1. INTRODUCTION:

Wound healing is an important but complicated process containing a multifaceted process. It is a complex and dynamic biological process involving a cascade of tissue interactions to restore of skin integrity and homeostasis after injury [1]. They can be continued for various periods of time depends on the extent of wounding and the process can be broadly categorized into three stages; inflammatory phase, proliferate phase, and finally the remodeling phase which ultimately determines the strength and appearance of the healed tissue [2,3] This process has two main roles, namely fight against infection and repair of tissue [4]. Healing involves various soluble mediators (including cytokines and growth factors), cell types (such as inflammatory, endothelial, blood, epithelial, and immune), and interactions with the extracellular matrix. It is typically divided into four main temporally and spatially overlapping stages: the hemostasis phase, inflammatory phase, the epithelial and proliferative phase, and the tissue remodeling phase [5,6]. Medicinal plants have been shown to possess wound healing activity in animal studies [7,8] In normally healing wounds, reactive oxygen species (ROS) are produced and act as cellular messengers to stimulating key processes associated to wound healing, including cell motility, cytokine action (including platelet-derived growth factor (PDGF) signal transduction), and angiogenesis. Several factors are responsible for impaired wound healing, such as nutrition, infection, age, gender, and oxygenation. In fact, injured tissues affect the healing process by increasing the formation of reactive oxygen products and reducing various enzymatic and non-enzymatic free radical scavengers. However, the ROS excess transcends the beneficial effect and causes additional tissue damage [9]. Antioxidant mechanisms (e.g. catalase and glutathione peroxidase (GPx)) protect cells from ROS induced damage. Nevertheless, if this balance is disrupted (because of various reasons), the tissue undergoes oxidative stress, which can cause damage to a wide range of molecular species, including lipids, proteins and nucleic acids [10]. Oxidative stress can also induce cytotoxicity and delay wound healing [11]. Several strategies, including dietary supplements, have been used to inhibit and prevent oxidative stress. In this respect, various medicinal herbs and plants have been reported to offer promising bio-sources of antioxidant molecules for use against oxidative stress. Indeed, The herbal medicines Moringa oleifera and Aloe Vera have been used to enhance wound repair. To recover from wound healing within the shortest time period with minimal pain, discomfort and scarring to the patient it is important to explore nutritional and herbal influences on wound outcome., have recently been granted a generally recognized as safe status by the World Health Organization and incorporated in several pharmaceutical products and formulations. Disruption of the integrity of skin, mucosal surfaces or organ tissue results in the formation of a wound. Wounds can occur as part of a disease process or have an accidental or intentional aetiology. [12] At the time of insult, multiple cellular and extracellular pathways are activated, in a tightly regulated and coordinated fashion, with the aim of restoring tissue integrity. Classically, this process of wound healing is divided into four distinct phases: hemostasis, inflammation, proliferation and tissue remodeling. Given the intricate nature of the healing cascade, it is remarkable how often it occurs without complication. Many factors can interfere with this process, resulting in delayed wound healing, increased patient morbidity, and mortality and poor cosmetic outcome. The health economic effects of chronic wounds and the psychological sequelae for the patients are often understated as they are difficult to quantify completely.[12]

