View source for Diabetic foot ulcer

<p><strong>Diabetic foot ulcer</strong> is one of <font color="#000000">the major complications of Diabetes mellitus. It occurs in 15% of all patients with diabetes and precedes 84% of all lower leg amputations.<sup id="cite_ref-Harold_0-0" class="reference"><font size="2"><span>[</span>1<span>]</span></font></sup>. 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 &lsquo;make-up&rsquo; 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&rsquo;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.<sup id="cite_ref-Iakovos_1-0" class="reference"><font size="2"><span>[</span>2<span>]</span></font></sup> 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.<sup id="cite_ref-McLennan_2-0" class="reference"><font size="2"><span>[</span>3<span>]</span></font></sup></font></p>
<p><font color="#000000">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.<sup id="cite_ref-Blume_3-0" class="reference"><font size="2"><span>[</span>4<span>]</span></font></sup> 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.<sup id="cite_ref-Sharman_4-0" class="reference"><font size="2"><span>[</span>5<span>]</span></font></sup> To address the physiological deficiencies underlying diabetic ulcer, various tissue engineering technologies have come up with cellular as well as acellular skin replacement products.</font></p>

<h2><span id="Prevention" class="mw-headline"><font color="#000000">Prevention</font></span></h2>
<p><font color="#000000">Prevention is by frequent chiropody review, good foot hygiene, diabetic socks and shoes, and avoiding injury.</font></p>
<ul>
    <li><font color="#000000"><strong>Foot-care education combined with increased surveillance</strong> can reduce the incidence of serious foot lesions <sup id="cite_ref-pmid8498761_5-0" class="reference"><font size="2"><span>[</span>6<span>]</span></font></sup>. </font></li>
</ul>
<ul>
    <li><font color="#000000"><strong>Footwear</strong>. </font></li>
</ul>
<dl><dd><font color="#000000">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. </font></dd></dl><dl><dd><font color="#000000">A meta-analysis by the Cochrane Collaboration concluded that &quot;there is very limited evidence of the effectiveness of therapeutic shoes&quot; <sup id="cite_ref-pmid10908550_6-0" class="reference"><font size="2"><span>[</span>7<span>]</span></font></sup>. The date of the literature search for this review is not clear. <em>Clinical Evidence</em> reviewed the topic and concluded &quot;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&quot; <sup id="cite_ref-pmid16620415_7-0" class="reference"><font size="2"><span>[</span>8<span>]</span></font></sup>. National Institute for Health and Clinical Excellence has reviewed the topic and concluded that for patients at &quot;high risk of foot ulcers (neuropathy or absent pulses plus deformity or skin changes or previous ulcer&quot; that &quot;specialist footwear and insoles&quot; should be provided <sup id="cite_ref-webNICE_8-0" class="reference"><font size="2"><span>[</span>9<span>]</span></font></sup> </font></dd></dl>
<p>The one <font color="#002bb8">randomized controlled trial</font> that showed benefit of custom foot wear was in patients with a prior foot ulceration <sup id="cite_ref-pmid8721941_9-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>10<span>]</span></font></font></sup>. In this trial, the <font color="#002bb8">number needed to treat</font> was 4 patients.</p>
<h2><span id="Risk_factors" class="mw-headline">Risk factors</span></h2>
<p>Two main risk factors that cause diabetic foot ulcer are <font color="#002bb8">Diabetic neuropathy</font> and micro as well as macro <font color="#002bb8">ischemia</font>.<sup id="cite_ref-Wu_10-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>11<span>]</span></font></font></sup> Diabetic patients often suffer from <font color="#002bb8">diabetic neuropathy</font> due to several metabolic and neurovascular factors. Type of <font color="#002bb8">neuropathy</font> called <font color="#002bb8">peripheral neuropathy</font> causes loss of pain or feeling in the toes, feet, legs and arms due to distal nerve damage and low blood flow. <font color="#002bb8">Blisters</font> and <font color="#002bb8">sores</font> 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 <font color="#002bb8">bacteria</font> and <font color="#002bb8">infection</font>.</p>
<h2><span id="Pathophysiology" class="mw-headline">Pathophysiology</span></h2>
