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Preparation of the Wound Bed of the Diabetic Foot Ulcer

  • Marta Otero-Viñas
  • Vincent Falanga
Chapter
Part of the Contemporary Diabetes book series (CDI)

Abstract

Diabetic ulcers are chronic wounds which, despite recent advanced therapies, still fail to heal; they result in infection and high amputation rates. Hyperglycemia induces the majority of micro- and macrovascular complications associated with impaired wound healing. Wound bed preparation (WBP) is an essential step of diabetic wound management in order to accelerate endogenous healing and/or facilitate the effectiveness of other therapies. The aim of WBP is to remove the barriers that impair wound healing, including the presence of necrotic tissue, senescent cells, altered extracellular matrix, hypoxia, high bacterial burden, and inflammatory enzymes within the wound bed. There are several steps for achieving WBP, including debridement, reduction of the bacterial burden, management of edema and exudate, and correction of resident cell abnormalities. Here we provide an overview of the current status, role, and key elements of WBP in the context of diabetic ulcers. We will also introduce a reappraisal of WBP.

Keywords

Wound bed preparation Diabetic wounds Debridement Wound management Cell-based therapies Growth factors 

Abbreviations

bFGF

Basic fibroblast growth factor

DNA

Deoxyribonucleic acid

ECM

Extracellular matrix

EGF

Epithelial growth factor

EPCs

Bone marrow-derived endothelial progenitor cells

FDA

Food and Drug Administration

HBOT

Hyperbaric oxygen therapy

iPSCs

Human induced pluripotent stem cells

M1

Macrophages proinflammatory phenotype

M2

Macrophages anti-inflammatory and prohealing phenotype

MMP-9

Metalloproteinase-9

MSC

Mesenchymal stem cells

PDGF-BB

Platelet-derived growth factor BB

PRP

Plasma rich in platelets

rhEGF

Human recombinant epidermal growth factor

TGF-β

Transforming growth factor beta

TIME

Necrotic Tissue, Infection/Inflammation, Moisture balance, healing of Edge of wound