2. THE PATHOGENESIS OF EXCESSIVE WOUND HEALING:

Excessive wound healing is caused by skin injury, which includes trauma, inset bite, burns, surgery, vaccinations, skin piercing, acne, and infections. Free radicals and other oxygen derived species are constantly generated in vivo, both by accidents of chemistry and for specific metabolic purposes. The reactivity of different free radical varies, but some can cause severe damage to biological molecules especially to DNA, lipids and proteins. [13] After an injury to skin, the inflammatory process begins to initiate wound healing. Although the pathogenesis of excessive wound healing is not fully elucidated, clinical experience suggests that excessive wound healing is an aberrant form of wound healing, which may occur as a result of dysregulation in one of the three phases of wound healing, and is characterized by continuously localized inflammation [14,15] Excessive wound healing often involves an exaggerated function of fibroblasts and excess accumulation of ECM during wound healing. [16] Two forms of excessive wound healing are reported, including keloid and hypertrophic scar. Dr. Ogawa defined “keloid” as strongly inflamed pathological process, and “hypertrophic scar” is a much more weakly inflamed pathological process, because both can be considered as successive stages of the same fibroproliferative skin disorders, with differing degrees of inflammation that might be affected by genetic predisposition (also shown below in Section 5 the epidemiology of excessive scarring). [17,18] All excessive wound healings include initial purulent inflammatory process, upregulated fibroblast function, and excessive ECM deposition.[19] Hypertrophic scar does not overgrowing over the original wound boundaries and generally fades as well as flattens to the surrounding skin level, although it may be raised above the normal skin level, and contracture or more raised or larger than normal wound healing might occur. Hypertrophic scar is often self-limited and sometimes can regress with time. The histological features of keloid are whorls and nodules of thick, hyalinized collagen bundles, known as keloidal collagen, and tongue-like projections of scar tissue that advance underneath the surrounding normal epidermis. Representing an abnormally vigorous scarring formation extending beyond the edges of the original wound, and causing symptoms of pruritus and hyperesthesia, keloid scar is often more of a cosmetic concern than a health on. Keloid scar does not regress and tends to recur after excision. Keloid scar contains disorganized type I collagen and type III collagen. Hypertrophic scar consists of mainly type III collagen arranged parallel with skin surface. [16] Elastic content was significantly different between normal and abnormal wound healings. [19] Keloid scars contain more elastin content in deep dermal layer than hypertrophic scar and normal skinIn the superficial dermis, elastin content was 51% and 37% higher in normal skin compared to hypertrophic scars or keloids Moreover, the significant decrease of fibrilin-1 is also noted throughout the dermis in both scar types, indicating the distortion of the composition of microfibrils.[17] Excessive collagen synthesis and abnormal collagen turnover, caused by dysregulation of matrix degrading enzymes contributes to excessive wound healing.[20,21] Tissue inhibitors of metalloproteinases (TIMPs) can inhibit MMPs by either binding to the zinc-binding domain of active MMPs or by binding to the inactive proMMP zymogen, thereby slowing the process of activation.[21] The MMP and TIMP proteins work in combination to regulate the synthesis and degradation of ECM at wound sites, and an imbalance of MMP and TIMP results in abnormal wound healing. These factors, including TGF-b and PG will be reviewed in the in vitro and in vivo models subsequently.

3. ETIOLOGICAL FACTORS CAUSING WOUND

4. CLASSIFICATION OF WOUNDS:

These are the classified into open wounds and closed wounds on the essential cause of wound creation and acute wounds and chronic wounds on the basis of the physiology of wound healing.

4.1. Open wounds:

In this case, blood escapes the body and bleeding is clearly visible. It is further classified as an Incised wound, Laceration or tear wound, Abrasions or superficial wounds, Puncture wounds, Penetration wounds and gunshot wounds [22]

4.2. Closed Wounds:

In closed wounds, blood escapes the circulatory system but remains in the body. It includes Contusion or bruises, hematomas or blood tumor, Crush injury etc.

4.3. Acute Wounds:

An acute wound is a tissue damage that usually precedes via a systematic and sensible reparative process that result in sustained restoration of anatomic and functional reliability. Acute wounds are generally caused by cuts or surgical incisions and complete the wound healing process within the expected time frame [23]

4.4. Chronic Wounds:

Chronic wounds are wounds that have include failed to progress via the normal stages of healing and hence go into a condition of pathologic inflammation chronic wounds either require a extended time to heal or recur frequently. Local infection, hypoxia, trauma, foreign bodies and systemic problems like such as diabetes mellitus, malnutrition, immunodeficiency or medications are the most frequent causes of chronic wounds. [24,25]

HEMOSTASIS:

At the time of surgical incision, vascular injury occurs on a macro- or microvascular scale. The immediate response of the body is to prevent exsanguinations and promote hemostasis. Damaged arterial vessels rapidly constrict through the contraction of smooth muscle in the circular layer of the vessel wall, mediated by increasing cytoplasmic calcium levels. [26] Vessels up to a diameter of 5mm can be completely closed through a contraction, although this can only occur if the injury is in a transverse plane. Within a few minutes, the reduced blood flow mediated by arteriole constriction leads to tissue hypoxia and acidosis. This promotes the production of nitric oxide, adenosine, and other vasoactive metabolites to cause a reflex vasodilatation and relaxation of the arterial vessels. Simultaneously, histamine release from mast cells also acts to increase vasodilatation and increase vascular permeability, facilitating the entry of inflammatory cells into the extracellular space around the wound. This explains the characteristic warm, red, swollen appearance of early wounds. Further blood loss at this stage is also prevented through the formation of a clot which is achieved through three key mechanisms:

