Diabetic foot ulcer

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Diabetic foot ulcer is one of the major complications of Diabetes mellitus. It occurs in 15% of all patients with diabetes and precedes 84% of all lower leg amputations.[1]. Major increase in mortality among diabetic patients, observed over the past 20 years is considered to be due to the development of macro and micro vascular complications, including failure of the wound healing process. Wound healing is a ‘make-up’ phenomenon for the portion of tissue that gets destroyed in any open or closed injury to the skin. Being a natural phenomenon, wound healing is usually taken care of by the body’s innate mechanism of action that works reliably most of the time. Key feature of wound healing is stepwise repair of lost extracellular matrix (ECM) that forms largest component of dermal skin layer.[2] Therefore controlled and accurate rebuilding becomes essential to avoid under or over healing that may lead to various abnormalities. But in some cases, certain disorders or physiological insult disturbs wound healing process that otherwise goes very smoothly in an orderly manner. Diabetes mellitus is one such metabolic disorder that impedes normal steps of wound healing process. Many histopathological studies show prolonged inflammatory phase in diabetic wounds, which causes delay in the formation of mature granulation tissue and a parallel reduction in wound tensile strength.[3]

Non-healing chronic diabetic ulcers are often treated with extracellular matrix replacement therapy. So far, it is a common trend in diabetic foot care domain to use advanced moist wound therapy, bio-engineered tissue or skin substitute, growth factors and negative pressure wound therapy.[4] No therapy is completely perfect as each type suffers from its own disadvantages. Moist wound therapy is known to promote fibroblast and keratinocyte proliferation and migration, collagen synthesis, early angiogenesis and wound contraction. At present, there are various categories of moist dressings available such as adhesive backing film, silicone coated foam, hydrogels, hydrocolloids etc. Unfortunately, all moist dressings cause fluid retention; most of them require secondary dressing and hence are not the best choice for exudative wounds.[5] To address the physiological deficiencies underlying diabetic ulcer, various tissue engineering technologies have come up with cellular as well as acellular skin replacement products.

Prevention

Prevention is by frequent chiropody review, good foot hygiene, diabetic socks and shoes, and avoiding injury.

  • Foot-care education combined with increased surveillance can reduce the incidence of serious foot lesions [6].
  • Footwear.
All major reviews recommend special footwear for patients with a prior ulcer or with foot deformities. One review added neuropathy as an indication for special footwear. The comparison of custom shoes versus well-chosen and well-fitted athletic shoes is not clear.
A meta-analysis by the Cochrane Collaboration concluded that "there is very limited evidence of the effectiveness of therapeutic shoes" [7]. The date of the literature search for this review is not clear. 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" [8]. National Institute for Health and Clinical Excellence has reviewed the topic and concluded that for patients 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 [9]

The one randomized controlled trial that showed benefit of custom foot wear was in patients with a prior foot ulceration [10]. In this trial, the number needed to treat was 4 patients.

Risk factors

Two main risk factors that cause diabetic foot ulcer are Diabetic neuropathy and micro as well as macro ischemia.[11] Diabetic patients often suffer from diabetic neuropathy due to several metabolic and neurovascular factors. Type of neuropathy called 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

Role of Extracellular matrix (ECM) in wound healing

Extra cellular matrix is the structurally stable material that lies under epidermal layer and surrounds connective tissue cells that form dermal layer of the skin. 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.[12] Wound healing, a repair mechanism is one of those cellular events that occur through controlled turnover of extracellular matrix components. Because of this extracellular matrix is often considered as a 'conductor of the wound healing symphony'.[13] 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.[14][15] 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.[15][16] Metabolically altered collagen is known to be highly inflexible and prone to breakdown, 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 like pattern 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.[15][16] 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.[17] 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.[17][18] Wound healing phases especially, granulation, re-epithelization and remodeling exhibit controlled turnover of extracellular matrix components.

