Impaired Wound Repair and Delayed Angiogenesis

  • Megan E. Schrementi
  • Matthew J. Ranzer
  • Luisa A. DiPietro
Living reference work entry


As the skin ages, the normal signs of aging such as alterations in pigmentation and increased wrinkling become more obvious. Although these changes appear to be mainly cosmetic, under the epidermis there is a gradual change in resident cell populations and loss of function. These changes result in a decreased ability to regulate homeostasis and underlie the delay in skin healing that occurs with age. Changes in hemostasis cause blood clotting to occur slowly and influence the healing progression. Likewise, age-related inflammatory changes in wounds most influence the latter phases of repair, including cellular proliferation and remodeling. Alterations in the stem cell populations that provide new cells to the healing wound occur, since this vital cell population is diminished in aged individuals. Thus, when a wound occurs, the normal stages of wound healing will proceed, although at an altered rate. In unfavorable conditions, this can result in an increased likelihood of infection or ulcer formation. Additionally, diseases associated with aging such as diabetes and vascular disease can amplify the alterations in wound healing, increasing the likelihood of wound complications. As research in the aged skin continues, the changes in the skin that affect wounding will continue to be elucidated, giving rise to new treatments for this growing patient population.


Wound Healing Hair Follicle Sweat Gland Aged Mouse Stem Cell Population 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Harris TJ. The skin. In: Rubin E, Faber J, editors. Pathology. Philadelphia: Lippincott-Raven; 1999. p. 1236–99.Google Scholar
  2. 2.
    Fisher GJ, et al. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med. 1997;337:1419–28.CrossRefPubMedGoogle Scholar
  3. 3.
    Gilchrest BA, et al. Aging and photoaging affect gene expression in cultured human keratinocytes. Arch Dermatol. 1994;130:82–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Census Bureau US. Population projections program. Washington, DC: Population Division, U.S. Census Bureau; 2000.Google Scholar
  5. 5.
    McMahon DJ, et al. Comorbidity and the elderly trauma patient. World J Surg. 1996;20:1113–9; discussion 9–20.CrossRefPubMedGoogle Scholar
  6. 6.
    DuNouy P. Cicatrization of wounds: the relation between the age of the patient, the area of the wound, and the index of cicatrization. J Exp Med. 1916;24:461–70.CrossRefGoogle Scholar
  7. 7.
    Agah A, et al. Thrombospondin 2 levels are increased in aged mice: consequences for cutaneous wound healing and angiogenesis. Matrix Biol. 2004;22:539–47.CrossRefPubMedGoogle Scholar
  8. 8.
    Ashcroft GS, et al. 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.CrossRefPubMedGoogle Scholar
  9. 9.
    Swift ME, et al. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol. 2001;117:1027–35.CrossRefPubMedGoogle Scholar
  10. 10.
    Kurban RS, Bhawan J. Histologic changes in skin associated with aging. J Dermatol Surg Oncol. 1990;16:908–14.CrossRefPubMedGoogle Scholar
  11. 11.
    Demaria M, et al. Cell autonomous and non-autonomous effects of senescent cells in the skin. J Invest Dermatol. 2015;135:1722–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Ashcroft GS, et al. The effects of ageing on cutaneous wound healing in mammals. J Anat. 1995;187(Pt 1):1–26.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Reed MJ, Edelberg JM. Impaired angiogenesis in the aged. Sci Aging Knowledge Environ. 2004;2004:pe7.CrossRefPubMedGoogle Scholar
  14. 14.
    Clausen B. Influence of age on connective tissue. Hexosamine and hydroxyproline in human aorta, myocardium, and skin. Lab Invest. 1962;11:229–34.PubMedGoogle Scholar
  15. 15.
    Swift ME, et al. Impaired wound repair and delayed angiogenesis in aged mice. Lab Invest. 1999;79:1479–87.PubMedGoogle Scholar
  16. 16.
