Review
23 October 2019
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1 Molecular Medicine Laboratory, Unidad Academica de Medicina Humana y Ciencias de la Salud, Universidad Autonoma de Zacatecas, Carretera Zacatecas-Guadalajara Km.6. Ejido la Escondida, C.P. 98160 Zacatecas, Mexico
2 Unidad Academica de Ingenieria Electrica, Universidad Autonoma de Zacatecas, Jardín Juárez 147, Centro, 98000 Zacatecas, Mexico
3 Laboratorio de Sintesis Asimetrica y Bioenergetica (LSAyB), PA de Ingeniería Química, UACQ, Universidad Autonoma de Zacatecas, Carretera Zacatecas-Guadalajara Km.6. Ejido la Escondida, C.P. 98160 Zacatecas, Mexico
* Authors to whom correspondence should be addressed.
Diabetic foot ulcers (DFUs) are very important diabetes-related lesions that can lead to serious physical consequences like amputations of limbs and equally severe social, psychological, and economic outcomes. It is reported that up to 25% of patients with diabetes develop a DFU in their lifetime, and more than half of them become infected. Therefore, it is essential to manage infection and ulcer recovery to prevent negatives outcomes. The available information plays a significant role in keeping both physicians and patients aware of the emerging therapies against DFUs. The purpose of this review is to compile the currently available approaches in the managing and treatment of DFUs, including molecular and regenerative medicine, antimicrobial and energy-based therapies, and the use of plant extracts, antimicrobial peptides, growth factors, ozone, devices, and nano-medicine, to offer an overview of the assessment of this condition.
Diabetic foot ulcers (DFUs) are very important microvascular diabetes-related lesions that are the consequence of several predisposed factors, such as peripheral arterial disease, bone abnormalities, diabetic neuropathy, or infections that, without appropriate management, can lead to very severe clinical conditions and, eventually, lower-limb amputation. The first cause of lower-limb amputation worldwide is diabetes, and it is reported that 15–25% of patients with diabetes present foot ulcerations over their lifetime [1]. With a certain preference for patients with type 2 diabetes, DFUs can be observed in patients with type 1 diabetes. DFUs also show an overall prevalence of 6.3%. It is a major public health issue with a very important economic impact estimated at about $8659 per patient (p/p) annually in just North America. Several reports estimated that about 85% of all patients with diabetes and lower-limb amputations were diagnosed with DFU at some point. The patients shown to be at a higher risk for DFUs are those with a low body mass index (BMI), a long clinical history of diabetes (especially old patients), and those with diabetic retinopathy or systemic arterial hypertension and a smoking history [2]. DFUs are one of the most severe complications of diabetes, and more than half of those ulcers become infected. Every single one of these infected lesions has the potential to get worse and compromise the integrity of the lower limbs. To avoid amputations and improve the patient’s quality of life, it is very important to implement a strict program for the prevention and treatment of ulcers, as well as proper management of infections [3]. Thus, it is critical to keep diabetes patients aware of new therapies and treatments and their availability in the healthcare system. The treatment of DFUs requires a multidisciplinary approach with proper medical tools, skills, and knowledge. This starts from patient education, with the application of new classifications to guide the treatment to prevent amputations. New diagnosis methods should become available, such as the 16S ribosomal DNA sequence in bacteria, to provide a better understanding of the microbiota in DFUs. It is reported that DFU has a polymicrobial nature, and, according to its geographical location, certain marked differences, wound characteristics, antibiograms according to local epidemiology, individualized antimicrobial guided therapy, regular debridement, regular assessment of wounds, and change of dressings. The latter characteristics are also aided by new biological and molecular therapies that were proven to improve infection control, the regulation of the local inflammatory profile, and improved quality of the cicatrizing process. In the next sections, this review presents an approach for the diagnosis and treatment of DFUs, focusing on the current advances in antimicrobial therapies, such as dressings, topical therapies, antibiotics, drugs, debridement methods, biological, cellular, and gene therapies, plant extracts, antimicrobial peptides, growth factors, devices, ozone, and energy-based therapies.
