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Advanced treatments for non-healing chronic wounds


Vincent Falanga
Professor of Dermatology and Biochemistry
School of Medicine
Boston University

Chairman and Training Program Director
Roger Williams Medical Centre
Providence, Rhode Island, USA

Published: Apr 2005
Last updated: Apr 2005
Revision: 1.0

Keywords: Wound healing; chronic wounds; non-healing wounds; biological products; growth factors; skin substitutes; gene therapy; stem cell therapy.

Key Points

  1. A renaissance in the biology of wound care has resulted in the development of a range of advanced therapeutic products: growth factors, skin substitutes, gene therapy and stem cell therapy.

  2. To make the best use of these advanced products and speed their introduction to standard practice, a more co-ordinated international approach to clinical trials is required and researchers need to broaden their remit to include more complex wound types.

  3. Further research is necessary to increase understanding of the clinical factors that impair healing and develop a rational strategy for the effective use of advanced therapeutic products.


The science of wound healing is advancing rapidly, particularly as a result of new therapeutic approaches such as growth factors, skin substitutes, and gene and stem cell therapy. This article reviews the latest developments in wound healing products and their progress through clinical trials, and suggests ways to maximise their clinical effectiveness and hasten their integration into wider clinical practice.


Clinicians' understanding of and ability to achieve wound healing has increased significantly over the past few years, particularly as a result of advances in molecular biology such as the use of growth factors, the ability to grow cells in vitro and the development of bioengineered tissue [1][2][3]. Knowledge of scarring has also increased fundamentally [4][5][6][7], and the science behind wound healing and the identification of the critical components of the healing process have benefited from technical advances such as transgenic and knock-out animal models [8]. This paper describes the clinical experiences to date of the advanced products being developed as a result of this dynamic process.

Clinical indications for use

Over the past two decades several recombinant growth factors have been tested for their ability to accelerate the healing of chronic wounds. Among others, some promising results have been obtained using epidermal growth factor [9] and keratinocyte growth factor-2 [10] for venous ulcers, and fibroblast growth factor [11] and platelet-derived growth factor (PDGF) for pressure ulcers [12],[13].

However, the only topically applied growth factor widely approved for use is PDGF, which randomised controlled clinical trials have shown accelerates the healing of neuropathic diabetic foot ulcers by about 15 percent [14][15][16]. Why, then, has a wider range of growth factors not been approved for clinical use and why have the results of clinical trials not lived up to the expectations created by preclinical data?

A number of explanations have been put forward, all of which may apply. It has been suggested that the dosage and mode of delivery for topically applied growth factors may have been incorrect and that growth factors need to be used in combination to achieve a better response [17][18][19]. It is also possible that closer attention should have been paid to appropriately preparing the chronic wound before treatment with the growth factor being tested [20]. Notably, there is evidence that the aggressive approach to surgical debridement taken in the initial PDGF trial for diabetic neuropathic ulcers seems to have worked synergistically with the application of the growth factor [15].

Bioengineered skin

A number of bioengineered skin products or skin equivalents have become available for the treatment of acute and chronic wounds as well as burns. Since the initial use of keratinocyte sheets [21][22][23], several more complex constructs have been developed and tested in human wounds. Skin equivalents may contain living cells, such as fibroblasts or keratinocytes, or both [2], [24][25][26], while others are made of acellular materials or extracts of living cells [27][28][29][30]. The clinical effect of these constructs is 15-20 percent better than conventional 'control' therapy, but there is debate over what constitutes an appropriate control.

In US trials, saline-soaked gauze and off-loading have been accepted by the Food and Drug Administration as the control. However, methods for off-loading differ between countries and the wound dressings to be used are also subject to controversy. As a result, in spite of notable successes with the use of bioengineered skin to treat diabetic neuropathic foot ulcers, acceptance of this type of therapy by clinicians is not likely to become as widespread as desired.

Bioengineered skin may work by delivering living cells which are known as a 'smart material' because they are capable of adapting to their environment. There is evidence that some of these living constructs are able to release growth factors and cytokines [31],[32], but this cannot yet be interpreted as their mechanism of action. It should be noted that some of these allogeneic constructs do not survive for more than a few weeks when placed in a chronic wound [33].

Gene therapy

The technology to introduce certain genes into wounds by a variety of physical means or biological vectors, including viruses, has existed for some time. These range from ex vivo approaches, where cells are manipulated before being re-introduced into the wound, to more direct in vivo techniques that may rely on a simple injection or the use of a gene gun [34][35][36]. Gene therapy as a whole is a very active area of research, with 320 clinical protocols submitted to regulatory bodies around the world since 1999 [37].

An inability to achieve stable and prolonged expression of a gene product, which has been a problem in the gene therapy treatment of systemic conditions, could be an advantage in the context of non-healing wounds, where only transient expression may be required [35].

Most work with gene therapy in relation to wounds has been done in experimental animal models [38], but there are promising indications that certain approaches may work in humans. For example, the introduction of naked plasmid DNA encoding the gene for vascular endothelial growth factor (VEGF) has been reported to enhance healing and angiogenesis in selected patients with ulcers resulting from arterial insufficiency [39].