VEGF

Vascular endothelium growth factor

WBP

Wound bed preparation

References

  1. 1.
    Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–46.CrossRefPubMedGoogle Scholar
  2. 2.
    Schultz GS, Sibbald RG, Falanga V, Ayello EA, Dowsett C, Harding K, et al. Wound bed preparation: a systematic approach to wound management. Wound Repair Regen. 2003;11(Suppl. 1):S1–28.CrossRefPubMedGoogle Scholar
  3. 3.
    Baltzis D, Eleftheriadou I, Veves A. Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights. Adv Ther. 2014;31:817–36.CrossRefPubMedGoogle Scholar
  4. 4.
    Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007;117(5):1219–22.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Falanga V. The chronic wound: impaired healing and solutions in the context of wound bed preparation. Blood Cells Mol Dis. 2004;32(1):88–94.CrossRefPubMedGoogle Scholar
  6. 6.
    Thushara RM, Hemshekhar M, Basappa KK, Rangappa KS, Girish KS. Biologicals, platelet apoptosis and human diseases: an outlook. Crit Rev Oncol Hematol. 2015;93(3):149–58.CrossRefPubMedGoogle Scholar
  7. 7.
    Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736–43.CrossRefPubMedGoogle Scholar
  8. 8.
    Nassiri S, Zakeri I, Weingarten MS, Spiller KL. Relative expression of proinflammatory and antiinflammatory genes reveals differences between healing and nonhealing human chronic diabetic foot ulcers. J Invest Dermatol. 2015;135(6):1700–3.CrossRefPubMedGoogle Scholar
  9. 9.
    Dinh T, Tecilazich F, Kafanas A, Doupis J, Gnardellis C, Leal E, et al. Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes. 2012;61(11):2937–47.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lichtman MK, Otero-Vinas M, Falanga V. Transforming growth factor beta (TGF-β) isoforms in wound healing and fibrosis. Wound Repair Regen. 2016;24:215–22.CrossRefPubMedGoogle Scholar
  11. 11.
    Peplow PV, Baxter GD. Gene expression and release of growth factors during delayed wound healing: a review of studies in diabetic animals and possible combined laser phototherapy and growth factor treatment to enhance healing. Photomed Laser Surg. 2012;30(11):617–36.CrossRefPubMedGoogle Scholar
  12. 12.
    Holmes CJ, Plichta JK, Gamelli RL, Radek KA. Dynamic role of host stress responses in modulating the cutaneous microbiome: implications for wound healing and infection. Adv Wound Care. 2015;4(1):24–37.CrossRefGoogle Scholar
  13. 13.
    Leung KP, D’Arpa P, Seth AK, Geringer MR, Jett M, Xu W, et al. Dermal wound transcriptomic responses to infection with Pseudomonas aeruginosa versus Klebsiella pneumoniae in a rabbit ear wound model. BMC Clin Pathol. 2014;14(1):20.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Percival SL, Finnegan S, Donelli G, Vuotto C, Rimmer SLB. Antiseptics for treating infected wounds: efficacy on biofilms and effect of pH. Crit Rev Microbiol. 2014 271–17;27:1–17.CrossRefGoogle Scholar
  15. 15.
    Davis SC, Martinez L, Kirsner R. The diabetic foot: the importance of biofilms and wound bed preparation. Curr Diab Rep. 2006;6(6):439–45.CrossRefPubMedGoogle Scholar
  16. 16.
    Shahi SK, Kumar A. Isolation and genetic analysis of multidrug resistant Bacteria from diabetic foot ulcers. Front Microbiol. 2015;6(January):1464.PubMedGoogle Scholar
  17. 17.
    Mah TFC, O’Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001;9(1):34–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Percival SL, McCarty SM, Lipsky B. Biofilms and wounds: an overview of the evidence. Adv Wound Care. 2014;4(7):373–81.CrossRefGoogle Scholar
  19. 19.
    Smith K, Collier A, Townsend EM, O’Donnell LE, Bal AM, Butcher J, et al. One step closer to understanding the role of bacteria in diabetic foot ulcers: characterising the microbiome of ulcers. BMC Microbiol. 2016;16(1):54.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Naghibi M, Smith RP, Baltch AL, Gates SA, Wu DH, Hammer MC, et al. The effect of diabetes mellitus on chemotactic and bactericidal activity of human polymorphonuclear leukocytes. Diabetes Res Clin Pract. 1987;4(1):27–35.CrossRefPubMedGoogle Scholar
  21. 21.
