Research into the healing of venous leg ulcers is increasing as they are a common problem. The wound fluid bathing an ulcer is thought to reflect the wound microenvironment, and the properties of wound fluids have been studied in attempts to find ways to promote healing. After a brief summary of normal wound healing, this article reviews some of the research that has been carried out on venous ulcer wound fluid, with respect to its biochemistry, proteolytic nature, growth factor profile, and effects on cell cultures. Some of the problems and pitfalls inherent in performing and interpreting wound fluid studies are discussed. Finally, a proposal is made for standardizing research on wound fluids that would improve comparisons between different studies.
Cornwall JV, Dore CJ, Lewis JD.Leg ulcers: epidemiology and aetiology. Br J Surg1986;73:693-696.
2.
Callam MJ, Ruckley CV, Harper DR, Dale JJ.Chronic ulceration of the leg: extent of the problem and provision of care. Br Med J (Clin Res Ed)1985;290:1855-1856.
3.
Nelzen O, Bergqvist D, Lindhagen A.The prevalence of chronic lower-limb ulceration has been underestimated: results of a validated population questionnaire. Br J Surg1996;83:255-258.
4.
Olin JW, Beusterien KM, Childs MB, Seavey C, McHugh L, Griffiths RI.Medical costs of treating venous stasis ulcers: evidence from a retrospective cohort study. Vasc Med1999;4:1-7.
5.
Marston WA, Carlin RE, Passman MA, Farber MA, Keagy BA.Healing rates and cost efficacy of outpatient compression treatment for leg ulcers associated with venous insufficiency. J Vasc Surg1999;30:491-498.
6.
Jopp-Mckay AG, Stacey MC, Rohr JB, Baker SR, Thompson PJ, Hoskin SE.Outpatient treatment of chronic venous ulcers in a specialized clinic. Austr J Dermatol1991;32:143-149.
7.
Browse NL.Diseases of the veins. London: Hodder Arnold;1999.
8.
Burnand KG, Whimster I, Naidoo A, Browse NL.Pericapillary fibrin in the ulcer-bearing skin of the leg: the cause of lipodermatosclerosis and venous ulceration. Br Med J (Clin Res Ed)1982;285:1071-1072.
9.
Fagrell B.Microcirculatory disturbances—the final cause for venous leg ulcers?Vasa1982;11:101-103.
10.
Leu HJ.The current concept of the pathogenesis of trophic skin lesions in chronic venous insufficiency from the morphologic viewpoint. Wien Med Wochenschr1994;144:199-200.
11.
Lindblad WJ.Animal models in wound healing research: do we need more?Wound Repair Regen2000;8:81-82.
12.
Barone EJ, Yager DR, Pozez AL, et al.Interleukin-1alpha and collagenase activity are elevated in chronic wounds [see comments]. Plast Reconstruct Surg1998;102:1023-1027.
13.
Nwomeh BC, Liang HX, Cohen IK, Yager DR.MMP-8 is the pre dominant collagenase in healing wounds and nonhealing ulcers. J Surg Res1999;81:189-195.
14.
Weckroth M, Vaheri A, Lauharanta J, Sorsa T, Konttinen YT.Matrix metalloproteinases, gelatinase and collagenase, in chronic leg ulcers. J Invest Dermatol1996;106:1119-1124.
15.
Rasmussen LH, Jensen LT, Avnstor PC, Karlsmark T, Peters K, Horslev-Petersen K.Collagen types I and III propeptides as markers of healing in chronic leg ulcers. A noninvasive method for the determination of procollagen propeptides in wound fluid—influence of growth hormone. Ann Surg1992;216:684-691.
16.
Hoffman R, Noble J, Eagle M.The use of proteases as prognostic markers for the healing of venous leg ulcers. J Wound Care1999;8:273-276.
17.
