1 Introduction

Diabetic patients are prone to develop wounds in the lower limbs. The predisposing factors include neuropathy, which is a common chronic complication of persistent hyperglycemia, affecting the autonomic nervous system render their skin dry, with a loss of the accommodating sweating reflex, furthermore, the sensory loss for touch and minor injuries let them a prey for repetitive injuries without adopting protective measures. The microvascular and macrovascular complications ultimately result in hemodynamics disturbances and peripheral ischemia. Immunological responses are dampened by diabetes, further enhancing the chance for deteriorating and delaying the healing of the wounds.

Wounds are defined as injury in the skin, mucus membranes, or connective tissues resulting in defects in the structure and/or the function of the organs. Skin ulcers are commonly encountered in diabetics, and they are defined as loss of the continuity of the lining epithelium, which is a stratified squamous epithelium of the dry variety, which reveals the raw surface of the underlying tissue. Ulcers cause a breach in the skin by the loss of the protective keratin, keratinocytes, and a defect in the anchoring basement membrane.

The body response and attempt to repair is dictated by the type of tissue inflicted and by local and systemic factors. The capacity of the cell in the different tissue holds different aptitudes to replicate, divide, and differentiate. The cleanest of the wounds, without foreign bodies contamination facilitating the production of biofilms of potential pathogens has the potential to heal utmost compared to dirty and contaminated wound sites. The cultivation of pathogens at the site of the wound in diabetics is augmented and fostered by hyperglycemia, and low immunity. Wound healing is notably slower in the lower limbs compared to the scalp or upper limbs. And the closure of the wound or advised timing of removal of the surgical suture is often delayed in the lower limb wounds, this mostly attributed to density of blood supply per surface area. Personal factors have a profound impact on healing. As healing a pone fide anabolic process, the availability of nutritional components essential for building and restoration influences the tempo and the structure of the healing process. Proteins are the building blocks for repairing the damaged structure of tissue and acts as chemical messengers among other substances, governing and orchestrating the healing process, the influx of inflammatory cells, and the differentiation of stromal, endothelial, and epithelial cells. Vitamin C has a pivotal role in cross-linking of collagen fibers and fostering their tensile strength.

2 Tissue Repair

In the attempt of repair, tissue may undertake tow routes, either healing by regeneration or healing by connective tissue and scar formation. The former route constitutes the complete restitution of the morphology and the function of the injured tissue, and this encompasses a myriad of barrier and secretary functions of the skin. In healing by connective tissue, the gap is filled by the lay down of collagen by fibroblasts and a nonspecialized cell, sealing the gap and resulting in a deranged morphology and function of the skin.

The main factors dictating which repair route execution prevail are:

  1. 1.

    The Capacity of the Indigenous Cells to Divide: Epithelial tissues constituting cells are considered as labile cell, and they are constantly dividing and replicating because they are shed on the surfaces, they are in a constant state of renewal, and stem cells often found in a specific niche are capable of divergent asymmetrical replications yielding two daughter cells, one aimed for further division, replication, and differentiation and the other to preserve the stem cell line. The stem cell reserve loses its merit of replication with the advancing age of the subject due to cumulative oxidative cell membrane, organelles, and DNA damage and telomere shortening. Visceral epithelial cells (Liver) assume a dormant behavior notwithstanding they have the capacity to replicate vividly if they summoned. They stay on the side track of the cell cycle and after stimulation enter the cycle and adopt a rapid dividing profile to renovate missing cells or part of organs in a brief time has been noticed after hepatic live donor lobe donation. On the other hand, permanent cells, are terminally differentiating cells incapable of replication, once lost by the injury they are replaced by scar formation. Injury endured on labile cells in case all the other confounding factors are optimized results in a rapid and cosmetically appealing scar.

  2. 2.

    The Maintenance of the Scaffolding Connective Tissue Frame: This constitutes the blueprint of the tissue and forms the track through which the new cells can pave and arrange to replace missing or injured cells. Without these blueprints, there is no trace of the repair system to follow, and this results in haphazard attempts, culminating in healing by collagen deposition and scar formation.

  3. 3.