<h3><span id="Role_of_Extracellular_matrix_.28ECM.29_in_wound_healing" class="mw-headline">Role of Extracellular matrix (ECM) in wound healing</span></h3>
<p><font color="#002bb8">Extra cellular matrix</font> is the structurally stable material that lies under epidermal layer and surrounds <font color="#002bb8">connective tissue</font> cells that form dermal layer of the <font color="#002bb8">skin</font>. Through the interaction of cell with its <font color="#002bb8">extracellular matrix</font>, there forms a continuous association between cell interior, <font color="#002bb8">cell membrane</font> and extracellular matrix components that help drive various cellular events in a regulated fashion.<sup id="cite_ref-11" class="reference"><font size="2"><font color="#002bb8"><span>[</span>12<span>]</span></font></font></sup> <font color="#002bb8">Wound healing</font>, a repair mechanism is one of those cellular events that occur through controlled turnover of <font color="#002bb8">extracellular matrix</font> components. Because of this <font color="#002bb8">extracellular matrix</font> is often considered as a 'conductor of the <font color="#002bb8">wound healing</font> symphony'.<sup id="cite_ref-Sweitzer_12-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>13<span>]</span></font></font></sup> In the Inflammatory phase, <font color="#002bb8">neutrophils</font> and <font color="#002bb8">macrophages</font> recruit and activate <font color="#002bb8">fibroblasts</font> which in subsequent granulation phase migrate into the wound, laying down new <font color="#002bb8">collagen</font> of the subtypes I and III. In the initial events of <font color="#002bb8">wound healing</font>, <font color="#002bb8">collagen III</font> predominates in the granulation tissue which later on in remodeling phase gets replaced by collagen I giving additional <font color="#002bb8">tensile strength</font> to the healing tissue.<sup id="cite_ref-Schultz_13-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>14<span>]</span></font></font></sup><sup id="cite_ref-Sussman_14-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>15<span>]</span></font></font></sup> 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.<sup id="cite_ref-Sussman_14-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>15<span>]</span></font></font></sup><sup id="cite_ref-Thomas_15-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>16<span>]</span></font></font></sup> 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.<sup id="cite_ref-Sussman_14-2" class="reference"><font size="2"><font color="#002bb8"><span>[</span>15<span>]</span></font></font></sup><sup id="cite_ref-Thomas_15-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>16<span>]</span></font></font></sup> Hyaluronic acid, a pure <font color="#002bb8">glycosaminoglycan</font> component is found in high amounts in damaged or growing tissues. It stimulates <font color="#002bb8">cytokine</font> production by <font color="#002bb8">macrophages</font> and thus promotes <font color="#002bb8">angiogenesis</font>. In normal skin <font color="#002bb8">chondroitin sulfate</font> <font color="#002bb8">proteoglycan</font> is mainly found in the <font color="#002bb8">basement membrane</font> but in healing wounds they are up regulated throughout the <font color="#002bb8">granulation tissue</font> especially during second week of wound repair, when they provide a temporary matrix with highly hydrative capacity.<sup id="cite_ref-Miriam_16-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>17<span>]</span></font></font></sup> Binding of <font color="#002bb8">growth factors</font> is clearly an important role of <font color="#002bb8">perlecan</font> in <font color="#002bb8">wound healing</font> and <font color="#002bb8">angiogenesis</font>. Poor wound healing in diabetes mellitus may be related to <font color="#002bb8">perlecan</font> expression. High levels of glucose can decrease perlecan expression in some cells probably through transcriptional and <font color="#002bb8">post-transcriptional modification</font>.<sup id="cite_ref-Miriam_16-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>17<span>]</span></font></font></sup><sup id="cite_ref-Decarlo_17-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>18<span>]</span></font></font></sup> <font color="#002bb8">Wound healing</font> phases especially, granulation, re-epithelization and remodeling exhibit controlled turnover of <font color="#002bb8">extracellular matrix</font> components.</p>
