By Temple University School of Podiatric Medicine Journal Review Club
Article Title: Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer
Authors: Cao Y, Gang X, Wang G
Journal: J Diabetes Res....
By the WoundSource Editors
Diabetic foot ulcers (DFUs) continue to be a major problem, causing patient suffering, burden, infections, and high mortality. The cost of DFU treatment was estimated at $1.3 trillion globally in 2015.1 Despite evolving advanced wound care technologies through the years, DFUs continue to be among the most challenging chronic wound types.
Stalling Factors in Diabetic Foot Ulcers and Standard of Care
Patients with diabetic wounds are likely to have what is referred to as a chronification phenotype. Diabetic wounds fail to stimulate proliferation or granulation type responses, and they have abnormal angiogenesis, impaired wound contraction, and stagnant aberrant re-epithelialization processes.2 DFUs are defined as full-thickness wounds located below the ankle in patients with diabetes. These patients are at an increased risk for limb loss and associated mortality.1
Current treatments for DFUs include offloading, antibiotics for confirmed infection, and revascularization for peripheral artery disease (PAD). Evidence available from clinical studies does not suggest using one specific treatment versus another in maximizing wound healing outcomes.3-5 The rate of DFU recurrence within 12 months of wound closure is 40%, projecting that when an ulcer has healed, there is a high chance it will recur within a year. This is a critical aspect of diabetic foot disease, emphasizing that when an ulcer heals, foot disease must be regarded not as cured, but in remission.6
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Diabetic peripheral neuropathy and ischemia are causative factors in poor wound healing, by damaging both the macrocirculation and the microcirculation. Impaired wound healing at a molecular level in patients with diabetes results from a cascade of critical events such as inflammation, chemoattraction, growth factor release, leucocyte adhesion, cytokine expression, and vascular permeability. Uncontrolled diabetes affects multiple organs and tissues that impose a pro-inflammatory phenotype leading to pro-inflammatory cytokines. Increased insulin resistance produces inflammatory cells within the wound, thus hindering the pro-anabolic function of insulin. Further damage includes reticular stress and apoptosis, autophagy, growth factor receptors signaling disruption, precocious senescence, and proliferative arrest. Hyperglycemia triggers vascular endothelial cell toxicity and thereby causes functional impairment. High blood glucose levels are thought to modify gene transcription in vascular and inflammatory cells. Glycemic levels help drive prolonged activity of epigenetic changes and inflammation. Toxicity develops by an accumulation of increased glycation that leads to wound chronification.2
DFU cells and pro-inflammatory cytokines are the same in non-diabetic wounds, but patients with diabetes are prone to an inflammatory condition versus a temporary reaction. Studies show that macrophages from diabetic wounds undergo efferocytosis, hindering inflammation as well. The required balance of matrix metalloproteinases (MMPs) limits the process of granulation tissue formation and maturation. Therefore, the diabetic wound environment is imbalanced, validating association with chronic non-healing wounds.2,6
After using standard of care for four weeks with no signs of improvement, it may be time to look at advanced therapies.7 Advanced therapies include negative pressure wound therapy (NPWT), biophysical agents, cellular and/or tissue-based treatments (CTPs), and others.
Negative Pressure Wound Therapy
NPWT can be used to manage high levels of exudate in wounds, to manage bioburden levels, and to encourage tissue growth. NPWT can also be very effective in patients who have had amputations.
Electrical stimulation, primarily used by physical therapists, has an abundance of studies advocating for the beneficial effects on chronic wounds.7 Pulsed radiofrequency energy has also been shown to have beneficial effects, including increased fibroblast and keratinocyte activity.7
Cellular and/or Tissue-Based Therapies
CTPs are commonly used in DFUs and come in a variety of formats and makeups, including human, bovine, porcine, and others. Dermal matrices then serve as scaffolds for cellular repopulation and angiogenesis.
Patients with DFUs have a high risk of complications such as infection, amputation, and death. It is paramount to identify and classify DFU severity to effectively focus and manage wound care, infection control, and offloading. Treating DFUs requires a multidisciplinary and patient-centered approach. Goals should focus on medical management of diabetes, good wound care standards, infection control, debridement, optimizing blood flow, nutrition, and offloading.
1. Bommer C, Heesemann E, Sagalova V, et al. The global economic burden of diabetes in adults aged 20-79 years: a cost of illness study. Lancet Diabetes Endocrinol. 2017;5:423-430. pmid:28456416.
2. Berlanga-Acosta J, Schultz GS, López-Mola E, et al. Glucose toxic effects on granulation tissue productive cells: the diabetics' impaired healing. Biomed Res Int. 2013;2013:256043.
3. Wu L, Norman G, Dumville JC, O’Meara S, Bell-Syer SE. Dressings for treating foot ulcers in people with diabetes: an overview of systematic reviews. Cochrane Database Syst Rev. 2015;(7):CD010471. pmid:26171906.
4. Game FL, Apelqvist J, Attinger C, et al.; International Working Group on the Diabetic Foot. 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):154-168. pmid:26344936.
5. Hinchliffe RJ, Brownrigg JR, Andros G, et al.; International Working Group on the Diabetic Foot. Effectiveness of revascularization of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. Diabetes Metab Res Rev. 2016;32(suppl 1):136-144. pmid:26342204.
6. Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376:2367-2375. pmid:2861467.
7. Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care. 2015;4(9)560-582.
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