1 Intrinsic pathway of the clotting cascade (contact activation pathway) e Endothelial damage as a result of tissue injury exposes the sub-endothelial tissues to blood which results in the activation of factor XII (Hageman factor). This initiates the proteolytic cleavage cascade which results in the activation of factor X which converts prothrombin to thrombin resulting in the conversion of fibrinogen to fibrin and the formation of a fibrin plug.

2 Extrinsic pathway of the clotting cascade (tissue factor pathway) e Endothelial damage results in exposure of tissue factor (which is present in most cells) to circulating blood. This results in activation of factor VII and the rest of the extrinsic pathway of the clotting cascade which eventually results in thrombin activation.

3 Platelet activation - Following activation by thrombin, thromboxane or ADP, platelets undergo a change in morphology and secrete the contents of their alpha and dense granules. [27] Activated platelets adhere and clump at sites of exposed collagen to form a platelet plug and temporarily arrest bleeding. This plug is strengthened by fibrin and von Will brand factor as well as the actin and myosin filaments within the platelets.

Platelets are unnucleated fragments of bone marrow megakaryocytes. They have a crucial role in wound healing process. They not only are essential for clot formation, they also produce multiple growth factors and cytokines which continue to control the healing cascade. In excess of 300 signaling molecules have been isolated from activated platelets, which influence and modulate the function of other platelets, leukocytes, and endothelial cells. [28] The main actions of platelet-derived molecules are listed in Table 1. In addition to these factors, in response to the injured cell membranes caused by the wounding stimulus, arachidonic acid is broken down into a number of potent signaling molecules such as the prostaglandins, leukotrienes, and thromboxanes which have roles in stimulating the inflammatory response.

INFLAMMATION:

The key aim of this stage of wound healing is to prevent infection. Regardless of the aetiology of the wound, the mechanical barrier which was the frontline against invading microorganisms is no longer intact. Neutrophils, the ‘first responders’, are highly motile cells which infiltrate the wound within an hour of the insult and migrate in sustained levels for the first 48hours. This is mediated through various chemical signalling mechanisms, including the complement cascade, interleukin activation and TGF-B signalling, which leads to neutrophils passing down a chemical gradient towards the wound, a process termed chemotaxis. [29] Neutrophils have three main mechanisms for destroying debris and bacteria. Firstly they can directly ingest and destroy foreign particles, a process termed phagocytosis. Secondly, neutrophils can degranulate and release a variety of toxic substances (lactoferrin, proteases, neutrophil elastase and cathepsin) which will destroy bacteria as well as dead host tissue. Recent evidence has shown that neutrophils can also produce chromatin and protease ‘traps’ which capture and kill bacteria in the extracellular space. Oxygen free radicals are produced as a by-product of neutrophil activity, which are known to have bactericidal properties but can also combine with chlorine to sterilize the wound. When the neutrophils have completed their task, they either undergo apoptosis, are sloughed from the wound surface or are phagocytosed by macrophages. Macrophages are much larger phagocytic cells that reach peak concentration in a wound at 48e72 hours after injury. They are attracted to the wound by the chemical messengers released from platelets and damaged cells and are able to survive in the more acidic wound environment present at this stage. [30] Macrophages harbour a large reservoir of growth factors, such as TGF-b and EGF, which are important in regulating the inflammatory response, stimulating angiogenesis and enhancing the formation of granulation tissue. Lymphocytes appear in the wound after 72 hours and are thought to be important in regulating wound healing, through the production of an extracellular matrix scaffold and collagen remodelling. Experimental studies have shown that inhibition of T-lymphocytes results in decreased wound strength and impaired collagen deposition. [31] A summary of the cells involved in inflammation is shown in Table 2. The inflammatory phase of wound healing will persist as long as there is a need for it, ensuring that all excessive bacteria and debris from the wound is cleared. Protracted inflammation can lead, however, to extensive tissue damage, delayed proliferation and result in the formation of a chronic wound. Multiple factors, including lipoxins and the products of arachidonic acid metabolism, are thought to have anti-inflammatory properties, which dampen the immune response and allow the next phase of wound healing to arise

Cells involved in wound healing:

Cell type

Time of action

Function

Platelets

Seconds

Thrombus formation

Activation of coagulation cascade

Release inflammatory mediators

(PDGF, TGF-b, FGF, EGF, histamine,

serotonin, bradykinin,

prostaglandins, thromboxane.

