Diabetic foot
Encyclopedia
Diabetic foot ulcer is one of the major complications 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 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. 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
.
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.
s and shoe
s, and avoiding injury.
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.
and micro as well as macro ischemia
. 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
.
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 tissue
s 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.
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
.
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. 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
.
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. 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.
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
. 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.
Briefly, we can summarise the effect of diabetes on the main structures of the foot-ankle complex as:
s. Treatment consists of appropriate bandages, antibiotic
s (against staphylococcus
, streptococcus
and anaerobe strains), debridement
and arterial revascularisation.
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.
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.
One or more codes, in combination with a current or prior diagnosis of diabetes may be sufficient to conclude diabetic foot:
Sohn et al. survey alternative methods used in published literature. In particular, they note:
Complications of diabetes mellitus
The complications of diabetes mellitus are far less common and less severe in people who have well-controlled blood sugar levels.Wider health problems accelerate the deleterious effects of diabetes...
, and probably the major component of the diabetic foot
Diabetic foot
Diabetic foot ulcer is one of the major complications 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...
. 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
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
process. Wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
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
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
is stepwise repair of lost extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(ECM) that forms largest component of dermal skin layer. 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
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
process that otherwise goes very smoothly in an orderly manner. Diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
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
Granulation tissue
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals...
and a parallel reduction in wound
Wound
A wound is a type of injury in which skin is torn, cut or punctured , or where blunt force trauma causes a contusion . In pathology, it specifically refers to a sharp injury which damages the dermis of the skin.-Open:...
tensile strength
Tensile strength
Ultimate tensile strength , often shortened to tensile strength or ultimate strength, is the maximum stress that a material can withstand while being stretched or pulled before necking, which is when the specimen's cross-section starts to significantly contract...
.
Non-healing chronic diabetic ulcers are often treated with extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
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
Negative Pressure Wound Therapy
Negative-pressure wound therapy is a therapeutic technique using a vacuum dressing to promote healing in acute or chronic wounds and enhance healing of first and second degree burns. The therapy involves the controlled application of sub-atmospheric pressure to the local wound environment, using a...
. No therapy is completely perfect as each type suffers from its own disadvantages.
Moist wound therapy is known to promote fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
and keratinocyte
Keratinocyte
Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...
proliferation and migration, collagen synthesis, early angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
and wound contraction. At present, there are various categories of moist dressings available such as adhesive
Adhesive
An adhesive, or glue, is a mixture in a liquid or semi-liquid state that adheres or bonds items together. Adhesives may come from either natural or synthetic sources. The types of materials that can be bonded are vast but they are especially useful for bonding thin materials...
backing film, silicone
Silicone
Silicones are inert, synthetic compounds with a variety of forms and uses. Typically heat-resistant and rubber-like, they are used in sealants, adhesives, lubricants, medical applications , cookware, and insulation....
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
Tissue engineering
Tissue engineering is the use of a combination of cells, engineering and materials methods, and suitable biochemical and physio-chemical factors to improve or replace biological functions...
technologies have come up with cellular as well as acellular skin replacement products.
Prevention
Prevention is by frequent chiropody review, good foot hygiene, diabetic sockDiabetic sock
A diabetic sock is a non-binding sock which is designed for those who need or want a sock that does not constrict the foot and/or leg. Typically sufferers of diabetes are the most common audience for this type of sock. Diabetes raises the blood sugar level, which can increase the risk of foot...
s and shoe
Diabetic shoe
Diabetic shoes, sometimes referred to as extra depth or therapeutic shoes, are specially designed shoes, or shoe inserts, intended to reduce the risk of skin breakdown in diabetics with co-existing foot disease....
s, and 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-analysisMeta-analysisIn statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
by the Cochrane CollaborationCochrane CollaborationThe Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...
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 ExcellenceNational Institute for Health and Clinical ExcellenceThe National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...
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
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
that showed benefit of custom foot wear was in patients with a prior foot ulceration. In this trial, the number needed to treat
Number needed to treat
The number needed to treat is an epidemiological measure used in assessing the effectiveness of a health-care intervention, typically a treatment with medication. The NNT is the average number of patients who need to be treated to prevent one additional bad outcome...
was 4 patients.
Risk factors
Two main risk factors that cause diabetic foot ulcer are Diabetic neuropathyDiabetic neuropathy
Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves in addition to macrovascular conditions that can culminate in diabetic neuropathy...
and micro as well as macro ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
. Diabetic patients often suffer from diabetic neuropathy
Diabetic neuropathy
Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves in addition to macrovascular conditions that can culminate in diabetic neuropathy...
due to several metabolic and neurovascular factors. Type of neuropathy called peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
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
Sores
Sores is a French surname, and may refer to:* Jacques de Sores , French pirate* Raoul II Sores , marshal of France...
