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Chronic wounds

Nature Reviews Disease Primers volume 8, Article number: 50 (2022) Cite this article

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Abstract

Chronic wounds are characterized by their inability to heal within an expected time frame and have emerged as an increasingly important clinical problem over the past several decades, owing to their increasing incidence and greater recognition of associated morbidity and socio-economic burden. Even up to a few years ago, the management of chronic wounds relied on standards of care that were outdated. However, the approach to these chronic conditions has improved, with better prevention, diagnosis and treatment. Such improvements are due to major advances in understanding of cellular and molecular aspects of basic science, in innovative and technological breakthroughs in treatment modalities from biomedical engineering, and in our ability to conduct well-controlled and reliable clinical research. The evidence-based approaches resulting from these advances have become the new standard of care. At the same time, these improvements are tempered by the recognition that persistent gaps exist in scientific knowledge of impaired healing and the ability of clinicians to reduce morbidity, loss of limb and mortality. Therefore, taking stock of what is known and what is needed to improve understanding of chronic wounds and their associated failure to heal is crucial to ensuring better treatments and outcomes.

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Fig. 1: Representative clinical photographs of typical chronic wounds.
Fig. 2: Wound healing in acute and chronic wounds.
Fig. 3: The inflammatory component of wound healing in normal healing and chronic wounds.
Fig. 4: Key pathway components to impaired healing in chronic wounds.
Fig. 5: General algorithm of evaluation, diagnosis and treatment of chronic wounds.
Fig. 6: Wound bed scoring system.

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References

  1. Frykberg, R. G. & Banks, J. Challenges in the treatment of chronic wounds. Adv. Wound Care 4, 560–582 (2015).

    Article  Google Scholar 

  2. Lazarus, G. S. et al. Definitions and guidelines for assessment of wounds and evaluation of healing. Arch. Dermatol. 130, 489–493 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Sen, C. K. et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair. Regen. 17, 763–771 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Janowska, A. et al. Atypical ulcers: diagnosis and management. Clin. Interv. Aging 14, 2137–2143 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sen, C. K. Human wound and its burden: updated 2020 compendium of estimates. Adv. Wound Care 10, 281–292 (2021).

    Article  Google Scholar 

  6. Martinengo, L. et al. Prevalence of chronic wounds in the general population: systematic review and meta-analysis of observational studies. Ann. Epidemiol. 29, 8–15 (2019).

    Article  PubMed  Google Scholar 

  7. Olsson, M. et al. The humanistic and economic burden of chronic wounds: a systematic review. Wound Repair Regen. 27, 114–125 (2019).

    Article  PubMed  Google Scholar 

  8. Lim, H. W. et al. The burden of skin disease in the United States. J. Am. Acad. Dermatol. 76, 958–972.e2 (2017).

    Article  PubMed  Google Scholar 

  9. Hall, J. et al. Point prevalence of complex wounds in a defined United Kingdom population. Wound Repair Regen. 22, 694–700 (2014).

    Article  PubMed  Google Scholar 

  10. Margolis, D. J., Bilker, W., Knauss, J., Baumgarten, M. & Strom, B. L. The incidence and prevalence of pressure ulcers among elderly patients in general medical practice. Ann. Epidemiol. 12, 321–325 (2002).

    Article  PubMed  Google Scholar 

  11. Margolis, D. J. et al. Location, location, location: geographic clustering of lower-extremity amputation among Medicare beneficiaries with diabetes. Diabetes Care 34, 2363–2367 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Margolis, D. J. & Jeffcoate, W. Epidemiology of foot ulceration and amputation: can global variation be explained? Med. Clin. North. Am. 97, 791–805 (2013).

    Article  PubMed  Google Scholar 

  13. Fletcher, J. Measuring the prevalence and incidence of chronic wounds. Prof. Nurse 18, 384–388 (2003).

    PubMed  Google Scholar 

  14. Mervis, J. S. & Phillips, T. J. Pressure ulcers: prevention and management. J. Am. Acad. Dermatol. 81, 893–902 (2019).

    Article  PubMed  Google Scholar 

  15. Courvoisier, D. S., Righi, L., Bene, N., Rae, A. C. & Chopard, P. Variation in pressure ulcer prevalence and prevention in nursing homes: a multicenter study. Appl. Nurs. Res. 42, 45–50 (2018).

    Article  PubMed  Google Scholar 

  16. Anthony, D., Alosoumi, D. & Safari, R. Prevalence of pressure ulcers in long-term care: a global review. J. Wound Care 28, 702–709 (2019).

    Article  PubMed  Google Scholar 

  17. Lopes, T. S., Videira, L., Saraiva, D., Agostinho, E. S. & Bandarra, A. J. F. Multicentre study of pressure ulcer point prevalence in a Portuguese region. J. Tissue Viability 29, 12–18 (2020).

    Article  PubMed  Google Scholar 

  18. Diaz-Herrera, M. A. et al. Multicentre study of chronic wounds point prevalence in primary health care in the southern metropolitan area of Barcelona. J. Clin. Med. 10, 797 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wei, M. et al. The prevalence and prevention of pressure ulcers: a multicenter study of nine nursing homes in eastern China. J. Tissue Viability 30, 133–136 (2021).

    Article  PubMed  Google Scholar 

  20. Baumgarten, M. et al. Risk factors for pressure ulcers among elderly hip fracture patients. Wound Repair. Regen. 11, 96–103 (2003).

    Article  PubMed  Google Scholar 

  21. Baumgarten, M. et al. Extrinsic risk factors for pressure ulcers early in the hospital stay: a nested case-control study. J. Gerontol. A Biol. Sci. Med. Sci. 63, 408–413 (2008).

    Article  PubMed  Google Scholar 

  22. Nelson, E. A. & Adderley, U. Venous leg ulcers. BMJ Clin. Evid. 2016, 1902 (2016).

    PubMed  PubMed Central  Google Scholar 

  23. Margolis, D. J., Bilker, W., Santanna, J. & Baumgarten, M. Venous leg ulcer: incidence and prevalence in the elderly. J. Am. Acad. Dermatol. 46, 381–386 (2002).

    Article  PubMed  Google Scholar 

  24. Homs-Romero, E. et al. Validity of chronic venous disease diagnoses and epidemiology using validated electronic health records from primary care: a real-world data analysis. J. Nurs. Scholarsh. 53, 296–305 (2021).

    Article  PubMed  Google Scholar 

  25. Forssgren, A., Fransson, I. & Nelzen, O. Leg ulcer point prevalence can be decreased by broad-scale intervention: a follow-up cross-sectional study of a defined geographical population. Acta Derm. Venereol. 88, 252–256 (2008).

    PubMed  Google Scholar 

  26. Berenguer Perez, M., Lopez-Casanova, P., Sarabia Lavin, R., Gonzalez de la Torre, H. & Verdu-Soriano, J. Epidemiology of venous leg ulcers in primary health care: Incidence and prevalence in a health centre — a time series study (2010-2014). Int. Wound J. 16, 256–265 (2019).

    Article  PubMed  Google Scholar 

  27. Walsh, J. W., Hoffstad, O. J., Sullivan, M. O. & Margolis, D. J. Association of diabetic foot ulcer and death in a population-based cohort from the United Kingdom. Diabet. Med. 33, 1493–1498 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Hoffstad, O., Mitra, N., Walsh, J. & Margolis, D. J. Diabetes, lower-extremity amputation, and death. Diabetes Care 38, 1852–1857 (2015).

    Article  PubMed  Google Scholar 

  29. Margolis, D. J., Hofstad, O. & Feldman, H. I. Association between renal failure and foot ulcer or lower-extremity amputation in patients with diabetes. Diabetes Care 31, 1331–1336 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Heyer, K., Herberger, K., Protz, K., Glaeske, G. & Augustin, M. Epidemiology of chronic wounds in Germany: analysis of statutory health insurance data. Wound Repair Regen. 24, 434–442 (2016).

    Article  PubMed  Google Scholar 

  31. Graves, N. How costs change with infection prevention efforts. Curr. Opin. Infect. Dis. 27, 390–393 (2014).

    Article  PubMed  Google Scholar 

  32. Malay, D. S., Margolis, D. J., Hoffstad, O. J. & Bellamy, S. The incidence and risks of failure to heal after lower extremity amputation for the treatment of diabetic neuropathic foot ulcer. J. Foot Ankle Surg. 45, 366–374 (2006).

