Hostname: page-component-cd9895bd7-dzt6s Total loading time: 0 Render date: 2024-12-25T14:07:36.025Z Has data issue: false hasContentIssue false

Delayed wound healing in elderly people

Published online by Cambridge University Press:  02 November 2009

Helen A. Thomason
Affiliation:
Faculty of Life Sciences, University of Manchester, UK
Matthew J. Hardman*
Affiliation:
Faculty of Life Sciences, University of Manchester, UK
*
Address for correspondence: Dr Matthew Hardman, Faculty of Life Sciences, A.V. Hill Building, Oxford Road, University of Manchester, Manchester M13 9PT, United Kingdom. Email: [email protected]

Summary

Our ability to heal wounds deteriorates with age, leading in many cases to a complete lack of repair and development of a chronic wound. Moreover, as the elderly population continues to grow the prevalence of non-healing chronic wounds is escalating. Cutaneous wound repair occurs through a combination of overlapping phases, including an initial inflammatory response, a proliferative phase and a final remodelling phase. In elderly subjects the inflammatory response is delayed, macrophage and fibroblast function compromised, angiogenesis reduced and re-epithelialization inhibited. Whilst a large body of historic research describes the defective processes that lead to delayed healing, only recently have the molecular mechanisms by which these defects arise begun to be elucidated. Current therapies available for treatment of chronic wounds in elderly people are surprisingly limited and generally ineffective. Thus there is an urgent need to develop new therapeutic strategies based on these recent molecular and cellular insights.

Type
Biological gerontology
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Wysocki, AB. Skin anatomy, physiology, and pathophysiology. Nurs Clin North Am 1999; 34: 777–97.Google Scholar
2Clark, RA. Fibronectin matrix deposition and fibronectin receptor expression in healing and normal skin. J Invest Dermatol 1990; 94 (suppl): 12834S.Google Scholar
3Anitua, E, Andia, I, Ardanza, B, Nurden, P, Nurden, AT. Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost 2004; 91: 415.CrossRefGoogle ScholarPubMed
4Schober, A, Weber, C. Mechanisms of monocyte recruitment in vascular repair after injury. Antioxid Redox Signal 2005; 7: 1249–57.Google Scholar
5Gillitzer, R, Goebeler, M. Chemokines in cutaneous wound healing. J Leukoc Biol 2001; 69: 513–21.CrossRefGoogle ScholarPubMed
6Ho, VW, Sly, LM. Derivation and characterization of murine alternatively activated (M2) macrophages. Methods Mol Biol 2009; 531: 173–85.CrossRefGoogle ScholarPubMed
7Martin, DE, Reece, MC, Maher, JE, Reese, SC. Tissue debris at the injury site is coated by plasma fibronectin and subsequently removed by tissue macrophages. Arch Dermatol 1988; 124: 226–9.CrossRefGoogle ScholarPubMed
8Fujiwara, N, Kobayashi, K. Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 2005; 4: 281–6.CrossRefGoogle ScholarPubMed
9Eckes, B, Zigrino, P, Kessler, D et al. Fibroblast–matrix interactions in wound healing and fibrosis. Matrix Biol 2000; 19: 325–32.CrossRefGoogle ScholarPubMed
10Clark, RA, An, JQ, Greiling, D, Khan, A, Schwarzbauer, JE. Fibroblast migration on fibronectin requires three distinct functional domains. J Invest Dermatol 2003; 121: 695705.Google Scholar