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
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
.
Extracellular matrix
Extra cellular matrix (or "ECM") is the external structural framework that cells attach to in multicellular organisms. The dermisDermis
The dermis is a layer of skin between the epidermis and subcutaneous tissues, and is composed of two layers, the papillary and reticular dermis...
lies below the epidermis, and these two layers are collectively known as the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
. Dermal skin is primarily a combination of fibroblasts growing in this matrix. The specific species of ECM of connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...
s often differ chemically, but collagen generally forms the bulk of the structure.
Through the interaction of cell with its extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(transmitted through the anchoring molecules classed as integrins) there forms a continuous association between cell interior, cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
and extracellular matrix components that help drive various cellular events in a regulated fashion. Wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
is a localized event involving the reaction of cells to the damage sustained.
The cells break down damaged ECM
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
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
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
is often considered as a 'conductor of the wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
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
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
of the subtypes I and III.
In the initial events of wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
, collagen III predominates in the granulation tissue which later on in remodeling phase gets replaced by collagen I giving additional tensile strength
Tensile strength
Ultimate tensile strength , often shortened to tensile strength or ultimate strength, is the maximum stress that a material can withstand while being stretched or pulled before necking, which is when the specimen's cross-section starts to significantly contract...
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
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
component is found in high amounts in damaged or growing tissues. It stimulates cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
production by macrophages and thus promotes angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
. In normal skin chondroitin sulfate
Chondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan composed of a chain of alternating sugars . It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities...
proteoglycan
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
is mainly found in the basement membrane
Basement membrane
The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...
but in healing wounds they are up regulated throughout the granulation tissue
Granulation tissue
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals...
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
Perlecan
Perlecan also known as basement membrane-specific heparan sulfate proteoglycan core protein or heparan sulfate proteoglycan 2 , is a protein that in humans is encoded by the HSPG2 gene....
in wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
and angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
. Poor wound healing in diabetes mellitus may be related to perlecan
Perlecan
Perlecan also known as basement membrane-specific heparan sulfate proteoglycan core protein or heparan sulfate proteoglycan 2 , is a protein that in humans is encoded by the HSPG2 gene....
expression. High levels of glucose can decrease perlecan expression in some cells probably through transcriptional and post-transcriptional modification
Post-transcriptional modification
Post-transcriptional modification is a process in cell biology by which, in eukaryotic cells, primary transcript RNA is converted into mature RNA. A notable example is the conversion of precursor messenger RNA into mature messenger RNA , which includes splicing and occurs prior to protein synthesis...
. Wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
phases especially, granulation, re-epithelization and remodeling exhibit controlled turnover of extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
components.
Altered metabolism
Diabetes mellitusDiabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
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
Granulation tissue
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals...
formation. Increased glucose levels in the body end up in uncontrolled covalent bonding of aldose
Aldose
An aldose is a monosaccharide that contains only one aldehyde group per molecule. The chemical formula takes the form Cnn. The simplest possible aldose is the diose glycolaldehyde, which only contains two carbon atoms....
sugars to a protein or lipid without any normal glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
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
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
proteins with slow turnover rate. AGEs alter the properties of matrix proteins such as collagen, vitronectin
Vitronectin
Vitronectin also known as VTN is a protein that in humans is encoded by the VTN gene.The protein encoded by this gene is a member of the pexin family...
, and laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
through AGE-AGE intermolecular covalent bonds or cross-linking. AGE cross-linking on type I collagen and elastin
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...
results in increased stiffness. AGEs are also known to increase synthesis of type III collagen that forms the granulation tissue
Granulation tissue
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals...
. AGEs on laminin result in reduced binding to type IV collagen in the basement membrane, reduced polymer elongation and reduced binding of heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
proteoglycan
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
.
Impaired NO synthesis
Nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
is known as an important stimulator of cell proliferation, maturation and differentiation. Thus, nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
increases fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
proliferation and thereby collagen production in wound healing. Also, L-arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
and nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
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
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
(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
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, which plays a major role in wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
. Thus, diabetic patients exhibit reduced ability to generate nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
from L-arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
. Reasons that have been postulated in the literature include accumulation of nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
inhibitor due to high glucose associated kidney dysfunction and reduced production of nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
due to ketoacidosis
Ketoacidosis
Ketoacidosis is a metabolic state associated with high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids. The two common ketones produced in humans are acetoacetic acid and β-hydroxybutyrate....
observed in diabetic patients and pH dependent nature of nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
.