DFUs are defined as foot lesions (ulcers) that may affect the skin, soft tissue, and bone in lower limbs, causing an aggravating infection in diabetic patients that can lead to very serious consequences such as lower-limb amputations. DFUs are caused by multifactorial etiologies as part of the microvascular complications of diabetes mellitus that can lead to major amputations, in most cases by the lack of the timely and correct management of diabetic feet. Indeed, diabetes is the leading cause of non-traumatic lower-extremity amputations worldwide [1]. These serious consequences are mostly due to the absence of data on many subjects including diabetes education, preventive measures, glycemic control, comorbidities, inappropriate multidisciplinary assessment and treatment of ulcers, and later treatment failures in the prevention of ulcer recurrence [4]. Based on the 2015 prevalence data from the International Diabetes Federation, it is estimated that foot ulcers develop in 9.1 million to 26.1 million people with diabetes annually worldwide [3]. A systematic review and meta-analysis of the global prevalence of DFUs showed that the global prevalence of DFUs was 6.3%, higher in males than in females, and higher in type 2 than in type 1 diabetic patients [2]. In Mexico, there are around 12 million cases of diabetes mellitus, and since the overall prevalence of DFUs is 6%, it is estimated that more than 700,000 people are affected with any grade of DFUs [5]. DFU treatment has a high cost worldwide. In the United States (US), this cost ranges from $8000 to $17,000, depending on the grade of infection and type of amputation, with the cost rising to $43,000 in the case of partial amputation to $63,100 after major amputation [6]. All of these costs not only affect the patient’s economic and psychological status but also the family’s economy, the patient’s disability and diminished quality of life, and the finances provided by the government and health insurance intended for diabetes treatment. In patients with diabetes, it is reported that, in most cases (60–80%), the ulcers become less aggressive, and, with the proper care, they heal. On the other hand, about 10% to 15% of these ulcers remain active and 5% to 24% lead to limb amputation in approximately 6–18 months [1]. As many as 40% of patients have a recurrence within one year after ulcer healing, almost 60% have a recurrence within three years, and 65% have a recurrence within five years, making a previous incident of a foot ulcer the strongest predictor for diabetic foot ulceration [3]. The median time to healing without surgery is about 12 weeks [4]. The five-year risk of death in diabetes patients is 2.5 times higher in those with DFUs than without them, and the five-year mortality after diabetes-related amputations exceeds 70%, which is worse than in many common cancers [3,4]. Osteomyelitis is another severe complication of DFUs, and it needs to be discarded in every patient with infected DFUs. A complete assessment with the measurement of blood pressure, and laboratory testing for complete blood cell counts, creatinine, glycated hemoglobin, erythrocyte sedimentation rate, C-reactive protein level, and ankle-brachial index (ABI, normal 0.8–1.2), as well as imaging (X-ray and MRI), needs to be done, and, in some cases, a bone biopsy may also be considered. This complication reflects the poor healthcare programs in the institutions that provide primary health attention, since primary care does not commonly provide foot examinations during routine office visits, with time being a major factor impeding routine foot assessments [7].
In addition to diabetes, the risk factors for DFU include the coexistence of neuropathy (sensory, motor, and autonomous), peripheral arterial disease (PAD), immune system factors, and, in some cases, repetitive external or minor trauma (which lead to skin breakdown and ultimately to the development of infection). Bony foot deformities (such as bunions and hammertoes), which can also create points of pressure (potential ulceration sites), are also considered to be risk factors ([Figure 1](https://www.frankenthalerfoundation.org [1,3,8].
Figure 1. Risk factors and predisposing factors for the development of diabetic foot ulcers (DFUs). There are two main protagonists among the risk factors and/or predisposing factors of DFUs: angiopathy and neuropathy, whose presence, together with intrinsic (foot deformity) and/or extrinsic triggers, such as trauma (mechanical, chemical or thermal), causes the loss of skin integrity. Aggravating factors, such as ischemia, abnormal immunity, and neuropathy, favor the development of DFU infections.