    Article  PubMed  Google Scholar 

  33. Margolis, D. et al. Prevelance of diabetes, diabetic foot ulcer, and lower extremity amputation among Medicare beneficiaries, 2006–2008, Rockville, MD (Agency for Healthcare Research and Quality, 2010).

  34. Holman, N., Young, R. J. & Jeffcoate, W. J. Variation in the recorded incidence of amputation of the lower limb in England. Diabetologia 55, 1919–1925 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Margolis, D. J., Gelfand, J. M., Hoffstad, O. & Berlin, J. A. Surrogate end points for the treatment of diabetic neuropathic foot ulcers. Diabetes Care 26, 1696–1700 (2003).

    Article  PubMed  Google Scholar 

  36. Margolis, D. J., Kantor, J., Santanna, J., Strom, B. L. & Berlin, J. A. Risk factors for delayed healing of neuropathic diabetic foot ulcers: a pooled analysis. Arch. Dermatol. 136, 1531–1535 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Margolis, D. J., Allen-Taylor, L., Hoffstad, O. & Berlin, J. A. Healing diabetic neuropathic foot ulcers: are we getting better? Diabet. Med. 22, 172–176 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Rodrigues, M., Kosaric, N., Bonham, C. A. & Gurtner, G. C. Wound healing: a cellular perspective. Physiol. Rev. 99, 665–706 (2019).

    Article  CAS  PubMed  Google Scholar 

  39. Falanga, V. Wound healing and its impairment in the diabetic foot. Lancet 366, 1736–1743 (2005).

    Article  PubMed  Google Scholar 

  40. Eming, S. A., Martin, P. & Tomic-Canic, M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci. Transl. Med. 6, 265sr6 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zindle, J. K., Wolinsky, E. & Bogie, K. M. A review of animal models from 2015 to 2020 for preclinical chronic wounds relevant to human health. J. Tissue Viability 30, 291–300 (2021).

    Article  PubMed  Google Scholar 

  42. Falanga, V. et al. Full-thickness wounding of the mouse tail as a model for delayed wound healing: accelerated wound closure in Smad3 knock-out mice. Wound Repair Regen. 12, 320–326 (2004).

    Article  PubMed  Google Scholar 

  43. Nunan, R., Harding, K. G. & Martin, P. Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity. Dis. Model. Mech. 7, 1205–1213 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Grada, A., Mervis, J. & Falanga, V. Research techniques made simple: animal models of wound healing. J. Invest. Dermatol. 138, 2095–2105.e1 (2018).

    Article  CAS  PubMed  Google Scholar 

  45. Elliot, S., Wikramanayake, T. C., Jozic, I. & Tomic-Canic, M. A modeling conundrum: murine models for cutaneous wound healing. J. Invest. Dermatol. 138, 736–740 (2018).

    Article  CAS  PubMed  Google Scholar 

  46. Ahn, S. T. & Mustoe, T. A. Effects of ischemia on ulcer wound healing: a new model in the rabbit ear. Ann. Plast. Surg. 24, 17–23 (1990).

    Article  CAS  PubMed  Google Scholar 

  47. Buck, D. W. 2nd et al. The TallyHo polygenic mouse model of diabetes: implications in wound healing. Plast. Reconstr. Surg. 128, 427e–437e (2011).

    Article  PubMed  Google Scholar 

  48. Davis, S. C. & Mertz, P. M. Determining the effect of an oak bark formulation on methicillin-resistant Staphylococcus aureus and wound healing in porcine wound models. Ostomy Wound Manag. 54, 16–18, 20, 22–25 (2008).

    Google Scholar 

  49. Dhall, S. et al. Generating and reversing chronic wounds in diabetic mice by manipulating wound redox parameters. J. Diabetes Res. 2014, 562625 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Eaglstein, W. H. & Mertz, P. M. New methods for assessing epidermal wound healing: the effects of triamcinolone acetonide and polyethelene film occlusion. J. Invest. Dermatol. 71, 382–384 (1978).

    Article  CAS  PubMed  Google Scholar 

  51. Fadini, G. P. et al. NETosis delays diabetic wound healing in mice and humans. Diabetes 65, 1061–1071 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Olson, H. M. & Nechiporuk, A. V. Using zebrafish to study collective cell migration in development and disease. Front. Cell Dev. Biol. 6, 83 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Seaton, M., Hocking, A. & Gibran, N. S. Porcine models of cutaneous wound healing. ILAR J. 56, 127–138 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Stone, R.II, Wall, J. T., Natesan, S. & Christy, R. J. PEG-plasma hydrogels increase epithelialization using a human ex vivo skin model. Int. J. Mol. Sci. 19, 3156 (2018).

    Article  PubMed Central  Google Scholar 

  55. Arenas Gomez, C. M., Sabin, K. Z. & Echeverri, K. Wound healing across the animal kingdom: crosstalk between the immune system and the extracellular matrix. Dev. Dyn. 249, 834–846 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  56. MacLeod, A. S. & Mansbridge, J. N. The innate immune system in acute and chronic wounds. Adv. Wound Care 5, 65–78 (2016).

    Article  Google Scholar 

  57. Weavers, H. & Martin, P. The cell biology of inflammation: from common traits to remarkable immunological adaptations. J. Cell. Biol. 219, e202004003 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nguyen, A. V. & Soulika, A. M. The dynamics of the skin’s immune system. Int. J. Mol. Sci. 20, 1811 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  59. Nestle, F. O., Di Meglio, P., Qin, J. Z. & Nickoloff, B. J. Skin immune sentinels in health and disease. Nat. Rev. Immunol. 9, 679–691 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Dasu, M. R. & Isseroff, R. R. Toll-like receptors in wound healing: location, accessibility, and timing. J. Invest. Dermatol. 132, 1955–1958 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Kirchner, S., Lei, V. & MacLeod, A. S. The cutaneous wound innate immunological microenvironment. Int. J. Mol. Sci. 21, 8748 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  63. Wilgus, T. A. Alerting the body to tissue injury: the role of alarmins and DAMPs in cutaneous wound healing. Curr. Pathobiol. Rep. 6, 55–60 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nelson, A. M. et al. dsRNA released by tissue damage activates TLR3 to drive skin regeneration. Cell Stem Cell 17, 139–151 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Borkowski, A. W., Park, K., Uchida, Y. & Gallo, R. L. Activation of TLR3 in keratinocytes increases expression of genes involved in formation of the epidermis, lipid accumulation, and epidermal organelles. J. Invest. Dermatol. 133, 2031–2040 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mangoni, M. L., McDermott, A. M. & Zasloff, M. Antimicrobial peptides and wound healing: biological and therapeutic considerations. Exp. Dermatol. 25, 167–173 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Strbo, N., Yin, N. & Stojadinovic, O. Innate and adaptive immune responses in wound epithelialization. Adv. Wound Care 3, 492–501 (2014).

    Article  Google Scholar 

  68. Gronberg, A., Mahlapuu, M., Stahle, M., Whately-Smith, C. & Rollman, O. Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial. Wound Repair Regen. 22, 613–621 (2014).

    Article  PubMed  Google Scholar 

  69. Heilborn, J. D. et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J. Invest. Dermatol. 120, 379–389 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Li, D. et al. Single-cell analysis reveals major histocompatibility complex II expressing keratinocytes in pressure ulcers with worse healing outcomes. J. Investig. Dermatol. 142, 705–716 (2022).

    Article  CAS  PubMed  Google Scholar 

  71. Shook, B. A. et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science 362, eaar2971 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Plikus, M. V. et al. Regeneration of fat cells from myofibroblasts during wound healing. Science 355, 748–752 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. desJardins-Park, H. E., Foster, D. S. & Longaker, M. T. Fibroblasts and wound healing: an update. Regen. Med. 13, 491–495 (2018).

    Article  CAS  PubMed  Google Scholar 

  74. Foster, D. S., Jones, R. E., Ransom, R. C., Longaker, M. T. & Norton, J. A. The evolving relationship of wound healing and tumor stroma. JCI Insight 3, e99911 (2018).

    Article  PubMed Central  Google Scholar 

  75. Jones, R. E., Foster, D. S. & Longaker, M. T. Management of chronic wounds — 2018. JAMA 320, 1481–1482 (2018).

    Article  PubMed  Google Scholar 

  76. Theocharidis, G. et al. Single cell transcriptomic landscape of diabetic foot ulcers. Nat. Commun. 13, 181 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mascharak, S. et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science 372, eaba2374 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Januszyk, M. et al. Characterization of diabetic and non-diabetic foot ulcers using single-cell RNA-sequencing. Micromachines 11, 815 (2020).

