Comprehensive review on diabetic foot ulcers and neuropathy: Treatment, prevention and management

Abstract

Diabetic foot (DF) is a major public health concern. As evident from numerous previous studies, supervision of DF ulcer (DFU) is crucial, and a specific quality check-up is needed. Patients should be educated about glycaemic management, DFUs, foot lesions, proper care for injuries, diet, and surgery. Certain reasonably priced treatments, such as hyperbaric oxygen and vacuum-assisted closure therapy, are also available for DFUs, along with modern wound care products and techniques. Nonetheless, DF care (cleaning, applying antimicrobial cream when wounded, and foot reflexology), blood glucose monitoring to control diabetes, and monthly or quarterly examinations in individuals with diabetes are effective in managing DFUs. Between 50% and 80% of DF infections are preventable. Regardless of the intensity of the lesion, it needs to be treated carefully and checked daily during infection. Tissue regeneration can be aided by cleaning, dressing, and application of topical medicines. The choice of shoes is also important because it affects blood circulation and nerve impulses. In general, regular check-ups, monitoring of the patient’s condition, measuring blood glucose levels, and providing frequent guidance regarding DFU care are crucial. Finally, this important clinical problem requires involvement of multiple professionals to properly manage it.

Key Words: Diabetic foot ulcers; Diabetic neuropathy; Diabetes mellitus; Peripheral neuropathy; Charcot neuroarthropathy

Core Tip: The present review examines the aetiology and pathology of diabetic foot ulcers (DFUs), with a detailed discussion on diabetic peripheral neuropathy as a key factor in the development of DFUs. Furthermore, conditions such as peripheral artery disease/ischaemia, wound infection, and impaired wound healing that are directly associated with the occurrence of ulcers are described in the next sections. Additionally, the review emphasises the importance of a multidisciplinary approach, glycaemic control, and patient education. This article will, therefore, contribute to the understanding of the new DFU screening systems and provide further insights for innovative treatment research.

INTRODUCTION

Diabetes is becoming increasingly common worldwide, contributing to an increase in cases of foot ulcers, referred as diabetic foot ulcers (DFUs). DFUs affects the lower extremities and is associated with neuropathy and/or peripheral vascular disease (PVD). Patients with diabetes also experience deep tissue destruction, ulceration, and infection due to a combination of factors caused by persistent and uncontrolled hyperglycaemia[1]. Patients with DFUs experience economic, psychological, and bodily suffering owing to this incapacitating illness. The multifactorial aetiology of these ulcers makes treatment difficult and has a significant negative impact on patients, families, healthcare systems, and society at large[2]. Approximately 6.4% of patients with diabetes worldwide have DFUs[3]. Overall, 15% of people with DFUs will have to have their feet amputated, and between 50% and 60% will develop diabetic foot infections (DFIs). Individuals with DFUs are 2.5 times more likely to die within 5 years compared to individuals without[4].

Globally, the estimated direct health expenditure on diabetes was over $700 billion in 2019 and is expected to grow to $825 billion by 2030. Medical expenses related to DFUs account for 33% of the total costs involved in managing diabetes[5]. In 2017, the United States spent $237 billion on diabetes mellitus (DM) care, one-third of which was related to lower extremity issues[6]. The United Kingdom spends even more on healthcare for diabetic foot (DF) care than for lung, prostate, and breast cancers combined[7]. These findings indicate that DF is a significant global health issue.

Apart from death, lower extremity amputation (LEA) is the most unpleasant potential outcome of DFUs. Several recent studies have reported the risk of amputation in patients with DFUs[8-10]. It is believed that with efficient DFU care and intervention, amputations can be prevented and the long-term financial strain on the health system and economy reduced. Numerous therapeutic and preventive methods have been devised to prevent DFUs and amputations. These include enhanced topical treatments and dressings, innovative techniques such as hyperbaric oxygen and vacuum-assisted closure (VAC) therapy, and more contemporary endeavours such as stem cell therapy, scaffolds, and regenerative medicine. A patient-centered approach is required to manage many illnesses, especially chronic ailments. This concept is based on the idea of considering patient as a central point of a circle with all strategies, facilities and treatment plans linked with individual patient requirements. Complications can be reduced, and compliance can be improved by educating patients about the disease, its complications and necessity for appropriate medical care. Because understanding the aetiology of DFUs is essential for its treatment, thus it has become an important research area. The pathophysiology of DFUs will be covered in the first section of this article, followed by a discussion of diabetic peripheral neuropathy (DPN) and diagnostic and therapeutic innervation. The article will address the overall handicap caused by these DF complications and will conclude with a summary of the therapeutic innervation for DF.

AETIOLOGY

DFUs can be caused by several underlying conditions, such as peripheral neuropathy (PN), trauma, foot deformities, and peripheral arterial disease (PAD)[11,12]. Additionally, a correlation was reported between the onset of DFUs and male sex[13]. Neuropathy leads to development of foot ulcers, affecting nearly 60% of individuals with diabetes. People with flat feet generally develop more foot ulcers as they experience unbalanced stress on their feet, which may lead to tissue inflammation in areas at greater risk. Elderly individuals with retinopathy or diminished vision have a higher risk of injuries and trauma (Figure 1). Recent statistics indicate that the inability of low-income individuals to control their diabetic behaviour is the primary cause of DFUs. Therefore, there is a > 20% risk of DFUs among people who smoke, drink, or have poor hygiene[14,15]. Table 1 shows the correlation between demographic factors (e.g., age, sex) and clinical outcomes (e.g., ulcer healing time, DFU risk)[16].

Figure 1 Risk factors of diabetic foot ulcer.

