Diabetic foot ulcer


Diabetic foot ulcer is a major complication of diabetes mellitus, and probably the major component of the diabetic foot.
Wound healing is an innate mechanism of action that works reliably most of the time. A key feature of wound healing is stepwise repair of lost extracellular matrix that forms the largest component of the dermal skin layer. But in some cases, certain disorders or physiological insult disturbs the wound healing process. Diabetes mellitus is one such metabolic disorder that impedes the normal steps of the wound healing process. Many studies show a prolonged inflammatory phase in diabetic wounds, which causes a delay in the formation of mature granulation tissue and a parallel reduction in wound tensile strength.
Treatment of diabetic foot ulcers should include: blood sugar control, removal of dead tissue from the wound, wound dressings, and removing pressure from the wound through techniques such as total contact casting. Surgery in some cases may improve outcomes. Hyperbaric oxygen therapy may also help but is expensive.
It occurs in 15% of people with diabetes, and precedes 84% of all diabetes-related lower-leg amputations.

Risk factors

Risk factors implicated in the development of diabetic foot ulcers are infection, older age, diabetic neuropathy, peripheral vascular disease, cigarette smoking, poor glycemic control, previous foot ulcerations or amputations, and ischemia of small and large blood vessels. Prior history of foot  disease, foot deformities that produce abnormally high forces of pressure, callus at pressure areas  renal  failure, oedema, impaired ability to look after personal care are further risk factors for diabetic foot ulcer.
People with diabetes often develop diabetic neuropathy due to several metabolic and neurovascular factors. Peripheral neuropathy causes loss of pain or feeling in the toes, feet, legs and arms due to distal nerve damage and low blood flow. Blisters and sores appear on numb areas of the feet and legs such as metatarso-phalangeal joints, heel region and as a result pressure or injury goes unnoticed and eventually become portal of entry for bacteria and infection.

Pathophysiology

Extracellular matrix

is the external structural framework that cells attach to in multicellular organisms. The dermis lies below the epidermis, and these two layers are collectively known as the skin. Dermal skin is primarily a combination of fibroblasts growing in this matrix. The specific species of ECM of connective tissues often differ chemically, but collagen generally forms the bulk of the structure.
Through the interaction of cell with its extracellular matrix there forms a continuous association between cell interior, cell membrane and extracellular matrix components that help drive various cellular events in a regulated fashion. Wound healing is a localized event involving the reaction of cells to the damage sustained.
The cells break down damaged ECM and replace it, generally increasing in number to react to the harm. The process is activated, though perhaps not exclusively, by cells responding to fragments of damaged ECM, and the repairs are made by reassembling the matrix by cells growing on and through it. Because of this extracellular matrix is often considered as a 'conductor of the wound healing symphony'. In the Inflammatory phase, neutrophils and macrophages recruit and activate fibroblasts which in subsequent granulation phase migrate into the wound, laying down new collagen of the subtypes I and III.
In the initial events of wound healing, collagen III predominates in the granulation tissue which later on in remodeling phase gets replaced by collagen I giving additional tensile strength to the healing tissue. It is evident from the known collagen assembly that the tensile strength is basically due to fibrillar arrangement of collagen molecules, which self-assemble into microfibrils in a longitudinal as well as lateral manner producing extra strength and stability to the collagen assembly. Metabolically altered collagen is known to be highly inflexible and prone to break down, particularly over pressure areas. Fibronectin is the major glycoprotein secreted by fibroblasts during initial synthesis of extracellular matrix proteins. It serves important functions, being a chemo-attractant for macrophages, fibroblasts and endothelial cells.
Basement membrane that separates epidermis from the dermal layer and endothelial basement membrane mainly contain collagen IV that forms a sheet and binds to other extra cellular matrix molecules like laminin and proteoglycans. In addition to collagen IV, epidermal and endothelial basement membrane also contain laminin, perlecan and nidogen. Hyaluronic acid, a pure glycosaminoglycan component is found in high amounts in damaged or growing tissues. It stimulates cytokine production by macrophages and thus promotes angiogenesis. In normal skin chondroitin sulfate proteoglycan is mainly found in the basement membrane but in healing wounds they are up regulated throughout the granulation tissue especially during second week of wound repair, when they provide a temporary matrix with highly hydrative capacity. Binding of growth factors is clearly an important role of perlecan in wound healing and angiogenesis. Poor wound healing in diabetes mellitus may be related to perlecan expression. High levels of glucose can decrease perlecan expression in some cells probably through transcriptional and post-transcriptional modification. Wound healing phases especially, granulation, re-epithelization and remodeling exhibit controlled turnover of extracellular matrix components.