    Article  PubMed Central  Google Scholar 

  79. Krzyszczyk, P., Schloss, R., Palmer, A. & Berthiaume, F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front. Physiol. 9, 419 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Hesketh, M., Sahin, K. B., West, Z. E. & Murray, R. Z. Macrophage phenotypes regulate scar formation and chronic wound healing. Int. J. Mol. Sci. 18, 1545 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  81. Nahrendorf, M. & Swirski, F. K. Abandoning M1/M2 for a network model of macrophage function. Circ. Res. 119, 414–417 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Minutti, C. M., Knipper, J. A., Allen, J. E. & Zaiss, D. M. Tissue-specific contribution of macrophages to wound healing. Semin. Cell Dev. Biol. 61, 3–11 (2017).

    Article  CAS  PubMed  Google Scholar 

  83. Kratofil, R. M., Kubes, P. & Deniset, J. F. Monocyte conversion during inflammation and injury. Arterioscler. Thromb. Vasc. Biol. 37, 35–42 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Lucas, T. et al. Differential roles of macrophages in diverse phases of skin repair. J. Immunol. 184, 3964–3977 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Shook, B., Xiao, E., Kumamoto, Y., Iwasaki, A. & Horsley, V. CD301b+ macrophages are essential for effective skin wound healing. J. Investig. Dermatol. 136, 1885–1891 (2016).

    Article  CAS  PubMed  Google Scholar 

  86. Pang, J., Maienschein-Cline, M. & Koh, T. J. Enhanced proliferation of Ly6C(+) monocytes/macrophages contributes to chronic inflammation in skin wounds of diabetic mice. J. Immunol. 206, 621–630 (2021).

    Article  CAS  PubMed  Google Scholar 

  87. Kim, S. Y. & Nair, M. G. Macrophages in wound healing: activation and plasticity. Immunol. Cell Biol. 97, 258–267 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Kimball, A. S. et al. The histone methyltransferase Setdb2 modulates macrophage phenotype and uric acid production in diabetic wound repair. Immunity 51, 258–271.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Aloysius, A., Saxena, S. & Seifert, A. W. Metabolic regulation of innate immune cell phenotypes during wound repair and regeneration. Curr. Opin. Immunol. 68, 72–82 (2021).

    Article  CAS  PubMed  Google Scholar 

  90. Eming, S. A., Wynn, T. A. & Martin, P. Inflammation and metabolism in tissue repair and regeneration. Science 356, 1026–1030 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Bodnar, E. et al. Redox profiling reveals clear differences between molecular patterns of wound fluids from acute and chronic wounds. Oxid. Med. Cell Longev. 2018, 5286785 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Szondi, D. C., Wong, J. K., Vardy, L. A. & Cruickshank, S. M. Arginase signalling as a key player in chronic wound pathophysiology and healing. Front. Mol. Biosci. 8, 773866 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jetten, N. et al. Wound administration of M2-polarized macrophages does not improve murine cutaneous healing responses. PLoS ONE 9, e102994 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Dreymueller, D., Denecke, B., Ludwig, A. & Jahnen-Dechent, W. Embryonic stem cell-derived M2-like macrophages delay cutaneous wound healing. Wound Repair Regen. 21, 44–54 (2013).

    Article  PubMed  Google Scholar 

  95. Sawaya, A. P. et al. Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Nat. Commun. 11, 4678 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Spiller, K. L. & Koh, T. J. Macrophage-based therapeutic strategies in regenerative medicine. Adv. Drug Deliv. Rev. 122, 74–83 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nassiri, S., Zakeri, I., Weingarten, M. S. & Spiller, K. L. Relative expression of proinflammatory and antiinflammatory genes reveals differences between healing and nonhealing human chronic diabetic foot ulcers. J. Investig. Dermatol. 135, 1700–1703 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Gould, L. et al. Chronic wound repair and healing in older adults: current status and future research. J. Am. Geriatr. Soc. 63, 427–438 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Kaplan, D. H. Ontogeny and function of murine epidermal Langerhans cells. Nat. Immunol. 18, 1068–1075 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Joshi, N. et al. Comprehensive characterization of myeloid cells during wound healing in healthy and healing-impaired diabetic mice. Eur. J. Immunol. 50, 1335–1349 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Stojadinovic, O. et al. Increased number of Langerhans cells in the epidermis of diabetic foot ulcers correlates with healing outcome. Immunol. Res. 57, 222–228 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rajesh, A. et al. Depletion of langerin(+) cells enhances cutaneous wound healing. Immunology 160, 366–381 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Grotendorst, G. R., Smale, G. & Pencev, D. Production of transforming growth factor beta by human peripheral blood monocytes and neutrophils. J. Cell Physiol. 140, 396–402 (1989).

    Article  CAS  PubMed  Google Scholar 

  104. Peiseler, M. & Kubes, P. More friend than foe: the emerging role of neutrophils in tissue repair. J. Clin. Investig. 129, 2629–2639 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Phillipson, M. & Kubes, P. The healing power of neutrophils. Trends Immunol. 40, 635–647 (2019).

    Article  CAS  PubMed  Google Scholar 

  106. Wilgus, T. A., Roy, S. & McDaniel, J. C. Neutrophils and wound repair: positive actions and negative reactions. Adv. Wound Care 2, 379–388 (2013).

    Article  Google Scholar 

  107. Wang, J. Neutrophils in tissue injury and repair. Cell Tissue Res. 371, 531–539 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wong, S. L. et al. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat. Med. 21, 815–819 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Pollenus, E. et al. Limitations of neutrophil depletion by anti-Ly6G antibodies in two heterogenic immunological models. Immunol. Lett. 212, 30–36 (2019).

    Article  CAS  PubMed  Google Scholar 

  110. Devalaraja, R. M. et al. Delayed wound healing in CXCR2 knockout mice. J. Investig. Dermatol. 115, 234–244 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Kienle, K. & Lammermann, T. Neutrophil swarming: an essential process of the neutrophil tissue response. Immunol. Rev. 273, 76–93 (2016).

    Article  CAS  PubMed  Google Scholar 

  112. Papayannopoulos, V. & Zychlinsky, A. NETs: a new strategy for using old weapons. Trends Immunol. 30, 513–521 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Deniset, J. F. & Kubes, P. Recent advances in understanding neutrophils. F1000Res. 5, 2912 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Gong, Y. & Koh, D. R. Neutrophils promote inflammatory angiogenesis via release of preformed VEGF in an in vivo corneal model. Cell Tissue Res. 339, 437–448 (2010).

    Article  PubMed  Google Scholar 

  115. Mukai, K., Tsai, M., Saito, H. & Galli, S. J. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol. Rev. 282, 121–150 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tellechea, A. et al. Mast cells regulate wound healing in diabetes. Diabetes 65, 2006–2019 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wilgus, T. A., Ud-Din, S. & Bayat, A. A review of the evidence for and against a role for mast cells in cutaneous scarring and fibrosis. Int. J. Mol. Sci. 21, 9673 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  118. Havran, W. L. & Jameson, J. M. Epidermal T cells and wound healing. J. Immunol. 184, 5423–5428 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. MacLeod, A. S. et al. Dendritic epidermal T cells regulate skin antimicrobial barrier function. J. Clin. Invest. 123, 4364–4374 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Jameson, J. et al. A role for skin gammadelta T cells in wound repair. Science 296, 747–749 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Li, Y. et al. Vgamma4 T cells inhibit the pro-healing functions of dendritic epidermal T cells to delay skin wound closure through IL-17A. Front. Immunol. 9, 240 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Taylor, K. R., Mills, R. E., Costanzo, A. E. & Jameson, J. M. Gammadelta T cells are reduced and rendered unresponsive by hyperglycemia and chronic TNFalpha in mouse models of obesity and metabolic disease. PLoS ONE 5, e11422 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Mathur, A. N. et al. Treg-cell control of a CXCL5-IL-17 inflammatory axis promotes hair-follicle-stem-cell differentiation during skin-barrier repair. Immunity 50, 655–667 e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Nosbaum, A. et al. Cutting edge: regulatory T cells facilitate cutaneous wound healing. J. Immunol. 196, 2010–2014 (2016).