Table 1 Correlation between demographic factors and clinical outcomes.

Demographic factors	Risk of DFU	Incidence of amputation/lower-extremity amputation	Healing time	Causes
Age	More	Higher	Longer	Longer duration of diabetes, the cumulative effects of hyperglycemia, and a higher prevalence of micro- and macrovascular complications
Sex	1.5 times more in male	1.4 to 3.5 times higher	Longer	Higher prevalence of PN, PAD, and cardiovascular disease
Race/ethnicity	More in Black, Hispanic, and other non-Whites than white groups	3 to 5 times higher	Longer	Unequal access to care manifests
Socioeconomic and geographic disparities	More	1.5 to 2.5 times higher	Longer	Lowest-income categories/lower education levels means disparities in access to care and biases in practice patterns
Overweight/obesity	No association	No association	Not defined	Not defined
Smoking	More	Higher	Longer	PN and PAD both

PN: Peripheral neuropathy; PAD: Peripheral arterial disease; DFU: Diabetic foot ulcer.

EPIDEMIOLOGY

According to estimates from the IDF, DFUs affect 40-60 million individuals worldwide[17]. Overall, 15% of individuals with DM develop DFUs. Of those with DFUs, 14%-24% develop complications leading to LEAs. In general, DFUs are the primary reason for LEA without trauma[18]. Amputation-related 5-year death rate varies from 50% to 59%[19], which is higher than the 5-year pooled death rate of 31.0% for the cancers[6]. The worldwide occurrence of DFUs is 6.3%, with North America accounting for 13.0% of cases[3].

Additionally, the recurrence rate of DFUs is 22.1% per person per year[20]. Although DFUs can appear at any stage of life, people with DM aged ≥ 45 years are most likely to develop DFUs. In the United States, foot ulcers are more common in Native Americans, African Americans, and Latinos. In 32 industrialised and developing nations, the frequency of DFUs varied from 1.5% in Australia to 16.6% in Belgium[3]. Although North America has historically had the highest reported rate of DFUs, recent cohort studies have found that diabetic population rates in South America and Africa can also reach up to 15%. Individuals with type 1 diabetes mellitus (T1DM) have a lower worldwide prevalence of DFUs than those with type 2 diabetes mellitus (T2DM)[3].

PATHOLOGY OF DFUS

DFUs are characterised by epidermal and partial dermal disruptions. Lesions such as calluses, blisters, warmth, or erythema and superficial lesions have a high potential to progress to ulcers[21]. There are three stages of progression of DFUs. The first stage is callus formation, caused by neuropathy. Motor neuropathy can result in foot deformities. Sensory neuropathy causes chronic stress and loss of sensation. Other imparting feature is autonomic neuropathy, with dry skin as its main symptom. Eventually, subcutaneous bleeding and callus erosions culminate in ulcer formation due to repeated trauma[17]. Patients with DM also have widespread atherosclerosis of tiny blood vessels in their feet and legs. This condition leads to arterial compromise. The wound does not receive enough blood supply, which delays healing and ultimately results in necrosis and gangrene formation. The main three components of DFUs are neuropathy, PAD and infection (Figure 2). To prevent amputation of limbs, it is critical to determine the primary cause and treat it with best possible ulcer healing procedure[22].

Figure 2 Pathophysiology of diabetic foot ulcer: Major factors involved in the pathogenesis of diabetic foot ulcers.

DIABETIC PERIPHERAL NEUROPATHY

Although DPN is a broad clinical term, it is commonly used to describe any combination of symptoms and signs associated with peripheral nerve dysfunction without a clear cause. Both vascular and metabolic factors are thought to contribute to chronic hyperglycaemia[23].

DPN occurs in a variety of types. About 75% of all diabetic neuropathies are distal symmetric polyneuropathy, the most common type, which can be divided into three categories: Mostly small-fibre, primarily large-fibre, and mixed small- and large-fibre neuropathy. Depending on the study population, neuropathic pain symptoms occur in between 10% and 30% of patients with distal symmetric polyneuropathy. The discomfort might be characterised as a profound ache, numbness, hyperaesthesia, or a searing or stabbing pain. The lower legs and feet are most afflicted, although some patients may also have pain in their hands, and the symptoms frequently worsen at night. Atypical or uncommon forms of DPN include mononeuropathies (such as mononeuritis multiplex), treatment-induced neuropathies, and (poly) radiculopathies[23]. Mononeuropathies typically affect the median, radial, ulnar, or common peroneal nerves and are closely linked to diabetes. Cranial nerve involvement is rare and usually presents as acute mononeuropathy. Treatment-induced neuropathy is a rare condition that arises in patients after episodes of severe metabolic dysregulation (e.g., ketoacidosis) or after abrupt and sub-stationary shifts in glycaemic control (e.g., insulin neuritis). Unilateral thigh discomfort and weight loss, followed by motor weakness, are the main symptoms of diabetic radiculopathies, which usually affect the lumbosacral plexus. Most atypical forms of DPN are self-limiting and resolve with supportive care, medications, and physical therapy over the course of several months. Although these neuropathies are mostly non-sensory, they have a diffuse pathophysiology that is comparable to distal symmetric polyneuropathy. Broadly, DPN can be classified into three forms, which are described below.