    The Resolution of Inflammation at the Site of Injury: Mikhail Bakunin once said “The urge to destroy is also a creative urge.” Repetitive injuries create a milieu of chronic inflammation. By definition chronic inflammation constitutes three processes going simultaneously hand-by-hand; inflammation, tissue injury and loss, and a unremitting attempts of repair. The halt of this vicious cycle compels cessation of the injurious process and its resultant inflammatory process.

3 Extracellular Matrix

These are structural proteins or proteins complexed with carbohydrates.

They maintain the tensile strength of the tissues, which is mainly attained by collagen, which is imposed by cross-linking of collagen fibers resulting in bundles arranged and aligned toward lines of stress. They give the elasticity of the tissues, which is mainly mediated by elastin. Glycoproteins and mucopolysaccharides can hold water in their cervices and provide the turgor of our organs and tissues. Many growth factors are quenched within their matrices and released after tissue injury to exert their actions. Basement membrane is composed of organized fibrillar collagen anchoring the surface epithelium on one side and attached to subepithelial connective tissue framework on the other side, it provides the sense of polarity to the surface epithelium cells and prevents anoikis, a type of programmed cell death occurring upon detachment of the epithelial cell from its basement membrane. Fibronectin, which acts as an adhesive protein anchoring other structural proteins and quenching growth factors.

4 Cytokines [1]

The cross-talk between the cells in our body is mediated by chemical compounds. These substances mediate and orchestrate highly complexed and tightly controlled processes including housekeeping, tissue maintenance, and repair. Cytokines, growth factors, and mediators ordinarily have hierarchical properties; in which one factor can activate many downstream factors. They are also promiscuous in a sense that many factors can activate or culminate in activating a singular downstream effectors or pathways. Many cytokines are promiscuous, in regard they can stimulate many effectors, and they are not faithful for one downstream effector. The cytokines are either secreted in a steady level and their actions determined by tipping of the scale between pro and anti-mediators, or they been secreted only on demand and disappear after achieving their purpose. Cytokines are labile chemical compounds with a finite lifespan, and their secretion start by their release from ready-made stored vesicles with a brief and limited storage, and a subsequent induced prompt synthesis and secretion with a potentially prolonged action.

The action of cytokines can be exerted by four means:

  1. (a)

    A paracrine mode of action when the cell secretes the chemical mediator, which exert its function in neighboring cells in its vicinity.

  2. (b)

    Autocrine stimulation when cell secretes the chemical substance that is released one it is surface to bound to a surface receptor, culminating in a self-stimulation loop.

  3. (c)

    An endocrine method in which an endocrine gland or cell secretes a chemical mediator to the bloodstream to circulate and activate distant cells, tissues, or organs.

  4. (d)

    Lastly, some neurotransmitters are secreted through synapses to activate postsynaptic cell.

The first three aforementioned modes of stimulation act in a cascade fashion with downstream amplification and feedback mechanism, the latter, synaptic stimulation often fades and weakens with increased distance.

Cytokines and chemical mediators are classified as cell derived or plasma (liver) derived.

Plasma-derived mediators are synthesized mainly in the liver and secreted and circulate in the plasma as inactive precursors forms, which upon activation enter a cascade loop of activation and amplification. Complement component system and Hageman factor system are examples of liver-derived mediators having intricate relations with the coagulation system and with other loops of amplifications and control proteins. Cell-derived mediators are secreted from inflammatory cells in areas of injury and from quenched reserve within the connective tissue matrix. The ultimate goal of these factors is the fine-tuning of the healing process, otherwise unchecked trophic stimuli might get strayed and result in suboptimal healing or emergence of neoplastic growth.

5 Healing by Regeneration [2]

It signifies the complete restitution of the original structure and function of the injured tissue with minimum or no scarring. The healing process must endure optimal conditions to secure this option; local factors must be permissible including small wound with approximated clean edges, noninfected wound, and the absence of detritus tissue or foreign bodies. The scaffolding connective tissue framework must be maintained, as the loss of the blueprint yield chaotic infidel restoration. Cell or tissue factors also can influence this option by the regenerative capacity of the injured cells; as labile tissues fare better than stable and permanent cells. Systemic factors also influence this option, including the well-being of the patient, the control of his diabetes, and nutritional status. The healing attempt under these conditions referred by clinicians as the first intension. Optimal conditions may present de novo in the wound or optimized after medical intervention.