Neutrophils

Peak at

24 hours

Phagocytosis of bacteria

Wound debridement

Release of proteolytic enzymes

Generation of oxygen free radicals

Increase vascular permeability

Keratinocytes

8 hours

Release of inflammatory mediators

Stimulate neighbouring

keratinocytes to migrate

Neovascularization

Lymphocytes

72-120 hours

Regulates proliferative phase of

wound healing although exact

mechanisms are unclear

Collagen deposition

Fibroblasts

120 hours

Synthesis of granulation tissue

Collagen synthesis

Produce components of

extracellular matrix

Release of proteases

Release of inflammatory mediators

PROLIFERATION:

The proliferative phase essentially involves the generation of the repair materials and majority of the skeletal muscle injuries. [32] Once the injuring stimulus has ceased, haemostasis has been achieved, the inflammatory response is balanced and the wound is debris free, the proliferative stage of the healing cascade can begin to repair the defect. This complex process incorporates angiogenesis, the formation of granulation tissue, collagen deposition, epithelialization and wound retraction which occur simultaneously. Angiogenesis Angiogenesis is triggered from the moment the haemostatic plug has formed as platelets release TGF-b, PDGF and FGF. In response to hypoxia, VEGF is released which, in combination with the other cytokines, induce endothelial cells to trigger neovascularization and the repair of damaged blood vessels. Mixed metalloproteinase (MMP) are a family of enzymes that are activated by invading neutrophils in hypoxic tissue. They promote angiogenesis through liberation of VEGF and remodelling of the extracellular matrix (ECM).[33] Initially the centre of the wound is relatively avascular, as it relies solely on diffusion from the undamaged capillaries at the wound edge. As the process of angiogenesis proceeds, a rich vascular network of capillaries is formed throughout the wound from offshoots of healthy vessels. Initially the capillaries are fragile and permeable which contributes further to tissue oedema and the appearance of healing granulation tissue. Fibroblast migration Following the wound insult, fibroblasts are stimulated to proliferate by growth factors released from the haemostatic clot and then migrate to the wound (predominantly by TGF-b and PDGF). By the third day, the wound becomes rich in fibroblasts which lay down extracellular matrix proteins (hyaluronan, fibronectins and proteoglycans) and subsequently produce collagen and fibronectin. The resulting pink, vascular, fibrous tissue which replaces the clot at the site of a wound is termed granulation tissue. This is composed of a different range of collagens (a higher proportion of type 3 collagen) to that seen in unwounded tissue. Once sufficient matrix has been laid down, fibroblasts change to a myofibroblast phenotype and develop pseudopodia. This enables them to connect to the surrounding proteins fibronectin and collagen and assist in wound contraction. Myofibroblasts also promote angiogenesis through mediation MMP activity. [34] Collagens synthesized by fibroblasts are the key component in providing strength to tissues. In wounds closed by primary intention, collagen deposition is maximal by day 5 and this can often be palpated beneath the skin as a ‘wound ridge’. When a wound ridge is not palpable, this is an indication that the wound is at risk of dehiscence. Overproduction of collagen can lead to the development of a hypertrophic scar. Hypertrophic scars remain raised and erythematous but remain within the confines of the original wound. Risks for their development include wound infections and those where there is excessive tension. Epithelialization Epithelial cells migrate from the edges of the wound very soon after the initial insult until a complete sheet of cells covers the wound and attaches to the matrix below. An embryological process, termed epithelial-mesenchymal transition (EMT), allows epithelial cells to gain motility and travel across the wound surface. [35] In wounds that are primarily closed, this phase can be completed within 24 hours. Changes in cytokine concentration result in epithelial cells switching from a motile phenotype to a proliferative one in order to repopulate epithelial cell levels and complete wound repair. [36] In wounds that heal by secondary intention, the area lacking epithelial cells can be large and the wound must contract significantly before epithelialization can be completed. In some cases this may never occur and skin grafting can be used to cover the defect. Wound retraction Wounds begin to contract about seven days after injury, mediated mainly by myofibroblasts. Interactions between actin and myosin pull the cell bodies closer together decreasing the area of tissue needing to heal. Contraction can occur at a rate of 0.75 mm per day leading to shortened scars. This is influenced by numerous factors including wound shape, with linear wounds contracting fastest and circular wounds the slowest. Disorders of this phase of healing can lead to deformity and the formation of contractures. [37]

