Burn - Wounds
Briefly defined as physical, chemical, thermal, radiation, disruption of tissue integrity due to spontaneous or surgical reasons, it is an event that is closely related to all physicians related to surgery and the health personnel have to treat them frequently. A series of complex events for tissue repair begins with injury. In fact, wound healing is a mechanism with both cellular and extracellular components. The effects and functions of the cells involved in wound healing are regulated by many growth factors and cytokines that function in the field of injury in vivo.
Ideal wound healing can be defined as regaining the normal anatomical, physiological and histological structure of the disintegrated tissue. However, wound healing is not a linear event in which growth factors trigger cell migration and proliferation. On the contrary, it is a dynamic and interactive event involving soluble factors, shaped blood elements, extracellular matrix and parenchymal cells.
In wound healing, there are 4 separate consecutive phases which cannot be clearly separated from each other. The first event following tissue injury is the initiation of both intrinsic and extrinsic coagulation and vasoconstriction as a result of injury to blood vessels and red blood cells as well as other blood cells.
Inflammation occurs as a second step in response to tissue damage and is initiated by histamine, quinines and prostoglandin products. In this phase, however, the dominant cell of the injury site is neutrophils in the early stages. In addition to phagocytosis, neutrophils secrete proinflammatory cytokines that enable the activation of local fibroblasts and keratinocytes. Within a few days, the dominance of neutrophils disappeared, while monocytes migrate from the capillaries to the extravascular space by diapedesis. Collagen fragments, fibronectin, elastin and transforming growth factor - β (TGF - β) are responsible for the chemotaxis and migration of monocytes. Macrophages, one of the most important cells in wound healing, are the primary source of cytokines that initiate fibroblast proliferation, collagen synthesis and other healing processes. These include tumor necrosis factor - α (TNF - α), platellet derived growth factor (PDGF), transforming growth factor - α (TGF - α), Insulin like growth factor (IL - GF) and fibroblast growth factor (FGF).
Mesenchymal cells have important roles in wound healing. In the early period after the injury, the wound matrix is formed by fibrin, clot and small amounts of fibronectin and vitronectin. However, fibroblasts migrate into the matrix with the effect of chemotactic cytokines in surrounding intact tissues. There are numerous chemotactic cytokines for fibroblasts. However, TGF - α and PDGF provide fibroblast chemotaxis and proliferation and differentiation of these cells.
Angiogenesis enables the repair of vascular structures of tissues damaged by injury. Endothelial cell proliferation with budding is mostly caused by cytokines released from macrophages.
Repair of the epidermal layer is necessary to reconstruct the barrier between the internal and external environment deteriorated by injury. For this purpose, epithelization occurs on the wound matrix. Cellular activity during this event can be listed as cellular separation, migration, proliferation and epirdermal cell differentiation. Thickening of the basal cell layer at the wound edge is the first step of reepithelization. The marginal basal cells then elongate, separate from the underlying basement membrane and migrate to the wound, allowing epithelialization. Epithelial cell migration and proliferation are stimulated by TGF - α and epidermal growth factor (EGF), whereas TGF - β provides only cell migration.
In late wound healing, collagen synthesis and destruction can be remodeled on foot while contraction occurs in the wound. The presence of foreign bodies or bacteria at the site of injury at the end of the inflammation period may turn a normal wound healing scenario into chronic inflammation. Similarly, failure of the cells involved in the injury site to respond to cytokines-induced stimuli for any reason, or disruption of these functions of cells that perform autocrine or paracrine stimulation, may prevent complete wound healing and result in chronic wound formation.
Bed wounds, diabetic wounds and venous ulcers are the most important examples of chronic wounds. Such wounds exhibit a very poor wound healing profile despite intensive surgical and medical treatment. It is known that fibroplasia, angiogenesis and reepithelization should occur with migration and proliferation of fibroblasts, endothelial cells and epithelial cells for normal wound healing. Wound contraction with a mechanism different from smooth muscle cells is an important component of healing. Although the mechanism of wound contraction provided by fibroblasts is not fully elucidated, it is thought to originate from specialized fibroblasts - myofibroblasts. However, it seems a rational approach to suggest that keratinocytes, which act as a modulator for the cells involved in wound healing, act as the most important task in wound healing.