Altered metabolism

is a metabolic disorder and hence the defects observed in diabetic wound healing are thought to be the result of altered protein and lipid metabolism and thereby abnormal granulation tissue formation. Increased glucose levels in the body end up in uncontrolled covalent bonding of aldose sugars to a protein or lipid without any normal glycosylation enzymes. These stable products then accumulate over the surface of cell membranes, structural proteins and circulating proteins. These products are called advanced glycation endproducts or Amadori products. Formation of AGEs occurs on extracellular matrix proteins with slow turnover rate. AGEs alter the properties of matrix proteins such as collagen, vitronectin, and laminin through AGE-AGE intermolecular covalent bonds or cross-linking. AGE cross-linking on type I collagen and elastin results in increased stiffness. AGEs are also known to increase synthesis of type III collagen that forms the granulation tissue. AGEs on laminin result in reduced binding to type IV collagen in the basement membrane, reduced polymer elongation and reduced binding of heparan sulfate proteoglycan.
;Impaired NO synthesis
;Structural and functional changes in fibroblasts
;Increased matrix metalloproteinases activity

Biomechanics

Complications in the diabetic foot and foot-ankle complex are wider and more destructive than expected, and may compromise structure and function of several systems: vascular, nervous, somatosensory, musculoskeletal. Thus, a deeper comprehension of the alteration of gait and foot biomechanics in the diabetic foot is of great interest, and may play a role in the design and onset of preventive as well as therapeutic actions.
Briefly, the effect of diabetes on the main structures of the foot-ankle complex can be summarised as:
Assessment of diabetic foot ulcer includes identifying risk factors such as diabetic peripheral neuropathy, noting that 50 percent of people are asymptomatic, and ruling out other causes of peripheral neuropathy such as alcohol abuse and  spinal injury.
The location of the ulcer, its size, shape, depth and whether the tissue is granulating or sloughy needs to be considered. Further considerations include whether there is malodour, condition of the border of the wound and palpable bone and sinus formation should be investigated. Signs of infection require to be considered such as development of grey or yellow tissue, purulent discharge, unpleasant smell, sinus, undermined edges and exposure of bone or tendon.
Identification of diabetic foot in medical databases, such as commercial claims and prescription data, is complicated by the lack of a specific ICD-9 code for diabetic foot and variation in coding practices. The following codes indicate ulcer of the lower limb or foot:
One or more codes, in combination with a current or prior diagnosis of diabetes may be sufficient to conclude diabetic foot:
Diabetic foot ulcer is a complication of diabetes. Diabetic foot ulcers are classified as either neuropathic, neuroischaemic or ischaemic.
Doctors also use the Wagner Grades to describe the severity of an ulcer. The purpose of the Wagner Grades is to allow specialists to better monitor and treat diabetic foot ulcers. This grading system classifies Diabetic foot ulcers using numbers, from 0 to 5.
Wagner Grades 0 through 5 are as follows:
Steps to prevent diabetic foot ulcers include frequent review by a foot specialist and multidisciplinary team, good foot hygiene, diabetic socks and shoes, as well as avoiding injury. Foot-care education combined with increased surveillance can reduce the incidence of serious foot lesions.
There is no high quality researches that evaluate complex intervention of combining two or more preventive strategies in preventing diabetic foot ulcer.