    Article  CAS  PubMed  Google Scholar 

  125. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Laurent, P. et al. Immune-mediated repair: a matter of plasticity. Front. Immunol. 8, 454 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Kroeze, K. L. et al. Autocrine regulation of re-epithelialization after wounding by chemokine receptors CCR1, CCR10, CXCR1, CXCR2, and CXCR3. J. Invest. Dermatol. 132, 216–225 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Johnson, B. Z., Stevenson, A. W., Prele, C. M., Fear, M. W. & Wood, F. M. The role of IL-6 in skin fibrosis and cutaneous wound healing. Biomedicines 8, 101 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  129. Gushiken, L. F. S., Beserra, F. P., Bastos, J. K., Jackson, C. J. & Pellizzon, C. H. Cutaneous wound healing: an update from physiopathology to current therapies. Life 11, 665 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Wolcott, R., Costerton, J. W., Raoult, D. & Cutler, S. J. The polymicrobial nature of biofilm infection. Clin. Microbiol. Infect. 19, 107–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Schultz, G. et al. Consensus guidelines for the identification and treatment of biofilms in chronic nonhealing wounds. Wound Repair Regen. 25, 744–757 (2017).

    Article  PubMed  Google Scholar 

  132. Granick, M., Boykin, J., Gamelli, R., Schultz, G. & Tenenhaus, M. Toward a common language: surgical wound bed preparation and debridement. Wound Repair Regen. 14 (Suppl. 1), S1–S10 (2006).

    Article  PubMed  Google Scholar 

  133. Versey, Z. et al. Biofilm-innate immune interface: contribution to chronic wound formation. Front. Immunol. 12, 648554 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kovacs, A. T. & Dragos, A. Evolved biofilm: review on the experimental evolution studies of Bacillus subtilis pellicles. J. Mol. Biol. 431, 4749–4759 (2019).

    Article  CAS  PubMed  Google Scholar 

  135. Ram, M. et al. Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats. Eur. J. Pharmacol. 764, 9–21 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Tchanque-Fossuo, C. N., Dahle, S. E., Buchman, S. R. & Isseroff, R. R. Deferoxamine: potential novel topical therapeutic for chronic wounds. Br. J. Dermatol. 176, 1056–1059 (2017).

    Article  CAS  PubMed  Google Scholar 

  137. Bonham, C. A., Kuehlmann, B. & Gurtner, G. C. Impaired neovascularization in aging. Adv. Wound Care 9, 111–126 (2020).

    Article  Google Scholar 

  138. DeFrates, K. G., Franco, D., Heber-Katz, E. & Messersmith, P. B. Unlocking mammalian regeneration through hypoxia inducible factor one alpha signaling. Biomaterials 269, 120646 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03137966 (2022).

  140. Duscher, D. et al. Optimization of transdermal deferoxamine leads to enhanced efficacy in healing skin wounds. J. Control. Rel. 308, 232–239 (2019).

    Article  CAS  Google Scholar 

  141. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04058197 (2021).

  142. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zhang, L., Stokes, N., Polak, L. & Fuchs, E. Specific microRNAs are preferentially expressed by skin stem cells to balance self-renewal and early lineage commitment. Cell Stem Cell 8, 294–308 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Hildebrand, J. et al. A comprehensive analysis of microRNA expression during human keratinocyte differentiation in vitro and in vivo. J. Invest. Dermatol. 131, 20–29 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Banerjee, J. & Sen, C. K. microRNA and wound healing. Adv. Exp. Med. Biol. 888, 291–305 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Li, D. et al. MicroRNA-132 enhances transition from inflammation to proliferation during wound healing. J. Clin. Invest. 125, 3008–3026 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Herter, E. K. & Xu Landen, N. Non-coding RNAs: new players in skin wound healing. Adv. Wound Care 6, 93–107 (2017).

    Article  Google Scholar 

  148. Mori, R., Tanaka, K. & Shimokawa, I. Identification and functional analysis of inflammation-related miRNAs in skin wound repair. Dev. Growth Differ. 60, 306–315 (2018).

    Article  CAS  PubMed  Google Scholar 

  149. Yang, X. et al. miR-21 promotes keratinocyte migration and re-epithelialization during wound healing. Int. J. Biol. Sci. 7, 685–690 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Li, C. X. et al. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat. Mater. 16, 379–389 (2017).

    Article  CAS  PubMed  Google Scholar 

  151. Pastar, I. et al. Induction of specific microRNAs inhibits cutaneous wound healing. J. Biol. Chem. 287, 29324–29335 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Vanden Oever, M., Muldoon, D., Mathews, W., McElmurry, R. & Tolar, J. miR-29 regulates type VII collagen in recessive dystrophic epidermolysis bullosa. J. Invest. Dermatol. 136, 2013–2021 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Suh, E. J. et al. A microRNA network regulates proliferative timing and extracellular matrix synthesis during cellular quiescence in fibroblasts. Genome Biol. 13, R121 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Li, B. et al. Long noncoding RNA H19 acts as a miR-29b sponge to promote wound healing in diabetic foot ulcer. FASEB J. 35, e20526 (2021).

    CAS  PubMed  Google Scholar 

  155. Auler, M. et al. miR-127-3p is an epigenetic activator of myofibroblast senescence situated within the microRNA-enriched Dlk1-Dio3Imprinted domain on mouse chromosome 12. J. Invest. Dermatol. 141, 1076–1086 e3 (2021).

    Article  CAS  PubMed  Google Scholar 

  156. Liu, P., Zhu, Y., Li, Q. & Cheng, B. Comprehensive analysis of differentially expressed miRNAs and mRNAs reveals that miR-181a-5p plays a key role in diabetic dermal fibroblasts. J. Diabetes Res. 2020, 4581954 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Biswas, S. et al. Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds. Proc. Natl Acad. Sci. USA 107, 6976–6981 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Li, X. et al. MicroRNA-132 with therapeutic potential in chronic wounds. J. Invest. Dermatol. 137, 2630–2638 (2017).

    Article  CAS  PubMed  Google Scholar 

  159. Naqvi, R. A., Gupta, M., George, A. & Naqvi, A. R. MicroRNAs in shaping the resolution phase of inflammation. Semin. Cell Dev. Biol. 124, 48 (2022).

    Article  CAS  PubMed  Google Scholar 

  160. Zhai, X. et al. Bibliometric analysis of global scientific research on lncRNA: a swiftly expanding trend. Biomed. Res. Int. 2018, 7625078 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Kretz, M. et al. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature 493, 231–235 (2013).

    Article  CAS  PubMed  Google Scholar 

  162. Kretz, M. et al. Suppression of progenitor differentiation requires the long noncoding RNA ANCR. Genes Dev. 26, 338–343 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Herter, E. K. et al. WAKMAR2, a long noncoding RNA downregulated in human chronic wounds, modulates keratinocyte motility and production of inflammatory chemokines. J. Invest. Dermatol. 139, 1373–1384 (2019).

    Article  CAS  PubMed  Google Scholar 

  164. Sawaya, A. P. et al. Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5. J. Biol. Chem. 293, 1439–1449 (2018).

    Article  CAS  PubMed  Google Scholar 

  165. Zhang, X. et al. LncRNA MACC1-AS1 sponges multiple miRNAs and RNA-binding protein PTBP1. Oncogenesis 8, 73 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Li, X. & Xu Landen, N. Evaluation of microRNA therapeutic potential using the mouse in vivo and human ex vivo wound models. Methods Mol. Biol. 2193, 67–75 (2021).

    Article  CAS  PubMed  Google Scholar 

  167. Brandwein, M., Steinberg, D. & Meshner, S. Microbial biofilms and the human skin microbiome. NPJ Biofilms Microbiomes 2, 3 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Stacy, A., McNally, L., Darch, S. E., Brown, S. P. & Whiteley, M. The biogeography of polymicrobial infection. Nat. Rev. Microbiol. 14, 93–105 (2016).

    Article  CAS  PubMed  Google Scholar 

  169. Fischbach, M. A. & Segre, J. A. Signaling in host-associated microbial communities. Cell 164, 1288–1300 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Castillo-Juarez, I. et al. Role of quorum sensing in bacterial infections. World J. Clin. Cases 3, 575–598 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Pouget, C. et al. Biofilms in diabetic foot ulcers: significance and clinical relevance. Microorganisms 8, 1580 (2020).