11Midwood, KS, Mao, Y, Hsia, HC, Valenick, LV, Schwarzbauer, JE. Modulation of cell–fibronectin matrix interactions during tissue repair. J Investig Dermatol Symp Proc 2006; 11: 73–8.CrossRefGoogle ScholarPubMed
12Salo, T, Mäkelä, M, Kylmäniemi, M, Autio-Harmainen, H, Larjava, H. Expression of matrix metalloproteinase-2 and -9 during early human wound healing. Lab Invest 1994; 70: 176–82.Google Scholar
13Desmoulière, A, Geinoz, A, Gabbiani, F, Gabbiani, G. Transforming growth factor-β1 induces α-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993; 122: 103–11.Google Scholar
14Vaughan, MB, Howard, EW, Tomasek, JJ. Transforming growth factor-β1 promotes the morphological and functional differentiation of the myofibroblast. Exp Cell Res 2000; 257: 180–9.CrossRefGoogle ScholarPubMed
15Hinz, B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007; 127: 526–37.CrossRefGoogle ScholarPubMed
16Barrandon, Y, Green, H. Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-α and epidermal growth factor. Cell 1987; 50: 1131–7.Google Scholar
17Décline, F, Okamoto, O, Mallein-Gerin, F et al. Keratinocyte motility induced by TGF-β1 is accompanied by dramatic changes in cellular interactions with laminin 5. Cell Motil Cytoskeleton 2003; 54: 6480.CrossRefGoogle ScholarPubMed
18Iwamoto, R, Mekada, E. Heparin-binding EGF-like growth factor: a juxtacrine growth factor. Cytokine Growth Factor Rev 2000; 11: 335–44.CrossRefGoogle ScholarPubMed
19Werner, S, Peters, KG, Longaker, MT, Fuller-Pace, F, Banda, MJ, Williams, LT. Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci USA 1992; 89: 6896–900.CrossRefGoogle ScholarPubMed
20Sivamani, RK, Garcia, MS, Isseroff, RR. Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front Biosci 2007; 12: 2849–68.Google Scholar
21Haase, I, Evans, R, Pofahl, R, Watt, FM. Regulation of keratinocyte shape, migration and wound epithelialization by IGF-1- and EGF-dependent signalling pathways. J Cell Sci 2003; 116: 3227–38.Google Scholar
22Grφndahl-Hansen, J, Lund, LR, Ralfkiaer, E, Ottevanger, V, Danφ, K. Urokinase- and tissue-type plasminogen activators in keratinocytes during wound re-epithelialization in vivo. J Invest Dermatol 1988; 90: 790–5.Google Scholar
23Rφmer, J, Lund, LR, Eriksen, J, Pyke, C, Kristensen, P, Danφ, K. The receptor for urokinase-type plasminogen activator is expressed by keratinocytes at the leading edge during re-epithelialization of mouse skin wounds. J Invest Dermatol 1994; 102: 519–22.Google Scholar
24Ossowski, L, Aguirre-Ghiso, JA. Urokinase receptor and integrin partnership: co-ordination of signalling for cell adhesion, migration and growth. Curr Opin Cell Biol 2000; 12: 613–20.Google Scholar
25Pilcher, BK, Dumin, J, Schwartz, MJ et al. Keratinocyte collagenase-1 expression requires an epidermal growth factor receptor autocrine mechanism. J Biol Chem 1999; 274: 10372–81.CrossRefGoogle ScholarPubMed
26McCawley, LJ, Matrisian, LM. Matrix metalloproteinases: they're not just for matrix anymore! Curr Opin Cell Biol 2001; 13: 534–40.CrossRefGoogle Scholar
27Seiki, M. The cell surface: the stage for matrix metalloproteinase regulation of migration. Curr Opin Cell Biol 2002; 14: 624–32.CrossRefGoogle ScholarPubMed
28Krawczyk, WS, Wilgram, GF. Hemidesmosome and desmosome morphogenesis during epidermal wound healing. J Ultrastruct Res 1973; 45: 93101.Google Scholar