The introduction of the gene rather than its product, for example a growth factor, is seen as a less expensive and potentially more efficient delivery method so there is no doubt that research into gene therapy for chronic wounds will increase over the next few years.

Stem cell therapy

Extending the hypothesis that cell therapy may be required to recondition chronic wounds and accelerate their healing leads to the conclusion that stem cells may offer even greater advantages. Pluripotential stem cells (PSCs), the precursors to all more specialised stem cells, are capable of differentiating into a variety of cell types, including fibroblasts, endothelial cells and keratinocytes, all of which are critical cellular components for healing. Although most PSCs are derived from human embryonic research, which is the subject of some controversy, pluripotential mesenchymal stem cells, which are the source of new connective tissue, may be present in bone marrow [40].

A recent report on an uncontrolled clinical trial suggests that direct application of autologous bone marrow and its cultured cells may accelerate the healing of non-healing chronic wounds [41]. This needs to be confirmed in a larger controlled trial, but when considering the pathophysiological abnormalities present in chronic wounds there is the potential that stem cells may reconstitute dermal, vascular and other components required for optimal healing.


Considerable progress has been made on advanced products in the field of wound healing and a number of new therapeutic approaches are now available. It is hoped that continued advances will come about which, when combined with basic medical and surgical approaches, will accelerate the healing of chronic wounds to an extent that is still not possible with current therapeutic agents.

It is important to note that the treatment of chronic wounds has evolved rapidly over the past few years and it could be argued that the increased number of randomised clinical trials for chronic wounds has improved standard wound care. If this is so, in the future new products will be required to perform much better than the controls to show efficacy.

In addition, to make the best use of advanced products clinical trials will have to include more complex wound types. For example, existing advanced therapeutic products tested on diabetic foot ulcers, such as growth factors and skin equivalents, have focused entirely on neuropathic ulcers of the metatarsal heads. Arterial insufficiency and more complex heel ulcers have been exclusion criteria in these trials. Purely neuropathic ulcers are relatively straightforward and many clinicians believe they can be effectively treated with sound surgical debridement and off-loading. While it might be argued that accelerating the healing of these relatively simple ulcers may prevent complications arising from infection, more needs to be done to show cost-effectiveness to our society as a whole.

A rational strategy for the effective use of advanced products in chronic wound healing is likely to require greater understanding of the clinical factors involved as well as the pathophysiological components that underlie impaired healing.


1. Bell E, Ehrlich HP, Buttle DJ, Nakatsuji T. Living tissue formed in vitro and accepted as skin-equivalent tissue of full thickness. Science 1981; 211(4486): 1052-54.

2. Boyce ST. Design principles for composition and performance of cultured skin substitutes. Burns 2001; 27(5): 523-33.

3. European Wound Management Association. Position Document: Wound Bed Preparation in Practice. London: MEP Ltd, 2004. Available from URL:

4. Longaker MT, Chiu ES, Adzick NS, Stern M, Harrison MR, Stern R. Studies in fetal wound healing. V. A prolonged presence of hyaluronic acid characterizes fetal wound fluid. Ann Surg 1991; 213(4): 292-96.

5. Longaker MT, Whitby DJ, Ferguson MW, Lorenz HP, Harrison MR, Adzick NS. Adult skin wounds in the fetal environment heal with scar formation. Ann Surg 1994; 219(1): 65-72.

6. Mackool RJ, Gittes GK, Longaker MT. Scarless healing. The fetal wound. Clin Plast Surg 1998; 25(3): 357-65.

7. Mast BA, Diegelmann RF, Krummel TM, Cohen IK. Scarless wound healing in the mammalian fetus. Surg Gynecol Obstet 1992; 174(5): 441-51.

8. Martin P. Wound healing--aiming for perfect skin regeneration. Science 1997; 276(5309): 75-81.

9. Falanga V, Eaglstein WH, Bucalo B, Katz MH, Harris B, Carson P. Topical use of human recombinant epidermal growth factor (h-EGF) in venous ulcers. J Dermatol Surg Oncol 1992; 18(7): 604-06.

10. Robson MC, Phillips TJ, Falanga V, Odenheimer DJ, Parish LC, Jensen JL, et al. Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor-2) to accelerate wound healing in venous ulcers. Wound Repair Regen 2001; 9(5): 347-52.

11. Robson MC, Phillips LG, Lawrence WT, Bishop JB, Youngerman JS, Hayward PG, et al. The safety and effect of topically applied recombinant basic fibroblast growth factor on the healing of chronic pressure sores. Ann Surg 1992; 216(4): 401-6; discussion 406-08.

12. Robson MC, Phillips LG, Thomason A, Robson LE, Pierce GF. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet 1992; 339(8784): 23-25.

13. Pierce GF, Tarpley JE, Allman RM, Goode PS, Serdar CM, Morris B, et al. Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB. Am J Pathol 1994; 145(6): 1399-410.

14. Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic Ulcer Study Group. J Vasc Surg 1995; 21(1): 71-8; discussion 79-81.

15. Steed DL, Donohoe D, Webster MW, Lindsley L. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group. J Am Coll Surg 1996; 183(1): 61-4.

