Wolfgang Meyer-Ingold

Wound therapy: growth factors as agents to promote healing

The development of recombinant growth factors for the treatment of nonhealing or badly healing wounds has reached the clinical-trial phase. These first studies in humans are yielding valuable information on the physiological role of growth factors in different types of wounds, their mode of action and their stability under in vivo conditions. Data from these early trials in humans can be interpreted in the light of the continuing scientific progress being made in wound-healing research, and thus lead to an improvement in the design of future studies. Growth-factor-based therapeutics are expected to enter the marketplace in the middle of this decade, and to become a highly profitable sector of the health-care industry by the turn of the century.

Hyaluronan, heterogeneity, and healing: the effects of ultrapure hyaluronan of defined molecular size on the repair of full-thickness pig skin wounds.

The extracellular matrix macromolecule, hyaluronan, is thought to modulate wound healing. However, the molecular size of hyaluronan and contaminating associated proteins may be important determinants of these effects. We have examined the results of seven daily topical treatments of full‐thickness skin wounds in pigs with ultrapure hyaluronan of defined molecular size. High molecular weight hyaluronan (>1000 kd) enhanced, whereas low molecular weight hyaluronan decreased, the rate of early wound contraction as compared with intermediate hyaluronan (molecular weight = 100 kd) and saline solution controls. Fracture strength at 21 days was reduced by high and intermediate molecular weight hyaluronan but not by low molecular weight hyaluronan. Wound perfusion, measured by means of a scanning laser‐Doppler technique as a noninvasive indicator of angiogenesis, showed depression by high and intermediate molecular weight hyaluronan on day 3, but all forms of hyaluronan caused elevated blood flow on day 7. The architecture of granulation tissue in this wet healing model was highly organized, but no gross histologic differences were seen because of treatment. Different molecular species of hyaluronan have differential effects on contraction, angiogenesis, and the evolution of wound strength. Where hyaluronan is used as a treatment or vehicle for wounds, its precise composition should be specified.

Localization of platelet-derived growth factor receptor subunit expression in chronic venous leg ulcers.

Cellular responses to platelet‐derived growth factor, which affects all phases of the wound healing process, are dependent on the interaction of the growth factor with its cell surface receptors. Recently, we have shown that the platelet‐derived growth factor‐receptor was not expressed in uninjured human skin. In acute human wounds healing by secondary intention, both platelet‐derived growth factor‐receptor subunits were coordinately expressed, whereas no expression was found after reepithelialization at day 47. Even though impaired wound healing may be due to uncoordinated expression or the failure to express platelet‐derived growth factor‐receptor subunits, little is known regarding their expression in chronic ulcers. We studied the localization of platelet‐derived growth factor‐receptor expression in chronic venous leg ulcers of 15 patients with a median age of 73 years. Cryostat sections of biopsy specimens were immunostained with the use of antibodies against the α‐ and the β‐platelet‐derived growth factor subunits. RNA was extracted from biopsy specimens and subjected to Northern blot analysis with the use of oligolabeled complementary DNA for the platelet‐derived growth factor‐receptor. Platelet‐derived growth factor‐receptor α‐ and β‐subunit expression was found in fibroblast‐like cells within the wound bed and in cells beneath the epidermis of the wound edge. Platelet‐derived growth factor‐receptor β‐subunit expression was detected in endothelial cells of the vessels, in the granulation tissue, and the wound edge, whereas platelet‐derived growth factor‐receptor α‐subunit was not expressed in endothelial cells of the uninjured skin. This finding suggests that the platelet‐derived growth factor α‐subunit may be involved in vessel formation during tissue repair. Both platelet‐derived growth factor‐receptor subunits were expressed at the messenger RNA level indicating that the synthesis is at least partly regulated at a pretranslational level. As the cellular responsiveness to growth factors depends on their specific receptors, our finding that both platelet‐derived growth factor‐receptor subunits are expressed in chronic venous ulcers substantiates the concept of therapeutic trials with recombinant platelet‐derived growth factor.