Timothy Crombleholme Seeks to Understand Wound Healing
As a fetal and pediatric surgeon at Cincinnati Children's, Timothy Crombleholme, MD, FACS, FAAP, knows that the groundbreaking clinical advances of today would not be possible without the years of extensive research that preceded them. As a researcher, Dr. Crombleholme is working to contribute to investigations that will lay the groundwork for generations of future clinical advances.
Dr. Crombleholme is director of the Fetal Care Center of Cincinnati, a collaborative partnership between Cincinnati Children's and two other Cincinnati-area hospitals. He also serves as director of the center's basic research component, the Center for Molecular Fetal Therapy.
One particular area that Dr. Crombleholme believes shows promise for future clinical implications is the study of wound healing and the possible use of gene therapy for wound healing and tissue repair. To further this research, Dr. Crombleholme has recently secured two new four-year grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). With these grants, he will study the role of bone marrow-derived endothelial precursor cells (EPCs) in eovascularization, and how the function of these cells differs in diabetes.
A Critical Step
Growing new blood vessels off existing ones, or angiogenesis, is a critical step in neovascularization and, says Dr. Crombleholme, EPCs play a key role in this process. "EPCs are essential to wound healing and in response to ischemia," he says. "We can demonstrate that you can't have normal angiogenesis without EPCs," Dr. Crombleholme explains.
"The recruitment of EPCs is a fundamental process in normal physiology. If you prevent that recruitment, you will not have normal neovascularization," he says. "If you block release EPCs from the marrow but give them exogenously in wound healing models, you can correct the defect in eovascularization." In addition, EPCs have been shown to play a role in compensatory lung growth. However, if the recruitment of EPCs from the bone marrow is blocked, Dr. Crombleholme says this process of compensatory growth does not take place.
Far-Reaching Implications
Understanding the vital role of EPCs in wound healing is sure to have far-reaching implications in a wide range of clinical specialties. One such specialty that Dr. Crombleholme has chosen to focus on initially is diabetes research. One of the most common complications arising from diabetes is the inability of wounds to heal properly. Heart, kidney and vascular disease are all associated with this condition, as are chronic non-healing wounds that can often lead to amputation. "We believe many of the complications of diabetes may be due to a fundamental defect in EPC biology," says Dr. Crombleholme. This defect is "probably responsible for the dysfunctional eovascularization" associated with diabetes.
Dr. Crombleholme envisions this esearch leading to a point in time where gene or cellular therapy can be used to correct neovascularization in diabetics. If dysregulated angiogenesis in diabetes is proven to be caused by the inability of EPCs to recruit properly, there may be hope that a therapy could be developed to fix this problem. "If you can correct EPC progenitor cell dysfunction, you can give back stem cell factors that can increase the release of EPCs from marrow and improve their function at sites of neovascularization," he says.
Dr. Crombleholme is excited by the potential for this and the other research being conducted at the Center for Molecular Fetal Therapy. "Every new treatment is preceded by five to 10 years of preclinical research," he says. "In the next five to 10 years, the goal of our center is to develop new treatments to take to clinical trials."