6 Repair with Scar Formation

This type of healing often referred to as second intention healing, and it results in a prolonged healing process, weak scar, and ugly scar (Fig. 4.1). All the aforementioned optimal conditions are not met in this case, or further appropriate interventions were not applied. Local factors controlling wound healing are many, one of the most important factors is the extend of the injury or tissue loss, considering the remaining of scaffolding structure of the tissue made by the basement membrane and tissue framework.

Fig. 4.1
figure 1

Healing by regeneration, the first and the second intention

Full size image

7 Predisposing Factors for Injuries in Diabetics (Fig. 4.2)

Glucose as a fuel providing molecules is often abundant, due to the relative insulin lacking or resistance, its surplus becomes a bacterial growth-enhancing factor rather than a tissue source of energy. The evidence supporting this notion is not conclusive yet and further researches in this matter are warranted, but some researchers found an increased incidence of surgical wound infection related to hyperglycemia [3, 4]. As the majority of diabetics presenting with DSF complications are elderly, and often share a myriad of diabetic associated macrovascular and microvascular complications, many confounding factors attribute to the slackening of the healing including cell senescence of fibroblasts and the limited capacity of epithelial cells to cover tissue defects. Diabetic patients often have reduced immunity toward infections. Such infections may cause death in about 5% of diabetics. The pathogenesis beyond this is attributed to the reduced chemotactic, phagocytic, and secretory function of inflammatory cells. Macrovascular and microvascular complications also adversely affect small blood vessels, and capillary culminating in less optimal inflammatory vascular events, vasodilatation, and enhanced permeability. Diabetic retinopathy and cataract affect visual fields and acuity. This may result in repeated and inadvertent traumatic pumping of the lower limbs in furniture within the household. Diabetic patients with DSF may show comorbidities of the cardiovascular and renal system resulting in reflective hemodynamic changes in the systemic and local circulation, and a buildup of toxic levels of metabolites adversely affecting hematopoiesis and the immune system. The loss of sensory feedback imposes the lower limb to repeated trauma, and subsequent gradual injuries and tear of ligaments culminating in subluxation of small joints, malposition of bones, and loss of the normal arches of the feet. This might result in repeated frictions and pressure ischemia of soft tissue due to unfitting shoes. These deformities lead to a condition known as Charcot joint and compel a special attention by chiropodist or at least a caring household personnel. Diabetic autonomic nervous system dysfunction may cause loss of the skin turgor, with shiny brittle dermis, loss of skin adnexa, and dryness due to lack of sweating.

Fig. 4.2
figure 2

Factors predisposing to foot injury in diabetics

Full size image

8 Phases of Wound Healing [5]

  1. 1.

    Inflammation Phase: This is the response of vascularized living tissue to injury and trauma. Ischemic limb may show minimal inflammatory response and necrotic gangrenous tissue only show inflammation at the interface with viable tissue margins. The attempt of the inflammation is to remove and debride the injured areas form offending agents and to scavenge dead cells. The main effectors of inflammation are to display a cellular response with an influx of a myriad of inflammatory cells through the blood vessel portal, which also facilitates edema formation.

  2. 2.

    Proliferative Phase: and This Is Comprised:

    1. (a)

      Angiogenesis: In acute inflammation, the vascular response comprises dilatation and hyperemia at the arterial end and increased permeability at the venular end of the vascular bed. In persistent and chronic inflammation, the continuous injury, inflammation, and attempt to repair go hand-by-hand simultaneously. This necessitates the formation and sprouting of new blood vessels to provide fuel and nutrients and building blocks for the repair process (Fig. 4.3).

      The process of angiogenesis in diabetics is dampened and not optimal, due to microvascular and microvacuolar complications usually encountered in long-standing diabetes and metabolic syndrome. After the injury, the defect of lost or crushed tissue will be filled by inflammatory cells and protein-rich exudation. Proteins dry on the surface and form a scab, which is a coagulated serum on the surface of the wound, and usually overlies a raw granular oozy surface. If the injured epidermis is overlined by a necrotic layer of tissue, an eschar is formed, which can be pearly white and pale in case of ischemia necrosis, or black/black brown in case of vascularized tissue. Circumferential eschar can some time act as napkin-ring or as a plaster which can induce compartment syndrome and impede blood flow to the distal part of the limb, causing Volkmann contracture or necrosis; escharotomy may resolve this issue [6].

