Guest Editorial Growth Factors: The Promise and the Problems G rowth factors are a collection of powerful, locally acting peptide hormones. Since their discovery 4 decades ago, these molecules have offered the tantalizing prospect of stimulating the repair of normal and defective injuries in the skin and elsewhere.1 Growth factors can variably promote cell division, cell differentiation, neovascularization, cell movement, and other biological responses. Each of these factors signals to its target cells by binding to a specific receptor on the cell surface. Different growth factors, however, can share common signal mechanisms within the cell. Several lines of evidence support the concept that growth factors could have therapeutic value in problem wounds. First, animal studies have repeatedly shown that addition or overexpression of excess growth factors, particularly in impaired healing models, can accelerate many aspects of repair, including wound closure, epithelial resurfacing, granulation tissue formation, neovascularization, and tensile strength. Second, many forms of defective wound healing are correlated with reduced growth factor levels or reduced sensitivity of the wound tissue to growth factor stimulation. Third, depletion of growth factors, their receptors, or their cellular response mechanisms by various types of antagonists or genetic engineering frequently leads to retarded wound healing.2 Conversely, overabundant growth factor activity or sensitivity can lead to excess healing in the form of fibrosis, granuloma, and scarring. Correspondence should be sent to: Jeffrey M Davidson, PhD, Department of Pathology C-3321 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232-2561; phone: +1-615-496-8900; fax: +1615-327-5393; e-mail: jeff.davidson@vanderbilt.edu. Conflict of interest: None. DOI: 10.1177/1534734607299180 © 2007 Sage Publications 8 LOWER EXTREMITY WOUNDS 6(1);2007 pp. 8-10 Despite the overwhelming evidence from preclinical studies that dozens of different growth factors can override healing defects in normal, diabetic, aged, steroid-treated, hypoxic, and ischemic wound models, only platelet-derived growth factor (PDGF) has successfully overcome the US Federal Drug Administration hurdle of demonstrating significant improvement (complete wound closure) in the diabetic foot ulcer population.3 Many other promising growth factors, including the classic, epidermal growth factor (EGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF, a subtype of FGF), transforming growth factor-ß, (TGF-ß), and vascular endothelial growth factor (VEGF), have failed to enter the clinic and the marketplace because of numerous biologic, economic, and strategic issues. First, each of these molecules has to be produced as a recombinant protein, either in bacteria or eukaryotic cells. Second, the standard mode of introduction—at least in wounds—is as a topical formulation, which leaves the peptide growth factor susceptible to the destructive, proteolytic effects of an ongoing inflammatory process. Third, regulatory and intellectual property issues negate the advantages and logic of growth factor combinations and/or sequences that better reflect the actual milieu during the repair process. It is clear that the primary requirement for successful healing is adequate tissue perfusion. A subset of growth factors that promotes new blood vessel formation has potential for correcting the macrocirculatory defects that underlie poor healing of the lower extremity in peripheral arterial disease and diabetes. Several forms of FGF and VEGF as well as hepatocyte growth factor/scatter factor (HGF) are certainly capable of generating collateral neovascularization. These agents are already under investigation for both cardiovascular and peripheral vascular applications.4 VEGF is also known as vascular permeability factor, and its GUEST EDITORIAL successful use may require partnering this agent with angiopoietin-1, which promotes the formation of stable vessels through recruitment of pericytes. Growth factor therapy can be a useful medical therapy in cases that are not amenable to surgical revascularization. What are the alternatives to applying industrial quantities of expensive recombinant proteins on a regular basis to achieve clinically significant improvement in wound healing outcomes? One approach is to create growth factor formulations that encapsulate or protect the agent to deliver it to the appropriate target. Such devices could take the form of films, microparticles, nanoparticles, or wound dressing components. Wound biomaterials could also be designed for sustained release of these factors, as many growth factors bind to the extracellular matrix. Indeed, there is evidence that biomaterial-based wound devices can help to reduce proteolytic destruction of growth factors as well as improve their sequestration. A second strategy is to induce the target tissue to produce higher/beneficial levels of the candidate molecule. Gene transfer, that is, the temporary introduction of a growth factor gene into