Altered metabolism

Diabetes mellitus 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.[19] 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.[20] These stable products then accumulate over the surface of cell membranes, structural proteins and circulating proteins. These products are called advanced glycation endproducts (AGEs) 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.[20][21][22] 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.[20]

Impaired NO synthesis

Nitric oxide is known as an important stimulator of cell proliferation, maturation and differentiation. Thus, nitric oxide increases fibroblast proliferation and thereby collagen production in wound healing. Also, L-arginine and nitric oxide are required for proper cross linking of collagen fibers, via proline, to minimize scarring and maximize the tensile strength of healed tissue.[23] Endothelial cell specific nitric oxide synthase (EcNOS) is activated by the pulsatile flow of blood through vessels. Nitric oxide produced by EcNOS, maintains the diameter of blood vessels and proper blood flow to tissues. In addition to this, nitric oxide also regulates angiogenesis, which plays a major role in wound healing.[24] Thus, diabetic patients exhibit reduced ability to generate nitric oxide from L-arginine. Reasons that have been postulated in the literature include accumulation of nitric oxide synthase inhibitor due to high glucose associated kidney dysfunction and reduced production of nitric oxide synthase due to ketoacidosis observed in diabetic patients and pH dependent nature of nitric oxide synthase.[20][25]

Structural and functional changes in fibroblasts

Diabetic ulcer fibroblasts show various morphological differences compared to fibroblasts from age matched controls. Diabetic ulcer fibroblasts are usually large and widely spread in the culture flask compared to the spindle shaped morphology of the fibroblasts in age-matched controls. They often show dilated endoplasmic reticulum, numerous vesicular bodies and lack of microtubular structure in transmission electron microscopy study. Therefore, interpretation of these observations would be that in spite of high protein production and protein turnover in diabetic ulcer fibroblasts, vesicles containing secretory proteins could not travel along the microtubules to release the products outside.[26][27] Fibroblasts from diabetic ulcer exhibit proliferative impairment that probably contributes to a decreased production of extracellular matrix proteins and delayed wound contraction and impaired wound healing.[26]

Increased matrix metalloproteinases (MMP) activity

In order for a wound to heal, extracellular matrix not only needs to be laid down but also must be able to undergo degradation and remodeling to form a mature tissue with appropriate tensile strength.[28] Proteases, namely matrix metalloproteinases are known to degrade almost all the extracellular matrix components. They are known to be involved in fibroblast and keratinocyte migration, tissue re-organization, inflammation and remodeling of the wounded tissue.[3][28] Due to persistently high concentrations of pro-inflammatory cytokines in diabetic ulcers, MMP activity is known to increase by 30 fold when compared to acute wound healing.[29] MMP-2 and MMP-9 show sustained overexpression in chronic non-healing diabetic ulcers.[3][30] Balance in the MMP activity is usually achieved by tissue inhibitor of metalloproteinases (TIMP). Rather than absolute concentrations of either two, it is the ratio of MMP and TIMP that maintains the proteolytic balance and this ratio is found to be disturbed in diabetic ulcer.[31][32] In spite of these findings, the exact mechanism responsible for increased MMP activity in diabetes is not known yet. One possible line of thought considers Transforming growth factor beta (TGF-β) as an active player. Most MMP genes have TGF-β inhibitory element in their promoter regions and thus TGF–β regulates the expression of both MMP and their inhibitor TIMP.[33] In addition to the importance of cell-cell and cell-matrix interactions, all phases of wound healing are controlled by a wide variety of different growth factors and cytokines. To mention precisely, growth factors promote switching of early inflammatory phase to the granulation tissue formation. Decrease in growth factors responsible for tissue repair such as TGF-β is documented in diabetic wounds. Thus, reduced levels of TGFβ in diabetes cases lower down the effect of inhibitory regulatory effect on MMP genes and thus cause MMPs to over express.[1][34][35]

Treatment

Foot ulcers in diabetes require multidisciplinary assessment, usually by diabetes specialists and surgeons. Treatment consists of appropriate bandages, antibiotics (against staphylococcus, streptococcus and anaerobe strains), debridement and arterial revascularisation.

It is often 500 mg to 1000 mg of flucloxacillin, 1 g of amoxicillin and also metronidazole to tackle the putrid smelling bacteria.

Specialists are investigating the role of nitric oxide in diabetic wound healing.[36] Nitric oxide is a powerful vasodilator, which helps to bring nutrients to the oxygen deficient wound beds. Specialists are using forms of light therapy, such as LLLT (Low level laser therapy) to treat diabetic ulcers.