    Vitellaro-Zuccarello L, et al. Immunocytochemical localization of collagen types I, III, IV, and fibronectin in the human dermis. Modifications with ageing. Cell Tissue Res. 1992;268:505–11.CrossRefPubMedGoogle Scholar
  17. 17.
    Lavker RM. Structural alterations in exposed and unexposed aged skin. J Invest Dermatol. 1979;73:59–66.CrossRefPubMedGoogle Scholar
  18. 18.
    Montagna W, Carlisle K. Structural changes in ageing skin. Br J Dermatol. 1990;122 Suppl 35:61–70.CrossRefPubMedGoogle Scholar
  19. 19.
    Pochi PE, et al. Age-related changes in sebaceous gland activity. J Invest Dermatol. 1979;73:108–11.CrossRefPubMedGoogle Scholar
  20. 20.
    Silver A. The effect of age on human eccrine sweating. In: Montagna W, editor. Advances in biology of the skin, vol. 6. Oxford: Pergamon; 1965. p. 129–49.Google Scholar
  21. 21.
    Tsuchida Y. The effect of aging and arteriosclerosis on human skin blood flow. J Dermatol Sci. 1993;5:175–81.CrossRefPubMedGoogle Scholar
  22. 22.
    Braverman IM, Fonferko E. Studies in cutaneous aging: II. The microvasculature. J Invest Dermatol. 1982;78:444–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Gniadecka M, et al. Age-related diurnal changes of dermal oedema: evaluation by high-frequency ultrasound. Br J Dermatol. 1994;131:849–55.CrossRefPubMedGoogle Scholar
  24. 24.
    Witte MB, Barbul A. General principles of wound healing. Surg Clin North Am. 1997;77:509–28.CrossRefPubMedGoogle Scholar
  25. 25.
    Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482–94.CrossRefPubMedGoogle Scholar
  26. 26.
    Ross R, Benditt EP. Wound healing and collagen formation. II. Fine structure in experimental scurvy. J Cell Biol. 1962;12:533–51.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Simpson DM, Ross R. The neutrophilic leukocyte in wound repair a study with antineutrophil serum. J Clin Invest. 1972;51:2009–23.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Mirza R, et al. Selective and specific macrophage ablation is detrimental to wound healing in mice. Am J Pathol. 2009;175:2454–62.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78:71–100.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. 2011;13:e23.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Ross R, Odland G. Human wound repair. II. Inflammatory cells, epithelial-mesenchymal interrelations, and fibrogenesis. J Cell Biol. 1968;39:152–68.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Degen KE, Gourdie RG. Embryonic wound healing: a primer for engineering novel therapies for tissue repair. Birth Defects Res C Embryo Today. 2012;96:258–70.CrossRefPubMedGoogle Scholar
  33. 33.
    Shaw TJ, Martin P. Wound repair at a glance. J Cell Sci. 2009;122:3209–13.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Mohebali D, et al. Alterations in platelet function during aging: clinical correlations with thromboinflammatory disease in older adults. J Am Geriatr Soc. 2014;62:529–35.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Hager K, et al. Blood coagulation factors in the elderly. Arch Gerontol Geriatr. 1989;9:277–82.CrossRefPubMedGoogle Scholar
  36. 36.
    Kovacs EJ. Aging, traumatic injury, and estrogen treatment. Exp Gerontol. 2005;40:549–55.CrossRefPubMedGoogle Scholar
  37. 37.
    Butcher SK, et al. Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J Leukoc Biol. 2001;70:881–6.PubMedGoogle Scholar
  38. 38.
    Di Lorenzo G, et al. Granulocyte and natural killer activity in the elderly. Mech Ageing Dev. 1999;108:25–38.CrossRefPubMedGoogle Scholar
  39. 39.
    Fortin CF, et al. Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions. J Leukoc Biol. 2006;79:1061–72.CrossRefPubMedGoogle Scholar
  40. 40.
    Dovi JV, et al. Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol. 2003;73:448–55.CrossRefPubMedGoogle Scholar
  41. 41.