<h3><span id="Altered_metabolism" class="mw-headline">Altered metabolism</span></h3>
<p><font color="#002bb8">Diabetes mellitus</font> 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 <font color="#002bb8">granulation tissue</font> formation.<sup id="cite_ref-Tweedie_18-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>19<span>]</span></font></font></sup> Increased glucose levels in the body end up in uncontrolled covalent bonding of <font color="#002bb8">aldose</font> sugars to a protein or lipid without any normal <font color="#002bb8">glycosylation</font> enzymes.<sup id="cite_ref-Goldin_19-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>20<span>]</span></font></font></sup> These stable products then accumulate over the surface of cell membranes, structural proteins and circulating proteins. These products are called <font color="#002bb8">advanced glycation endproducts</font> (AGEs) or Amadori products. Formation of AGEs occurs on <font color="#002bb8">extracellular matrix</font> proteins with slow turnover rate. AGEs alter the properties of matrix proteins such as collagen, <font color="#002bb8">vitronectin</font>, and <font color="#002bb8">laminin</font> through AGE-AGE intermolecular covalent bonds or cross-linking.<sup id="cite_ref-Goldin_19-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>20<span>]</span></font></font></sup><sup id="cite_ref-Singh_20-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>21<span>]</span></font></font></sup><sup id="cite_ref-Brownlee_21-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>22<span>]</span></font></font></sup> AGE cross-linking on <font color="#002bb8">type I collagen</font> and <font color="#002bb8">elastin</font> results in increased stiffness. AGEs are also known to increase synthesis of <font color="#002bb8">type III collagen</font> that forms the <font color="#002bb8">granulation tissue</font>. AGEs on laminin result in reduced binding to <font color="#002bb8">type IV collagen</font> in the basement membrane, reduced polymer elongation and reduced binding of <font color="#002bb8">heparan sulfate</font> <font color="#002bb8">proteoglycan</font>.<sup id="cite_ref-Goldin_19-2" class="reference"><font size="2"><font color="#002bb8"><span>[</span>20<span>]</span></font></font></sup></p>
<dl><dt>Impaired NO synthesis </dt></dl>
<p><font color="#002bb8">Nitric oxide</font> is known as an important stimulator of cell proliferation, maturation and <font color="#002bb8">differentiation</font>. Thus, <font color="#002bb8">nitric oxide</font> increases <font color="#002bb8">fibroblast</font> proliferation and thereby collagen production in wound healing. Also, L-<font color="#002bb8">arginine</font> and <font color="#002bb8">nitric oxide</font> are required for proper cross linking of collagen fibers, via proline, to minimize scarring and maximize the tensile strength of healed tissue.<sup id="cite_ref-Kei_22-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>23<span>]</span></font></font></sup> Endothelial cell specific <font color="#002bb8">nitric oxide synthase</font> (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 <font color="#002bb8">angiogenesis</font>, which plays a major role in <font color="#002bb8">wound healing</font>.<sup id="cite_ref-Dan_23-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>24<span>]</span></font></font></sup> Thus, diabetic patients exhibit reduced ability to generate <font color="#002bb8">nitric oxide</font> from L-<font color="#002bb8">arginine</font>. Reasons that have been postulated in the literature include accumulation of <font color="#002bb8">nitric oxide synthase</font> inhibitor due to high glucose associated kidney dysfunction and reduced production of <font color="#002bb8">nitric oxide synthase</font> due to <font color="#002bb8">ketoacidosis</font> observed in diabetic patients and pH dependent nature of <font color="#002bb8">nitric oxide synthase</font>.<sup id="cite_ref-Goldin_19-3" class="reference"><font size="2"><font color="#002bb8"><span>[</span>20<span>]</span></font></font></sup><sup id="cite_ref-Linden_24-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>25<span>]</span></font></font></sup></p>
<dl><dt>Structural and functional changes in fibroblasts </dt></dl>