Footwear

The evidence for special footwear to prevent foot ulcers is poor.
Clinical Evidence reviewed the topic and concluded "Individuals with significant foot deformities should be considered for referral and assessment for customised shoes that can accommodate the altered foot anatomy. In the absence of significant deformities, high quality well fitting non-prescription footwear seems to be a reasonable option". National Institute for Health and Clinical Excellence concluded that for people at "high risk of foot ulcers (neuropathy or absent pulses plus deformity or skin changes or previous ulcer" that "specialist footwear and insoles" should be provided.
People with loss of feeling in their feet should inspect their feet on a daily basis, to ensure that there are no wounds starting to develop. They should not walk around barefoot, but use proper footwear at all times.

Treatment

Foot ulcers in diabetes require multidisciplinary assessment, usually by diabetes nurse specialist, a tissue viability nurse, podiatrists, diabetes specialists and surgeons. An aim to improve glycaemic  control, if poor, forms part of the management, to slow disease progression. Individuals who have sausage shaped toes, a positive 'probe to bone' test, evidence suggesting osteomyelitis, suspected charcot neuroarthropathy, or those whose ulcers do not improve within 4 weeks of standard care and where there is evidence that exudate is of synovial membrane in origin. When osteomyelitis is suspected to be involved in the foot ulcer, but not evidenced on an x-ray, an MRI scan should be obtained.
With regards to infected foot ulcers, the presence of microorganisms is not in itself enough to determine whether an infection is present. Signs such as inflammation and purulence are the best indicators of an active infection. The most common organism causing infection is staphylococcus. The treatment consists of debridement, appropriate bandages, managing peripheral arterial disease and appropriate use of antibiotics, and arterial revascularisation.

Antibiotics

The length of antibiotic courses depend on the severity of the infection and whether bone infection is involved but can range from 1 week to 6 weeks or more. Current recommendations are that antibiotics are only used when there is evidence of infection and continued until there is evidence that the infection has cleared, instead of evidence of ulcer healing. Choice of antibiotic depends on common local bacterial strains known to infect ulcers. Microbiological swabs are believed to be of limited value in identifying causative strain. Microbiological investigation is of value in cases of osteomyelitis. Most ulcer infections involve multiple microorganisms.
There is limited safety and efficacy data of topical antibiotics in treating diabetic foot ulcers.

Wound dressings

There are many types of dressings used to treat diabetic foot ulcers such as absorptive fillers, hydrogel dressings, and hydrocolloids. There is no good evidence that one type of dressing is better than another for diabetic foot ulcers. In selecting dressings for chronic non healing wounds it is recommended that the cost of the product be taken into account.
Hydrogel dressings may have shown a slight advantage over standard dressings, but the quality of the research is of concern. Dressings and creams containing silver have not been properly studied nor have alginate dressings. Biologically active bandages that combine hydrogel and hydrocolloid traits are available, however more research needs to be conducted as to the efficacy of this option over others.

Total contact casting

is a specially designed cast designed to take weight of the foot in patients with DFUs. Reducing pressure on the wound by taking weight of the foot has proven to be very effective in DFU treatment. DFUs are a major factor leading to lower leg amputations among the diabetic population in the US with 85% of amputations in diabetics being preceded by a DFU. Furthermore, the 5 year post-amputation mortality rate among diabetics is estimated at around 45% for those suffering from neuropathic DFUs.
TCC has been used for off-loading DFUs in the US since the mid-1960s and is regarded by many practitioners as the “reference standard” for off-loading the bottom surface of the foot.
TCC helps patients to maintain their quality of life. By encasing the patient’s complete foot — including the toes and lower leg — in a specialist cast to redistribute weight and pressure from the foot to the lower leg during everyday movements, patients can remain mobile. The manner in which TCC redistributes pressure protects the wound, letting damaged tissue regenerate and heal. TCC also keeps the ankle from rotating during walking, which helps prevent shearing and twisting forces that can further damage the wound.
Effective off loading is a key treatment modality for DFUs, particularly those where there is damage to the nerves in the feet. Along with infection management and vascular assessment, TCC is vital aspect to effectively managing DFUs. TCC is the most effective and reliable method for off-loading DFUs.
A 2013 meta-analysis by the Cochrane Collaboration compared the effectiveness of non-removable pressure relieving interventions, such as casts, with therapeutic shoes, dressings, removable pressure relieving orthotic devices, and surgical interventions. Non-removable pressure relieving interventions, including non-removable casts with an Achilles tendon lengthening component, were found to be more effective at healing foot ulcers related to diabetes that therapeutic shoes and other pressure relieving approaches.