    Martin P, et al. Wound healing in the PU.1 null mouse – tissue repair is not dependent on inflammatory cells. Curr Biol. 2003;13:1122–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Danon D, et al. Promotion of wound repair in old mice by local injection of macrophages. Proc Natl Acad Sci U S A. 1989;86:2018–20.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Gosain A, DiPietro LA. Aging and wound healing. World J Surg. 2004;28:321–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Plowden J, et al. Innate immunity in aging: impact on macrophage function. Aging Cell. 2004;3:161–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Herrero C, et al. Immunosenescence of macrophages: reduced MHC class II gene expression. Exp Gerontol. 2002;37:389–94.CrossRefPubMedGoogle Scholar
  46. 46.
    Gomez CR, et al. Innate immunity and aging. Exp Gerontol. 2008;43:718–28.PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Donnini A, et al. Phenotype, antigen-presenting capacity, and migration of antigen-presenting cells in young and old age. Exp Gerontol. 2002;37:1097–112.CrossRefPubMedGoogle Scholar
  48. 48.
    Goh J, Ladiges WC. Exercise enhances wound healing and prevents cancer progression during aging by targeting macrophage polarity. Mech Ageing Dev. 2014;139:41–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Holm-Pedersen P, Viidik A. Tensile properties and morphology of healing wounds in young and old rats. Scand J Plast Reconstr Surg. 1972;6:24–35.CrossRefPubMedGoogle Scholar
  50. 50.
    Mendoza Jr CB, et al. Veterans Administration cooperative study of surgery for duodenal ulcer. II. Incidence of wound disruption following operation. Arch Surg. 1970;101:396–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Holt DR, et al. Effect of age on wound healing in healthy human beings. Surgery. 1992;112:293–7; discussion 7–8.PubMedGoogle Scholar
  52. 52.
    Gilchrest BA. In vitro assessment of keratinocyte aging. J Invest Dermatol. 1983;81:184s–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell. 1975;6:331–43.CrossRefPubMedGoogle Scholar
  54. 54.
    Morris GM, et al. The cell kinetics of the epidermis and follicular epithelium of the rat: variations with age and body site. Cell Tissue Kinet. 1989;22:213–22.PubMedGoogle Scholar
  55. 55.
    Ross C, et al. Oxygen tension changes the rate of migration of human skin keratinocytes in an age-related manner. Exp Dermatol. 2011;20:58–63.PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Xia YP, et al. 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.CrossRefPubMedGoogle Scholar
  57. 57.
    Albini A, et al. Decline of fibroblast chemotaxis with age of donor and cell passage number. Coll Relat Res. 1988;8:23–37.CrossRefPubMedGoogle Scholar
  58. 58.
    Pienta KJ, Coffey DS. Characterization of the subtypes of cell motility in ageing human skin fibroblasts. Mech Ageing Dev. 1990;56:99–105.CrossRefPubMedGoogle Scholar
  59. 59.
    Plisko A, Gilchrest BA. Growth factor responsiveness of cultured human fibroblasts declines with age. J Gerontol. 1983;38:513–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Pieraggi MT, et al. Fibroblast changes in cutaneous ageing. Virchows Arch A Pathol Anat Histopathol. 1984;402:275–87.CrossRefPubMedGoogle Scholar
  61. 61.
    Phillips PD, et al. Progressive loss of the proliferative response of senescing WI-38 cells to platelet-derived growth factor, epidermal growth factor, insulin, transferrin, and dexamethasone. J Gerontol. 1984;39:11–7.CrossRefPubMedGoogle Scholar
  62. 62.
    Stanulis-Praeger BM, Gilchrest BA. Growth factor responsiveness declines during adulthood for human skin-derived cells. Mech Ageing Dev. 1986;35:185–98.CrossRefPubMedGoogle Scholar
  63. 63.
    Mogford JE, et al. Effect of age and hypoxia on TGFbeta1 receptor expression and signal transduction in human dermal fibroblasts: impact on cell migration. J Cell Physiol. 2002;190:259–65.CrossRefPubMedGoogle Scholar
  64. 64.