Patients with chronic wound problems are generally elderly and in negative catabolic state; The main problems in wound healing in these patients can be summarized as delay in wound contraction, decrease in neovascularization, slowing of epithelialization and proliferation and dysfunction of cells contributing to wound healing.
The number of patients admitted to hospitals due to chronic wound is increasing as a result of prolongation of their survival with the development of medical and surgical approaches. USA. Considering the fact that approximately 5 million people were hospitalized and treated for chronic wounds, it can be predicted how great a material loss is. Inpatient treatment of patients places a great burden on hospitals. In another study conducted in Sweden, foot wounds were found to be a health problem involving 0.2 to 0.3% of the population. Although there is no healthy statistical study in our country, considering that we have more negative health conditions than the countries in question, it can be argued that a significant number of people face such a problem. In addition to the complications that cause delayed wound healing, wounds that develop due to corticosteroid use, radiotherapy, chemotherapy and malnutrition are also included in this group. Nevertheless, no effective treatment has been developed for chronic wounds or delayed wound healing.
The most important cause of bed sores is the degeneration of the subdermal and perforator vessels formed by pressure on the bone protrusions and circulatory disorders in the tissues. However, bed sores are a pathology that occurs only in humans. Although the clinical significance of this problem is clear, the biochemical mechanism of pathological events in the healing of bed sores is not fully understood. Approximately 3 to 4% of hospitalized patients have been reported to develop pressure sores. It is recommended to eliminate the risk factors such as eliminating the pressure on certain areas in the treatment, taking measures that increase tissue perfusion and treatment of primary disease. In surgical treatment of bed sores, wound debridement, appropriate dressing and surgical closure of the wound is recommended. However, the use of cultured keratinocytes to accelerate wound healing has been reported to yield satisfactory results.
The causes of wound healing in venous ulcers have been partially demonstrated, but improvements in treatment are far from satisfying clinicians. The lower extremity is a problematic area for wound healing. Arterial disorders, causes due to hematological diseases and infectious pathogens should also be considered, although the wounds that arise here are usually of venous origin. Deep venous thrombosis is the main pathology in venous ulcers due to subfacial and epifacial venous insufficiency. In its physiopathology, lymphatic insufficiency, microtrombosis, pericapillary fibrosis and microedema and leukocyte dysfunction are accused. However, the clear clinical result is a wound that does not heal in the lower extremity. Compressive bandage, increased venous tone and edema prophylaxis are recommended for treatment. However, in the surgical treatment of these types of wounds, there are fasciatomies, vein dissection and by-pass procedures other than direct wound closure methods such as skin grafting. There are no studies in the literature on interactive wound dressing with cultured keratinocytes. Similarly, the most important approach is the closure of the wound with skin grafts, as well as attempts to correct the actual pathology in arterial wounds. However, in this type of wound, the treatment of the wound with the recommended method-interactive dressing- is not yet included in the literature.
Diabetic wounds are the most important and common examples of chronic wounds. Approximately 25% of diabetic patients have wound complications and 10-15% of them require surgical treatment. Diabetic foot causes prolongation of hospitalization more than other diabetic complications. Chronic and delayed healing of dermal ulcers is one of the most important problems of diabetic patients. Delayed wound healing, inadequate granulation tissue formation and absence of wound contraction by epithelialization seem to be due to cellular dysfunction in fibroblasts and keratinocytes. Oxidative stress is considered to be one of the most important pathogenic factors in diabetic wound complications and is thought to inhibit the survival and replication of cells. Depending on the source, diabetic wounds can be classified as atherosclerotic, peripheral neuropathy and microangiopathy. In diabetic atherosclerosis, the lesion is characterized as a necrotic lesion due to local ischemia located at the sole of the foot and heel or lateral to the foot. Polyneuropathy in diabetes leads to sensory and motor losses and results in paresis and paralysis. With the loss of pain stimulus, disruption of the position and pressure sores may occur and impairment of the innervation of small vessels contributes to local ischemia. Microangiopathy develops as a result of vascular wall damage caused by high glucose level in endothelial cells. All wounds in diabetic patients are highly prone to infection because the immune response in patients is already impaired. Apart from controlling high glycemia in the treatment of this type of wounds, mechanical wound care and, if necessary, debridement are recommended, but there are no publications in the literature about the predicted culture of keratinocyte with interactive wound dressing.