    2. (b)

      Collagen Formation: As the wound mature granulation tissue is formed, which is composed of immature leaky blood vessels within edematous stroma rich in proteins and newly formed extracellular matrix with a plethora of inflammatory cells.

    3. (c)

      Epithelization: Epithelial cells from the base of the epidermis of flanking skin edges start to form a monolayer from the edges to cover the gap, and as they reach the mid-line and seal the gap they activate a contact inhibition program, a merit of normal non-neoplastic cells, they stop dividing and start a vertical maturation step. This is mediated by the APC β-catenin pathway, in which β-catenin is located in sub-membranous location associated with E-cadherin, a transmembrane protein which functions as an adhesive structure linked in homodimer fashion with adjacent cell proteins. Some times in case of repetitive trauma an exuberant granulation tissue is formed protruding as a hill above the horizontal level of the wound plane, which impedes the union of the epithelial cells coming from the edges of the wound, the term proud flesh is applied to this condition, mimicking the lordotic posture of a proud person. In this case, the epithelial cell should climb up the protuberance of the granulation tissue to meat at the summit.

  3. 3.

    Maturation Phase: This is a continuous process. The color of the scar fades from cherry red to pale pink to white as it matures and ages with a more organized matrix and more mature blood vessel surrounded by a dual layer of endothelial and pericyte.

Fig. 4.3
figure 3

Angiogenesis is a step of paramount importance in healing

Full size image

9 Timing Sequences of Skin Wound Healing

  1. 1.

    Blood clot (scab): its purpose is to stanch the bleeding and provides a matrix rich in growth factors and chemokines. It is formed within 24 h, and neutrophils are noticed crouching from the margins.

  2. 2.

    Granulation tissue: starts to develop 1–2 days (peaking at 5–7 days), and is composed of proliferating fibroblasts and endothelium (vascularized loose CT). The vessels are leaky leading to extravasation of proteins and fluids and creating edema. It provides a framework for subsequent scar formation and continues remodeling.

  3. 3.

    Cell proliferation and collagen deposition: primes within 2–4 days after wounding, and neutrophils are largely replaced by macrophages. The granulation tissue scaffolding is converted into a scar (fibroblasts and collagen).

  4. 4.

    Scar formation: starts 2 weeks with sequential collagen deposition and gradual fading of the vasculature. The red granulation tissue is converted into a relatively avascular scar with a reduction of the inflammatory cells and marching of the epithelial cells to seal the gap.

  5. 5.

    Wound contraction: of larger wounds, proceed with the dominance of myofibroblasts having combined features of fibroblasts with laying downing of collagen, and smooth muscle contractile features causing wound contracture culminating in reduction the surface of the wound.

  6. 6.

    Tensile strength: within 1 week is 10% of the initial strength of the healthy tissue, and increases gradually with advanced bundling and alignment of the collagen fibers towards the line of stress reaching about 70–80% of the initial strength within 3–4 months.

10 Complications of Wounds in Diabetics

  1. 1.

    Venous leg ulcers (congested): occur in elderly people with chronic venous hypertension (severe varicose veins or congestive heart failure). It fails to heal because of the poor delivery of oxygen to the site of the ulcer.

  2. 2.

    Arterial ulcers (pale): atherosclerosis, Ischemia → atrophy, and necrosis of the skin and underlying tissues (painful).

  3. 3.

    Neurotrophic ulcers: found at sites under mechanical pressure, and characteristically appear as friable punched out ulcers surrounded with dry scaly skin [7].

  4. 4.

    Pressure sores (Decubitus ulcer): mechanical pressure and local ischemia pose a dramatic impact in wound healing; this leads to a vicious circle of partial healing and repeated injuries. Protection and guarding against it is more attenable than healing.

  5. 5.