    Zykova SN, Jenssen TG, Berdal M, Olsen R, Myklebust R, Seljelid R. Altered cytokine and nitric oxide secretion in vitro by macrophages from diabetic type II-like db/db mice. Diabetes. 2000;49(9):1451–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Patel V, Chivukula IV, Roy S, Khanna S, He GL, Ojha N, et al. Oxygen: from the benefits of inducing VEGF expression to managing the risk of hyperbaric stress. Antioxid Redox Signal. 2005;7(9–10):1377–87.CrossRefPubMedGoogle Scholar
  23. 23.
    Li M, Zhao Y, Hao H, Dai H, Han Q, Tong C, et al. Mesenchymal stem cell-conditioned medium improves the proliferation and migration of keratinocytes in a diabetes-like microenvironment. Int J Low Extrem Wounds. 2015;14(1):73–86.CrossRefPubMedGoogle Scholar
  24. 24.
    Bodnar RJ. Chemokine regulation of angiogenesis during wound healing. Adv Wound Care. 2014;4(11):641–50.CrossRefGoogle Scholar
  25. 25.
    Flegg JA, Menon SN, Maini PK, McElwain DLS. On the mathematical modeling of wound healing angiogenesis in skin as a reaction-transport process. Front Physiol. 2015;6(Sep):1–17.Google Scholar
  26. 26.
    Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146(6):873–87.CrossRefGoogle Scholar
  27. 27.
    Matabi Ayuk S, Abrahamse HNHN. The role of matrix metalloproteinases in diabetic wound healing in relation to photobiomodulation sandra. J Diabetes Res. 2016;2016:2897656.PubMedGoogle Scholar
  28. 28.
    Lazaro JL, Izzo V, Meaume S, Davies AH, Lobmann R, Uccioli L. Elevated levels of matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence. J Wound Care. 2016;25(5):277–87.CrossRefPubMedGoogle Scholar
  29. 29.
    Signorelli SS, Malaponte G, Libra M, Di Pino L, Celotta G, Bevelacqua V, et al. Plasma levels and zymographic activities of matrix metalloproteinases 2 and 9 in type II diabetics with peripheral arterial disease. Vasc Med. 2005;10(1):1–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Loot MA, Kenter SB, Au FL, van Galen WJ, Middelkoop E, Bos JD, Mekkes JR. Fibroblasts derived from chronic diabetic ulcers differ in their response to stimulation with EGF, IGF-I, bFGF and PDGF-AB compared to controls. Eur J Cell Biol. 2002;8(3):153–60.CrossRefGoogle Scholar
  31. 31.
    Otero-Viñas M, Lin X, Yufit T, Carson P, Falanga V. Dermal fibroblasts derived from human venous ulcers show high migratory and proliferative activity in vitro. J Invest Dermatol. 2015;135:126.Google Scholar
  32. 32.
    Panuncialman J, Falanga V. The science of wound bed preparation. Surg Clin North Am. 2009;89(3):611–26.CrossRefPubMedGoogle Scholar
  33. 33.
    Falabella AF. Debridement and wound bed preparation. Dermatol Ther. 2006;19:317–25.CrossRefPubMedGoogle Scholar
  34. 34.
    Falanga V. Classifications for wound bed preparation and stimulation of chronic wounds. Wound Repair Regen. 2000;8:347–52.CrossRefPubMedGoogle Scholar
  35. 35.
    Ayello EA, Dowsett C, Schultz GS, Sibbald RG, Falanga V, Harding K, Romanelli M, Stacey M, Teot L, Vanscheidt W. TIME heals all wounds. Nursing (Lond). 2004;34(4):36–41.CrossRefGoogle Scholar
  36. 36.
    Smith F, Dryburgh N, Donaldson J, Mitchell M. Debridement for surgical wounds (Review). Cochrane Database Syst Rev. 2013;9:CD006214.Google Scholar
  37. 37.
    Lebrun E, Tomic-Canic M, Kirsner RS. The role of surgical debridement in healing of diabetic foot ulcers. Wound Repair Regen. 2010;18(5):433–8.CrossRefPubMedGoogle Scholar
  38. 38.
    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.PubMedGoogle Scholar
  39. 39.
    Brem H, Stojadinovic O, Diegelmann RF, Entero H, Lee B, Pastar I, et al. Molecular markers in patients with chronic wounds to guide surgical debridement. Mol Med. 2007;13(9):30–9.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Falanga V, Brem H, Ennis WJ, Wolcott R, Gould LJ, Ayello EA. Maintenance debridement in the treatment of difficult-to-heal chronic wounds. Recommendations of an expert panel. Ostomy Wound Manag. 2008;(Suppl. 2–13):14–5.Google Scholar
  41. 41.
    Hsu C, Chang C, Chen Y, Lin W, Chen MY. Organization of wound healing services: the impact on lowering the diabetes foot amputation rate in a ten-year review and the importance of early debridement. Diabetes Res Clin Pract. 2015;109:77–84.CrossRefPubMedGoogle Scholar