It is reported that patients with severe neuropathy commonly have higher mechanical pain thresholds than diabetes patients without it [9]. The existence of infection is the most frequent cause of amputation, as infection happens in patients with severe infections, more lost tissue, and systemic organ dysfunction. Anemia (hemoglobin <11 g/dL), old age, and the presence of PAD can also participate in the progress of infection and, eventually, lead to major amputation [10]. In México, the following were reported as risk factors for major amputation: leukocytosis (>9), low serum albumin (<2), HbAc1 (>7), and chronic kidney disease in K/DOQI (Kidney Disease Outcomes Quality Initiatives), with K/DOQI-III being the most common stage. It was also found that the most affected areas by DFUs were the forefoot (48%) and the plantar region (55%) of the foot. Most patients had advanced stages of DFUs, where 93% of the lesions were grades III–V, according to the Wagner classification [11]. In 2016, a report revealed evidence that hemoglobin A1c (HbA1c) <5.8% works as a beneficial factor [12]. The factors associated with poor healing include advanced end-organ disease (congestive heart failure, peripheral artery disease, or end-stage kidney disease) [3]. Therefore, it is imperative to invest in the research for new treatments, diagnosis, and technology intended for DFUs [4]. The complexity of DFU physiopathology and the lack of uniform criteria are evident in the variety and number of existing classifications. The American Diabetes Association (ADA) recommends criteria or variables for an ideal DFU classification. These criteria include determination of the etiology, size, depth, and edema, as well as identification of perilesional damage, the state and degree of infection, vascular and neurological factors, severity of the injury, and prognosis and guidance in management and treatment. This classification should also facilitate communication between health professionals and the understanding of the patient and his family [13]. However, there are different systems of classifications for DFUs recommended by the ADA that offer guidance for the treatments needed (Table 1).
Table 1. Classifications of diabetic feet. Comparison of clinical variables according to the criteria recommended by the American Diabetes Association (in terms of management standards, etiology, size, and depth, as well as damage to the deep neighboring structures, degree of infection, evaluation of the vascular and nervous system, and systemic involvement) [13].
DFUs have a complex pathogenesis, and the main factors that influence their development are diabetic neuropathy and PAD, with trauma being a triggering factor. All of these factors together take part in different stages of ulcer development, before and after its occurrence as a delay in wound healing [3].
Hyperglycemia produces oxidative stress (OS) on nerve cells and leads to neuropathy, which affects sensitive, motor, and autonomous nerves [14]. There is an increased production of some enzymes, such as aldose reductase and sorbitol dehydrogenase, through the polyol metabolic pathway that consumes nicotinamide adenine dinucleotide phosphate (NADPH), which is further reduced by activation of the hexosamine pathway, which limits the conversion of nicotinamide adenine dinucleotide to NADPH by inhibiting the activity of glucose-6-phosphate dehydrogenase [15]. These enzymes convert glucose into sorbitol and fructose. As these sugar products accumulate, the synthesis of nerve cell myoinositol is decreased, resulting in nerve conduction, antioxidants such as glutathione, and increased production of reactive oxygen species (ROS) [14,15,16]. Additional nerve dysfunction follows from the glycosylation of nerve cell proteins, abnormalities in the fatty-acid metabolism activation of protein kinase C, increased hexosamine pathway flux, and the polyol pathway, as well as the altered production of substance P, nerve growth factor, and calcitonin gene-related peptide, leading to further ischemia [15,16,17]. Damage to the motor neurons of the foot’s musculature may lead to an imbalance of flexors and extensors, anatomic deformities, and eventual skin ulcerations. Damage to autonomic nerves impairs sweat gland functions, and the foot may develop a decreased ability to moisturize their skin, leading to epidermal cracks and skin breakdown [16,18]. Lastly, patients may not notice foot wounds because of decreased peripheral sensation, as it depletes the foot skin of intraepidermal nerve fiber endings of the afferent A-delta and C-fibers, which are mostly nociceptors and excitable by noxious stimuli only. This affliction could be aggravated by other neuropathic conditions seen in the diabetic population, like vitamin B12 deficiency, alcohol toxicity, and end-stage renal failure [16,18]. Epidemiological studies suggest that lipid lipoproteins may contribute to PAD, as well as hypertension and s