29Litjens, SH, de Pereda, JM, Sonnenberg, A. Current insights into the formation and breakdown of hemidesmosomes. Trends Cell Biol 2006; 16: 376–83.CrossRefGoogle ScholarPubMed
30Garlick, JA, Taichman, LB. Fate of human keratinocytes during re-epithelialization in an organotypic culture model. Lab Invest 1994; 70: 916–24.Google Scholar
31Ito, M, Liu, Y, Yang, Z et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 2005; 11: 1351–4.Google Scholar
32Li, J, Zhang, YP, Kirsner, RS. Angiogenesis in wound repair: angiogenic growth factors and the extracellular matrix. Microsc Res Tech 2003; 60: 107–14.CrossRefGoogle ScholarPubMed
33Brooks, PC, Clark, RA, Cheresh, DA. Requirement of vascular integrin α v. β3 for angiogenesis. Science 1994; 264: 569–71.CrossRefGoogle Scholar
34Reed, MJ, Corsa, AC, Kudravi, SA, McCormick, RS, Arthur, WT. A deficit in collagenase activity contributes to impaired migration of aged microvascular endothelial cells. J Cell Biochem 2000; 77: 116–26.3.0.CO;2-7>CrossRefGoogle ScholarPubMed
35Moses, MA, Marikovsky, M, Harper, JW et al. Temporal study of the activity of matrix metalloproteinases and their endogenous inhibitors during wound healing. J Cell Biochem 1996; 60: 379–86.Google Scholar
36Lobmann, R, Ambrosch, A, Schultz, G, Waldmann, K, Schiweck, S, Lehnert, H. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia 2002; 45: 1011–6.Google Scholar
37Kurban, RS, Bhawan, J. Histologic changes in skin associated with aging. J Dermatol Surg Oncol 1990; 16: 908–14.Google Scholar
38Branchet, MC, Boisnic, S, Frances, C, Robert, AM. Skin thickness changes in normal aging skin. Gerontology 1990; 36: 2835.Google Scholar
39Branchet, MC, Boisnic, S, Frances, C, Lesty, C, Robert, L. Morphometric analysis of dermal collagen fibers in normal human skin as a function of age. Arch Gerontol Geriatr 1991; 13: 114.CrossRefGoogle ScholarPubMed
40Shuster, S, Black, MM, McVitie, . The influence of age and sex on skin thickness, skin collagen and density. Br J Dermatol 1975; 93: 639–43.CrossRefGoogle ScholarPubMed
41El-Domyati, M, Attia, S, Saleh, F et al. Intrinsic aging vs. photoaging: a comparative histopathological, immunohistochemical, and ultrastructural study of skin. Exp Dermatol 2002; 11: 398405.CrossRefGoogle ScholarPubMed
42Swift, ME, Kleinman, HK, DePietro, LA. Impaired wound repair and delayed angiogenesis in aged mice. Lab Invest 1999; 79: 1479–87.Google ScholarPubMed
43Reed, MJ, Ferara, NS, Vernon, RB. Impaired migration, integrin function, and actin cytoskeletal organization in dermal fibroblasts from a subset of aged human donors. Mech Ageing Dev 2001; 122: 1203–20.Google Scholar
44Andrew, W, Behnke, RH, Sato, T. Changes with advancing age in the cell population of the human dermis. Gerontologia 1964; 10: 119.Google Scholar
45Charruyer, A, Barland, CO, Yue, L et al. Transit-amplifying cell frequency and cell cycle kinetics are altered in aged epidermis. J Invest Dermatol 2009 (Epub ahead of print).Google Scholar
46Montagna, W, Carlisle, K. Structural changes in ageing skin. Br J Dermatol 1990; 122 (suppl 35): 6170.Google Scholar
47Pochi, PE, Strauss, JS, Downing, DT. Age-related changes in sebaceous gland activity. J Invest Dermatol 1979; 73: 108–11.Google Scholar
48Ashcroft, GS, Horan, MA, Ferguson, MW. Aging is associated with reduced deposition of specific extracellular matrix components, an upregulation of angiogenesis, and an altered inflammatory response in a murine incisional wound healing model. J Invest Dermatol 1997; 108: 430–7.Google Scholar