<p>Diabetic ulcer <font color="#002bb8">fibroblasts</font> 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 <font color="#002bb8">endoplasmic reticulum</font>, numerous vesicular bodies and lack of microtubular structure in <font color="#002bb8">transmission electron microscopy</font> 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 <font color="#002bb8">microtubules</font> to release the products outside.<sup id="cite_ref-fibroblasts_25-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>26<span>]</span></font></font></sup><sup id="cite_ref-Rowe_26-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>27<span>]</span></font></font></sup> Fibroblasts from diabetic ulcer exhibit proliferative impairment that probably contributes to a decreased production of <font color="#002bb8">extracellular matrix</font> proteins and delayed wound contraction and impaired wound healing.<sup id="cite_ref-fibroblasts_25-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>26<span>]</span></font></font></sup></p>
<dl><dt>Increased matrix metalloproteinases (MMP) activity </dt></dl>
<p>In order for a wound to heal, <font color="#002bb8">extracellular matrix</font> not only needs to be laid down but also must be able to undergo degradation and remodeling to form a mature tissue with appropriate <font color="#002bb8">tensile strength</font>.<sup id="cite_ref-Ravanti_27-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>28<span>]</span></font></font></sup> Proteases, namely <font color="#002bb8">matrix metalloproteinases</font> are known to degrade almost all the <font color="#002bb8">extracellular matrix</font> components. They are known to be involved in <font color="#002bb8">fibroblast</font> and <font color="#002bb8">keratinocyte</font> migration, tissue re-organization, inflammation and remodeling of the wounded tissue.<sup id="cite_ref-McLennan_2-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>3<span>]</span></font></font></sup><sup id="cite_ref-Ravanti_27-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>28<span>]</span></font></font></sup> Due to persistently high concentrations of pro-inflammatory <font color="#002bb8">cytokines</font> in diabetic ulcers, MMP activity is known to increase by 30 fold when compared to acute wound healing.<sup id="cite_ref-Vaalamo_28-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>29<span>]</span></font></font></sup> MMP-2 and MMP-9 show sustained overexpression in chronic non-healing diabetic ulcers.<sup id="cite_ref-McLennan_2-2" class="reference"><font size="2"><font color="#002bb8"><span>[</span>3<span>]</span></font></font></sup><sup id="cite_ref-Wysocki_29-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>30<span>]</span></font></font></sup> 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.<sup id="cite_ref-Lobman_30-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>31<span>]</span></font></font></sup><sup id="cite_ref-Muller_31-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>32<span>]</span></font></font></sup> 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 <font color="#002bb8">Transforming growth factor</font> beta (TGF-&beta;) as an active player. Most MMP genes have TGF-&beta; inhibitory element in their promoter regions and thus TGF&ndash;&beta; regulates the expression of both MMP and their inhibitor TIMP.<sup id="cite_ref-Susan_32-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>33<span>]</span></font></font></sup> In addition to the importance of cell-cell and cell-matrix interactions, all phases of <font color="#002bb8">wound healing</font> are controlled by a wide variety of different <font color="#002bb8">growth factors</font> and <font color="#002bb8">cytokines</font>. To mention precisely, growth factors promote switching of early inflammatory phase to the <font color="#002bb8">granulation tissue</font> formation. Decrease in growth factors responsible for tissue repair such as TGF-&beta; is documented in diabetic wounds. Thus, reduced levels of TGF&beta; in diabetes cases lower down the effect of inhibitory regulatory effect on MMP genes and thus cause MMPs to over express.<sup id="cite_ref-Harold_0-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>1<span>]</span></font></font></sup><sup id="cite_ref-Bennet_33-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>34<span>]</span></font></font></sup><sup id="cite_ref-Galkowska_34-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>35<span>]</span></font></font></sup></p>
<h2><span id="Treatment" class="mw-headline">Treatment</span></h2>