    Article  PubMed Central  Google Scholar 

  172. Tomic-Canic, M., Burgess, J. L., O’Neill, K. E., Strbo, N. & Pastar, I. Skin microbiota and its interplay with wound healing. Am. J. Clin. Dermatol. 21 (Suppl. 1), 36–43 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Johnson, T. R. et al. The cutaneous microbiome and wounds: new molecular targets to promote wound healing. Int. J. Mol. Sci. 19, 2699 (2018).

    Article  PubMed Central  Google Scholar 

  174. Metcalf, D. G. & Bowler, P. G. Biofilm delays wound healing: a review of the evidence. Burns Trauma 1, 5–12 (2013).

    Article  PubMed  Google Scholar 

  175. Williams, H. et al. Cutaneous Nod2 expression regulates the skin microbiome and wound healing in a murine model. J. Invest. Dermatol. 137, 2427–2436 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Wolcott, R. D. et al. Analysis of the chronic wound microbiota of 2,963 patients by 16S rDNA pyrosequencing. Wound Repair. Regen. 24, 163–174 (2016).

    Article  PubMed  Google Scholar 

  177. Harrison, O. J. et al. Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury. Science 363, eaat6280 (2019).

    Article  CAS  PubMed  Google Scholar 

  178. Loesche, M. et al. Temporal stability in chronic wound microbiota is associated with poor healing. J. Invest. Dermatol. 137, 237–244 (2017).

    Article  CAS  PubMed  Google Scholar 

  179. Tipton, C. D. et al. Patient genetics is linked to chronic wound microbiome composition and healing. PLoS Pathog. 16, e1008511 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Bar, J. et al. Evidence for cutaneous dysbiosis in dystrophic epidermolysis bullosa. Clin. Exp. Dermatol. 46, 1223–1229 (2021).

    Article  CAS  PubMed  Google Scholar 

  181. Kalan, L. R. et al. Strain- and species-level variation in the microbiome of diabetic wounds is associated with clinical outcomes and therapeutic efficacy. Cell Host Microbe 25, 641–655 e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Kashem, S. W. et al. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity 43, 515–526 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Pinho-Ribeiro, F. A. et al. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell 173, 1083–1097.e22 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Cohen, J. A. et al. Cutaneous TRPV1(+) neurons trigger protective innate type 17 anticipatory immunity. Cell 178, 919–932.e14 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Bagood, M. D. & Isseroff, R. R. TRPV1: role in skin and skin diseases and potential target for improving wound healing. Int. J. Mol. Sci. 22, 6135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Kalan, L. et al. Redefining the chronic-wound microbiome: fungal communities are prevalent, dynamic, and associated with delayed healing. mBio 7, e1058-16 (2016).

    Article  Google Scholar 

  187. Hurabielle, C. et al. Immunity to commensal skin fungi promotes psoriasiform skin inflammation. Proc. Natl Acad. Sci. USA 117, 16465–16474 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Patel, S., Maheshwari, A. & Chandra, A. Biomarkers for wound healing and their evaluation. J. Wound Care 25, 46–55 (2016).

    Article  CAS  PubMed  Google Scholar 

  189. Eaglstein, W. H. & Falanga, V. Chronic wounds. Surg. Clin. North. Am. 77, 689–700 (1997).

    Article  CAS  PubMed  Google Scholar 

  190. Falanga, V. Wound healing and chronic wounds. J. Cutan. Med. Surg. 3 (Suppl. 1), S1-1-5 (1998).

    PubMed  Google Scholar 

  191. O’Donnell, T. F. Jr & Passman, M. A. Clinical practice guidelines of the Society for Vascular Surgery (SVS) and the American Venous Forum (AVF) — management of venous leg ulcers. introduction. J. Vasc. Surg. 60(2 Suppl.), 1S–2S (2014).

    PubMed  Google Scholar 

  192. O’Donnell, T. F. Jr et al. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery (R) and the American Venous Forum. J. Vasc. Surg. 60 (2 Suppl.), 3S–59S (2014).

    Article  PubMed  Google Scholar 

  193. Browse, N. L. & Burnand, K. G. The cause of venous ulceration. Lancet 2, 243–245 (1982).

    Article  CAS  PubMed  Google Scholar 

  194. Burnand, K. G., Clemenson, G., Whimster, I., Gaunt, J. & Browse, N. L. The effect of sustained venous hypertension on the skin capillaries of the canine hind limb. Br. J. Surg. 69, 41–44 (1982).

    Article  CAS  PubMed  Google Scholar 

  195. Kirsner, R. S., Pardes, J. B., Eaglstein, W. H. & Falanga, V. The clinical spectrum of lipodermatosclerosis. J. Am. Acad. Dermatol. 28, 623–627 (1993).

    Article  CAS  PubMed  Google Scholar 

  196. Morton, L. M. & Phillips, T. J. Wound healing and treating wounds: differential diagnosis and evaluation of chronic wounds. J. Am. Acad. Dermatol. 74, 589–605 (2016). quiz 605–606.

    Article  PubMed  Google Scholar 

  197. Powers, J. G., Higham, C., Broussard, K. & Phillips, T. J. Wound healing and treating wounds: chronic wound care and management. J. Am. Acad. Dermatol. 74, 607–625; quiz 625–626 (2016).

    Article  PubMed  Google Scholar 

  198. Armstrong, D. G., Boulton, A. J. M. & Bus, S. A. Diabetic foot ulcers and their recurrence. N. Engl. J. Med. 376, 2367–2375 (2017).

    Article  PubMed  Google Scholar 

  199. Boulton, A. J., Kirsner, R. S. & Vileikyte, L. Clinical practice. Neuropathic diabetic foot ulcers. N. Engl. J. Med. 351, 48–55 (2004).

    Article  CAS  PubMed  Google Scholar 

  200. Ghotaslou, R., Memar, M. Y. & Alizadeh, N. Classification, microbiology and treatment of diabetic foot infections. J. Wound Care 27, 434–441 (2018).

    Article  PubMed  Google Scholar 

  201. Li, W. W., Carter, M. J., Mashiach, E. & Guthrie, S. D. Vascular assessment of wound healing: a clinical review. Int. Wound J. 14, 460–469 (2017).

    Article  PubMed  Google Scholar 

  202. Kirsner, R. S. & Vivas, A. C. Lower-extremity ulcers: diagnosis and management. Br. J. Dermatol. 173, 379–390 (2015).

    Article  CAS  PubMed  Google Scholar 

  203. Alvaro-Afonso, F. J. et al. Interobserver reliability of the ankle-brachial index, toe-brachial index and distal pulse palpation in patients with diabetes. Diab Vasc. Dis. Res. 15, 344–347 (2018).

    Article  PubMed  Google Scholar 

  204. Rayman, G. et al. Guidelines on use of interventions to enhance healing of chronic foot ulcers in diabetes (IWGDF 2019 update). Diabetes Metab. Res. Rev. 36 (Suppl. 1), e3283 (2020).

    PubMed  Google Scholar 

  205. Moore, Z. E. & Patton, D. Risk assessment tools for the prevention of pressure ulcers. Cochrane Database Syst. Rev. 1, CD006471 (2019).

    PubMed  Google Scholar 

  206. Oliveira, A. L., Moore, Z., Connor, T. O. & Patton, D. Accuracy of ultrasound, thermography and subepidermal moisture in predicting pressure ulcers: a systematic review. J. Wound Care 26, 199–215 (2017).

    Article  CAS  PubMed  Google Scholar 

  207. Gottrup, F. et al. Antimicrobials and non-healing wounds. Evidence, controversies and suggestions-key messages. J. Wound Care 23, 477–478 (2014). 480, 482.

    Article  PubMed  Google Scholar 

  208. Haalboom, M. et al. Culture results from wound biopsy versus wound swab: does it matter for the assessment of wound infection? Clin. Microbiol. Infect. 25, 629.e7–629.e12 (2019).

    Article  CAS  Google Scholar 

  209. Tang, J. C., Vivas, A., Rey, A., Kirsner, R. S. & Romanelli, P. Atypical ulcers: wound biopsy results from a university wound pathology service. Ostomy Wound Manage. 58, 20–22, 24, 26–29 (2012).

    PubMed  Google Scholar 

  210. Panuncialman, J., Hammerman, S., Carson, P. & Falanga, V. Wound edge biopsy sites in chronic wounds heal rapidly and do not result in delayed overall healing of the wounds. Wound Repair Regen. 18, 21–25 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Falanga, V., Kirsner, R. S., Eaglstein, W. H., Katz, M. H. & Kerdel, F. A. Stanozolol in treatment of leg ulcers due to cryofibrinogenaemia. Lancet 338, 347–348 (1991).

