Growth factors and skin repair and regeneration
Authors: Fu X.B. 
Published: September 2010

Skin is the largest and much easily injured organ of the human body, averaging over 2 m2 in surface area, and yet in most places is less than 2 mm in thickness. After severe injury, such as in severe burns and traffic accident, the skin will be damaged and lost its normal anatomy and physiologic function. Usually, the wound healing in these injured tissues is a major health‐care problem with considerable socioeconomic impact [1, 2]. Burn injury primarily involves a destruction and disruption of the normal structure and physiologic function of the skin and the formation of hypertrophic scar affects not only the skin cosmetic problem, but also the skin function, such as body temperature regulation. It has been found that sweat glands do not regenerate to form their three‐dimensional organization via the division and terminal differentiation of sweat gland cells. Because of the lack of sweat glands in regenerated scar tissue, the function of body temperature regulation is impaired, markedly affecting the patient's quality of life [3]. Another aspect, if the wound healing process is affected in such ailments as diabetes, infection, venous diseases and malnutrition or in those who have previously undergone chemotherapy or radiotherapy, the chronic, non‐healing wounds will give both prolonged suffering to patients and frustration to attending physicians [1, 2]. Thus, how to prevent the scar formation and accelerate chronic wounds healing are the main tasks faced to all doctors.

Usually, wound healing and tissue repair are the dynamic biological process, consisting of a complex interaction of cellular and biochemical events. The process of wound healing differs little from one kind of tissue to another, and is generally independent of the type of injury. Although different elements of the wound healing process proceed in a continuous and integrated manner, it is still convenient to divide the whole process into three overlapping phases, e.g. inflammatory phase, proliferative phase and maturation phase, and several natural components for descriptive purpose. Traditionally, the treatment of skin wounds consist local wound care, surgery, skin grafting, debridement and vascular reconstruction. Recent investigators have shown that growth factors play a key role in the natural mechanism of skin wound healing. These growth factors attract inflammatory cells into the wound, stimulate cellular proliferation and enhance neovascularization and epithelial migration. These properties have aroused a great deal of interest in trying to prove efficacy in enhancing all forms of tissue repair. The topical application of growth factors has been reported to promote wound healing in partial‐thickness burns, skin‐graft donor sites and other wounds [4, 5]. The combination between the genetic engineering and traumatology make it possible to produce some of genetically engineered drugs in the trauma and tissue regeneration fields. Since 1990, some of genetically engineered drugs have been produced and used in the fields of skin wound repair and regeneration and the successful clinical results have achieved. These genetically engineered drugs include the recombinant human epidermal growth factor (rhEGF), recombinant bovine basic fibroblast growth factor (rbFGF) and platelet derived growth factor (PDGF), etc. The basic research found that these growth factors are involved in tissue development in embryo and repair in adult after injury. After application in local wound, it is found that the wound healing velocity can be accelerated and wound‐healing quality improved with their powerful mitogenic and non‐mitogenic effects. The clinical trial indicated that all of superficial second‐degree burns, deep second‐burns, donor sites and chronic skin ulcers treated with recombinant bovine basic fibroblast growth factor or recombinant human epidermal growth factor had an accelerated rate of granulation tissue formation and epidermal regeneration as compared with that in the controls (Table I) [6, 7].

Although the successful clinical results have achieved, however, some concern about these drugs such as their safety and detailed mechanisms should be answered and studied in the future. Also, treatment with growth factors in skin wounds just accelerate the wound healing velocity, but, the functional repair, such as regeneration of hair follicles, sebaceous glands and sweat glands cannot be achieved for the moment. After screening the results from different centers, some results are found to be encouraging, while some discouraging. Although the interpretation of these results depends on the angle of views whether the cup is half full or half empty, however, it may also depend on different criteria, different wounds and even different aims. In this article, the relationship between growth factors and skin development, the results of current clinical trials about growth factors and their application in accelerating acute or chronic skin wound healing and regeneration have been screened. The successful experiences or failure lessons in these fields are summarized. Finally, I would like to give our comments about the concerns raised by people, such as is there a need for exogenous application of growth factors in acute or chronic skin wounds? [8, 9] Do we need a special delivery system for the growth factors in local wound healing? Whether the growth factor treatment has solved all problems involved in skin wound repair and regeneration? Whether is it safe to use growth factors to promote skin wound healing and regeneration? Whether perfect wound healing can be achieved in those wounds treated with growth factors, such as regeneration of sebaceous glands and sweat glands in repaired skin? [10].

References

 1. Fu, X.B., Wang, Z.G., Sheng, Z.Y. et al. Advances in wound healing research in China: from antiquity to modernity. Wound Rep. Reg. 9, 2–10 (2001).

2. Fu, X.B., Sheng, Z.Y., Cherry, G.W. et al. Epidemiological study of chronic dermal ulcers in China. Wound Rep. Reg. 6, 21–27 (1998).

3. Li, J.F., Fu, X.B., Sheng, Z.Y. et al. The interaction between epidermal growth factor and matrix metalloproteinases induces the development of sweat glands in human fetal skin. J. Surg. Res. 106, 258–263 (2002).

4. Steed, D.L. and Group, D.U.S. Clinical evaluation of recombinant human platelet‐derived growth factor for the treatment of lower extremity diabetic ulcers. Vasc. Surg. 21, 71–81 (1995).

5. Fu, X.B., Guo, Z.R., Sheng, Z.Y. et al. Healing of chronic cutaneous wounds by topical treatment with basic fibroblast growth factor. Chin Med. J. 115, 331–335 (2002).

6. Fu, X.B., Shen, Z.Y., Chen, Y.L. et al. Recombinant bovine basic fibroblast growth factor accelerates wound healing in patients with burns, donor sites and chronic dermal ulcers. Chin. Med. J. 113, 367–371 (2000).

7. Fu, X.B., Shen, Z.Y., Chen, Y.L. et al. Randomized placebo controlled trial of use of topical recombinant bovine basic fibroblast growth factor for second‐degree burns. Lance.352, 1661–1664 (1998).

8. Fu, X.B., Sun, X.Q., Li, X.Q. et al. Dedifferentiation of epidermal cells to stem cells in vivo. Lancet 358, 1067–1068 (2001).

9. Fu, X.B., Yang, Y.H., Sun, T.Z. et al. Ischemia and reperfusion impair the gene expression of endogenous basic fibroblast growth factor in rat skeletal muscles. J. Surg. Res. 80, 88–93 (1998).

10. Chen, W., Fu, X.B., Sun, X.Q., et al. Analysis of differentially expressed genes in keloids and normal skin with cDNA microarray. J. Surg. Res. 113, 208–216 (2003).