Rao CN, Lodin DA, Liu YY, Chilukuri K, Hou ZZ, Woodley DI.Alpha 1-antitrypsin is degraded and non-functional in chronic wounds but intact and functional in acute wounds: the inhibitor protects fibronectin from degradation by chronic wound fluid enzymes. J Invest Dermatol1995;105:572-578.
18.
Oono T, Fujiwara Y, Yoshioka T, Arata J.Prolidase activity in chronic wound and blister fluids. J Dermatol1997;24:626-629.
19.
Phillips TJ, al Amoudi HO, Leverkus M, Park HY.Effect of chronic wound fluid on fibroblasts. J Wound Care1998;7:527-532.
20.
Bullen EC, Longaker MT, Updike DL, et al.Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds. J Invest Dermatol1995;104:236-240.
21.
Tarlton JF, Bailey AJ, Crawford E, Jones D, Moore K, Harding KD.Prognostic value of markers of collagen remodeling in venous ulcers. Wound Repair Regen1999;7:347-355.
22.
James TJ, Hughes MA, Cherry GW, Taylor RP.Simple biochemical markers to assess chronic wounds. Wound Repair Regen2000;8:264-269.
23.
Trengove NJ, Stacey MC, MacAuley S, et al.Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound Repair Regen1999;7:442-452.
24.
Katz MH, Alvarez AF, Kirsner RS, Eaglstein WH, Falanga V.Human wound fluid from acute wounds stimulates fibroblast and endothelial cell growth. J Am Acad Dermatol1991;25:1054-1058.
25.
Bullen EC, Longaker MT, Updike DL, et al.Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds. J Invest Dermatol1995;104:236-240.
26.
Wysocki AB, Staiano-Coico L, Grinnell F.Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol1993;101:64-68.
27.
Agren MS, Jorgensen LN, Andersen M, Viljanto J, Gottrup F.Ma trix metalloproteinase 9 level predicts optimal collagen deposition during early wound repair in humans. Br J Surg1998;85:68-71.
28.
Wysocki AB, Grinnell F.Fibronectin profiles in normal and chronic wound fluid. Lab Invest1990;63:825-831.
29.
Falanga V.Growth factors and chronic wounds: the need to understand the microenvironment. J Dermatol1992;19:667-672.
30.
Harris IR, Yee KC, Walters CE, et al.Cytokine and protease levels in healing and non-healing chronic venous leg ulcers. Exp Dermatol1995;4:342-349.
Wysocki AB.Fibronectin in acute and chronic wounds. J ET Nurs1992;19:166-170.
33.
Wysocki AB, Grinnell F.Fibronectin profiles in normal and chronic wound fluid. Lab Invest1990;63:825-831.
34.
Grinnell F, Ho CH, Wysocki A.Degradation of fibronectin and vitronectin in chronic wound fluid: analysis by cell blotting, immunoblotting, and cell adhesion assays. J Invest Dermatol1992;98:410-416.
35.
Grinnell F, Zhu M.Identification of neutrophil elastase as the proteinase in burn wound fluid responsible for degradation of fibronectin. J Invest Dermatol1994;103:155-161.
36.
Wysocki AB, Staiano-Coico L, Grinnell F.Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol1993;101:64-68.
37.
Wysocki AB, Kusakabe AO, Chang S, Tuan TL.Temporal expression of urokinase plasminogen activator, plasminogen activator inhibitor and gelatinase-B in chronic wound fluid switches from a chronic to acute wound profile with progression to healing. Wound Repair Regen1999;7:154-165.
38.
Aberg M, Hedner U, Jacobsson S, Rothman U.Fibrinolytic activity in wound secretions. Scand J Plast Reconstr Surg1976;10:103-105.
39.
Hoffman R, Starkey S, Coad J.Wound fluid from venous leg ulcers degrades plasminogen and reduces plasmin generation by keratinocytes. J Invest Dermatol1998;111:1140-1144.
40.