    Article  CAS  PubMed  Google Scholar 

  212. Baby, D. et al. Calciphylaxis and its diagnosis: a review. J. Fam. Med. Prim. Care 8, 2763–2767 (2019).

    Article  Google Scholar 

  213. Dini, V. et al. Improvement of idiopathic pyoderma gangrenosum during treatment with anti-tumor necrosis factor alfa monoclonal antibody. Int. J. Low. Extrem. Wounds 6, 108–113 (2007).

    Article  PubMed  Google Scholar 

  214. Fox, J. D. et al. Adalimumab treatment leads to reduction of tissue tumor necrosis factor-alpha correlated with venous leg ulcer improvement: a pilot study. Int. Wound J. 13, 963–966 (2016).

    Article  PubMed  Google Scholar 

  215. Ahmed, S., O’Neill, K. D., Hood, A. F., Evan, A. P. & Moe, S. M. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am. J. Kidney Dis. 37, 1267–1276 (2001).

    Article  CAS  PubMed  Google Scholar 

  216. Tardaguila-Garcia, A. et al. Metalloproteinases in chronic and acute wounds: a systematic review and meta-analysis. Wound Repair Regen. 27, 415–420 (2019).

    Article  PubMed  Google Scholar 

  217. Dini, V. et al. Potential correlation of wound bed score and biomarkers in chronic lower leg wounds: an exploratory study. J. Wound Care 26, S9–S17 (2017).

    Article  CAS  PubMed  Google Scholar 

  218. Stacey, M. C. Biomarker directed chronic wound therapy-a new treatment paradigm. J. Tissue Viability 29, 180–183 (2020).

    Article  PubMed  Google Scholar 

  219. Boyd, G., Butcher, M., Glover, D. & Kingsley, A. Prevention of non-healing wounds through the prediction of chronicity. J. Wound Care 13, 265–266 (2004).

    Article  CAS  PubMed  Google Scholar 

  220. Gethin, G., Probst, S., Stryja, J., Christiansen, N. & Price, P. Evidence for person-centred care in chronic wound care: a systematic review and recommendations for practice. J. Wound Care 29, S1–S22 (2020).

    Article  PubMed  Google Scholar 

  221. Candan, C., Nergis, B., Cimilli Duru, S. & Koyuncu, B. Development of a care labelling process for compression stockings based on natural (cotton) fibers. Polymers 13, 2107 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Lindsay, E. The Lindsay Leg Club Model: a model for evidence-based leg ulcer management. Br. J. Community Nurs. 9 (Suppl. 2), S15–S20 (2004).

    Article  Google Scholar 

  223. Nukada, H. Ischemia and diabetic neuropathy. Handb. Clin. Neurol. 126, 469–487 (2014).

    Article  PubMed  Google Scholar 

  224. Crews, R. T., King, A. L., Yalla, S. V. & Rosenblatt, N. J. Recent advances and future opportunities to address challenges in offloading diabetic feet: a mini-review. Gerontology 64, 309–317 (2018).

    Article  PubMed  Google Scholar 

  225. Lim, E., Mordiffi, Z., Chew, H. S. J. & Lopez, V. Using the Braden subscales to assess risk of pressure injuries in adult patients: a retrospective case-control study. Int. Wound J. 16, 665–673 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Padula, W. V., Chen, Y. H. & Santamaria, N. Five-layer border dressings as part of a quality improvement bundle to prevent pressure injuries in US skilled nursing facilities and Australian nursing homes: a cost-effectiveness analysis. Int. Wound J. 16, 1263–1272 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Phillips, C. J. et al. Estimating the costs associated with the management of patients with chronic wounds using linked routine data. Int. Wound J. 13, 1193–1197 (2016).

    Article  PubMed  Google Scholar 

  228. Guest, J. F., Fuller, G. W. & Vowden, P. Cohort study evaluating the burden of wounds to the UK’s National Health Service in 2017/2018: update from 2012/2013. BMJ Open 10, e045253 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Obagi, Z., Damiani, G., Grada, A. & Falanga, V. Principles of wound dressings: a review. Surg. Technol. Int. 35, 50–57 (2019).

    PubMed  Google Scholar 

  230. Herrick, S. E. et al. Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am. J. Pathol. 141, 1085–1095 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Boulton, A. J., Meneses, P. & Ennis, W. J. Diabetic foot ulcers: a framework for prevention and care. Wound Repair Regen. 7, 7–16 (1999).

    Article  CAS  PubMed  Google Scholar 

  232. Falanga, V. Classifications for wound bed preparation and stimulation of chronic wounds. Wound Repair Regen. 8, 347–352 (2000).

    Article  CAS  PubMed  Google Scholar 

  233. Ayello, E. A. et al. TIME heals all wounds. Nursing 34, 36–41 quiz, 41-2 (2004).

    Article  PubMed  Google Scholar 

  234. Schultz, G. S. et al. Wound bed preparation: a systematic approach to wound management. Wound Repair Regen. 11 (Suppl. 1), S1–S28 (2003).

    Article  PubMed  Google Scholar 

  235. Sibbald, R. G. et al. Wound bed preparation 2021. Adv. Skin. Wound Care 34, 183–195 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  236. Falanga, V. et al. Systemic treatment of venous leg ulcers with high doses of pentoxifylline: efficacy in a randomized, placebo-controlled trial. Wound Repair Regen. 7, 208–213 (1999).

    Article  CAS  PubMed  Google Scholar 

  237. Jull, A., Waters, J. & Arroll, B. Pentoxifylline for treatment of venous leg ulcers: a systematic review. Lancet 359, 1550–1554 (2002).

    Article  CAS  PubMed  Google Scholar 

  238. & Falanga, V. et al. Maintenance debridement in the treatment of difficult-to-heal chronic wounds. Recommendations of an expert panel. Ostomy Wound Manage. 54 (Suppl.), 2–15 (2008).

    Google Scholar 

  239. Bucalo, B., Eaglstein, W. H. & Falanga, V. Inhibition of cell proliferation by chronic wound fluid. Wound Repair Regen. 1, 181–186 (1993).

    Article  CAS  PubMed  Google Scholar 

  240. Katz, M. H., Alvarez, A. F., Kirsner, R. S., Eaglstein, W. H. & Falanga, V. Human wound fluid from acute wounds stimulates fibroblast and endothelial cell growth. J. Am. Acad. Dermatol. 25, 1054–1058 (1991).

    Article  CAS  PubMed  Google Scholar 

  241. Langer, V., Bhandari, P. S., Rajagopalan, S. & Mukherjee, M. K. Negative pressure wound therapy as an adjunct in healing of chronic wounds. Int. Wound J. 12, 436–442 (2015).

    Article  PubMed  Google Scholar 

  242. Seidel, D. et al. Negative pressure wound therapy compared with standard moist wound care on diabetic foot ulcers in real-life clinical practice: results of the German DiaFu-RCT. BMJ Open 10, e026345 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  243. Wang, G. et al. Bacteria induce skin regeneration via IL-1beta signaling. Cell Host Microbe 29, 777–791.e6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Karinja, S. J. & Spector, J. A. Treatment of infected wounds in the age of antimicrobial resistance: contemporary alternative therapeutic options. Plast. Reconstr. Surg. 142, 1082–1092 (2018).

    Article  CAS  PubMed  Google Scholar 

  245. Gareau, M. G., Sherman, P. M. & Walker, W. A. Probiotics and the gut microbiota in intestinal health and disease. Nat. Rev. Gastroenterol. Hepatol. 7, 503–514 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  246. Fijan, S. et al. Efficacy of using probiotics with antagonistic activity against pathogens of wound infections: an integrative review of literature. Biomed. Res. Int. 2019, 7585486 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  247. Mohseni, S. et al. The beneficial effects of probiotic administration on wound healing and metabolic status in patients with diabetic foot ulcer: a randomized, double-blind, placebo-controlled trial. Diabetes Metab. Res. Rev. 34, e2970 (2018).

    Article  Google Scholar 

  248. De Pessemier, B. et al. Gut–skin axis: current knowledge of the interrelationship between microbial dysbiosis and skin conditions. Microorganisms 9, 353 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  249. Falanga, V. Occlusive wound dressings. Why, when, which? Arch. Dermatol. 124, 872–877 (1988).