Hyperbaric oxygen

In 2015, a Cochrane review concluded that for people with diabetic foot ulcers, hyperbaric oxygen therapy reduced the risk of amputation and may improve the healing at 6 weeks. However, there was no benefit at one year and the quality of the reviewed trials was inadequate to draw strong conclusions.

Negative pressure wound therapy

This treatment uses vacuum to remove excess fluid and cellular waste that usually prolong the inflammatory phase of wound healing. Despite a straightforward mechanism of action, results of negative pressure wound therapy studies have been inconsistent. Research needs to be carried out to optimize the parameters of pressure intensity, treatment intervals and exact timing to start negative pressure therapy in the course of chronic wound healing.
There is low-certainty evidence that negative pressure wound therapy would improve wound healing in diabetic foot ulcers.

Other treatments

– there is only limited and poor-quality information available regarding the effectiveness of ozone therapy for treating foot ulcers in people with diabetes.
Growth factors - there is some low-quality evidence that growth factors may increase the likelihood that diabetic foot ulcers will heal completely.
Continuous diffusion of oxygen - CDO delivers continuous oxygen to an occluded, moist wound site at much lower flow rates of 3–12 mL/h for 24 h 7 days a week for up to several weeks or months, depending on the wound status.
Phototherapy - there is very weak evidence to suggest that people with foot ulcers due to diabetes may have improved healing. There is no evidence to suggest that phototherapy improves the quality of life for people with foot ulcers caused by diabetes.
Sucrose-octasulfate impregnated dressing is recommended by the International Working Group on the Diabetic Foot Ulcer for the treatment of non-infected, neuro-ischaemic diabetic foot ulcers that do not show an improvement with a standard of care regimen
Autologous combined leucocyte, platelet and fibrin as an adjunctive treatment, in addition to best standard of care is also recommended by IWGDF However, there is only low quality evidence that such treatment is effective in treating diabetic foot ulcer.
There is limited evidence that granulocyte colony-stimulating factor may not hasten the resolution of diabetic foot ulcer infection. However, it may reduce the need for surgical interventions such as amputations and hospitalizations.
It is unknown that whether intensive or conventional blood glucose control is better for diabetic foot ulcer healing.
Skin grafting and tissue replacements can help to improve the healing of diabetic foott ulcer.

Epidemiology

Approximately 15 percent of people with diabetes experience foot ulcers. And approximately 84 percent of lower limb amputations have a history of ulceration with only approximately half of amputees surviving for more than 2 years. 56 percent of individuals with foot ulcers who do not have an amputations survive for 5 years. Foot ulcers and amputations significantly reduce the quality of life. Approximately 8.8 percent of hospital admissions of diabetic patients are for foot related problems, and such hospital admissions are about 13 days longer than for diabetics without foot related admissions. Approximately 35 to 40 percent of ulcers recur within 3 years and up to 70 percent recur within 5 years. Diabetic foot disease is the leading cause of non-traumatic lower limb amputations.

Research

Stem cell therapy may represent a treatment for promoting healing of diabetic foot ulcers. Diabetic foot ulcers develop their own, distinctive microbiota. Investigations into characterizing and identifying the phyla, genera and species of nonpathogenic bacteria or other microorganisms populating these ulcers may help identify one group of microbiota that promotes healing.
The recent advances in epigenetic modifications, with special focus on aberrant macrophage polarisation is giving increasing evidences that epigenetic modifications might play a vital role in changing the treatment of diabetic foot ulcer in the near future.