<p>Foot ulcers in diabetes require multidisciplinary assessment, usually by diabetes specialists and <font color="#002bb8">surgeons</font>. Treatment consists of appropriate bandages, <font color="#002bb8">antibiotics</font> (against <font color="#002bb8">staphylococcus</font>, <font color="#002bb8">streptococcus</font> and <font color="#002bb8">anaerobe</font> strains), <font color="#002bb8">debridement</font> and arterial revascularisation.</p>
<p>It is often 500 mg to 1000 mg of flucloxacillin, 1 g of amoxicillin and also metronidazole to tackle the putrid smelling bacteria.</p>
<p>Specialists are investigating the role of <font color="#002bb8">nitric oxide</font> in diabetic wound healing.<sup id="cite_ref-35" class="reference"><font size="2"><font color="#002bb8"><span>[</span>36<span>]</span></font></font></sup> Nitric oxide is a powerful vasodilator, which helps to bring nutrients to the oxygen deficient wound beds. Specialists are using forms of <font color="#002bb8">light therapy</font>, such as <font color="#002bb8">LLLT</font> (Low level laser therapy) to treat diabetic ulcers.</p>
<p>In 2004, The <font color="#002bb8">Cochrane review panel</font> concluded that for people with diabetic foot ulcers, <font color="#002bb8">hyperbaric oxygen therapy</font> reduced the risk of <font color="#002bb8">amputation</font> and may improve the healing<sup id="cite_ref-36" class="reference"><font size="2"><font color="#002bb8"><span>[</span>37<span>]</span></font></font></sup> at 1 year.<sup id="cite_ref-CochraneHBO_37-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>38<span>]</span></font></font></sup> They also suggest that the availability of hyperbaric facilities and economic evaluations should be interpreted.<sup id="cite_ref-CochraneHBO_37-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>38<span>]</span></font></font></sup></p>
<dl><dt>Cellular wound matrices </dt></dl>
<p>These type of matrices are used as dermal or both dermal-epidermal substitutes. They are made up of <em><font color="#002bb8">In vitro</font></em> cultured <font color="#002bb8">fibroblasts</font> or <font color="#002bb8">keratinocytes</font> onto a <font color="#002bb8">biomaterial</font> mesh. As cells proliferate across the mesh, they secrete human dermal collagen, matrix proteins, <font color="#002bb8">growth factors</font> and <font color="#002bb8">cytokines</font> to create three-dimensional human dermal substitute containing metabolically active living cells. Thus by restoring the dermal tissue, they cause patient&rsquo;s own epithelial cells to migrate and close the wound.<sup id="cite_ref-Blume_3-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>4<span>]</span></font></font></sup><sup id="cite_ref-Veves_38-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>39<span>]</span></font></font></sup> Unlike dermal substitutes, dermal-epidermal substitutes have a combined dermal and epidermal layer. The epidermal layer is composed of live, differentiating <font color="#002bb8">keratinocytes</font>, while the dermal layer consists of living <font color="#002bb8">fibroblasts</font>.<sup id="cite_ref-Falanga_39-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>40<span>]</span></font></font></sup></p>
<dl><dt>Acellular wound matrices </dt></dl>
<p>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 <font color="#002bb8">fibroblast</font> and <font color="#002bb8">keratinocyte</font> 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.<sup id="cite_ref-Mostow_40-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>41<span>]</span></font></font></sup> 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.<sup id="cite_ref-Brigido_41-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>42<span>]</span></font></font></sup> 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 <font color="#002bb8">glycosaminoglycan</font> and a semi permeable <font color="#002bb8">polysiloxane</font> (<font color="#002bb8">silicone</font>) layer. Semi permeable <font color="#002bb8">silicone</font> 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.<sup id="cite_ref-Voigt_42-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>43<span>]</span></font></font></sup></p>
<dl><dt>Negative pressure wound therapy </dt></dl>
<div class="rellink relarticle mainarticle">Main article: <font color="#002bb8">Negative pressure wound therapy</font></div>