    Article  CAS  PubMed  Google Scholar 

  250. Barros Almeida, I. et al. Smart dressings for wound healing: a review. Adv. Skin. Wound Care 34, 1–8 (2021).

    Article  PubMed  Google Scholar 

  251. Falanga, V. et al. Topically applied recombinant tissue plasminogen activator for the treatment of venous ulcers. Preliminary report. Dermatol. Surg. 22, 643–644 (1996).

    Article  CAS  PubMed  Google Scholar 

  252. Steed, D. L. et al. Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. CT-102 activated platelet supernatant, topical versus placebo. Diabetes Care 15, 1598–1604 (1992).

    Article  CAS  PubMed  Google Scholar 

  253. Steed, D. L. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic Ulcer Study Group. J. Vasc. Surg. 21, 71–78 discussion 79-81 (1995).

    Article  CAS  PubMed  Google Scholar 

  254. Rees, R. S., Robson, M. C., Smiell, J. M. & Perry, B. H. Becaplermin gel in the treatment of pressure ulcers: a phase II randomized, double-blind, placebo-controlled study. Wound Repair Regen. 7, 141–147 (1999).

    Article  CAS  PubMed  Google Scholar 

  255. Smiell, J. M. et al. 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. 7, 335–346 (1999).

    Article  CAS  PubMed  Google Scholar 

  256. Wieman, T. J. Clinical efficacy of becaplermin (rhPDGF-BB) gel. Becaplermin Gel Studies Group. Am. J. Surg. 176 (2A Suppl.), 74S–79S (1998).

    Article  CAS  PubMed  Google Scholar 

  257. Steed, D. L., Donohoe, D., Webster, M. W. & Lindsley, L. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group. J. Am. Coll. Surg. 183, 61–64 (1996).

    CAS  PubMed  Google Scholar 

  258. Falanga, V. The chronic wound: impaired healing and solutions in the context of wound bed preparation. Blood Cell Mol. Dis. 32, 88–94 (2004).

    Article  CAS  Google Scholar 

  259. Yamakawa, S. & Hayashida, K. Advances in surgical applications of growth factors for wound healing. Burns Trauma 7, 10 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  260. Falanga, V. et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch. Dermatol. 134, 293–300 (1998).

    Article  CAS  PubMed  Google Scholar 

  261. Falanga, V. & Sabolinski, M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen. 7, 201–207 (1999).

    Article  CAS  PubMed  Google Scholar 

  262. Veves, A., Falanga, V., Armstrong, D. G. & Sabolinski, M. L. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care 24, 290–295 (2001).

    Article  CAS  PubMed  Google Scholar 

  263. MacNeil, S. Progress and opportunities for tissue-engineered skin. Nature 445, 874–880 (2007).

    Article  CAS  PubMed  Google Scholar 

  264. Phillips, T. J. et al. The longevity of a bilayered skin substitute after application to venous ulcers. Arch. Dermatol. 138, 1079–1081 (2002).

    Article  PubMed  Google Scholar 

  265. Falanga, V. et al. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 13, 1299–1312 (2007).

    Article  CAS  PubMed  Google Scholar 

  266. Harding, K., Sumner, M. & Cardinal, M. A prospective, multicentre, randomised controlled study of human fibroblast-derived dermal substitute (Dermagraft) in patients with venous leg ulcers. Int. Wound J. 10, 132–137 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  267. Marston, W. A., Hanft, J., Norwood, P. & Pollak, R. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care 26, 1701–1705 (2003).

    Article  PubMed  Google Scholar 

  268. Mostow, E. N. et al. Effectiveness of an extracellular matrix graft (OASIS wound matrix) in the treatment of chronic leg ulcers: a randomized clinical trial. J. Vasc. Surg. 41, 837–843 (2005).

    Article  PubMed  Google Scholar 

  269. Omar, A. A., Mavor, A. I., Jones, A. M. & Homer-Vanniasinkam, S. Treatment of venous leg ulcers with Dermagraft. Eur. J. Vasc. Endovasc. Surg. 27, 666–672 (2004).

    Article  CAS  PubMed  Google Scholar 

  270. Bosanquet, D. C. et al. Development and validation of a gene expression test to identify hard-to-heal chronic venous leg ulcers. Br. J. Surg. 106, 1035–1042 (2019).

    Article  CAS  PubMed  Google Scholar 

  271. Rahim, K. et al. Bacterial contribution in chronicity of wounds. Microb. Ecol. 73, 710–721 (2017).

    Article  PubMed  Google Scholar 

  272. Jeffcoate, W. J. et al. Randomised controlled trial of the use of three dressing preparations in the management of chronic ulceration of the foot in diabetes. Health Technol. Assess. 13, 1–86 iii–iv (2009).

    Article  CAS  PubMed  Google Scholar 

  273. Grey, J. E., Leaper, D. & Harding, K. How to measure success in treating chronic leg ulcers. BMJ 338, b1434 (2009).

    Article  PubMed  Google Scholar 

  274. Franks, P. J. & Moffatt, C. J. Who suffers most from leg ulceration? J. Wound Care 7, 383–385 (1998).

    Article  CAS  PubMed  Google Scholar 

  275. Zhou, K. & Jia, P. Depressive symptoms in patients with wounds: a cross-sectional study. Wound Repair Regen. 24, 1059–1065 (2016).

    Article  PubMed  Google Scholar 

  276. Kapp, S., Miller, C. & Santamaria, N. The quality of life of people who have chronic wounds and who self-treat. J. Clin. Nurs. 27, 182–192 (2018).

    Article  PubMed  Google Scholar 

  277. Kapp, S. & Santamaria, N. The financial and quality-of-life cost to patients living with a chronic wound in the community. Int. Wound J. 14, 1108–1119 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  278. Fayne, R. A., Borda, L. J., Egger, A. N. & Tomic-Canic, M. The potential impact of social genomics on wound healing. Adv. Wound Care 9, 325–331 (2020).

    Article  Google Scholar 

  279. Sen, C. K. & Roy, S. Sociogenomic approach to wound care: a new patient-centered paradigm. Adv. Wound Care 8, 523–526 (2019).

    Article  Google Scholar 

  280. Ware, J. E. Jr & Sherbourne, C. D. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care 30, 473–483 (1992).

    Article  PubMed  Google Scholar 

  281. EuroQol, G. EuroQol-a new facility for the measurement of health-related quality of life. Health Policy 16, 199–208 (1990).

    Article  Google Scholar 

  282. Price, P. & Harding, K. Cardiff Wound Impact Schedule: the development of a condition-specific questionnaire to assess health-related quality of life in patients with chronic wounds of the lower limb. Int. Wound J. 1, 10–17 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  283. Martinez-Gonzalez, D. et al. Adaptation and validation of the diabetic foot ulcer scale-short form in Spanish subjects. J. Clin. Med. 9, 2497 (2020).

    Article  PubMed Central  Google Scholar 

  284. Moore, Z. et al. Exploring the concept of a team approach to wound care: managing wounds as a team. J. Wound Care 23 (Suppl. 5b), S1–S38 (2014).

    PubMed  Google Scholar 

  285. Kapp, S. & Santamaria, N. How and why patients self-treat chronic wounds. Int. Wound J. 14, 1269–1275 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  286. Miller, C. & Kapp, S. Informal carers and wound management: an integrative literature review. J. Wound Care 24, 489–490 (2015).

    Article  CAS  PubMed  Google Scholar 

  287. Kapp, S. & Santamaria, N. Chronic wounds should be one of Australia’s national health priority areas. Aust. Health Rev. 39, 600–602 (2015).

    Article  PubMed  Google Scholar 

  288. Hellmann, J., Tang, Y. & Spite, M. Proresolving lipid mediators and diabetic wound healing. Curr. Opin. Endocrinol. Diabetes Obes. 19, 104–108 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Pils, V., Terlecki-Zaniewicz, L., Schosserer, M., Grillari, J. & Lammermann, I. The role of lipid-based signalling in wound healing and senescence. Mech. Ageing Dev. 198, 111527 (2021).

    Article  CAS  PubMed  Google Scholar 

  290. Hu, M. S., Borrelli, M. R., Lorenz, H. P., Longaker, M. T. & Wan, D. C. Mesenchymal stromal cells and cutaneous wound healing: a comprehensive review of the background, role, and therapeutic potential. Stem Cell Int. 2018, 6901983 (2018).