Sensory neuropathy

Insensitivity of the foot to pain, pressure, vibration, and temperature is caused by injury to nerves responsible for afferent sensations in the foot. This is known as sensory neuropathy. Both patients and physicians underestimate serious ulcerations because of the absence or diminished sensation of pain[24,25]. Owing to the lack of feelings, pre-ulcerative lesions and small wounds go unnoticed and are frequently re-traumatised, which leads to ulcer formation and delayed identification. A person may experience repetitive cumulative stress from poorly fitted shoes, which can cause friction. In contrast to a normal innervated foot, an insensate foot does not notify its wearer when adjustments or modifications are needed to halt insults that can progress to wound formation and wound infections. Microvascular insufficiency is exacerbated by the insensate foot because it fails to cause vascular neuroregulatory alterations necessary to adequately provide nutrients and oxygen to the wounded area to promote wound healing.

A reduced sense of temperature is typically observed in patients with sensory neuropathy. Initially, the loss of sensation is symmetrical at the outer edge. These neuropathies also result in muscle ailments; frequently, lower limb atrophy of the anterior muscle group results in stress throughout the rollover process, elevating anterior foot pressure. Local ischaemic decay occurs when continuous pressure is applied for several hours (e.g., without any discomfort while wearing tight shoes). Immediate injuries result from high strain applied over a short period. Sharp objects such as needles, nails, and stones may result in direct physical damage. The tissue undergoes inflammatory autolysis when subjected to repeated application of mild pressure. Ulcerations develop more readily when continuous pressure is applied to tissues that are already inflamed or structurally compromised. In addition, hot objects as hot water pads, warm quilts, prolonged and unprotected sunlight, and acrid burns (or ‘corn plaster’) may result in burns, and incorrect use of disinfectants can also result in gangrene formation[26].

Motor neuropathy

Muscle denervation directly affects foot function. Commonly impacted are the lumbrical, interosseous, and extensor digitorum brevis, which are small muscles of the foot[27]. The interphalangeal joints flex and the metatarsophalangeal joints hyperextend as a result of paralysis of these tiny muscles. Initially, the joints are still movable; however, as degenerative changes occur, they become fixed[28]. The extensors are typically the muscles most affected by muscle wasting, which is triggered by motor neuropathy. Flexor-extensor imbalance results in abnormal gait, foot deformities (such as clawed toes and equinus foot deformity), and abnormal pressure distribution, which creates new pressure points which are at the risk of ulceration. Motor neuropathy is indicated by atrophy of the tiny foot muscles that results in claw toe and mispositioning of the toes. In addition, there is a lack of muscle self-reflexes and motor paresis. The patellar reflex and Achilles reflex are occasionally diminished. Absence of the Achilles tendon reflex is a precursor to motor neuropathy[29]. Uneven foot burden and unsteady walking are outcomes of coexisting sensory and motor PN. In due course, hyperkeratosis is caused by neuropathy and a high plantar pressure burden, which results in hematoma, malum perforans, and subepidermal hygroma formation. The heel area and metatarsal are the usual sites of predilection.

Autonomic neuropathy

Neuropathic oedema, Charcot arthropathy, and ulceration have pathophysiological relationship with to autonomic neuropathy[28]. Arteriovenous shunts of the subcutaneous vascular network are caused by vasomotor paresis due to autonomic PN. Autonomic neuropathy causes sudomotor paresis, which impairs sweat secretion. Skin overheating results from an increase in blood perfusion in the deeper skin layers. Deficits in sweating contribute to the development of skin fissures and hyperkeratotic plaques. Increased keratin glycation causes callus to thicken and press against the soft tissues below, which can lead to ulceration[18]. A callus, characterised by the accumulation of keratinised skin resulting from continuous pressure, may apply force to the soft tissues of the foot. The underlying factors that contribute to dry and cracked feet include anhidrosis, poor temperature control, and neuropathy. Medial arterial sclerosis is associated with a three-fold increase in amputation risk and a two-fold increase in ulceration risk. PN is frequently diagnosed using specialised sensory and monofilament testing. These tests, particularly when performed by untrained practitioners, may not identify mild neuropathy. Adults with diabetes are estimated to have a lifetime prevalence of PN of at least 50%, and any type of neuropathy increases the risk of DFUs by approximately seven times[30].

Role of neuropathy in the development of ulcers and subsequent infection

Diabetic neuropathy, particularly complex polyneuropathy, significantly increases the risk of ulceration, infection, and ultimately, amputation. Ulceration in neuropathic feet typically develops on the plantar surface, which is subjected to elevated mechanical pressure. Persistent hyperglycaemia impairs circulation by damaging the endothelial lining of blood vessels in previously healthy tissue. Insufficient circulatory support causes nerves to die off, and diminished sweat production causes the skin to become dry and prone to cracking. Foot numbness caused by neuronal ischaemia may result in unnoticed injuries. Moreover, the possibility of wound infection increases with the presence of microorganisms in the dried skin's fissures. Microorganisms invading the trauma site result in vasodilation, inflammation, and soft tissue necrosis. Reduced vascularisation slows down the healing process and impairs the immune system's ability to fight off infection. If the infection continues, typically due to inadequate therapy or delayed care, microbes may infiltrate the bone tissue, resulting in osteomyelitis and bone deformation. Diabetic neuropathy, poor perfusion, neutrophil dysfunction, and inflammatory molecule imbalance contribute to the formation and progression of infections, ischaemic ulcers, and/or gangrene, which can ultimately lead to the most devastating complication, i.e., amputation[31].