On the other hand, it is vital that the human epidermis be replaced as soon as possible after traumas such as burns, which separate the internal environment of the body from the external environment, create a physical barrier against microorganisms and provide heat balance. In large burns, this is often not possible and requires the use of different methods to cover the patient's wounds. These include allogeneic or xenogenic skin grafts, homografts and synthetic skin equivalents. However, in recent years, increasing the incidence of burn wounds with cultured keratinocyte grafts obtained in the laboratory has been observed as a method that saves the lives of patients. In addition, dermis equivalents obtained in the laboratory environment have an important place in wound closure. It has been used in recent years to provide temporary closure with the silicone layer on the human dermis, which is then replaced with cultured keratinocytes resulting in permanent wound closure.
The application of cultured skin in the closure of burn wounds is achieved by a real graft retention. The cultured skin graft applied here is an average of 4-6 layers of graft obtained in tissue culture laboratories, but in chronic wounds, the application of cultured skin grafts is often unsuccessful in the treatment of such wounds due to the insufficient quality of the graft bed to retain the skin graft. The most important reason here can be summarized as the lack of sufficient blood flow in the bed for graft retention and the active involvement of the cells involved in wound healing. Therefore, it can be summarized as producing small signals used in the treatment of chronic wounds and transmitting this to other cells involved in wound healing. In this sense, it would not be wrong to suggest that cultured keratinocytes are a initiator and promoter of wound healing.
Many agents, such as many growth factors and antioxidants, have been exogenously applied to both normal and pathological wound healing and have been reported to have a beneficial effect on wound healing in the experimental field. These include (-FGF, KGF, TGF (1, PDGF, PDGF-SYMBOL 98 \ f "Symbol" \ s 12 b). Although these studies show that treatment approaches with growth factor have clinical importance, the value of local use is still controversial. In the treatment of chronic wounds, it is of great importance to treat primary stress that causes the cells to respond correctly to the signals, but it seems that the most important mechanism of this approach is to ensure that the cells involved in wound healing respond to the signals in the wound healing.
Cell Technologies in Wound Treatment
Wound healing consists of 3 components that can be influenced mainly.
1. Epithelialization (Keratinocyte)
2. Contraction (Fibroblast)
3. Angiogenesis (Endothelium)
In addition to this cellular organization, numerous cytokines and growth factors have to be taken into consideration. However, the most important perspective in this regard is the need to know the time - dose parameters very well for the effectiveness of these factors. In addition, it is important to note that the microenvironment in which the cells will respond to these factors and their own metabolism and proliferation are of considerable importance.
1. The use of cells in the classical layer (cultured epidermis)
a. Autogenous cultured epidermis
b. Allogeneic cultured epidermis
2. Dermal regenerators
3. Real synthetic leather
4. Normal and genetically modified transient cell treatments
a. Liquid phase
b. Carrier systems
5. Cell products
a. Platelet-rich plasma
b. GPS
6. Culture mediums believed to contain cytokines and growth factors (Experimental)
7. Commercial growth factors
Synthetic leather equivalents (SDE) are another product group that is not included in this classification but can be defined more specifically. Accordingly, SDE is examined in three groups.
a. Epidermis equivalents: These correspond to group 1 in the above classification.
b. Dermis equivalents: Dermal regenerators.
c. Epidermis and dermis equivalents: Can be defined as real synthetic skin.
1. Production of epidermal cells of autogenous or allogeneic origin, known as keratinocytes that are essentially free of other cells, differentiation to form 4-6 layers and their application to the open surface in layers. it also suggests that only keratinocytes can contact the wound and remain there for a certain period of time.
2. In cases where the dermis is lost, this method can be defined as the application of a very thin structure of autogenous or allogeneic skin grafts followed by the formation of a dermal equivalent, sufficient dermal component to the wound surface in order to eliminate the drawbacks of the application of the epidermis only to the wound surface and thus provide adequate dermal support. often applied.
3. It has been shown that wound healing is accelerated or better organized by applying various methods to the wound surface, which are believed to play a key role in wound healing, including keratinocytes and fibroblasts. In this approach, where keratinocytes are mainly used, it has been experimentally shown that genetic modification of cells at the same time makes the results more effective.
4. The use of autogenous blood products has become increasingly popular, given the assumption that wound growth can be accelerated by the application of some growth factors believed to play the most important roles in wound healing. Among these, platelet rich plasma is the most preferred product.