49Ashcroft, GS, Horan, MA, Ferguson, MW. Aging alters the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous wound healing. Lab Invest 1998; 78: 4758.Google ScholarPubMed
50Swift, ME, Burns, AL, Gray, KL, DiPietro, LA. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol 2001; 117: 1027–35.Google Scholar
51Danon, D, Kowatch, MA, Roth, GS. Promotion of wound repair in old mice by local injection of macrophages. Proc Natl Acad Sci USA 1989; 86: 2018–20.CrossRefGoogle ScholarPubMed
52Plisko, A, Gilchrest, BA. Growth factor responsiveness of cultured human fibroblasts declines with age. J Gerontol 1983; 38: 513–8.CrossRefGoogle ScholarPubMed
53Bruce, SA, Deamond, SF. Longitudinal study of in vivo wound repair and in vitro cellular senescence of dermal fibroblasts. Exp Gerontol 1991; 26: 1727.Google Scholar
54Freedland, M, Karmiol, S, Rodriguez, J, Normolle, D, Smith, D Jr, Garner, W. Fibroblast responses to cytokines are maintained during aging. Ann Plast Surg 1995; 35: 290–6.CrossRefGoogle ScholarPubMed
55Ballas, CB, Davidson, JM. Delayed wound healing in aged rats is associated with increased collagen gel remodelling and contraction by skin fibroblasts, not with differences in apoptotic or myofibroblast cell populations. Wound Repair Regen 2001; 9: 223–37.Google Scholar
56Holt, DR, Kirk, SJ, Regan, MC, Hurson, M, Lindblad, WJ, Barbul, A. Effect of age on wound healing in healthy human beings. Surgery 1992; 112: 293–7.Google Scholar
57Ashcroft, GS, Horan, MA, Ferguson, MW. The effects of ageing on wound healing: immunolocalisation of growth factors and their receptors in a murine incisional model. J Anat 1997; 190: 351–65.Google Scholar
58Xia, YP, Zhao, Y, Tyrone, JW, Chen, A, Mustoe, TA. Differential activation of migration by hypoxia in keratinocytes isolated from donors of increasing age: implication for chronic wounds in the elderly. J Invest Dermatol 2001; 116: 50–6.Google Scholar
59Arthur, WT, Vernon, RB, Sage, EH, Reed, MJ. Growth factors reverse the impaired sprouting of microvessels from aged mice. Microvasc Res 1998; 55: 260–70.Google Scholar
60Ashcroft, GS, Kielty, CM, Horan, MA, Ferguson, MW. Age-related changes in the temporal and spatial distributions of fibrillin and elastin mRNAs and proteins in acute cutaneous wounds of healthy humans. J Pathol 1997; 183: 80–9.3.0.CO;2-N>CrossRefGoogle ScholarPubMed
61Halasz, NA. Dehiscence of laparotomy wounds. Am J Surg 1968; 116: 210–4.CrossRefGoogle ScholarPubMed
62Sandblom, P. Determination of the tensile strength of the healing wound as a clinical test. J Int Chir 1953; 13 (4): extra pages, 14.Google ScholarPubMed
63Holm-Pedersen, P, Zederfeldt, B. Strength development of skin incisions in young and old rats. Scand J Plast Reconstr Surg 1971; 5: 712.Google ScholarPubMed
64Beck, LS, DeGuzman, L, Lee, WP, Xu, Y, Siegel, MW, Amento, EP. One systemic administration of transforming growth factor-β1 reverses age- or glucocorticoid-impaired wound healing. J Clin Invest 1993; 92: 2841–9.Google Scholar
65Labrie, F, Bélanger, A, Cusan, L, Gomez, JL, Candas, B. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 1997; 82: 2396–402.Google Scholar