the wound site, has repeatedly been shown to be an efficient and effective method to deliver growth factors to wounds.5 This has been accomplished with physical methods that introduce (naked) plasmid DNA into cells and also by biological delivery with noninfectious viruses. Preliminary evaluation shows this strategy is safe, and additional safety could be incorporated into these vectors by placing the gene of interest under local, external regulation by compounds such as RU-486 or tetracycline. Because gene delivery promotes the expression of proteins inside cells, there is a much wider range of cellular processes accessible to intervention. This strategy would expand the pharmacopoeia to gene products that turn on growth factor expression, regulate growth factor signaling, or control other aspects of cell differentiation. An adenoviral construct that expresses PDGF-BB is in commercial development, and clinical trials are under way. A third approach to enhancing growth factor delivery is cell-based production. This could involve the use of cultured, living skin equivalents into which are introduced cells that express one or more growth factors at therapeutic levels, or genetically modified (stem) cells could be directly applied to the wound site.6 The critical issues pertaining to all of these advanced technologies are to make them cost-effective, safe, and part of a systematic, aggressive wound care program. LOWER EXTREMITY WOUNDS 6(1);2007 Much of recent wound therapy research has been targeted at augmenting activities that appear to limit the rate or quality of wound healing. However, it is very likely that negative regulation is a part of the normal sequence of events that proceed from inflammation to resolution. The systems, agents, and genes that suppress wound healing would include proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 as well as less well-defined (transcription) factors that affect the down-regulation of growth factor expression. In these circumstances, antagonists will be required for therapy. The most promising approach at present appears to be engineered antibodies, which are already used extensively for controlling tumor growth and chronic inflammatory disease.7 In the future, small inhibitory RNA or a variant approach could come into its own as a means to down-regulate unwanted or excess gene activity that was associated with wound-healing defects. Wound care at this time requires an enormous investment of manpower and materials. Despite the remarkable variety of etiologies leading to defective healing, we still lack the diagnostic precision to determine when and where the addition of powerful growth-promoting proteins or genes will serve the patient best. Most experts agree that growth factor and/or gene delivery is not a substitute for good medical practice, and this approach will be reserved for treatment of wounds that persistently fail treatment with the standard of care. These advanced therapies have been thus far shown to be safe, and the fact that they can be applied externally provides an intrinsic limitation to systemic complications. We need to identify sound, practical solutions to growth factor delivery. More effort should be expended to determine when and in what combinations these molecules work best in a clinical setting. Industry and government should support the development of gene- and cell-based concepts for improving wound care. Basic scientists, on the other hand, should not lose sight of the fact that these molecules can only be effective in concert with well-designed and thorough wound care programs. ACKNOWLEDGMENTS Supported by the Department of Veterans Affairs, the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Biomedical Imaging and BioEngineering. 9 DAVIDSON REFERENCES 1. Davidson J, DiPietro L. The wound-healing process. In: Veves A, Giurini J, LoGerfo F, editors. The diabetic foot. 2nd ed. Totowa, NJ: Humana; 2006. p. 59-82. 2. Grose R, Werner S. Wound-healing studies in transgenic and knockout mice. Mol Biotechnol 2004;28:147-66. 3. Steed DL. Clinical evaluation of recombinant human plateletderived growth factor for the treatment of lower extremity ulcers. Plast Reconstr Surg 2006;117(7 Suppl):143S-9S; discussion 50S-51S. 4. Hughes GC, Annex BH. Angiogenic therapy for coronary artery and peripheral arterial disease. Expert Rev Cardiovasc Ther 2005;3:521-35. 5. Eming SA, Krieg T, Davidson JM. Gene transfer in tissue repair: status, challenges and future directions. Expert Opin Biol Ther 2004;4:1373-86. 10 LOWER EXTREMITY WOUNDS 6(1);2007 6. Goessler UR, Riedel K, Hormann K, et al. Perspectives of gene therapy in stem cell tissue engineering. Cells Tissues Organs 2006;183:169-79. 7. Holash J, Thurston G, Rudge JS, et al. Inhibitors of growth factor receptors, signaling pathways and angiogenesis as therapeutic molecular agents. Cancer Metastasis Rev 2006;25:243-52. Jeffrey M. Davidson Research Service VA Tennessee Valley Healthcare System and Department of Pathology Vanderbilt University School of Medicine Nashville, Ten