REMODELLING:

The remodelling phase is an essential component of tissue repair and is often overlooked. The final outcome of these combine events is that the damaged tissue will be repaired with the scar. [32] The final stage of wound healing can take up to 2 years and results in the development of normal epithelium and maturation of the scar tissue. This phase involves a balance between synthesis and degradation, as the collagen and other proteins deposited in the wound become increasingly well organized. Eventually they will regain a structure similar to that seen in unwounded tissue (replacing type 1 collagen with type 3 collagen). Despite this, wounds never achieve the same level of tissue strength, on average reaching 50% of the original tensile strength by 3 months and only 80% long term. As the scar matures, the level of vascularity decreases and the scar changes from red to pink to grey with time. [38]

IMPORTANT FACTORS IN WOUND HEALING:

Nutrition:

It has long been recognized that nutritional status can influence wound healing. In the fifteenth century, the Portuguese explorer Vasco de Gama noted that sailors with scurvy had multiple, non-healing skin lesions. It was not until 1747 that James Lind, a Scottish surgeon, demonstrated that citrus fruits could successfully treat scurvy and enhance wound repair. Malnutrition adversely affects healing by prolonging inflammation, inhibiting fibroblast function and reducing angiogenesis and collagen deposition. There are many essential nutrients which are important for wound healing, including vitamin A (involved in epidermal growth), carbohydrates (for collagen synthesis) and omega-3 fatty acids (modulate arachidonic acid pathway). In recent years, extensive research in the field of clinical nutrition has shown clear benefit for the use of nutritional support techniques to enhance wound healing. This topic has been the subject of a number of recent review articles. [39]

Hypoxia:

All wounds are hypoxic to some extent as their local vascular supply is disrupted. While a degree of hypoxia is required to facilitate re-epithelialization, sufficient oxygen is an essential requirement for wounds to heal. It is clear in surgical practice that elderly patients and those with peripheral vascular disease have poor healing and in contrast hyperbaric oxygen improves wound healing. Although hypoxia is one of the chemoattractants for neutrophils and macrophages, oxygen is needed to allow phagocytosis and for their optimal function. A randomized controlled trial demonstrated that supplemental oxygen given during the perioperative period reduced the risk of wound infections. [40] Oxygen is also essential for collagen deposition as it acts as a substrate in the hydroxylation of proline and lysine residues. Smoking Smoking impairs wound healing by its effects on chemotaxis, migratory function and oxidative bactericidal mechanisms in the inflammatory phase. In addition, it also reduces fibroblast migration and proliferation. Furthermore, smoking affect immune function, downregulates collagen synthesis and deposition. [41]

Infection:

Antibiotic prophylaxis prior to making a surgical incision was proven to reduce risk of wound infections firstly in guinea pigs in 1958 and subsequently in humans in 1960. Delayed primary closure, or closing by tertiary intention, should be considered when suturing heavily contaminated wounds as this has been shown to decrease wound infection rates.

Immunosuppression:

Patients with HIV, cancer and malnutrition all have a degree of immunosuppression which can lead to delayed wound healing. In addition, any drugs which impair the inflammatory response can impede the healing cascade. Oral steroids, such as rednisolone, have been shown to decrease cytokine concentrations during wound repair, leading to reduced collagen deposition. Chemotherapy and radiotherapy may also have a negative effect on the process of wound healing. Chemotherapy medications affect vascular endothelial growth factor (VEGF) that is an important regulator in the angiogenesis phase of wound healing. [42] Radiation injury to overlying skin causes tissue ischemia and may lead to skin ulcers. Surgical incisions over irradiated are more likely to develop wound complication and these wounds heal very slowly. [43]

Medicinal plants having wound healing activity:

Aloe Vera:

It is one of the oldest healing plants known to mankind Also the major polysaccharide of Aloe vera stimulates expressionof VEGF and other wound healing-related factors (e.g., keratinocyte growth factor-1 and type I collagen) in gingivalfibroblasts. This can be especially beneficial in the case of oral woundhealing. Thus, crude Aloe Vera extract or isolated pro angiogenic components may have potential pharmaceuticalapplications for the management of wounds.

