Diabetic foot ulcer

Diabetic foot ulcer is a major complication of diabetes mellitus, and probably the major component of the diabetic foot. It occurs in 15% of all patients with diabetes and precedes 84% of all lower leg amputations. 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 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 (ECM) that forms the largest component of the dermal skin layer. Controlled and accurate rebuilding is essential to avoid under- or over-healing that may lead to various abnormalities. 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 histopathological 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.

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. 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. To address the physiological deficiencies underlying diabetic ulcer, various tissue engineering technologies have come up with cellular as well as acellular skin replacement products. New therapies in development are also promising, such as platelet rich fibrin wound patch therapy, which is often simpler and proving effective in chronic diabetic foot ulcers.

Prevention
Steps to prevent diabetic foot ulcers include frequent chiropody review, 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.


 * 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". 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". 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

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

Risk factors
Risk factors implicated in the development of diabetic foot ulcers are diabetic neuropathy, peripheral vascular disease, cigarette smoking, poor glycemic control, previous foot ulcerations or amputations, diabetic nephropathy, and ischemia of small and large blood vessels. Diabetic patients often suffer from 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.

Extracellular matrix
Extra cellular matrix (or "ECM") 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 (transmitted through the anchoring molecules classed as integrins) 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
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. 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 (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. 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.

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. 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. 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.
 * Impaired NO synthesis

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. 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.
 * Structural and functional changes in fibroblasts

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. 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. 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. MMP-2 and MMP-9 show sustained overexpression in chronic non-healing diabetic ulcers. 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. 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. 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.
 * Increased matrix metalloproteinases (MMP) 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, we can summarise the effect of diabetes on the main structures of the foot-ankle complex as:
 * effects on skin: skin – and the soft tissues immediately underneath the skin - undergo greater compression and shear loading than usual, thus explaining the onset of tissue damage so deeply correlated to traumatic ulceration processes. Besides this, skin of the Diabetic foot suffers from loss of autonomic nervous control and consequently reduced hydration, making it less elastic and thus more vulnerable to the action of increased mechanical stress;
 * effects on tendons and ligaments: protein glycosylation and the resulting collagen abnormalities lead to greater transversal section – i.e. thickening - of tendons and ligaments and a greater coefficient of elasticity. Particularly impacted by this process are Plantar Fascia and Achilles Tendon. Both causes lead to an increased stiffness of those structures;
 * effects on cartilage: similar to what happens to tendons and ligaments, cartilage changes its composition mainly due to the modification of collagen fibers; this increases its stiffness and decreases the range of motion of all joints in the foot and ankle;
 * effects on muscles: Diabetes mellitus causes severe damage to nerve conduction, thus causing a worsening in the management of the related muscle fibers. As a consequence, both intrinsic and extrinsic muscles of the foot-ankle complex are damaged in structure (reduction of muscle volume) and function (reduction of muscle strength);
 * effects on peripheral sensory system: impaired nerve conduction has a dramatic effect on the peripheral sensory system, since it leads to loss of protective sensation under the sole of the foot. This exposes the Diabetic foot to thermal or mechanical trauma, and to the late detection of infection processes or tissue breakdown;
 * effects on foot morphology (deformities): due to most of the above alterations, a significant imbalance of peripheral musculature and soft tissue occur in the foot which seriously alters its morphology and determines the onset of foot deformities. Most common deformities of the Diabetic foot are represented by a high longitudinal arch (rigid cavus foot), hammer toes and hallux valgus. A completely different morphologic degeneration is represented by the Charcot foot, whose analysis is not part of this discussion.

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, arterial revascularisation and platelet-rich fibrin therapies.

Wound dressings
There are many types of dressings used to treat diabetic foot ulcers such as absorptive fillers, hydrogel dressings, and hydrocolloids. Previously, hydrogel dressings have shown to have 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. Thus it is recommended that the cost of the product be taken into account. A recent advancement in wound dressing are biologically active bandages that combine hydrogel and hydrocolloid traits, however more research needs to be conducted as to the efficacy of this option over others.

Platelet-Rich Fibrin Therapy
These treatments utilize techniques that process a patient’s blood to isolate a fibrin or plasma, which is rich in platelets as well as growth factors that promote the natural healing process. Application of these components to diabetic foot ulcers has been shown to produce accelerated healing. Leucopatch, one such product being developed in Denmark by the company Reapplix, is a three-layered fibrin patch that can be prepared rapidly in a closed system from a small sample of the patient’s blood. It is composed entirely of a patient’s own cells and growth factors, containing high levels of leukocytes and platelets. In preliminary studies, Leucopatch application has significantly reduced wound area of ulcers by 65% after six weeks of treatment. In particular, it has shown effectiveness in chronic or hard-to-treat diabetic foot ulcers, which often end in amputation. Reapplix is currently conducting clinical trials to determine the safety and efficacy of Leucopatch in foot ulcer treatment, as well as research into use for the treatment of other chronic wounds.

Hyperbaric oxygen
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 at 1 year. They also suggest that the availability of hyperbaric facilities and economic evaluations should be interpreted.

"Drs. Ted Sosiak and Wayne Evans make a shocking claim in the Ontario Medical Review. They say that HBOT [Hyperbaric Oxygen Therapy] could save up to 75% of the more than 2,160 amputations that occur every year in Ontario due to diabetic foot ulcers that will not heal. And that HBOT treatment could save $100 million and the costs of chronic disability caused by amputation".

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.

Topical administration of stem cells
Stem cell therapy may represent an innovative and promising treatment for promoting healing of diabetic foot ulcers.

Classification
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:


 * 707.1 Ulcer of lower limbs, except pressure ulcer
 * 707.14 Ulcer of heel and midfoot
 * 707.15 Ulcer of other part of foot
 * 707.19 Ulcer of other part of lower limb

One or more codes, in combination with a current or prior diagnosis of diabetes may be sufficient to conclude diabetic foot:
 * 250.0 Diabetes Mellitus
 * 250.8 Diabetes with other specified manifestations

Sohn et al. survey alternative methods used in published literature. In particular, they note:

"'Ramsey et al. [3,15] used the simplest method, involving only one diagnostic code (ICD-9-CM 707.1×, 'Ulcer of lower limbs, except decubitus'), in a study of incidence rates and treatment costs of foot ulcers among individuals enrolled in a HMO. In a validation study, this method was shown to have 74% sensitivity and 94% specificity compared to medical records.'"