Latijnhouwers MA, Bergers M, Veenhuis RT, Beekman B, Ankersmit-Terhorst MF, Schalkwijk J.Tenascin-C degradation in chronic wounds is dependent on serine proteinase activity. Arch Dermatol Res1998;290:490-496.
41.
Li WW, Grayson G, Folkman J, D’Amore PA.Sustained-release endotoxin. A model for inducing corneal neovascularization. Invest Ophthalmol Vis Sci1991;32:2906-2911.
42.
Ono I, Gunji H, Suda K, Iwatsuki K, Kaneko F.Evaluation of cytokines in donor site wound fluids. Scand J Plast Reconstr Surg Hand Surg1994;28:269-273.
43.
Ono I, Gunji H, Zhang JZ, Maruyama K, Kaneko F.Studies on cytokines related to wound healing in donor site wound fluid. J Dermatol Sci1995;10:241-245.
44.
Vogt PM, Lehnhardt M, Wagner D, Jansen V, Krieg M, Steinau HU.Determination of endogenous growth factors in human wound fluid: temporal presence and profiles of secretion. Plast Reconstruct Surg1998;102:117-123.
45.
Breuing K, Andree C, Helo G, Slama J, Liu PY, Eriksson E.Growth factors in the repair of partial thickness porcine skin wounds. Plast Reconstruct Surg1997;100:657-664.
46.
Trengove NJ, Bielefeldt-Ohmann H, Stacey MC.Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers. Wound Repair Regen2000;8:13-25.
47.
Wallace HJ, Stacey MC.Levels of tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors in chronic venous leg ulcers—correlations to healing status. J Invest Dermatol1998; 110:292-296.
48.
He C, Hughes MA, Cherry GW, Arnold F.Effects of chronic wound fluid on the bioactivity of platelet-derived growth factor in serum-free medium and its direct effect on fibroblast growth. Wound Repair Regen1999;7:97-105.
49.
Lauer G, Sollberg S, Cole M, et al.Expression and proteolysis of vascular endothelial growth factor is increased in chronic wounds. J Invest Dermatol2000;115:12-18.
50.
Mills CD, Pricolo VE, Albina JE, Caldwell MD.Concomitant macrophage activation and fibroblast/lymphocyte inhibition by wound fluid: the “arginine-deficiency of inflammation” is a partial explanation. Prog Clin Biol Res1991;365:193-203.
51.
Picardo M, Grey AM, McGurk M, Ellis I, Schor SL.Detection of migration stimulating activity in wound fluid. Exp Mol Pathol1992;57:8-21.
52.
Greenburg GB, Hunt TK.The proliferative response in vitro of vascular endothelial and smooth muscle cells exposed to wound fluids and macrophages. J Cell Physiol1978;97:353-360.
53.
Banda MJ, Knighton DR, Hunt TK, Werb Z.Isolation of a nonmitogenic angiogenesis factor from wound fluid. Proc Natl Acad Sci U S A1982;79:7773-7777.
54.
Bucalo B, Eaglstein WH, Falanga V.Inhibition of cell proliferation by chronic wound fluid. Wound Repair Regen1993;1:181-186.
55.
Shakespeare V, Shakespeare P.Effects of granulation-tissue-conditioned medium on the growth of human keratinocytes in-vitro. Br J Plast Surg1991;44:219-223.
56.
Bishop ET, Bell GT, Bloor S, Broom IJ, Hendry NFK, Wheatley DN.An in vitro model of angiogenesis: basic features. Angiogenesis1999;3:335-344.
57.
Drinkwater SL, Smith A, Sawyer BM, Burnand KG.Effect of venous ulcer exudates on angiogenesis in vitro. Br J Surg2002;89:709-713.
Mendez MV, Stanley A, Park HY, Shon K, Phillips T, Menzolan JO.Fibroblasts cultured from venous ulcers display cellular characteristics of senescence. J Vasc Surg1998;28:876-883.