Charcot neuroarthropathy: A special feature of DF syndrome

Neuropathy accompanied by bone and joint damage, also known as Charcot neuroarthropathy (Figure 3), is a hallmark of Charcot feet[32]. Due to neuropathy, the procedure does not involve pain. Visual diagnosis reveals the characteristic reactive hyperaemia, osseous structure destruction, swelling, and metatarsal sintering. It is frequently mistaken for erysipelas or phlegmons. In Charcot, the neurovascular component of a diseased foot causes local hyper-perfusion, which washes out and demineralises the osseous structures. Bone resistance reduces the risk of bone deformities and fractures. Volkmann proposed another theory that links repeated traumas to ongoing inappropriate stress caused by sensorimotor neuropathy. Ongoing deterioration of the osseous and soft tissue structures occur next. According to recent theories, the RANK/RANKL/OPG cytokine system and nuclear factor kappa B may play a larger role (Figure 4). In addition to the forefoot and hindfoot, the midfoot is typically affected. Given the higher likelihood of ankle instability, the prognosis for the hindfoot is difficult. Charcot neuroarthropathy can result in amputations, ulcerations, deformities, and infections. It has a detrimental impact on daily living activities and significantly increases morbidity and premature mortality[33]. One study reported one case of Charcot neuroarthropathy for every 680 diabetics[34], and another study reported one case for every 333 patients with diabetes[35]. The prevalence of Charcot ranges from 0.1% to 8% depending on various factors. For instance, 0.12% of T2DM cases were found to possess a new Charcot neuroarthropathy diagnosis in a recent investigation conducted in the United States[36]. Seven subsidiary guidance facilities in the East Midlands of England were examined for the frequency of vital Charcot illness within 1 month. In another investigation, among 205033 people with diabetes, 90 instances of Charcot were found (4.3 per 10000 people)[37]. T1DM and T2DM have different demographic characteristics in patients with Charcot neuroarthropathy[38]. Patients with Charcot foot and T1DM were younger than those with T2DM. The maximum age at which Charcot neuroarthropathy can manifest in patients with T1DM is in the third and fourth decades; it can appear in the sixth and seventh decade in patients with T2DM. Major amputation may be necessary in the event of an ulceration or infection that poses a lifelong risk to the limb in patients with Charcot deformity. The risk of amputation is seven times higher in people with Charcot deformity than in those without Charcot foot, and the risk nearly doubles when an ulcer aggravates the deformity[39]. Individuals with Charcot illness have lower standards of living and higher rates of despondency. Patients with Charcot neuroarthropathy require lifelong support, which is a significant burden on society. In one study, 115 individuals with Charcot foot were monitored for 4 years; approximately 37% of them experienced new ulcerations over deformities[35].

Figure 3 Representation of Charcot foot entity.

Figure 4 Underlying the pivotal function of the RANKL-OPG system in the development of deleterious bone changes is the pathophysiology of diabetic osteoarthropathy. PTH: Parathyroid hormone; AGE: Advanced glycation end product; PI3K: Phosphoinositide 3-kinase; PKC: Protein kinase C; CGRP: Calcitonin gene-related peptide.; RANKL: Receptor activator of nuclear factor-kappa B ligand; eNOS: Endothelial nitric oxide synthase; IL: Interleukin; OPG: Osteoprotegerin; RAGE: Receptor for advanced glycation end products; TNF: Tumour necrosis factor.

In patients with known neuropathy, clinical analysis suggests that Charcot foot has inflammatory features, usually without pain. A traditional radiographic imaging system to evaluate the following five dimensions of radiological presentation is necessary for the diagnosis of Charcot foot: (1) Joint inflation; (2) Joint and bone disruptions; (3) Rubble of bones; (4) Joint and bone disorganization; and (5) Density increase in bones.

Additionally, a magnetic resonance imaging (MRI) should be performed to precisely check for periosteal reactions, cortical destruction, sequestra, and gas formation.

Primary neurological evaluation

The standard evaluation process (Table 2) should consist of vibration measuring a 128-Hz marked tuning fork and testing the feeling and pressure using a 10 g microfilament (Semmes-Weinstein filament). It is common practice to examine sensory function using Semmes-Weinstein single-strand braiding and a 128 Hz tuning fork[28]. Notable warning signs include poor 2-point discrimination, lower warmth/cold feeling (tip-therm testing), pain perception, and state of muscle self-reflex. The Achilles tendon reflex is an indicator of vulnerability. Moreover, tests such as the Neuropathy Signs Score (NSS) and Neuropathy Deficiency Score (NDS) fulfil the clinical examination criteria. NSS scoring is a useful tool to assess the severity of neuropathy based on number of various signs. It divides this range into mild, moderate, and extreme based on scores assigned to various signs, their localization, timing and relationship with nighttime awakening. Likewise, NDS is also available for measuring neuropathy levels. This scoring system also utilizes parameters like pain, temperature, vibration, blood supply and Achilles tendon reflex to categories neuropathy into mild, moderate, and extreme levels[26] (Tables 3 and 4). Other biochemical estimations should be part of the distinctive prognosis at an early stage, such as erythrocyte sedimentation rate, haemogram test, TSH, vitamin B12, creatinine, folic acid, alanine aminotransferase, gamma-GT, high-sensitivity C-reactive protein, and immune-electrophoresis (paraproteinemia). In normal outpatient department, in addition to screening for peripheral sensory neuropathy, the latest scientific techniques, such as the Ipswich Touch Test and VibraTip vibration perception test, could help in better neurological examination.

Table 2 Essential elements for sensorimotor polyneuropathy diagnosis in neurological basic assessment.