  42. 42.
    Elraiyah T, Domecq JP, Prutsky G, Tsapas A, Nabhan M, Frykberg RG, et al. A systematic review and meta-analysis of débridement methods for chronic diabetic foot ulcers. J Vasc Surg Elsevier. 2016;63(2):29S–36S.CrossRefGoogle Scholar
  43. 43.
    Otero-Viñas M, Ferrer Solà M, Clapera Cros J, González Martinez V, Sureda Vidal H, Espaulella-Panicot J. Hydrosurgery as an efficient debridement method in a clinical wound unit. Wound Repair Regen. 2015;23(2):A34–5.Google Scholar
  44. 44.
    Dabiri G, Damstetter E, Phillips T. Choosing a wound dressing based on common wound characteristics. Adv Wound Care. 2016;5(1):32–41.CrossRefGoogle Scholar
  45. 45.
    Sun X, Jiang K, Chen J, et al. A systematic review of maggot debridement therapy for chronically infected wounds and ulcers. Int J Infect Dis. 2014;25:32–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Smith F, Dryburgh N, Donaldson J, Mitchell M. Debridement for surgical wounds. Cochrane Database Syst Rev. 2013;9:CD006214.Google Scholar
  47. 47.
    Gethin G, Cowman S, Kolbach DN. Debridement for venous leg ulcers. Cochrane Database Syst Rev. 2015;9:CD008599.Google Scholar
  48. 48.
    Sun X, Chen J, Zhang J, Wang W, Sun J, Wang A. Maggot debridement therapy promotes diabetic foot wound healing by up-regulating endothelial cell activity. J Diabetes Complicat. 2015;30:318–22.CrossRefPubMedGoogle Scholar
  49. 49.
    Horobin AJ, Shakesheff KM, Woodrow S, Robinson C, Pritchard DI. Maggots and wound healing: an investigation of the effects of secretions from Lucilia sericata larvae upon interactions between human dermal fibroblasts and extracellular matrix components. Br J Dermatol. 2003;148(5):923–33.CrossRefPubMedGoogle Scholar
  50. 50.
    Demidova-rice TN, Geevarghese A, Herman IM. Bioactive peptides derived from vascular endothelial cell extracellular matrices promote microvascular morphogenesis and wound healing in vitro. Wound Repair Regen. 2011;19(1):59–70.CrossRefPubMedGoogle Scholar
  51. 51.
    Falanga V, Saap LJ, Ozonoff A. Wound bed score and its correlation with healing of chronic wounds. Dermatol Ther. 2006;19(6):383–90.CrossRefPubMedGoogle Scholar
  52. 52.
    Nicolau DP, Stein GE. Therapeutic options for diabetic foot infections: a review with an emphasis on tissue penetration characteristics. J Am Pod Med Assoc. 2010;100(1):52–63.CrossRefGoogle Scholar
  53. 53.
    Amin N, Doupis J. Diabetic foot disease: from the evaluation of the “foot at risk” to the novel diabetic ulcer treatment modalities. World J Diabetes. 2016;7(7):153–64.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Jhamb S, Vangaveti VN, Malabu UH. Genetic and molecular basis of diabetic foot ulcers: clinical review. J Tissue Viability. 2016;25(4):229.CrossRefPubMedGoogle Scholar
  55. 55.
    Hilton JR, Williams DT, Beuker B, Miller DR, Harding KG. Wound dressings in diabetic foot disease. Clin Infect Dis. 2004;39(Suppl 2):S100–3.CrossRefPubMedGoogle Scholar
  56. 56.
    Wu L, Norman G, Jc D, Meara OS, Sem B, Wu L, et al. Dressings for treating foot ulcers in people with diabetes: an overview of systematic reviews (review) dressings for treating foot ulcers in people with diabetes: an overview of systematic reviews. Cochrane Database Syst Rev. 2015;7:CD010471.Google Scholar
  57. 57.
    Boulton AJM. Pressure and the diabetic foot: Clinical science and offloading techniques. Am J Surg. 2004;187(5 Suppl. 1):17–24.CrossRefGoogle Scholar
  58. 58.
    Game FL, Apelqvist J, Attinger C, Hartemann A, Hinchliffe RJ, Löndahl M, Price PE, Jeffcoate WJ. Effectiveness of interventions to enhance healing of chronic ulcers of the foot in diabetes: a systematic review. Diabetes Metab Res Rev. 2016;32(Suppl 1):154–68.CrossRefPubMedGoogle Scholar
  59. 59.
    Eskes AM, Ubbink DT, Lubbers MJ, Lucas C, Vermeulen H. Hyperbaric oxygen therapy: solution for difficult to heal acute wounds? Systematic review. World J Surg. 2011;35(3):535–42.CrossRefPubMedGoogle Scholar
  60. 60.