5. It is believed that the collection and application of some autocrine and paracrine-functional cytokines into the wound medium in the cell culture medium of both keratinocytes and fibroblasts will contribute to wound healing, but is only partially experimentally demonstrated.
Diabetic Foot
Many complications affecting diabetic patients are not more destructive than the psychological and economic aspects of extremity gangrene and consequently the risk of major limb amputation. The pathophysiology of diabetic foot ulceration is numerous.
Pathophysiology
In metabolic and biomechanical pathogenesis, hyperglycemia is the most characteristic metabolic feature in Type I and Type II diabetes. Hyperglycemia shows the damaging effect of tissues in the following four ways. These;
a) polyol path; glucose is reduced to sorbitol by the aldose-reductase enzyme. Accumulation of sorbitol in the cell increases the osmotic load and leads to irreversible cell damage.
b) Diacylglycerol-protein kinase c pathway; Protein kinase c is the only enzyme activated in the cell. Activation of this enzyme results in structural changes in the vessel structure and in particular the lumen.
c) Nonenzymatic glycolization; Covalent coupling of aldoses to reactive amino groups results in excessive glycosylation.
d) increased protein catabolism; Negative protein balance adversely affects the healing process.
neuropathy
Peripheral neuropathy, including motor, sensory and autonomic pathways, is the main abnormality that causes plantar ulceration in patients with diabetes. Indonesian edema and slow axoplasmic flow play a role in nerve dysfunction called “diabetic peripheral neuropathy..
Vascular Disease
Peripheral vascular disease may play a role in the continuation of diabetic foot ulceration in some patients, but it is clear that there is no major etiological interest. Many patients with diabetes develop a disease in the tibioperoneal trunk without affecting the pedal circulation. This “pedal protection bir is an important concept and is the reason for excellent results in bypass graft surgery of the ankle or foot dorsum. Adequate arterial flow is the successful closure of wounds in these patients.
the hemorheology
Blood flow in diabetic patients varies due to increases in blood viscosity and abnormalities in erythrocyte deformability. Platelet aggregation, erythrocyte aggregation, and elevated fibrinogen levels are among the various factors that cause high blood viscosity and are well documented in diabetic patients and are the cause of many changes.
Immunology
Both cell-mediated and humoral-mediated types of immune system dysfunction are seen in patients with diabetes. A small fissure formed on the plantar surface of the diabetic foot provides access for bacteria. In these patients, functional deformations of polymorphonuclear neutrophil leukocytes (PMNs) facilitate foot infections.
Biomechanics
Up to 35% of patients with diabetes show significant signs of peripheral neuropathy, and most of them have gait abnormalities. The most serious indicator of this neuropathic condition is the Charcot foot. The most accepted explanation of these degenerative changes is that they are neurotraumatic.
Preoperative evaluation
1.Systemic Evaluation
Most of these patients also have coronary, cerebrovascular, pulmonary and renal diseases. Every effort should be made to systematically optimize the patient's condition before starting surgical reconstruction. Poor glucose control, characterized by elevated serum hemoglobin A1c levels, should be corrected to improve associated hemorrhagic and immunological abnormalities.
2. Radiological Analysis
Flat bone radiographs should be obtained before planning any intervention to the foot. High-resolution 3D imaging techniques can provide much information about abnormal bone anatomy. After film evaluation, most patients undergo nuclear screening, which is misleading and unnecessary. These studies are generally positive at wrist, midfoot and forefoot levels in patients with diabetes without associated foot ulceration. Neuroarthropathy in these patients often results in false-positive screenings.
Regardless of the radiological method used for the diagnosis of osteomyelitis, bone biopsy is essential before long-term IV antibiotic therapy is used.
3. Vascular Evaluation
Vascular studies begin with careful physical examination of atrophic skin changes associated with chronic ischemia and enduring skin disolorization associated with prolonged vascular insufficiency. Palpation of the pedal pulses provides a qualitative assessment of blood flow, but quantitative assessment can be achieved by measurements of ankle-brachial index and Doppler waveforms.
Transcutaneous oxygen pressure measurements are among the reliable methods. Normally TcPO is around 80% of arterial oxygen pressure and is usually above 55 mmHg. Wound healing is impaired when this value falls below 20-30 mmHg.