Predictors	Test	Outcome
Pain perception	Pinprick testing such as 10-g monofilament and Semmes-Weinstein monofilament at the distal plantar sections of the big toe, the plantar side of metatarsals 1 or 2	Decreased distal symmetry sensation at least at one location
Temperature	Infrared thermometer (contact or noncontact) to generate thermal image	Raised temperature especially around DFUs
Vibration	Tuning fork test near the toes and fingers	VPT testing. Reference range vary between 5/8 or 6/8 according to age
Proprioception	Position perception when toes are moved passively by examiner e.g., at distal interphalangeal joints	Errors in detecting small amplitude movements
Autonomic muscle reactions	Achilles tendon reflex, patellar reflex	Decreased or lost in symmetrical way

VPT: Vibration perception threshold; DFU: Diabetic foot ulcer.

Table 3 Neuropathy signs score parameters.

Signs (lower extremities and/or foot)	Focus of signs and symptoms	Relationship with time	Nighttime awakening
Cramps of muscles; debility feeling; pain; prickling sensation; scorching feeling; tingling	Foot; lower extremity; other locations	Only at night; only during the day; both, night and day	Yes/no

Table 4 Neuropathy deficiency score.

Assessment category	Scoring
Achilles tendon reflex testing	Checking both sides for normal or deranged reflex
Assessment of blood supply to feet	Checking pulses on both sides
Perception of pain	Pain perception testing by using clinical tests on both sides
Temperature perception testing	On both sides by using clinical methods
Vibration perception	Checking on both sides for being normal or level of derangement

PAD/ISCHAEMIA

PAD is characterised by restricted blood flow to parts of the body, usually the lower limbs, due to vascular narrowing or obstruction[40]. Distal lower limb arterial disease, which usually affects the small arteries in the foot and below the knee and causes ischaemia, is more common in patients with diabetes. Ischaemia is a significant contributing element for DF development[41]. Patients with diabetes not only have a higher incidence of atherosclerosis, but also have an accelerated natural course of the disease[42]. An abnormal ankle-brachial index (ABI) indicates PAD, which is present in > 20% of cases of diabetics[43]. The United Kingdom Prospective Diabetes Study showed that the prevalence increases with the duration of diabetes, reporting a prevalence of 1.2% at the time of diagnosis and 12.5% after 18 years[44]. The symptoms of PAD may be obscured by limited activity and PN[40]. Furthermore, the conventional ABI is risky because of the incompressible arteries caused by intermediate calcification. To evaluate PAD in these individuals, toe pressures with or without toe-cutaneous oxygenation are necessary adjuncts[40,45]. Therefore, PAD is probably underdiagnosed; however, 20%-50% of people with diabetes have PAD at some point in their lifetime[46]. Moreover, it poses a significant problem such as delayed wound healing, infection, and death in both patients with T1DM and T2DM. PAD contributes to 50%-70% of cases of DFUs in these patients[47,48].

Diabetes causes a distinct phenotype of PAD that is strongly associated with the onset and acceleration of PAD[40,46]. The infra-popliteal arteries are primarily affected by PAD in individuals with diabetes; the femoral and iliac arteries are also affected at rates comparable to those in adults without diabetes[49]. Compared with adults without diabetes, people with PAD are more likely to have diffuse PAD accompanied by medial arterial calcification, which differs from intraluminal atherosclerosis commonly noted in non-diabetic individuals with PAD. Long-segment artery occlusion (as opposed to stenosis) is another condition that these individuals are more likely to exhibit[40,45].

PAD increases the risk of amputation, infection, and persistent ulcers[50]. People with critical lower limb ischaemia are more likely to have diabetes and PAD concurrently[51]. Furthermore, PAD, especially after amputation, significantly impairs mobility and causes long-term disability in patients with diabetes[52]. PAD is a sign of atherosclerosis in the cardiovascular, cerebrovascular, and renovascular systems as well as an increased risk of heart attack and ischaemia[42,53]. The extracellular matrix (ECM), fibroblasts, vascular smooth muscle cells, endothelial cells, and constituents, such as collagen and elastin, are among the tissues and cells that form the arterial wall[54]. Damage to the vascular endothelium may occur due to unusual metabolism of carbohydrates, fats, and proteins in patients with diabetes, along with increased production of reactive oxygen species and stimulation of inflammatory intermediates[55,56]. Risk factors that contribute to atherosclerosis include blood hypercoagulability, inflammatory states, vascular smooth muscle dysfunction, injury to the arterial endothelium, and aberrant platelet changes[57]. Patients with diabetes mostly have affected inferior genicular artery, which includes the posterior and anterior tibial arteries. The femoral and popliteal artery segments or superficial femoral and popliteal arteries are implicated at the secondary level. The chief iliac artery is typically unaffected. Eventually, arterial circulation of the foot is insufficient to maintain the functional integrity of the skin, and ischaemic ulcers or gangrene may develop along with tibial or proximal artery blockage[31].

WOUND HEALING IN DIABETIC FOOT

DFUs encompass a broad range of acuities and severities. Important wound and foot examination variables include location of the ulcer, its size and depth, existence and gravity of infection, and appearance of PAD/PN[58]. The four main phases of normal wound healing are haemostasis, inflammation, re-epithelialisation, and remodelling. Every stage overlaps in both space and time, and lacks discernible boundaries[59]. Many types of cells and their products play an organized role in normal repair of healing in wounds[60]. At the haemostasis phase, the wound contracts, platelets clump together, and circulating coagulation factors are drawn in. During the inflammatory phase, neutrophils and macrophages release neutrophil extracellular reticular traps and matrix metalloproteinase-9, respectively. All immune cells assemble and secrete these inflammatory factors. The proliferation stage is characterised by reduction of inflammation and migration of skin cells to the wound bed, such as keratinocytes that secrete epidermal growth factor. The remodelling stage is characterised by reshaping and deposition of new tissue through neovascularisation and ECM and involves the secretion of vascular endothelial growth factor (VEGF) by vascular endothelial cells and release of fibroblast cytokines by fibroblasts[61-63].