66Mills, SJ, Ashworth, JJ, Gilliver, SC, Hardman, MJ, Ashcroft, GS. The sex steroid precursor DHEA accelerates cutaneous wound healing via the estrogen receptors. J Invest Dermatol 2005; 125: 1053–62.Google Scholar
67Verdier-Sévrain, S, Bonté, F, Gilchrest, B. Biology of estrogens in skin: implications for skin aging. Exp Dermatol 2006; 15: 8394.CrossRefGoogle ScholarPubMed
68Ashcroft, GS, Greenwell-Wild, T, Horan, MA, Wahl, SM, Ferguson, MW. Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol 1999; 155: 1137–46.Google Scholar
69Margolis, DJ, Knauss, J, Bilker, W. Hormone replacement therapy and prevention of pressure ulcers and venous leg ulcers. Lancet 2002; 359: 675–7.Google Scholar
70Berard, A, Kahn, SR, Abenhaim, L. Is hormone replacement therapy protective for venous ulcer of the lower limbs? Pharmacoepidemol Drug Saf 2001; 10: 245–51.CrossRefGoogle ScholarPubMed
71Ashcroft, GS, Dodsworth, J, van Boxtel, E et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-β1 levels. Nat Med 1997; 3: 1209–15.CrossRefGoogle ScholarPubMed
72Hardman, MJ, Waite, A, Zeef, L, Burow, M, Nakayama, T, Ashcroft, GS. Macrophage migration inhibitory factor: a central regulator of wound healing. Am J Pathol 2005; 167: 1561–74.Google Scholar
73Hardman, MJ, Ashcroft, GS. Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly. Genome Biol 2008; 9: R80.Google Scholar
74Emmerson, E, Campbell, L, Ashcroft, GS, Hardman, MJ. Unique and synergistic roles for 17β-estradiol and macrophage migration inhibitory factor during cutaneous wound closure are cell type specific. Endocrinology 2009; 150: 2749–57.CrossRefGoogle ScholarPubMed
75Lundgren, D. Influence of estrogen and progesterone on exudation, inflammatory cell migration and granulation tissue formation in preformed cavities. Scand J Plast Reconstr Surg 1973; 7: 1014.Google Scholar
76Routley, CE, Ashcroft, GS. Effect of estrogen and progesterone on macrophage activation during wound healing. Wound Repair Regen 2009; 17: 4250.Google Scholar
77Ashcroft, GS, Mills, SJ, Lei, K et al. Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor. J Clin Invest 2003 May; 111: 1309–18.Google Scholar
78Taylor, RJ, Taylor, AD, Smyth, JV. Using an artificial neural network to predict healing times and risk factors for venous leg ulcers. J Wound Care 2002; 11: 101–5.CrossRefGoogle ScholarPubMed
79Ashcroft, GS, Mills, SJ. Androgen receptor-mediated inhibition of cutaneous wound healing. J Clin Invest 2002; 110: 615–24.Google Scholar
80Ashcroft, GS, Mills, SJ, Flanders, KC et al. Role of Smad3 in the hormonal modulation of in vivo wound healing responses. Wound Repair Regen 2003; 11: 468–73.CrossRefGoogle ScholarPubMed
81Gilliver, SC, Ruckshanthi, JP, Hardman, MJ, Nakayama, T, Ashcroft, GS. Sex dimorphism in wound healing: the roles of sex steroids and macrophage migration inhibitory factor. Endocrinology 2008; 149: 5747–57.CrossRefGoogle ScholarPubMed
82Gilliver, SC, Ruckshanthi, JP, Hardman, MJ, Zeef, LA, Ashcroft, GS. 5α-dihydrotestosterone (DHT) retards wound closure by inhibiting re-epithelialization. J Pathol 2009; 217: 7382.Google Scholar
83Rossouw, JE, Anderson, GL, Prentice, RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288: 321–33.Google ScholarPubMed
84Anderson, GL, Limacher, M, Assaf, AR et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291: 1701–12.Google Scholar