    Atrophic scar this leads to a very scant and weak connective tissue lay down, rendering the injured tissue a prey for repeated trauma and dehiscence, which can be brought upon by trivial trauma.

  6. 6.

    Hypertrophic scar: this results from excessive scar tissue confined to the edges of the wound. Adversely this may cause ugly big protruding scar and contracture of the skin.

  7. 7.

    Keloid formation: this occurs with racial predisposition noticed in black ethnicity. The healing is characterized by exuberant scar formation which is not confined to the edges of the wound.

  8. 8.

    Wound contracture occurs if a large area of fibrotic tissue is crossing a joint, this might restrict the full range of joint movement. This is usually anticipated if the wound left to heal under low tension on the relaxed flexed position of the joint.

11 Factors Influencing Wound Healing [8]

  1. 1.

    Site of the wound, it is noticeable that skin injuries in head and neck heals faster than torso, abdomen, and lower limb injury in a descendant order. This is credited to the density of blood supply per surface area in the corresponding tissues.

  2. 2.

    Type of the tissue: determine the outcome of the healing process. Labile continuously dividing cells are capable of continuous division and can replace the lost and injured tissues as long as other confounding factors are controlled. Stable tissues have a lesser potential for division. On the other hand, permanent cells or tissue are incapable of division, and cell death is only replaced by fibrosis.

  3. 3.

    Amount of lost tissue: small superficial tissue with minimal loss of cells has the potential to heal optimally compared to big wounds with large gaps. With a proper surgical intervention, healing can be augmented.

  4. 4.

    General condition of the patient: the presence comorbidities, such as critical atherosclerosis, ischemic heart disease, and heart failure among others, which are frequently encountered in long-lasting and poorly controlled diabetes may adversely interfere or delay healing.

  5. 5.

    Nutritional status: well-fed subjects replenished with nutrients, essential minerals and vitamin fare better than starved or deficient subjects. Vitamin D is required for the optimization of almost all steps of cutaneous wound healing [9], nonetheless, vitamin C is also required for the cross-linking of collagen bundles the building blocks of scar tissue. Diabetic patients often are deficient in micronutrient and this may interfere with proper wound healing process [10].

  6. 6.

    Steroid use retards the process of wound healing, the administration of dexamethasone in postoperatively increase morbidity and delay wound healing [11]. Glucocorticoids slow the healing and dampen the strength and the abundance of collagen fibers. Researchers found the excess glucocorticoids in patients with Cushing syndrome reduces the level of heat shock proteins in wounds, this results in a consequent reduction in angiogenesis and resultant delayed healing [12].

  7. 7.

    Direction of the wound: if injuries run parallel to the Langer lines, they heal with an esthetically minimal scar compared with injuries running perpendicular to these lines.

  8. 8.

    Age: wounds in young individuals or patients with short-lasting diabetes, characteristically have a good and prompt wound healing compared with elderly, long-lasting diabetes, and poorly controlled diabetes [13]. Some researchers argue that the healing in elderlies is merely delayed but the end results are almost the same [14]. There are both undisputable evidence supporting that skin of the geriatric population has both morphological features of skin atrophy and reduction of physiological qualities with advanced aging [15].

  9. 9.

    Racial factor also may influence the healing of wounds, as an example, patients with the black ethnic background may have a higher tendency to develop keloids, exuberant scar tissue often exceeds the limit of the wound lead to disfiguring ugly scars [16].

  10. 10.

    Infection: can adversely sluggish wound healing as clean wound fares better than, contaminated, dirty, and infected wounds.

  11. 11.

    Foreign body: debridement of wounds and removal of contaminants and foreign bodies foster the speed of wound healing.

  12. 12.

    Genetics: polymorphism in genes controlling inflammatory response have a slightly deranged healing process. Mutations of structural proteins present with the noticeably delayed healing process.

12 Muscle, Tendon and Bone Healing

  1. 1.

    Skeletal muscular tissues are incapable of dividing and is usually replaced by connective tissues. If severe infection spread and induce a systemic inflammatory response syndrome, skeletal muscles (not necessary at the site of injury) may undergo a waxy coagulative necrosis pattern known as Zenker’s degeneration.

  2. 2.