[44]

Moringaoleifera Linn:

Moringaoleifera Linn. (Moringaceae) has been an ingredient of Indian diet since centuries. The leaves of the plant have also been reported for its anti-tumor, hypotensive, antioxidant, radio-protective, anti- inflammatory and diuretic properties. The aqueous extract was studied and it was found that there was significant increase in wound closure rate, skin breaking strength, granuloma breaking strength, hydroxyproline content, granuloma dry weight and decrease in scar area was observed. [45]

PARAMETERS USED IN ASSESSING WOUND HEALING ACTIVITY:

Physical Parameters:

Physical attributes like wound contraction, epithelization and scar remodeling can be monitored by measuring the total wound area, open wound area, and noting the physical changes in scar e.g. size, shape and colour etc. Excision wound is ideal to study these attributes. The area measurement not only gives the rate of healing, but can distinguish between contraction and epithelization. The extent of epithelization is determined by measuring the raw wound, bound by hairless belt intervening between wound margin and then by deducting the raw wound area from total wound area. Different methods for measuring the areas are available. T hese may be traced on a paper, weighed and compared with that of a reference piece of same thickness and unit area or the same can be retraced on a graph paper to directly measure the area. The completion of epithelization can be assessed by noting the time for complete covering of the raw surface of the wound. “Thorotrast” a sophisticated technique with the electron opaque marker is reported for the identification of migrating epithelial cellsGranuloma study is another physical attribute of wound healing study which can be assessed by quantifying the granuloma itselfby noting its overnight dried weight [46].

Mechanical Parameters:

Mechanical attributes like breaking strength or tensile strength, can be monitored by measuring the force required to break a wound or tissue without regard to the dimensions. Tensile strength measurement are made in terms of load applied per unit of cross sectional area and expresses as lbs/ sq. inch or kg/sq.cm or14 kg/sq.mmTensiometer or constant water flow techniquemay be applied for uniform application of force. [47]

Biochemical Parameters:

Various chemical agents including collagen that are elaborated in the wound may be estimated. Collagen estimation in wound, is most reliable, since it contributes for wound strength. Hydroxyproline, an important amino acid in collagen, is estimated to determine the total collagen content, on index of progress in healing. Calorimetric and spectrometric or chromatographic methods are also available for its estimation [47].

Histological Parameters:

Monitoring the histological attribute, quantifying various cellular elements and collagen content makes this an equally useful parameter in wound healing studies. It is monitored by microscopic examination of the granulation tissue have shown that the depth of collagen invasion at the periphery of the disc is proportional to the total collagen content and fibroblast accumulation in experimental animals. [48]

CONCLUSION:

Wound healing is a complex and dynamic process of replacing devitalized and missing cellular structures and tissue layers. Wound healing process can be divided into 3 or 4 distinct phases. Earlier authors referred to 3 phases- inflammatory, fibroblastic, and maturation, It is a requiring the co-ordinated actions of multiple cell types in response to a variety of differing cytokines and micro-environmental conditions. This is essential that surgeons understand the key physiological processes involved and the important factors which can influence these such that successful wound healing can be maximized to reduce morbidity and mortality from disturbed wound healing. The anti-oxidant effects and health benefits of flavonols are fascinating. Most of the pharmacological reports of plant/plant extract screening the organic soluble extracts of the current review may be combined sensibly in the development of a globally acceptable wound healing formulation. Thus, the current review is the combination traditional medicines can produce better effect on wound healing with few side effects.

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Received on 12.05.2018 Modified on 20.06.2018

Res. J. Pharmacology and Pharmacodynamics.2019; 11(1):37-45.

DOI: 10.5958/2321-5836.2019.00008.9