The exact mechanism underlying delayed healing of DFUs remains to be explored further. However, in DFUs, significant flaws in the healing process lead to a delay in the curing of ulcers and formation of a chronic wound that is extremely pro-inflammatory[64]. The main causes are tissue hypoxia, neuropathy, insufficient neovascularisation, high risk of infection, and non-physiological inflammatory responses[65,66]. In addition, aberrant cellular and gene expression patterns, imbalances in metabolism and nutritional transport, excess AGE formation, and elevated metalloprotease aggregation have been reported[67,68]. DFUs pathologically lower NO production, which in turn lowers endothelial progenitor cell recruitment[63]. Additionally, cytokine deficiency is associated with delayed wound healing in DFUs, including VEGF, platelet-derived growth factor, keratinocyte growth factor, and transforming growth factor-β[67]. Moreover, the immune system malfunction in DM increases the risk of ulcer infections[69]. The incidence and severity of infections are related to the inefficiency and protracted nature of the healing process[70].

Due to the complexity of the pathophysiology and mechanism of DFUs and limited number of available effective treatment techniques that can promote healing, there is an urgent need to discover novel treatments that can both lower costs and cure DFUs successfully. The main molecular regulatory processes that lead to DFUs healing remain unknown; therefore, further research is required to better understand these conditions.

EXAMINATION

Obtaining a complete medical history is crucial before initiating treatment for patients with DFUs and should include assessment of the diabetes persistence period, glucose regulation, additional comorbidities (such as sensory neuropathy), PVD, previous ulcer or callus development, previous treatment, and the overall outcome. Foot and shoe information should be incorporated into the detailed history.

Among the scientific tools developed for early diagnosis is the DFU early detection instrument, which offers multiple advantages. To verify the quality of thorough evaluation, the designed instrument must be validated using both classical and modern test theory. Additionally, this tool can be integrated into the patient's smartphone applications depending on the estimated values, enabling patients and their families to conduct screenings at home. Table 5 provides a list of the recent scientific tools, including the DFU early detection instrument, used in the assessment of DFUs and their applications.

Table 5 Representation of techniques used for early diagnosis of diabetic foot ulcers.

Techniques/tools	Assessment	Procedure	Utilization
Conventional tools		Direct physical examination	Help provide an assessment of the healing status of the wound
Footwear connected to computer	Pressure perception	Analyze risk factors for DFU based on recorded foot pressure	Use of footwear is considered good for identifying ulcerations, because there is a walking practice carried out by the patient
Biothesiometer or tuning fork	Vibration perception threshold testing	Vibration perception is tested over the pulp of the hallux	Patients who are at risk of DFU will feel relatively shorter vibration than normal people
Sudoscan medical device	Sudomotor/sweat glands function	Consist of a set of two electrodes for the feet and hands connected to a computer	Based on stimulation of sweat glands by low level voltage allowing evidence of sweat dysfunction that is not detectable under physiological conditions
Pinpricks		Inserted into pain receptors, namely the Meissner and Pacini nerves in the legs	Simple and can identify the risk of DFU well. Inability to perceive pinprick over either hallux would be regarded as an abnormal test result
3D thermal camera assessment system (e.g., FLIR or DSLR camera integrated smartphones)	Temperature perception	Helps in detecting the increase in temperature over the point of sole susceptible for ulcer	Help in taking preventive measures and stop further progression of disease. This is important to accelerate healing
DFU screening instrument; questionnaire/images, e.g., NeuDiaCan	Motor/sensitivity/autonomic, color segmentation of images	Allows the examination to be completed with an objective score	Help stratify the risk of diabetic foot and can be combined with standard nursing interventions

DFUs: Diabetic foot ulcers.

Examining the patient, measuring the pulse, checking for loss of protective feeling using a tuning fork and monofilament, and measuring the pulse should all be part of this screening[45]. For patients at greater risk, screening examinations should be conducted every 3-6 months[45]. Podiatry and vascular surgery should be included in multidisciplinary foot care as this is especially important for high-risk individuals[71].

Laboratory tests such as examination of blood glucose levels, glycosylated haemoglobin levels, absolute metabolic profiles, total blood counts, CRP levels, and erythrocyte sedimentation rates are frequently performed[72].

Upon inspection, PN may be detected through lower-limb neurological screening. Unusual thickening, yellowing, and crumbling of the toenails may indicate sensory neuropathy, autonomic neuropathy, or both. Autonomic neuropathy can also manifest as extremely moist or dry, scaly skin on the balls of the foot or toes with hyperkeratosis. Muscle wasting results from denervation of the lumbricals and interossei, which creates visible channels between the metatarsals. Lumbrical denervation is another cause of hammer toes. Advanced PN is indicated by loss of the Achilles reflex. Sensory neuropathy can be assessed using a tuning fork and mild touch[73]. Charcot foot is another visual diagnosis. Intense blood pressure, marked by severe swelling and osseous structure destruction, is the hallmark of Charcot foot, which leads to sintering of the metatarsal region.

Simple radiography is a type of radiological investigation used to identify foreign bodies, air pockets in the subcutaneous tissue, and any indications of basic fractures. They also look for the presence of osteomyelitis if present. If osteomyelitis is suspected, MRI is considered the best diagnostic modality. Basal osteomyelitis can be evaluated using technetium-enhanced bone scans. When combined with the ABI, arterial Doppler can help rule out PVD. Another diagnostic test that can aid in the imaging of basal osteomyelitis is the probe-to-bone test (PTB), which uses a sterile metal probe to poke the ulcer. The result is considered positive if the probe makes contact with the bone[74]. Positive PTB results are particularly useful when applied to individuals with DM[75].