<p>This treatment uses <font color="#002bb8">vacuum</font> 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 <font color="#002bb8">negative pressure wound therapy</font> 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.<sup id="cite_ref-Armstrong_43-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>44<span>]</span></font></font></sup></p>
<dl><dt>Application of growth factors </dt></dl>
<p>This treatment strategy consists of use of <font color="#002bb8">growth factors</font> 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 <font color="#002bb8">epidermal growth factor</font> (EGF), <font color="#002bb8">platelet derived growth factor</font> (PDGF), <font color="#002bb8">transforming growth factor beta</font> (TGF-&beta;), <font color="#002bb8">vascular endothelial growth factor</font> (VEGF) and <font color="#002bb8">insulin-like growth factor-1</font> (IGF-1) accelerate tissue repair in an experimental wound model. They attach to cell receptors regulating <font color="#002bb8">gene expression</font> of several <font color="#002bb8">cytokines</font> and <font color="#002bb8">chemokines</font> via different signaling pathways. They promote <font color="#002bb8">cell division</font>, migration, <font color="#002bb8">angiogenesis</font> and thus start tissue regeneration and remodeling process.<sup id="cite_ref-Bennet_33-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>34<span>]</span></font></font></sup><sup id="cite_ref-Tsang_44-0" class="reference"><font size="2"><font color="#002bb8"><span>[</span>45<span>]</span></font></font></sup></p>
<h2><span id="Future_directions" class="mw-headline">Future directions</span></h2>
<p>Though, diabetic foot ulcer develops secondary to <font color="#002bb8">Diabetes mellitus</font>, it is usually considered as a separate entity in the medicinal realm from the treatment perspective. With frequent and common incidences of <font color="#002bb8">Diabetes mellitus</font> all over the world, diabetic foot care study is becoming a priority especially in the field of <font color="#002bb8">podiatry</font>. Though, treatment approaches such as topical formulations of <font color="#002bb8">growth factors</font>, 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 <font color="#002bb8">cadaver</font> and other animal <font color="#002bb8">skin</font> sometimes faces the problem of tissue rejection or failure of <font color="#002bb8">revascularization</font>. 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.<sup id="cite_ref-Sweitzer_12-1" class="reference"><font size="2"><font color="#002bb8"><span>[</span>13<span>]</span></font></font></sup></p>
<h2><span id="References" class="mw-headline">References</span></h2>
<div class="references-small">
<ol class="references">
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    <li id="cite_note-35"><strong><font color="#002bb8">^</font></strong> <span class="citation Journal">Sch&auml;ffer M, Bongartz M, Fischer S, Proksch B, Viebahn R (July 2007). &quot;Nitric oxide restores impaired healing in normoglycaemic diabetic rats&quot;. <em>J Wound Care</em> <strong>16</strong> (7): 311&ndash;6. <font color="#002bb8">PMID</font> <font color="#3366bb">17708383</font>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Nitric+oxide+restores+impaired+healing+in+normoglycaemic+diabetic+rats&amp;rft.jtitle=J+Wound+Care&amp;rft.aulast=Sch%C3%A4ffer+M%2C+Bongartz+M%2C+Fischer+S%2C+Proksch+B%2C+Viebahn+R&amp;rft.au=Sch%C3%A4ffer+M%2C+Bongartz+M%2C+Fischer+S%2C+Proksch+B%2C+Viebahn+R&amp;rft.date=July+2007&amp;rft.volume=16&amp;rft.issue=7&amp;rft.pages=311%E2%80%936&amp;rft_id=info:pmid/17708383&amp;rfr_id=info:sid/en.wikipedia.org:Diabetic_foot"><span style="DISPLAY: none">&nbsp;</span></span> </li>
    <li id="cite_note-36"><strong><font color="#002bb8">^</font></strong> <span class="citation Journal">Zamboni WA, Wong HP, Stephenson LL, Pfeifer MA (September 1997). <font color="#3366bb">&quot;Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study&quot;</font>. <em>Undersea Hyperb Med</em> <strong>24</strong> (3): 175&ndash;9. <font color="#002bb8">PMID</font> <font color="#3366bb">9308140</font><span class="printonly">. <font color="#3366bb">http://archive.rubicon-foundation.org/2279</font></span><span class="reference-accessdate">. Retrieved 2008-05-16</span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Evaluation+of+hyperbaric+oxygen+for+diabetic+wounds%3A+a+prospective+study&amp;rft.jtitle=Undersea+Hyperb+Med&amp;rft.aulast=Zamboni+WA%2C+Wong+HP%2C+Stephenson+LL%2C+Pfeifer+MA&amp;rft.au=Zamboni+WA%2C+Wong+HP%2C+Stephenson+LL%2C+Pfeifer+MA&amp;rft.date=September+1997&amp;rft.volume=24&amp;rft.issue=3&amp;rft.pages=175%E2%80%939&amp;rft_id=info:pmid/9308140&amp;rft_id=http%3A%2F%2Farchive.rubicon-foundation.org%2F2279&amp;rfr_id=info:sid/en.wikipedia.org:Diabetic_foot"><span style="DISPLAY: none">&nbsp;</span></span> </li>