4. Neurological Evaluation:
Careful medical evaluation of sensory and motor deficits in patients with diabetes should be completed before any reconstructive procedure. If partial sensory loss in the ulcerated area is limited, the surgeon may construct a reconstructive plan that involves the transfer of sensory tissue during soft tissue reconstruction.
Sensory evaluation of the foot is important in neurological examination. The most commonly used method is the evaluation with mes Semmes-Weinstein monofilaments.. If multiple nerve entrapments occur in the tarsal canal region, the Tinel sign is usually obtained by percussion of the posterior tibial nerve in this region. The same applies to the peroneal nerve in the proximal calf (fibula head region).
5. Gait Analysis
Most of the candidates for soft tissue repair have gait abnormalities. Mid-foot and forefoot ulceration occurs during ambulation with more weight being given to these areas and usually shortening of the Achilles tendon. Preoperative evaluation of gait should include measurement of wrist dorsiflexion and computerized gait analysis.
The first step in the assessment of diabetic wound is to determine the depth of the wound. Wagner classification is widely accepted in the evaluation of diabetic wound.
Table 1. Wagner classification
Degree Definition
0. Skin is firm but there are bone deformities that can cause wounds
I. Localized superficial ulcer
II. Deep ulcer reaching up to bone, tendon, ligament, insertion
III. Deep abscess, osteomyelitis
IV. Gangrene of the forefoot or toes
V. Whole standing gangrene
Ischemic ulcers: The most common symptom in diabetics with circulatory disorders is painful and non-healing ulcers that occur within a short period of time. Decreased or absent foot pulses, pallor in the foot, slowing of venous filling after elevation of the foot and hair loss are physical findings. Loss of sensation due to neuropathy may mask pain associated with ischemic disease.
Neuropathic ulcers: Classic “trophic” or “mal-perforance ser ulcers seen in diabetic patients are ulcer on the neuropathic ground. Neuropathic ulcers are characteristic ulcers with thick edges, coarse and coarse skin, less necrotic tissue and more granulation tissue. They are painless and can last for years. There is usually a deformity that causes ulcers.
Treatment
Growth factors are given to the wound as platelet products, bioengineered products (cultured cells or composite skin) or as recombinant growth factors. Another natural source of growth factors is cultured cells and bioengineered tissues. The first cells tested were cultured keratinocytes. They reported that keratinocytes were useful in the treatment of all chronic dermal wounds. The most important criterion for an ideal skin equivalent is the functional and structural similarity expected from an autograft. The products used with immediate and permanent wound closure paste are examined in three main groups. Class I products contain only epidermal equivalents to culture. Class II skin equivalents consist of dermal components containing collagen and other matrix proteins obtained by processing or synthetically producing leather. Class III skin equivalents, on the other hand, contain completely separate dermal and epidermal components and can be called composite skin. Both keratinocytes and fibroblasts produce different cytokines and growth factors. The combination of the two cell types leads to a synergistic increase in the production of growth factor. Recombinant growth factors are another treatment option in the treatment of diabetic foot wounds. Regranex, a recombinant PDGF, has been approved by the FDA for the treatment of chronic diabetic foot wounds.
Surgical Techniques
The surgical plan should ensure stable wound closure using the simplest technique available. Skin graft, local flaps, limited amputations, midfoot amputations, regional flaps, and free tissue transfer procedures should be available to the reconstructive surgeon. In patients with wounds to the anterior aspect of the foot, limited finger or ray or more aggressive transmetatarsal or lisfranc amputation provides the best functional outcome compared to complex microvascular reconstruction.
However, despite the increase in the number of pedicled and free flaps, the characteristics of the patient affect the choice of wound closure.
Recently, the use of vacuum assisted closure techniques has greatly simplified the pressure wound closure procedures (especially in weak patients who are somehow candidates for amputation). It requires free tissue transfer if the wounds are large or unsuitable or safe for local flaps. Recent publications have shown that some patients benefit from combination of lower extremity by-pass or free flap reconstruction. Abnormalities of bone and tendon should be presented beforehand to prevent recurrent ulceration. The reconstructive plastic surgeon should assist with a skilled orthopedist or podiatrist who is interested in diabetic biomechanical abnormalities. Some patients may have to undergo tendon lengthening, tendon transfer, ostectomy, osteotomy, joint fusion or middle foot fusion in order to have an uncomplicated period in the future.
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