Limited Treatment Options for Diabetic Wounds: Barriers to Clinical Translation Despite Therapeutic Success in Murine Models

Abstract

Significance: Millions of people worldwide suffer from diabetes mellitus and its complications, including chronic diabetic wounds. To date, there are few widely successful clinical therapies specific to diabetic wounds beyond general wound care, despite the vast number of scientific discoveries in the pathogenesis of defective healing in diabetes. Recent Advances: In recent years, murine animal models of diabetes have enabled the investigation of many possible therapeutics for diabetic wound care. These include specific cell types, growth factors, cytokines, peptides, small molecules, plant extracts, microRNAs, extracellular vesicles, novel wound dressings, mechanical interventions, bioengineered materials, and more. Critical Issues: Despite many research discoveries, few have been translated from their success in murine models to clinical use in humans. This massive gap between bench discovery and bedside application begs the simple and critical question: what is still missing? The complexity and multiplicity of the diabetic wound makes it an immensely challenging therapeutic target, and this lopsided progress highlights the need for new methods to overcome the bench-to-bedside barrier. How can laboratory discoveries in animal models be effectively translated to novel clinical therapies for human patients? Future Directions: As research continues to decipher deficient healing in diabetes, new approaches and considerations are required to ensure that these discoveries can become translational, clinically usable therapies. Clinical progress requires the development of new, more accurate models of the human disease state, multifaceted investigations that address multiple critical components in wound repair, and more innovative research strategies that harness both the existing knowledge and the potential of new advances across disciplines.

Keywords: diabetes; diabetic ulcer; diabetic wound; murine; therapeutic; wound healing.

Luisa A. DiPietro, DDS, PhD

Lin Chen, MD, PhD

Figure 1.

Examples of diabetic wounds. Representative images of nonhealing neuropathic, ischemic, or neuroischemic diabetic ulcers affecting the lower extremities. All images generously provided by Dr. Stephanie Wu, DPM, MSc, FACFAS; Dean of Dr. William M. Scholl College of Podiatric Medicine; Professor, Department of Podiatric Surgery and Applied Biomechanics; Professor, Center for Stem Cell and Regenerative Medicine; and Director, Center for Lower Extremity Ambulatory Research (CLEAR) for Dr. William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine and Science. Color images are available online.

Figure 2.

Stages of wound healing. A schematic (not to scale) depicting the four phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. Artwork and renderings in this and subsequent figures are courtesy of Smart Servier Medical Art, freely available at https://smart.servier.com Color images are available online.

Figure 3.

Current standards of diabetic foot care. A summary of the most important components of diabetic foot care and the treatment and prevention of diabetic foot ulcers. These are good glycemic control, regular foot care and examination, early detection, and appropriate wound care and dressings. There are currently no gold standard pharmaceutical therapies that are specific for and widely usable to treat diabetic wounds, although there are a few FDA-approved options available. FDA, Food and Drug Administration. Color images are available online.

Figure 4.

Common rodent models of DM. An overview of some of the most common murine models of type 1 and type 2 DM. For type 1 DM, these include the streptozotocin and/or alloxan-induced models and the nonobese diabetic mouse.^, For type 2 DM, they include the high-fat diet mouse, leptin and leptin receptor mutants, Zucker diabetic fatty rats, and polygenic models such as the New Zealand Obese mouse and the Otsuka Long-Evans Tokushima Fatty Rat.^,, DM, diabetes mellitus. Color images are available online.

Figure 5.

Common experimental methods of wound healing. A summary depicting some of the most commonly used experimental wounding models, including excisional wounds, incisional wounds, ischemic wounds, burn wounds, and abrasion wounds.^, Color images are available online.