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
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
, numerous vesicular bodies and lack of microtubular structure in transmission electron microscopy
Transmission electron microscopy
Transmission electron microscopy is a microscopy technique whereby a beam of electrons is transmitted through an ultra thin specimen, interacting with the specimen as it passes through...
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
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
proteins and delayed wound contraction and impaired wound healing.
Increased matrix metalloproteinases (MMP) activity
In order for a wound to heal, extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
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
Tensile strength
Ultimate tensile strength , often shortened to tensile strength or ultimate strength, is the maximum stress that a material can withstand while being stretched or pulled before necking, which is when the specimen's cross-section starts to significantly contract...
. Proteases, namely matrix metalloproteinases are known to degrade almost all the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
components. They are known to be involved in fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
and keratinocyte
Keratinocyte
Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...
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
Transforming growth factor
Transforming growth factor is used to describe two classes of polypeptide growth factors, TGFα and TGFβ....
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
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
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
Granulation tissue
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals...
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.
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 - undergoes to greater compressive and shear loading than usual, thus explaining from a mechanically point of view the onset of tissue damages so deeply correlated to traumatic ulceration processes. Besides this, skin of the Diabetic foot suffers from loss of autonomic control and a consequent reduced hydration, which renders it less elastic and thus more vulnerable to the action of increased mechanical stress;
- effects on tendons and ligaments: protein glycosilation and the consequent collagen abnormalities entail greater transversal section – i.e. thickening - of tendons and ligaments, and, reasonably, greater coefficient of elasticity. Particularly interested 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 represents an obstacle in the performance of physiological range of motion of each and every foot and ankle joint;
- effects on muscles: Diabetes mellitus entails a 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 as for structure (reduction of muscle volume) and function (reduction of muscle strength);
- effects on peripheral sensory system: nerve conduction degeneration 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 does have place 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 surgeonSurgeon
In medicine, a surgeon is a specialist in surgery. Surgery is a broad category of invasive medical treatment that involves the cutting of a body, whether human or animal, for a specific reason such as the removal of diseased tissue or to repair a tear or breakage...
s. Treatment consists of appropriate bandages, antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s (against staphylococcus
Staphylococcus
Staphylococcus is a genus of Gram-positive bacteria. Under the microscope they appear round , and form in grape-like clusters....
, streptococcus
Streptococcus
Streptococcus is a genus of spherical Gram-positive bacteria belonging to the phylum Firmicutes and the lactic acid bacteria group. Cellular division occurs along a single axis in these bacteria, and thus they grow in chains or pairs, hence the name — from Greek στρεπτος streptos, meaning...
and anaerobe strains), debridement
Debridement
Debridement is the medical removal of a patient's dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue...
and arterial revascularisation.
Wound dressings
While there are many types of dressings used to treat diabetic foot ulcers there is little evidence of superiority of one over the other. Hydrogel dressings may have a slight advantage over standard dressings by the quality of the research is of concern. Thus it is recommended that the cost of the product be taken into account.Hyperbaric oxygen
In 2004, The Cochrane review panelCochrane Library
The Cochrane Library is a collection of databases in medicine and other healthcare specialties provided by the Cochrane Collaboration and other organisations. At its core is the collection of Cochrane Reviews, a database of systematic reviews and meta-analyses which summarize and interpret the...
concluded that for people with diabetic foot ulcers, hyperbaric oxygen therapy
Hyperbaric oxygen therapy
Hyperbaric medicine, also known as hyperbaric oxygen therapy , is the medical use of oxygen at a level higher than atmospheric pressure. The equipment required consists of a pressure chamber, which may be of rigid or flexible construction, and a means of delivering 100% oxygen...
reduced the risk of amputation
Amputation
Amputation is the removal of a body extremity by trauma, prolonged constriction, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventative surgery for...
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 vacuumVacuum
In everyday usage, vacuum is a volume of space that is essentially empty of matter, such that its gaseous pressure is much less than atmospheric pressure. The word comes from the Latin term for "empty". A perfect vacuum would be one with no particles in it at all, which is impossible to achieve in...
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
Negative Pressure Wound Therapy
Negative-pressure wound therapy is a therapeutic technique using a vacuum dressing to promote healing in acute or chronic wounds and enhance healing of first and second degree burns. The therapy involves the controlled application of sub-atmospheric pressure to the local wound environment, using a...
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.
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.”
External links
- Diabetic Foot Research Page at the Southern Arizona Limb Salvage Alliance (SALSA); for Professionals and Patients
- Imaging of the Diabetic Foot and Its Complications
- The Diabetic Foot Blog
- Assessing The Potential of Nitric Oxide in the Diabetic Foot