    Tendons have a capacity of healing and should be optimally kept under tension to reduce contracture and restriction of joint movement.

  3. 3.

    Bone has a virtuous capacity to heal, and if infected this capacity is noticeably hindered. Treatment of infection and removal of dead sequestrum hasten healing, on the other hand, the persistence of infection with resurging draining sinuses may be almost sturdy to healing. Diabetic patients may suffer from stubborn bone injuries and delayed union of bone fragments, there are noticeable reduced osteoblastic activity and increased apoptosis especially with accompanied infections. The growth factors controlling the healing process are scarce in the milieu of diabetic ulcers including bone morphogenetic protein and tumor necrosis factor (BMP, TNF) [17, 18].

13 Gangrene

Diabetic patient develops as a consequence of progressive macroangiopathy and microangiopathy a broad spectrum of potential complications. Gangrene is an atrocious known concern of poorly controlled diabetics. It is a consequence of vascular, neural, and immunological dysfunctions often encountered in diabetic patients. The term originates from the Latin root gangraena, which literally means “an eating or gnawing sore.” This a special type of cell death is due to peripheral ischemia owed to vascular comprise [7].

  1. 1.

    Dry gangrene is a type of gangrene characterized by changes in skin color from shades of redness and blackness with a subsequent tissue breakdown and putrefaction of protein contents resulting in a foul odor [19]. Inflammation only occurs at the margin of the living tissue, manifesting the cardinal signs of inflammation; redness, swelling, hotness, pain (which may be dampened as a result of peripheral neuropathy), and loss of function. Systemic manifestations develop as a response of the body to injury manifesting as fever, anorexia, nausea, and fatigue. Dead tissue falls off spontaneously, with unnoticeable minor trauma, or by surgical debridement [20]. There are no signs of infections at the site of the injury.

  2. 2.

    Wet gangrene ensues with secondary bacterial infections, noticeable with pockets of pus and weeping wounds. This poses a more serious impact on the health of the subject and warrants an urgent surgical and medical intervention. Septicemia and septic shock are a frightful complication.

  3. 3.

    Gas gangrene on the other hand results from infection with Clostridium perfringens, a gram-positive spore-forming bacilli, with a resultant myonecrosis, the spread of infection through tissue plains and liberation of toxins into the bloodstream. Grossly the wound is crepitus upon palpation and shows bubbles and air-filled bullae.

14 Classification of Diabetic Wounds [21]

Classification systems help to triage patients for suitable clinical care and follow-up. A score also services as a fast-universal way to describe the wound, and alarms for deterioration or assures in case of improvement.

There are multiple widely used classification systems for diabetic wounds, nevertheless, the widely used systems in clinical practice are Wagner (Fig. 4.4) and of the University of Texas systems.

  1. 1.

    Wagner system: in this system, there are 5 grades, grade-0 indicates an intact skin in a diabetic patient, grade-1 signifies the presence of a superficial wound involving the epidermis, dermis, or down to the subcutaneous tissues, grade-2 designates deep extension of the wound to the tendons, underlying bone or a joint capsule, grade-3 indicates grade-2 lesions with a superimposed infection of the bone or a localized suppurative inflammation, while grade-4 and 5 reserved for partial or extensive gangrene of the foot [22].

  2. 2.

    University of Texas system: is a combined system in which stages and grades the wound. Grading of the wound starts with grad-0 for intact skin or a healed remote wound in diabetic patients, grade-1 indicates a superficial cutaneous wound, grade-2 describes a deep wound affecting muscle, tendons, or a joint capsule, grade-3 denotes an extensive wound penetrating the underlying bone or reaching a joint cavity. The staging system of wounds classifies them according to ischemia and infection as follows; stage-A for clean wounds, stage-B for infected wound without peripheral ischemia, stage-C for ischemic clean noninfected wound, and stage-D for infected wounds with ischemia [22].

Fig. 4.4
figure 4

Wagner classification of diabetic wounds, 0 = intact skin, 1 = epidermal, dermal and subcutaneous tissues, 2 = extension to tendons, muscle, capsule, and bone, 3 = 2+ infection (abscess or osteomyelitis), 4 = partial gangrene, 5 = extensive gangrene

Full size image