16. Smiell JM, Wieman TJ, Steed DL, Perry BH, Sampson AR, Schwab BH. Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Repair Regen 1999; 7(5): 335-46.

17. Robson MC. Growth factors as wound healing agents. Curr Opin Biotechnol 1991; 2(6): 863-67.

18. Cross SE, Roberts MS. Defining a model to predict the distribution of topically applied growth factors and other solutes in excisional full-thickness wounds. J Invest Dermatol 1999; 112(1): 36-41.

19. Robson MC, Hill DP, Smith PD, Wang X, Meyer-Siegler K, Ko F, et al. Sequential cytokine therapy for pressure ulcers: clinical and mechanistic response. Ann Surg 2000; 231(4): 600-11.

20. Falanga V. Classifications for wound bed preparation and stimulation of chronic wounds. Wound Repair Regen 2000; 8(5): 347-52.

21. Leigh IM, Navsaria H, Purkis PE, McKay I. Clinical practice and biological effects of keratinocyte grafting. Ann Acad Med Singapore 1991; 20(4): 549-55.

22. Gallico GG. Biologic skin substitutes. Clin Plast Surg 1990; 17(3): 519-26.

23. Phillips TJ, Gilchrest BA. Clinical applications of cultured epithelium. Epithelial Cell Biol 1992; 1(1): 39-46.

24. Sabolinski ML, Alvarez O, Auletta M, Mulder G, Parenteau NL. Cultured skin as a 'smart material' for healing wounds: experience in venous ulcers. Biomaterials 1996; 17(3): 311-20.

25. Hansbrough JF, Doré C, Hansbrough WB. Clinical trials of a living dermal tissue replacement placed beneath meshed, split-thickness skin grafts on excised burn wounds. J Burn Care Rehabil 1992; 13(5): 519-29.

26. Hansbrough JF, Mozingo DW, Kealey GP, Davis M, Gidner A, Gentzkow GD. Clinical trials of a biosynthetic temporary skin replacement, Dermagraft-Transitional Covering, compared with cryopreserved human cadaver skin for temporary coverage of excised burn wounds. J Burn Care Rehabil 1997; 18(1 Pt 1): 43-51.

27. Margolis DJ, Lewis VL. A literature assessment of the use of miscellaneous topical agents, growth factors, and skin equivalents for the treatment of pressure ulcers. Dermatol Surg 1995; 21(2): 145-48.

28. Phillips TJ. Biologic skin substitutes. J Dermatol Surg Oncol 1993; 19(8): 794-800.

29. Gentzkow GD, Iwasaki SD, Hershon KS, Mengel M, Prendergast JJ, Ricotta JJ, et al. Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care 1996; 19(4): 350-54.

30. Veves A, Falanga V, Armstrong DG, Sabolinski ML, Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care 2001; 24(2): 290-95.

31. Mansbridge J, Liu K, Patch R, Symons K, Pinney E. Three-dimensional fibroblast culture implant for the treatment of diabetic foot ulcers: metabolic activity and therapeutic range. Tissue Eng 1998; 4(4): 403-14.

32. Falanga V, Isaacs C, Paquette D, Downing G, Kouttab N, Butmarc J, et al. Wounding of bioengineered skin: cellular and molecular aspects after injury. J Invest Dermatol 2002; 119(3): 653-60.

33. Phillips TJ, Manzoor J, Rojas A, Isaacs C, Carson P, Sabolinski M, et al. The longevity of a bilayered skin substitute after application to venous ulcers. Arch Dermatol 2002; 138(8): 1079-81.

34. Slama J, Davidson JM, Eriksson E. Gene therapy of wounds. In: Falanga V, editor. Cutaneous Wound Healing. London: Martin Dunitz, 2001; 123-140.

35. Badiavas EV, Falanaga V. Gene therapy. Hum Gene Ther 1999; 28(4): 175-192.

36. Eming SA, Medalie DA, Tompkins RG, Yarmush ML, Morgan JR. Genetically modified human keratinocytes overexpressing PDGF-A enhance the performance of a composite skin graft. Hum Gene Ther 1998; 9(4): 529-39.

37. Human gene marker/therapy clinical protocols. Hum Gene Ther 1999; 10(12): 2037-88.

38. Yao F, Eriksson E. Gene therapy in wound repair and regeneration. Wound Repair Regen 2000; 8(6): 443-51.

39. Isner JM, Baumgartner I, Rauh G, Schainfeld R, Blair R, Manor O, et al. Treatment of thromboangiitis obliterans (Buerger's disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results. J Vasc Surg 1998; 28(6): 964-73; discussion 73-5.

40. Quesenberry PJ, Colvin GA, Lambert JF, Frimberger AE, Dooner MS, Mcauliffe CI, et al. The new stem cell biology. Trans Am Clin Climatol Assoc 2002; 113: 182-206; discussion 206-07.

41. Badiavas EV, Falanga V. Treatment of chronic wounds with bone marrow-derived cells. Arch Dermatol 2003; 139(4): 510-16.

All materials copyright © 1992-Feb 2001 by SMTL, March 2001 et seq by SMTL unless otherwise stated.

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