Abstract and Introduction
Abstract
Wounds continue to pose significant challenges to clinicians. Data based on randomized controlled trials from the US Wound Registry showed that less than 50% of wounds heal in an unpredictable period of time. Chronic wounds are difficult to heal, with multiple barriers to healing that include inadequate nutrient flow, an inflammatory-coagulation vicious cycle, redox imbalance, and anatomical, physiological, and biochemical dysfunction in the endothelium. In clinical practice, wounds that fail to heal within an appropriate time are at higher risk for deterioration as well as development of infection that further complicates the pathology. Wounds complicated by deep abscess and osteomyelitis often result in amputation. Higher level amputations, below the knee and above the knee, are associated with increased morbidity and mortality rates. However, the most consequential barrier to healing is the prolonged inflammatory phase, which prevents progression to the proliferation phase of wound healing. Diabetic foot ulcers are especially difficult to heal because of angiopathy, hypoxia and ischemia, AGEs, and other factors related to impaired hemodynamics. Restoration of physiological levels of blood flow to DFUs will concomitantly bring about normalization of laminar SS on the endothelium. These multifaceted healing mechanisms, specifically related to the effects of vascular SS on the endothelium, are reviewed here. Such mechanisms involve anti-inflammation, anticoagulation, antioxidation, vasodilation, and angiogenesis. A concluding inference is made that if normalized SS could be produced in the vasculature serving chronic wounds, the sequential healing processes would be enhanced.
Introduction
Chronic lower extremity wounds, especially those related to diabetes, are a major health care challenge in the United States. Lower extremity wounds affect up to 49 million people worldwide; in the United States alone, the estimated annual cost of chronic wound management is $96.8 billion.[1,2] Problematically, chronic wounds do not always heal, which can lead to an amputation that results in increased debilitation, health care costs, morbidity, and mortality. Up to one-third of the estimated 500 million persons with diabetes worldwide may eventually develop a DFU, which is the greatest risk factor for future DFU development.[3,4] In 2014, the average cost of an amputation among US military veterans was $60 640 per amputation.[3–5] In 2017, overall health care plus lost productivity costs of treating diabetes plus lost productivity in the United States was $237 billion.[4] Treatment alone costs billions of dollars, and the incidence of diabetes is projected to increase 50% by 2030.[4–6] The mechanisms of a prolonged or nonhealing DFU are addressed in this review, specifically those related to improved blood flow and the associated physiological vascular mechanotransduction and sequelae for healing.[7] Etiologies of chronic wounds include macro- and microangiopathies, diabetes, venous insufficiency, prolonged vascular closure, and autonomic neuropathy.The pathophysiology of DFUs makes healing difficult for systemic, anatomic, microbiologic, immunologic, molecular, and epigenetic reasons. Nevertheless, compromised blood flow comprehensively exacerbates the above pathophysiologic mechanisms. For example, cellular hypoxia resulting from vascular dysfunction in addition to increased oxygen consumption due to inflammation both affect HIF-1. This transcription factor for approximately 1000 genes responds to SS and regulates oxygen homeostasis by angiogenesis, erythropoiesis, cellular proliferation, migration, and survival, which enhances healing in diabetic wounds. Hypoxia-inducible factor-1α of the heterodimer HIF-1 is both destabilized and inhibited in persons with diabetes.[7–9]
Generally, wound healing follows 4 sequential, overlapping phases: hemostasis/coagulation, inflammation, proliferation, and remodeling.[8–10] However, diabetes may complicate, delay, or stall healing. Adequate circulation and normal SSs are vital for healing processes in these 4 phases, but micro- and macroangiopathies in diabetes impair each phase of healing. Diabetic foot ulcers are characterized by prolonged inflammation, persistent infections, bacterial biofilms, impaired dermal and/or epidermal cells in remodeling, and senescent cells (fibroblasts, keratinocytes, ECs, macrophages). Cell populations exhibit impaired proliferative and secretory abilities. Thus, DFU is typically a chronic wound. Cellular senescence is related either to prolonged oxidative stress and DNA-damaged cell cycles or to abnormal metabolism in persons with diabetes.[10] Mesenchymal stem cells that normally engraft into remodeling the microcirculation during healing are deficient and defective in the setting of DFU.[11,12] Healing of DFUs requires not only amelioration of wound causes, but also of systemic and metabolic disturbances, including infection and imbalance of cytokines, growth factors, proteases, mesenchymal stem cells, and other metabolically incompetent cells.[12–16]
The authors of this review searched the following databases and source materials for studies on abnormal blood flow with altered endothelial mechanotransduction in diabetic microangiopathy affecting multiple molecular mechanisms of wound healing:[16–18] National Library of Medicine, PubMed, ScienceDirect, HighWire Press, and Scopus. This review focuses on wound healing mechanisms that connect physiologic blood flow and SS with chronic wounds such as DFUs during each phase of healing.[18] Healing of DFUs is multifactorial, and healing parameters unrelated to SS are not included in this review. Adequate blood flow and hemodynamic SS at homeostatic levels affect inflammation, coagulation, cytokines, angiogenesis, NO, AR, and MMPs. Each of these biochemical and physiological parameters plays a significant role in chronic wound healing and is reviewed in the context of the sequential stages of wound healing.
Wounds. 2022;34(11):254-262. © 2022 HMP Communications, LLC
