**1. Introduction**

Diabetes patients experience diabetic foot ulcer (DFU) as a result of prolonged hyperglycaemia, and it is the most common reason for hospitalisation. It is also associated with severe morbidity and mortality and, if not recognised and treated promptly, can result in limb amputation [1]. It also had an influence on the financial burden placed on patients, their families, society and the government for the treatment and management of DFU [2]. The risk of a patient with diabetes developing a foot ulcer has been estimated to be 19–34%, and the incidence rates for ulcer recurrence remain high which is 40% within 1 year after healing and 65% within 5 years [3].

Hyperglycaemia stimulates enzymes such as aldose reductase and sorbitol dehydrogenase, resulting in the conversion of intracellular glucose to sorbitol and fructose. The accumulation of these converted glucose products reduces the synthesis of myoinositol in nerve cells that are essential for energy production [4]. The chemical change caused by glucose also resulted in the depletion of nicotinamide adenine dinucleotide phosphate (NADP), which is required for the detoxification of reactive oxygen species (ROS) and the synthesis of the vasodilator, nitric oxide (NO). As a result, there is an increase in oxidative stress on nerve cells, as well as an increase in vasoconstriction on blood vessel, which leads to ischemia, which causes nerve cell damage and death [5]. The common sites for ulceration on foot are dorsal or plantar aspects of the toes, plantar metatarsal heads and heel.

There are numerous events in diabetic progress that can contribute to the development of DFU. The most important events are diabetic peripheral neuropathy (DPN), which affects half of all diabetics, peripheral vascular disease (PVD) and trauma and infection [6].

### **1.1 Diabetic peripheral neuropathy (DPN)**

DPN can be sensory, motor or autonomic. Sensory neuropathy reduces the patient's sensory awareness and manifests clinically as burning, tingling or paraesthesia in the stocking and glove distribution, which worsens after numbness symptoms appear [7]. The peripheral nerve fibres in diabetic patients are affected in a length-dependent manner, with the longest nerves being affected first, resulting in a stocking distribution of sensory loss. Sensory loss involving type A myelin fibres results in loss of proprioception, pressure sensation, vibratory perception and gait impairment. The destruction of type C sensory fibres results in an inability to recognise painful stimuli. As a result of these impaired sensations, the diabetic patient may suffer from repetitive foot trauma, such as blister formation or even metatarsal bone fracture, without realising it. Poor balance due to loss of proprioception, decreased sweating and dry skin that can develop skin cracks and fissures are all consequences of DPN [8].

Motor neuropathy can result in structural changes in the shape of the foot. It is typically presents as wasting of the intrinsic muscles of the foot, resulting in clawing of the toes and changes to the architecture of the mid-foot and subsequently in pressure redistribution over the metatarsal heads. Loss of the Achilles reflex is the earliest sign of these changes. With atrophy of the lumbricals and interosseous muscles, the anatomy of the foot arch changes, with a relative increase in extensor tendon forces producing a "claw" deformity of the toes. A shift to extrinsic muscle/tendon function contributes to depression of the metatarsal heads, hammer-toe contracture of the digits and equine ankle deformity [9].

Whereas autonomic neuropathy can impair the microvascular thermoregulation and anhidrosis process that adds to the motor and sensory disturbance. From this malfunction, the skin becomes dry as it loses the ability to moisturise its surface due to decreased secretory functions of the sebaceous and sweat glands and prone to fissuring, diminishes its effectiveness as a barrier to microorganism invasion, becoming susceptible to dermal infection, that is, cellulitis [10].