In 2004, The Cochrane review panel concluded that for people with diabetic foot ulcers, hyperbaric oxygen therapy reduced the risk of amputation and may improve the healing[37] at 1 year.[38] They also suggest that the availability of hyperbaric facilities and economic evaluations should be interpreted.[38]

Cellular wound matrices

These type of matrices are used as dermal or both dermal-epidermal substitutes. They are made up of In vitro cultured fibroblasts or keratinocytes onto a biomaterial mesh. As cells proliferate across the mesh, they secrete human dermal collagen, matrix proteins, growth factors and cytokines to create three-dimensional human dermal substitute containing metabolically active living cells. Thus by restoring the dermal tissue, they cause patient’s own epithelial cells to migrate and close the wound.[4][39] Unlike dermal substitutes, dermal-epidermal substitutes have a combined dermal and epidermal layer. The epidermal layer is composed of live, differentiating keratinocytes, while the dermal layer consists of living fibroblasts.[40]

Acellular wound matrices

Along the same line, some diabetic wounds may be treated by application of natural or synthetic acellular wound matrices that act as a scaffold at the tissue site to promote fibroblast and keratinocyte migration, to assist in wound closure and thus provide an optimal environment for a restoration of tissue structure and function. These matrices come in different forms. 1. sterile peel open packages for one time use only: In this form, matrix is formulated in the form of a sheet, which has to be cut in a size larger than the outline of wound area either in a dry state or in rehydrated state.[41] 2. Flowable Soft tissue Scaffold: Sometimes, even after surface portion of wound has healed, a remaining tunnel that left treated can lead to breakdown of the wound and formation of new ulcer with easy access to bacteria to cause potentially deep infection.[42] Therefore, this matrix form is made to be applied with a syringe into tunnels or extensions in case of deep wounds. 3. Bilayer matrix wound dressing: This is a tissue engineered porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan and a semi permeable polysiloxane (silicone) layer. Semi permeable silicone membrane controls water vapor loss, provides a flexible adherent covering for the wound surface and adds tear strength to the device. Moreover, the collagen-glycosaminoglycan biodegradable matrix provides a scaffold for cellular invasion and capillary growth. Wound closure is typically complete within 30 days.[43]

Negative pressure wound therapy
Main article: Negative pressure wound therapy

This treatment uses vacuum to remove excess fluid and cellular waste that usually prolong the inflammatory phase of wound healing. In spite of very straightforward mechanism of action, there are lots of inconsistent results of negative pressure wound therapy studies. 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.[44]

Application of growth factors

This treatment strategy consists of use of growth factors either as one of the components in matrix therapy or via topical application of formulation containing required growth factors. Research shows that growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) accelerate tissue repair in an experimental wound model. They attach to cell receptors regulating gene expression of several cytokines and chemokines via different signaling pathways. They promote cell division, migration, angiogenesis and thus start tissue regeneration and remodeling process.[34][45]

Future directions

Though, diabetic foot ulcer develops secondary to Diabetes mellitus, it is usually considered as a separate entity in the medicinal realm from the treatment perspective. With frequent and common incidences of Diabetes mellitus all over the world, diabetic foot care study is becoming a priority especially in the field of podiatry. Though, treatment approaches such as topical formulations of growth factors, cellular and acellular matrix applications show very promising results, these formulations are expensive and are generally either dermal or epidermal analogs; mostly being dermal analogs. Use of human cadaver and other animal skin sometimes faces the problem of tissue rejection or failure of revascularization. Among all other causes of delayed wound healing, except the metabolic cause i.e. excess glycation cannot be treated with either topical formulation or matrix application at wound site. Therefore, pharmaceutical companies should focus their research on development of drugs that can inhibit AGE formation and their potential formulations for diabetic patients. Topical or systemic administration of EcNOS can be one more potential treatment that needs to be considered in diabetic ulcers as well. Thus, while treating diabetic ulcers, generalized treatment approach does not seem to be appropriate instead, selection of a particular treatment should be carried out on case-by-case evaluation considering severity of the wound and by using combination therapy if necessary.[13]

References

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See also

  • Diabetic diet
  • Diabetic foot ulcer healing

External links

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