Synergistic actions of platelet-derived growth factor and the insulin-like growth factors in vivo.

Topical application of growth factors has been shown to benefit both normal and impaired wound healing. In normal tissue repair, resident cells produce a "cocktail" of various types of growth factors that overlap in function. In vitro studies have proved that growth factor combinations can act synergistically to enhance cellular function beyond that achieved with individual growth factors. To determine whether similar combinations have a synergistic effect in vivo, we applied growth factor combinations topically to full-thickness skin wounds created in genetically diabetic mice. The C57BL/KsJ-db/db mouse is obese and has insulin-resistant diabetes, and it has been proved that this mouse has markedly impaired wound healing. Topical application of platelet-derived growth factor, insulin-like growth factor-I, or insulin-like growth factor-II enhances healing in this model. Marked synergism was found when platelet-derived growth factor and insulin-like growth factor-II were combined to produce augmentation in wound closure beyond that achieved by application of the individual growth factors. The synergistic effect allowed for improved tissue repair at doses of platelet-derived growth factor and insulin-like growth factor-II that were ineffective when applied individually. The addition of insulin-like growth factor-I or insulin to platelet-derived growth factor produced no significant synergism. Because multiple growth factors are released in the wound during the healing process, it is not surprising that their combination further enhances healing. Growth factor combinations should become an important addition to the armamentarium for the treatment of chronic, nonhealing wounds.