Ischaemic wounds are typically found in the vicinity of the medial first and lateral fifth metatarsal head, usually on the foot, which is cool and has poor blood flow. Determining the extent of ischaemia is crucial for wound assessment. Careful palpation of the posterior tibial arteries and dorsalis pedis is essential. The pulse may not be palpable in approximately 12% of patients because the dorsalis pedis artery is absent or significantly smaller than usual[76]. A cool foot that shows no discernible pedal pulses should be further examined using non-invasive lower-limb arterial Doppler ultrasonography. In patients with diabetes, other techniques for determining peripheral perfusion may be inaccurate. Because of arterial calcification, patients with diabetes may have a falsely elevated ABI. In this patient group, toe pressure assessments are more dependable than ABI assessments, although recent research has suggested that their applicability is constrained. Normal wound healing requires an absolute toe pressure of > 30 mmHg; however, in patients with diabetes, vascular surgical consultation is warranted if the toe pressure is < 30-40 mmHg or ABI is < 0.7 and a wound is present[28,77]. These conditions are associated with inadequate wound healing and are signs of insufficient vascular perfusion[77].

Influence of DFU on the standard of living and productivity

DFUs have a well-documented negative impact on general health and quality of life of affected individuals. Patients with DFUs generally have a low quality of life in terms of physical workouts. There is a negative correlation between a patient’s quality of life and factors such as major amputations, persistent ulcers, and restricted mobility[78,79]. People with recovered DFU enjoy overall self-reported quality of life that is comparable to that of non-diabetic groups, and they experience a significant increase in their self-reported physical functioning, even after mild amputation[79].

TREATMENT

Wounds are generally divided into three categories which are healable, non-healable and maintenance wounds[80,81]. Currently, a standard approach of wound management involves wound cleaning and debridement, application of dressing and use of antimicrobials. Compression bandages are also used for selected patients[60]. Certain preventive practices and treatment modalities are outlined in Table 6 based on current guidelines. An organized wound management plan would include the following steps and assessment methods[82,83].

Table 6 Preventive care and different treatment plans for the management of diabetic foot ulcers.

Management of DFUs	Preventive practices	Therapy strategies
		Non-invasive techniques	Invasive techniques
Methods	Self-screening; health care screening; podiatric care; selection of footwear; nutrition and psychological care; right foot care education	Wound dressing; antibiotics; hyperbaric oxygen therapy; right foot care education; shock wave therapy; topical growth factors; stem-cell therapy; -ve pressure wound therapy; laser therapy; larvae (maggot therapy); offloading methods; glycemic control; multidisciplinary care	Debridement; skin grafting; revascularization

Adopted from Intersocietal Peripheral Arterial Disease Guideline[104]. DFUs: Diabetic foot ulcers; -ve: Negative pressure.

(1) Identifying the presence of such ailments which can cause healing delays and derangements;

(2) Determining the type of wound based in healing potential i.e., healable, non-healable or maintenance wound;

(3) Formulate an individualized treatment plan for every patient, where possible, involving a multidisciplinary team or referral to an expert;

And (4) Manage and treat any underlying correctable cause(s).

Wounds unable to resolve completely by eight weeks are considered as chronic wounds in the “non-healing” category[84]. The patients who develop non-healing ulcers can potentially benefit from advanced modalities to treat wounds. Few of such treatment options are laser therapy, negative pressure wound therapy, topical negative pressure dressings, photodynamic therapy, electrical stimulation and ultrasound therapy. Three groups of patients can be candidate of such modalities; those who fail to respond to routine wound management, patients with known factors contributing to non-healing of wounds such as DM and patients who adapt these modalities instead of surgical management of wound[85].

To obtain the best outcomes, DFUs should be dealt with using a methodological approach. The most crucial step is determining whether there is any evidence of an ongoing infection. This can be done by asking the patient about a history of chills and fever or by looking for purulence or a minimum of two inflammatory markers such as soreness, erythema, heat, or ulcer induration. The next step is determining whether a patient’s ulcers should be managed in an inpatient or outpatient setting. Most DFIs are polymicrobial and require treatment with broad-spectrum antibiotics. When treating mild-to-moderate DFIs, oral broad-spectrum antibiotics are first administered, which are subsequently narrowed down based on the outcomes of deep tissue culture[76]. Intravenous antibiotics must be started for severe infections such as cellulitis and osteomyelitis, and necrotic tissue must be debrided quickly. It is important to continue administering antibiotics until the clinical symptoms of the infection disappear.

Treatment of any underlying PVD is the next step in therapy. Revascularization improves both oxygen supply and antibiotic delivery to the ulcer, which increases the ulcer’s likelihood of healing. Inadequate blood supply limits both processes. Callus removal, also known as local debridement, is the next step. DFUs should heal if the foot has enough arterial supply. Any infections can be treated with the right antibiotics, with the necrotic tissue debrided, and with pressure released.

For nonhealing ulcers advanced treatment methods should be implemented, where available. Hydrotherapy may be beneficial for eliminating infected debris. After 30 days, hyperbaric oxygen therapy may be considered if the wound does not heal[86]. Other successful story to treat DFU is enhancing blood perfusion in local soft tissue using a combination of low-intensity ultrasound with microbubbles[87]. The best treatment options for uninfected neuropathic ulcers include callus tissue removal and efficient pressure offloading. Offloading should be continued for 4 weeks after the wound has healed to allow the formation of scar tissue that will be able to withstand weight bearing in the future. Additionally, wound healing could be promoted using recent therapeutic strategies include nerve taps, nanotechnology-based formulations, microneedle patches and stem cell[88]. Complementary modalities have also shown promise as therapies in recent years. These techniques include moxibustion, fumigation, foot baths, acupuncture, massage, and external acupoint injections.

