECM).
I. Extracellular Matrix
We have used a collagen-GAG matrix as developed by our collaborator Dr. I.V. Yannas from MIT and have seeded this with autologous keratinocytes and implanted these in both a guinea pig and porcine model. Dr. Charles Butler directed this study and collaborated with Carolyn Compton, M.D., Ph.D., at the Shriner’s Burns Institute (now at McGill University) to do the immunohistochemistry. We found a re-capitulation of the basement membrane within several days after the study with re-formation of rete-like ridges with blood vessels forming between the ridges.
II. Growth Factors
We have been fascinated by the rich source of growth factors platelets have within their alpha granules, and we are seeking the best methods to apply these to the wound. Working with C. Robert Valeri, Ph.D., and Herbert Hechtman, M.D., Dr. Rodney Chan has demonstrated that platelets stored for 21 days retained growth factor concentrations of PDGF-AA and TGF-β (ELISA) and further showed that platelet extracts could stimulate fibroblasts in culture 21 days after harvest.
III. Mechanical Forces
Mechanical forces are well known to have a stimulatory effect in fracture healing and in the pathophysiology of cardiovascular disease. Much less is known about them in wound healing. When Quentin Eichbaum, M.D., Ph.D., was a medical student, he began to explore the idea that mechanical forces might be a principal mechanism of action of the Vacuum Assisted Closure device (KCI, San Antonio). We assembled a team from MIT, Children’s Hospital and Brigham and Women’s Hospital to explore this problem. Vishal Saxena, a doctoral candidate at MIT, then constructed a finite element model of the VAC device and found that this device would stretch wounds by inducing surface undulations and varying degrees of tension and compression.
Horacio Mayer, M.D. went on to construct a rat ear stretch model where the vessels in the ear could be monitored over time for changes in diameter. Perry Liu, M.D. performed additional work on this and presented the results of his studies at the American College of Surgeons in October of 2004. He showed that both static and cyclic forces could increase vessel diameters, but that there was a more rapid response with cyclic application. Bart Kane, M.D., Ph.D. has built a servo-controlled tension device that allows us to apply precise loads in a pre-determined wave-form. Dr. Giorgio Pietrammagiori is currently studying growth factor up-regulation in these specimens. Vishal Saxena, working with Issac Kohane, M.D. at Children’s Hospital is now doing gene chip analysis of the rat ear specimens. We hope to compare these molecular biological changes in the simple rat stretch model with those of the clinically applied VAC sponge to find similar gene pathway responses.
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Clinical Studies
We have participated in studies sponsored by KCI to study the effect of the VAC device on abdominal wounds, chest wounds, and pressure sores. We lead a national consensus study on the treatment of chest wounds and will participate in a national consensus panel on abdominal wounds. We continue to participate in several other clinical studies both internally and externally funded.
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Future Directions
We believe that with this is an ideal time to apply the recent advances in basic science to wound healing. We have been impressed with the change in clinical practice that the VAC device has made in the clinical practice of medicine and believe that this is the first of many devices used clinically that will be based on mechanical stimulation of cell mitosis. Mechanical stimulation combined with other mitogenic factors including properly designed extracellular matrices and approporiate growth factors will allow clinicians to more reliably treat complex wounds in the future.
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