    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):604–6.CrossRefPubMedGoogle Scholar
  61. 61.
    Zhang Y, Wang T, He J, Dong J. Growth factor therapy in patients with partial-thickness burns: a systematic review and meta-analysis. Int Wound J. 2014;8:1–13.Google Scholar
  62. 62.
    Gomez-Villa R, Aguilar-Rebolledo F, Lozano-Platonoff A, Teran-Soto JM, Fabian-Victoriano MR, Kresch-Tronik NS, et al. Efficacy of intralesional recombinant human epidermal growth factor in diabetic foot ulcers in Mexican patients: a randomized double-blinded controlled trial. Wound Repair Regen. 2014;22(4):497–503.CrossRefPubMedGoogle Scholar
  63. 63.
    Singla S, Garg R, Kumar A, Gill C. Efficacy of topical application of beta urogastrone (recombinant human epidermal growth factor) in Wagner’s grade 1 and 2 diabetic foot ulcers: comparative analysis of 50 patients. J Nat Sci Biol Med. 2014;5(2):273–7.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Yang S, Geng Z, Ma K, Sun X, Fu X. Efficacy of topical recombinant human epidermal growth factor for treatment of diabetic foot ulcer: a systematic review and meta-analysis. Int J Low Extrem Wounds. 2016;15(2):120–5.CrossRefPubMedGoogle Scholar
  65. 65.
    Fang RC, Galiano RD. A review of becaplermin gel in the treatment of diabetic neuropathic foot ulcers. Biologics. 2008;2(1):1–12.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Buchberger B, Follmann M, Freyer D, Huppertz H, Ehm A, Wasem J. The importance of growth factors for the treatment of chronic wounds in the case of diabetic foot ulcers. GMS Heal Technol Assess. 2010;1:6.Google Scholar
  67. 67.
    Martinez-Zapata MJ, Martí-Carvajal AJ, Solà I, et al. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2012;17:10.Google Scholar
  68. 68.
    Perez-zabala E, Basterretxea A, Larrazabal A, Perez-del-Pecho K, Rubio-Azpeitia E, Andia I. Biological approach for the management of non-healing diabetic foot ulcers. J Tissue Viability. 2016;25:157–63.CrossRefPubMedGoogle Scholar
  69. 69.
    Martinez-Zapata MJ, Marti-Carvajal AJ, Sola I, Exposito JA, Bolibar I, Rodriguez L, et al. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2016;5:CD006899.Google Scholar
  70. 70.
    Lazic T, Falanga V. Bioengineered skin constructs and their use in wound healing. Plast Reconstr Surg. 2011;127(Suppl):75S–90S.CrossRefPubMedGoogle Scholar
  71. 71.
    Santema TKB, Poyck PPC, Ubbink DT. Systematic review and meta-analysis of skin substitutes in the treatment of diabetic foot ulcers: highlights of a Cochrane systematic review. Wound Repair Regen. 2016;24:737.CrossRefPubMedGoogle Scholar
  72. 72.
    Otero-Viñas M, Falanga V. Mesenchymal stem cells in chronic wounds: the Spectrum from basic to advanced therapy. Adv Wound Care. 2016;5(4):149–63.CrossRefGoogle Scholar
  73. 73.
    Şener LT, Albeniz I. Challenge of mesenchymal stem cells against diabetic foot ulcer. Curr Stem Cell Res Ther. 2015;10(6):530–4.CrossRefPubMedGoogle Scholar
  74. 74.
    Gallagher KA, Liu ZJ, Xiao M, Chen H, Goldstein LJ, Buerk DG, et al. Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α. J Clin Invest. 2007;117(5):1249–59.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Gerami-Naini B, Smith A, Maione AG, Kashpur O, Carpinito G, Veves A, et al. Generation of induced pluripotent stem cells from diabetic foot ulcer fibroblasts using a nonintegrative Sendai virus. Cell Reprogram. 2016;18(4):214.  https://doi.org/10.1089/cell.2015.0087.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Maione AG, Brudno Y, Stojadinovic O, Park LK, Smith A, Tellechea A, et al. Three-dimensional human tissue models that incorporate diabetic foot ulcer-derived fibroblasts mimic in vivo features of chronic wounds. Tissue Eng Part C Methods. 2015;21(5):499–508.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of DermatologyBoston University School of MedicineBostonUSA
  2. 2.Faculty of Sciences and Technology, The Tissue Repair and Regeneration LaboratoryUniversity of Vic—Central University of CataloniaVicSpain
  3. 3.Department of BiochemistryBoston University School of MedicineBostonUSA

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