Glycaemic control

In individuals with DM, strict glycaemic management has been shown to promote wound healing by delaying the development of retinopathy, PN, and nephropathy - all of which are major risk factors for DFU. Optimizing blood glucose is generally advised to promote wound healing and minimise the negative effects of infections and impaired cellular immunity[76]. Furthermore, a Cochrane analysis evaluating the impact of glycaemic targets in type 2 diabetes revealed that people with strict glycaemic control had a 35% reduction in the incidence of lower-extremity amputations[89].

Patient education and self-care of foot

A patient-centered approach is required to manage many illnesses, especially chronic ailments. This concept is based on the idea of considering patients as a central point of a circle with all strategies, facilities and treatment plans linked with individual patient requirements[90].

For DFU prevention, self-examination and education on foot care are important protective measures[91]. Intensive nursing education, comprehensive foot care guidance, and enhanced patient understanding of their disease are simple, practical, and highly effective strategies for preventing DFUs[92]. Medical facilities should focus on increasing public awareness of preventive actions to help patients manage their own care. The promotion of self-management should encompass a variety of activities, such as teaching people how to take care of their feet, using appropriate footwear, examining their own skin lesions, and assessing their own foot sensations. Patients can easily prevent autonomic neuropathy fissures and typical redness of the skin due to overpressure, which can be avoided by advising and motivating patients to wash their feet with lukewarm water, softly clean and dry them, and examine their foot condition as well as checking their feet for colour changes[91]. Routine screening for diabetic comorbidities, including ocular problems, has also proven more economical than neglecting such screenings[92]. Patients can follow the below checklist to reduce their risk of ulceration: (1) Foot hygiene (avoid walking barefoot, examine the feet daily before going to bed, apply moisturiser, check and clean the footwear before wearing); (2) Avoid wearing tight socks or stockings; (3) Avoid self-nail cutting, scrubbing, hard massages, or soaking feet in hot water; (4) Identify at-risk feet; (5) Schedule routine foot examinations; (6) Control hyperglycaemia; (7) Use appropriate footwear; (8) Address and manage risk factors promptly; (9) Educate yourself about the disease; and (10) Consult a podiatrist if unsure about any conditions.

REHABILITATION AND PREVENTION

To reduce the likelihood of recurrent ulcers and amputation, implementing preventive and routine aftercare is crucial. Approximately 70% of patients with subpar care experience at least one ulcer recurrence, and 12% require amputation 5 years after the first foot injury. After amputation, the cumulative risk of having another amputation in the following year is approximately 27%, and it is 61% after 5 years[93-96]. The main focus of preventive measures is on providing customised orthopaedic shoes and insole therapy to adjust the pressure distribution for each foot, so as to increase chances of preventing new lesions[93,97].

Moreover, nerve decompression surgery is currently being researched to avoid ulceration and amputation. According to recent clinical research, improving sensitivity and lowering the incidence of ulcers and amputations are directly correlated with the removal of chronically compressed peripheral nerves[98,99].

MULTIDISCIPLINARY CARE

As mentioned previously, the treatment of patients with DF syndrome is frequently difficult. Collaboration amongst professionals from different fields and disciplines is crucial for meeting these complex requirements[100-102]. Furthermore, it is crucial to integrate non-physician healthcare professionals (podiatrists, orthopaedic master shoemakers, and diabetes advisors/diet assistants) to foster multidisciplinary and intersectoral collaboration in medicine. Effective cooperation requires adherence to both content and ritual related standards. Management of the wound, achievement of metabolic control, patient education, foot mechanics, and circulation are the six components of treatment that should be discussed within a multidisciplinary network. Internal guidelines can be applied in addition to national and international guidelines. The consistent implementation of this shared care strategy and effective communication among all professional groups are essential.

CONCLUSION

Patients, their relatives, the medical community, and society all suffer from DFUs. DFUs can result in several complications, such as infections, amputations, impairment, reduced standard of living, and even death. A significant proportion of diabetics (between 15% and 34%) will experience DFUs at some point in their lives. Patients with major infections, amputations, and the resulting handicap and incapacity experience financial hardships and decreased output. In addition to a higher 5-year mortality rate, these patients have a lower standard of living. Both the sufferer and society are impacted by the costs associated with the care of this disease. Comprehending the fundamental processes and pathogenesis associated with DFUs outlined in the present review is essential to recognise the importance of a thorough assessment and support of the medical staff’s strategy for averting additional complications from DFUs and their early development or recurrence. This strategy has significant clinical and public health implications for the effective treatment of DFUs. If successful wound healing is accelerated, adverse outcomes may be avoided. According to international guidelines, podiatrists are included at each of the three levels of foot care management that are recommended based on foot risk level 1. Studies on multifunctional healthcare facilities in the United States and Europe have demonstrated that this strategy decreases amputation rates by 36%-86%[103]. Nonetheless, the delivery method and system of multidisciplinary care teams vary across countries[70]. Podiatrists act as "gateways" within a multidisciplinary team, helping to prevent and treat diabetes-related foot complications. The success of this approach relies on the primary medical practitioner and the DFU care team administering the treatment appropriately, communicating, and adjusting the plan of care based on the various factors discussed, as there is no predetermined protocol for treating DFUs. The choice of therapeutic strategies and application of additional supportive wound care treatments could be beneficial for clinicians in the future.