    <li id="cite_note-CochraneHBO-37">^ <sup><em><strong><font color="#002bb8" size="2">a</font></strong></em></sup> <sup><em><strong><font color="#002bb8" size="2">b</font></strong></em></sup> <span class="citation Journal">Kranke P, Bennett M, Roeckl-Wiedmann I, Debus S (2004). &quot;Hyperbaric oxygen therapy for chronic wounds&quot;. <em>Cochrane Database Syst Rev</em> (2): CD004123. <font color="#002bb8">doi</font>:<span class="neverexpand"><font color="#3366bb">10.1002/14651858.CD004123.pub2</font></span>. <font color="#002bb8">PMID</font> <font color="#3366bb">15106239</font>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Hyperbaric+oxygen+therapy+for+chronic+wounds&amp;rft.jtitle=Cochrane+Database+Syst+Rev&amp;rft.aulast=Kranke+P%2C+Bennett+M%2C+Roeckl-Wiedmann+I%2C+Debus+S&amp;rft.au=Kranke+P%2C+Bennett+M%2C+Roeckl-Wiedmann+I%2C+Debus+S&amp;rft.date=2004&amp;rft.issue=2&amp;rft.pages=CD004123&amp;rft_id=info:doi/10.1002%2F14651858.CD004123.pub2&amp;rft_id=info:pmid/15106239&amp;rfr_id=info:sid/en.wikipedia.org:Diabetic_foot"><span style="DISPLAY: none">&nbsp;</span></span> </li>
    <li id="cite_note-Veves-38"><strong><font color="#002bb8">^</font></strong> Veves A et.al, Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial, Diabetes Care(2001). 24: 2001&ndash;295 <font color="#3366bb">PMID 11213881</font>. </li>
    <li id="cite_note-Falanga-39"><strong><font color="#002bb8">^</font></strong> Falanga V et.al, A bilayered living skin construct (Apligraf) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen(1999). 7:201-207 <font color="#3366bb">PMID 10781211</font>. </li>
    <li id="cite_note-Mostow-40"><strong><font color="#002bb8">^</font></strong> Mostow EN, et.al. Effectiveness of an Extracellular Matrix Graft (OASIS Wound Matrix) in the Treatment of Chronic Leg Ulcers: A Randomized Clinical Trial. J Vas Surg(2005). 41:856-862 <font color="#3366bb">PMID 15886669</font>. </li>
    <li id="cite_note-Brigido-41"><strong><font color="#002bb8">^</font></strong> Stephen A. Brigido et.al,Use of an Acellular Flowable Dermal Replacement Scaffold on Lower Extremity Sinus Tract Wounds,Foot &amp; Ankle Specialist(2009),2(2):67-72 </li>
    <li id="cite_note-Voigt-42"><strong><font color="#002bb8">^</font></strong> David W. Voigt et.al, Economic Study of Collagen-Glycosaminoglycan Biodegradable Matrix for Chronic Wounds, Wounds(2006). 18(1):1-7 <font color="#3366bb">[3]</font> </li>
    <li id="cite_note-Armstrong-43"><strong><font color="#002bb8">^</font></strong> Armstrong DG et al, Outcomes of subatmospheric pressure dressing therapy on wounds of the diabetic foot. Ostomy Wound Manage(2002). 48(4): 64&ndash;68 <font color="#3366bb">PMID 11993062</font>. </li>
    <li id="cite_note-Tsang-44"><strong><font color="#002bb8">^</font></strong> Tsang MWet.al, Human Epidermal Growth Factor Enhances Healing of Diabetic Foot Ulcers. Diabetes Care(2003).26 (6):1856 <font color="#3366bb">PMID 12766123</font>. </li>
</ol>
</div>
<h2><span id="See_also" class="mw-headline">See also</span></h2>
<ul>
    <li><font color="#002bb8">Diabetic diet</font> </li>
    <li><font color="#002bb8">Diabetic foot ulcer healing</font> </li>
</ul>
<h2><span id="External_links" class="mw-headline">External links</span></h2>
<ul>
    <li><a class="external text" rel="nofollow" href="http://diabetic-foot.net"><font color="#3366bb">Diabetic Foot Research Page</font></a> at the Southern Arizona Limb Salvage Alliance (SALSA); for Professionals and Patients </li>
    <li><a class="external text" rel="nofollow" href="http://gentili.net/diabeticfoot/"><font color="#3366bb">Imaging of the Diabetic Foot and Its Complications</font></a> </li>
    <li><a class="external text" rel="nofollow" href="http://diabeticfootonline.blogspot.com/"><font color="#3366bb">The Diabetic Foot Blog</font></a> </li>
    <li><a class="external text" rel="nofollow" href="http://www.podiatrytoday.com/article/5164"><font color="#3366bb">Assessing The Potential of Nitric Oxide in the Diabetic Foot</font></a> </li>
</ul>
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