    Google Scholar 

  291. Kucharzewski, M. et al. Novel trends in application of stem cells in skin wound healing. Eur. J. Pharmacol. 843, 307–315 (2019).

    Article  CAS  PubMed  Google Scholar 

  292. Otero-Vinas, M. & Falanga, V. Mesenchymal stem cells in chronic wounds: the spectrum from basic to advanced therapy. Adv. Wound Care 5, 149–163 (2016).

    Article  Google Scholar 

  293. Li, P. & Guo, X. A review: therapeutic potential of adipose-derived stem cells in cutaneous wound healing and regeneration. Stem Cell Res. Ther. 9, 302 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  294. van Dongen, J. A., Harmsen, M. C., van der Lei, B. & Stevens, H. P. Augmentation of dermal wound healing by adipose tissue-derived stromal cells (ASC). Bioengineering 5, 91 (2018).

    Article  PubMed Central  Google Scholar 

  295. Brockmann, I. et al. Skin-derived stem cells for wound treatment using cultured epidermal autografts: clinical applications and challenges. Stem Cell Int. 2018, 4623615 (2018).

    Google Scholar 

  296. Gonzales, K. A. U. & Fuchs, E. Skin and its regenerative powers: an alliance between stem cells and their niche. Dev. Cell 43, 387–401 (2017).

    Article  CAS  PubMed  Google Scholar 

  297. Himal, I., Goyal, U. & Ta, M. Evaluating Wharton’s jelly-derived mesenchymal stem cell’s survival, migration, and expression of wound repair markers under conditions of ischemia-like stress. Stem Cell Int. 2017, 5259849 (2017).

    Google Scholar 

  298. Lin, X. et al. An in vitro priming step increases the expression of numerous epidermal growth and migration mediators in a tissue-engineering construct. J. Tissue Eng. Regen. Med. 11, 713–723 (2017).

    Article  CAS  PubMed  Google Scholar 

  299. Magne, B., Lataillade, J. J. & Trouillas, M. Mesenchymal stromal cell preconditioning: the next step toward a customized treatment for severe burn. Stem Cell Dev. 27, 1385–1405 (2018).

    Article  Google Scholar 

  300. Xu, W., Xu, R., Li, Z., Wang, Y. & Hu, R. Hypoxia changes chemotaxis behaviour of mesenchymal stem cells via HIF-1alpha signalling. J. Cell Mol. Med. 23, 1899–1907 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Yang, H. Y. et al. Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice. Stem Cell Transl. Med. 9, 1353–1364 (2020).

    Article  CAS  Google Scholar 

  302. Ariyanti, A. D. et al. Salidroside-pretreated mesenchymal stem cells enhance diabetic wound healing by promoting paracrine function and survival of mesenchymal stem cells under hyperglycemia. Stem Cell Transl. Med. 8, 404–414 (2019).

    Article  CAS  Google Scholar 

  303. Larsen, L. et al. Combination therapy of autologous adipose mesenchymal stem cell-enriched, high-density lipoaspirate and topical timolol for healing chronic wounds. J. Tissue Eng. Regen. Med. 12, 186–190 (2018).

    Article  CAS  PubMed  Google Scholar 

  304. Yoshikawa, T. et al. Wound therapy by marrow mesenchymal cell transplantation. Plast. Reconstr. Surg. 121, 860–877 (2008).

    Article  CAS  PubMed  Google Scholar 

  305. Dash, N. R., Dash, S. N., Routray, P., Mohapatra, S. & Mohapatra, P. C. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res. 12, 359–366 (2009).

    Article  CAS  PubMed  Google Scholar 

  306. Falanga, V. et al. Autologous cultured bone marrow-derived mesenchymal stem cells in a fibrin spray to treat venous ulcers: a randomized controlled double-blind pilot study. Surg. Technol. Int. 40, 47–54 (2022).

    Article  PubMed  Google Scholar 

  307. Ferreira, A. D. F. & Gomes, D. A. Stem cell extracellular vesicles in skin repair. Bioengineering 6, 4 (2018).

    Article  PubMed Central  Google Scholar 

  308. McBride, J. D., Rodriguez-Menocal, L. & Badiavas, E. V. Extracellular vesicles as biomarkers and therapeutics in dermatology: a focus on exosomes. J. Invest. Dermatol. 137, 1622–1629 (2017).

    Article  CAS  PubMed  Google Scholar 

  309. Phinney, D. G. & Pittenger, M. F. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cell 35, 851–858 (2017).

    Article  CAS  Google Scholar 

  310. Roefs, M. T., Sluijter, J. P. G. & Vader, P. Extracellular vesicle-associated proteins in tissue repair. Trends Cell Biol. 30, 990–1013 (2020).

    Article  CAS  PubMed  Google Scholar 

  311. Sung, B. H., Parent, C. A. & Weaver, A. M. Extracellular vesicles: critical players during cell migration. Dev. Cell 56, 1861–1874 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  312. Bailey, A. J. M. et al. MSC-derived extracellular vesicles to heal diabetic wounds: a systematic review and meta-analysis of preclinical animal studies. Stem Cell Rev. Rep. 18, 968–979 (2022).

    Article  PubMed  Google Scholar 

  313. Margolis, D. J., Gross, E. A., Wood, C. R. & Lazarus, G. S. Planimetric rate of healing in venous ulcers of the leg treated with pressure bandage and hydrocolloid dressing. J. Am. Acad. Dermatol. 28, 418–421 (1993).

    Article  CAS  PubMed  Google Scholar 

  314. Tallman, P., Muscare, E., Carson, P., Eaglstein, W. H. & Falanga, V. Initial rate of healing predicts complete healing of venous ulcers. Arch. Dermatol. 133, 1231–1234 (1997).

    Article  CAS  PubMed  Google Scholar 

  315. Falanga, V. Measurements in wound healing. Int. J. Low. Extrem. Wounds 7, 9–11 (2008).

    Article  PubMed  Google Scholar 

  316. Otero, M., Lin, X., MacLauchlan, S., Carson, P. & Falanga, V. Dermal fibroblasts from chronic wounds exhibit paradoxically enhanced proliferative and migratory activities that may be related to the non-canonical Wnt signaling pathway. Surg. Technol. Int. 39, 59–66 (2021).

    Google Scholar 

  317. Panuncialman, J. & Falanga, V. The science of wound bed preparation. Surg. Clin. North Am. 89, 611–626 (2009).

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Dermatology, Boston University, Boston, MA, USA

    Vincent Falanga

  2. Department of Biochemistry, Boston University, Boston, MA, USA

    Vincent Falanga

  3. Department of Dermatology, University of California at Davis, Davis, CA, USA

    Roslyn Rivkah Isseroff & Athena M. Soulika

  4. Dermatology Section, VA Northern California Health Care System, Mather, CA, USA

    Roslyn Rivkah Isseroff & Athena M. Soulika

  5. Shriners Hospital for Children, Sacramento, CA, USA

    Athena M. Soulika

  6. Department of Dermatology, University of Pisa, Pisa, Italy

    Marco Romanelli

  7. Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA

    David Margolis

  8. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA

    David Margolis

  9. Department of Nursing, University of Melbourne, Melbourne, Australia

    Suzanne Kapp

  10. Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA

    Mark Granick

  11. Clinical Innovation Hub Cardiff University, Cardiff, Wales, UK

    Keith Harding

  12. Skin Research Institute of Singapore (SRIS), Singapore, Singapore

    Keith Harding

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  1. Vincent Falanga
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  8. Keith Harding
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Contributions

Introduction (V.F.); Epidemiology (D.M.); Mechanisms/pathophysiology (R.R.I. and A.M.S.); Diagnosis, screening and prevention (M.R. and M.G.); Management (K.H.); Quality of life (S.K.); Outlook (V.F.).

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Correspondence to Vincent Falanga.

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Nature Reviews Disease Primers thanks R. D. Galiano, L. Téot and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Cochrane Wounds systematic reviews database: https://wounds.cochrane.org/news/reviews

Diabetic Foot Consortium: http://diabeticfootconsortium.org/

Lindsay Leg Club Foundation: https://www.legclub.org/

United States Diabetes Surveillance System: https://gis.cdc.gov/grasp/diabetes/DiabetesAtlas.html

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Falanga, V., Isseroff, R.R., Soulika, A.M. et al. Chronic wounds. Nat Rev Dis Primers 8, 50 (2022). https://doi.org/10.1038/s41572-022-00377-3

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