85Kerlikowske, K, Miglioretti, DL, Buist, DS et al. Declines in invasive breast cancer and use of postmenopausal hormone therapy in a screening mammography population. J Natl Cancer Inst 2007; 99: 1335–39.CrossRefGoogle Scholar
86Ravdin, PM, Cronin, KA, Howlader, N et al. The decrease in breast cancer incidence in 2003 in the United States. N Engl J Med 2007; 356: 1670–74.Google Scholar
87Kumle, M. Declining breast cancer incidence and decreased HRT use. Lancet 2008; 372: 608–10.Google Scholar
88Bluming, AZ, Tavris, C. Hormone replacement therapy: real concerns and false alarms. Cancer J 2009; 15: 93104.Google Scholar
89Hardman, MJ, Emmerson, E, Campbell, L, Ashcroft, GS. Selective estrogen receptor modulators accelerate cutaneous wound healing in ovariectomized female mice. Endocrinology 2008; 149: 551–7.Google Scholar
90Collins, P, Mosca, L, Geiger, MJ et al. Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for The Heart trial: results of subgroup analyses by age and other factors. Circulation 2009; 119: 922–30.Google Scholar
91Sumino, H, Ichikawa, S, Kasama, S et al. Effects of raloxifene and hormone replacement therapy on forearm skin elasticity in postmenopausal women. Maturitas 2009; 62: 53–7.CrossRefGoogle ScholarPubMed
92Gennari, L. Lasofoxifene, a new selective estrogen receptor modulator for the treatment of osteoporosis and vaginal atrophy. Expert Opin Pharmacother 2009; 10: 2209–20.Google Scholar
93Kung, AW, Chu, EY, Xu, L. Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis. Expert Opin Pharmacother 2009; 10: 1377–85.Google Scholar
94Nath, A, Sitruk-Ware, R. Pharmacology and clinical applications of selective estrogen receptor modulators. Climacteric 2009; 12: 188205.Google Scholar
95McDonnell, DP, Wijayaratne, A, Chang, CY, Norris, JD. Elucidation of the molecular mechanism of action of selective estrogen receptor modulators. Am J Cardiol 2002; 90A: 3543F.Google Scholar
96Shah, M, Foreman, DM, Ferguson, MW. Control of scarring in adult wounds by neutralising antibody to transforming growth factor β. Lancet 1992; 339: 213–4.Google Scholar
97Shah, M, Foreman, DM, Ferguson, MW. Neutralisation of TGF-β1 and TGF-β2 or exogenous addition of TGF-β3 to cutaneous rat wounds reduces scarring. J Cell Sci 2005; 108: 9851002.Google Scholar
98Uchi, H, Igarashi, A, Urabe, K et al. Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer. Eur J Dermatol 2009 (Epub ahead of print).Google Scholar
99Margolis, DJ, Cromblehome, T, Herlyn, M et al. Clinical protocol. Phase I trial to evaluate the safety of H5.020CMV.PDGF-β and limb compression bandage for the treatment of venous leg ulcer: trial A. Hum Gene Ther 2004; 15: 1003–19.Google Scholar
100Margolis, DJ, Morris, LM, Papadopoulos, M et al. Phase I Study of H5.020CMV.PDGF-β to treat venous leg ulcer disease. Mol Ther 2009 (Epub ahead of print).Google Scholar
101Horch, RE, Kopp, J, Kneser, U, Beier, J, Bach, AD. Tissue engineering of cultured skin substitutes. J Cell Mol Med 2005; 9: 592608.Google Scholar
102Hata, K. Current issues regarding skin substitutes using living cells as industrial materials. J Artif Organs 2007; 10: 129–32.Google Scholar
103Dinh, TL, Veves, A. The efficacy of Apligraf in the treatment of diabetic foot ulcers. Plast Reconstr Surg 2006; 117 (7 suppl): 15257S; discussion 158–59S.Google Scholar
104Edmonds, M. Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds 2009; 8: 11–8.Google Scholar