    Reenstra WR, et al. Effect of donor age on epidermal growth factor processing in man. Exp Cell Res. 1993;209:118–22.CrossRefPubMedGoogle Scholar
  65. 65.
    Komi-Kuramochi A, et al. Expression of fibroblast growth factors and their receptors during full-thickness skin wound healing in young and aged mice. J Endocrinol. 2005;186:273–89.CrossRefPubMedGoogle Scholar
  66. 66.
    Furth JJ. The steady-state levels of type I collagen mRNA are reduced in senescent fibroblasts. J Gerontol. 1991;46:B122–4.CrossRefPubMedGoogle Scholar
  67. 67.
    Lovell CR, et al. Type I and III collagen content and fibre distribution in normal human skin during ageing. Br J Dermatol. 1987;117:419–28.CrossRefPubMedGoogle Scholar
  68. 68.
    Burke EM, et al. Altered transcriptional regulation of human interstitial collagenase in cultured skin fibroblasts from older donors. Exp Gerontol. 1994;29:37–53.CrossRefPubMedGoogle Scholar
  69. 69.
    Hornebeck W. Down-regulation of tissue inhibitor of matrix metalloprotease-1 (TIMP-1) in aged human skin contributes to matrix degradation and impaired cell growth and survival. Pathol Biol (Paris). 2003;51:569–73.CrossRefGoogle Scholar
  70. 70.
    Tan EM, et al. Extracellular matrix gene expression by human keratinocytes and fibroblasts from donors of varying ages. Trans Assoc Am Physicians. 1993;106:168–78.PubMedGoogle Scholar
  71. 71.
    Sussman MD. Aging of connective tissue: physical properties of healing wounds in young and old rats. Am J Physiol. 1973;224:1167–71.PubMedGoogle Scholar
  72. 72.
    Szauter KM, et al. Lysyl oxidase in development, aging and pathologies of the skin. Pathol Biol (Paris). 2005;53:448–56.CrossRefGoogle Scholar
  73. 73.
    Au V, Madison SA. Effects of singlet oxygen on the extracellular matrix protein collagen: oxidation of the collagen crosslink histidinohydroxylysinonorleucine and histidine. Arch Biochem Biophys. 2000;384:133–42.CrossRefPubMedGoogle Scholar
  74. 74.
    Ulrich P, Cerami A. Protein glycation, diabetes, and aging. Recent Prog Horm Res. 2001;56:1–21.CrossRefPubMedGoogle Scholar
  75. 75.
    Quaglino D, et al. Extracellular matrix modifications in rat tissues of different ages. Correlations between elastin and collagen type I mRNA expression and lysyl-oxidase activity. Matrix. 1993;13:481–90.CrossRefPubMedGoogle Scholar
  76. 76.
    Reiser KM, et al. Analysis of age-associated changes in collagen crosslinking in the skin and lung in monkeys and rats. Biochim Biophys Acta. 1987;926:339–48.CrossRefPubMedGoogle Scholar
  77. 77.
    Fornieri C, et al. Correlations between age and rat dermis modifications. Ultrastructural-morphometric evaluations and lysyl oxidase activity. Aging (Milano). 1989;1:127–38.Google Scholar
  78. 78.
    Chung JH, Eun HC. Angiogenesis in skin aging and photoaging. J Dermatol. 2007;34:593–600.CrossRefPubMedGoogle Scholar
  79. 79.
    Yamaura H, Matsuzawa T. Decrease in capillary growth during aging. Exp Gerontol. 1980;15:145–50.CrossRefPubMedGoogle Scholar
  80. 80.
    Reed MJ, et al. Neovascularization in aged mice: delayed angiogenesis is coincident with decreased levels of transforming growth factor beta1 and type I collagen. Am J Pathol. 1998;152:113–23.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Rivard A, et al. Age-dependent impairment of angiogenesis. Circulation. 1999;99:111–20.CrossRefPubMedGoogle Scholar
  82. 82.
