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Pathogenesis and Treatment of Impaired Wound Healing in Diabetes Mellitus: New Insights

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Abstract

Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes mellitus, as wound healing is impaired in the diabetic foot. Wound healing is a dynamic and complex biological process that can be divided into four partly overlapping phases: hemostasis, inflammation, proliferative and remodeling. These phases involve a large number of cell types, extracellular components, growth factors and cytokines. Diabetes mellitus causes impaired wound healing by affecting one or more biological mechanisms of these processes. Most often, it is triggered by hyperglycemia, chronic inflammation, micro- and macro-circulatory dysfunction, hypoxia, autonomic and sensory neuropathy, and impaired neuropeptide signaling. Research focused on thoroughly understanding these mechanisms would allow for specifically targeted treatment of diabetic foot ulcers. The main principles for DFU treatment are wound debridement, pressure off-loading, revascularization and infection management. New treatment options such as bioengineered skin substitutes, extracellular matrix proteins, growth factors, and negative pressure wound therapy, have emerged as adjunctive therapies for ulcers. Future treatment strategies include stem cell-based therapies, delivery of gene encoding growth factors, application of angiotensin receptors analogs and neuropeptides like substance P, as well as inhibition of inflammatory cytokines. This review provides an outlook of the pathophysiology in diabetic wound healing and summarizes the established and adjunctive treatment strategies, as well as the future therapeutic options for the treatment of DFUs.

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Acknowledgments

Sponsorship for this study was funded by the National Institute of Health Grants 1R01DK091949 (AV), 1R01NS066205 (AV, LPN) 1R01DK076937 (AV), 1R01NS046710 (AV) and 1R24DK091210-01 (AV). All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Conflict of interest

Dimitrios Baltzis, Ioanna Eleftheriadou and Aristidis Veves declare that they have no conflict of interest.

Compliance with ethics guidelines

The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.

Funding

Sponsorship for this study was funded by the National Institute of Health Grants.

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Authors and Affiliations

  1. Joslin-Beth Israel Deaconess Foot Center and Microcirculation lab, One Deaconess Rd, Boston, MA, USA

    Dimitrios Baltzis & Ioanna Eleftheriadou

  2. Beth Israel Deaconess Medical Center, One Deaconess Road, Boston, MA, PA-321A, USA

    Aristidis Veves

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  1. Dimitrios Baltzis
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  3. Aristidis Veves
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Correspondence to Aristidis Veves.

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Baltzis, D., Eleftheriadou, I. & Veves, A. Pathogenesis and Treatment of Impaired Wound Healing in Diabetes Mellitus: New Insights. Adv Ther 31, 817–836 (2014). https://doi.org/10.1007/s12325-014-0140-x

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