    Arthur WT, et al. Growth factors reverse the impaired sprouting of microvessels from aged mice. Microvasc Res. 1998;55:260–70.CrossRefPubMedGoogle Scholar
  83. 83.
    Jimenez B, et al. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med. 2000;6:41–8.CrossRefPubMedGoogle Scholar
  84. 84.
    Sadoun E, Reed MJ. Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression. J Histochem Cytochem. 2003;51:1119–30.CrossRefPubMedGoogle Scholar
  85. 85.
    Brekken RA, Sage EH. SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol. 2001;19:816–27.CrossRefPubMedGoogle Scholar
  86. 86.
    Kupprion C, et al. SPARC (BM-40, osteonectin) inhibits the mitogenic effect of vascular endothelial growth factor on microvascular endothelial cells. J Biol Chem. 1998;273:29635–40.CrossRefPubMedGoogle Scholar
  87. 87.
    Reed MJ, et al. Enhanced angiogenesis characteristic of SPARC-null mice disappears with age. J Cell Physiol. 2005;204:800–7.CrossRefPubMedGoogle Scholar
  88. 88.
    Shiba H, et al. Effects of ageing on proliferative ability, and the expressions of secreted protein, acidic and rich in cysteine (SPARC) and osteoprotegerin (osteoclastogenesis inhibitory factor) in cultures of human periodontal ligament cells. Mech Ageing Dev. 2000;117:69–77.CrossRefPubMedGoogle Scholar
  89. 89.
    King A, et al. The role of stem cells in wound angiogenesis. Adv Wound Care (New Rochelle). 2014;3:614–25.CrossRefGoogle Scholar
  90. 90.
    Wu W, et al. The effect of age on human adipose-derived stem cells. Plast Reconstr Surg. 2013;131:27–37.CrossRefPubMedGoogle Scholar
  91. 91.
    Alt EU, et al. Aging alters tissue resident mesenchymal stem cell properties. Stem Cell Res. 2012;8:215–25.CrossRefPubMedGoogle Scholar
  92. 92.
    Blanpain C, Fuchs E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol. 2009;10:207–17.PubMedCentralCrossRefPubMedGoogle Scholar
  93. 93.
    Sun BK, et al. Advances in skin grafting and treatment of cutaneous wounds. Science. 2014;346:941–5.CrossRefPubMedGoogle Scholar
  94. 94.
    da Silva Meirelles L, et al. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119:2204–13.CrossRefPubMedGoogle Scholar
  95. 95.
    Hanson SE, et al. Mesenchymal stem cell therapy for nonhealing cutaneous wounds. Plast Reconstr Surg. 2010;125:510–6.PubMedCentralCrossRefPubMedGoogle Scholar
  96. 96.
    Maxson S, et al. Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med. 2012;1:142–9.PubMedCentralCrossRefPubMedGoogle Scholar
  97. 97.
    Efimenko A, et al. Angiogenic properties of aged adipose derived mesenchymal stem cells after hypoxic conditioning. J Transl Med. 2011;9:10.PubMedCentralCrossRefPubMedGoogle Scholar
  98. 98.
    Madonna R, et al. Age-dependent impairment of number and angiogenic potential of adipose tissue-derived progenitor cells. Eur J Clin Invest. 2011;41:126–33.CrossRefPubMedGoogle Scholar
  99. 99.
    Duscher D, et al. Aging disrupts cell subpopulation dynamics and diminishes the function of mesenchymal stem cells. Sci Rep. 2014;4:7144.PubMedCentralCrossRefPubMedGoogle Scholar
  100. 100.
    Lee S, et al. Activated mesenchymal stem cells increase wound tensile strength in aged mouse model via macrophages. J Surg Res. 2013;181:20–4.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Megan E. Schrementi
    • 1
    • 2
  • Matthew J. Ranzer
    • 1
    • 2
  • Luisa A. DiPietro
    • 1
    • 2
  1. 1.Center for Wound Healing and Tissue Regeneration, College of DentistryUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of BiologyDePaul UniversityChicagoUSA

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