**5. Factors involved in wound healing**

Physiological responses as well as cellular functions influence wound healing, and interruptions at any stage enhance the chances of scar development.

#### **5.1 Local factors**

#### *5.1.1 Ischemia*

Inadequate supply of blood to any part of the body is termed as ischemia, and since wounds require multiple elements such as energy (in the form of adenosine triphosphate or ATP), glucose and oxygen; that are all borne by the blood to the site of the wound, ischemia affects wound healing dramatically. The rate of wound healing is significantly lower in cases of Hypoxia*,* which in turn may be triggered by ischemia [26].

Hypoxia leads to vasodilation and stimulates fibrin deposition which increases pro-inflammatory activity, capillary leak and neovascularisation. Pro-inflammatory property is stimulated by Tumour Necrosis Factor (TNF)-α, leading to apoptosis and affecting the collagen organisation of the injured tissue [26, 27].

Similarly, fibroblasts exposed to long periods of hypoxia may not involve in extra cellular matrix, thereby delaying wound healing/closure [27].

### *5.1.2 Oedema (edema)*

Swelling that arises due to excess fluid trapped in the body's tissues is medically termed as an Oedema (/edema). This is most commonly associated with ischemia and severely delay wound healing as inflammatory response is delayed due to raised tissue pressure. This in turn compromises cellular function and lead to severe hypoxia or even cell death, thereby leading to necrosis and impairing wound healing [26].

#### *5.1.3 Foreign bodies*

Clinically, any object found in the wound, apart from its natural tissues is demarcated as a foreign body, the presence of which severely inhibits wound closure. This is primarily because foreign bodies prevent wound contraction and epithelialisation, thereby leading to the development of necrotic tissues. Unfortunately, necrotic tissues further prevent wound healing to the extent that *all* the necrotic tissue has to be removed before wound healing can commence [28].

'Foreign bodies', which may also indicate non-viable tissue; further complicate matters by serving as an asylum to bacteria and other pathogens.

#### *5.1.4 Infection*

Presence of bacteria or other pathogens at the site of the wound is termed as 'wound infection', and characterised by the one or more of the four cardinal signs of inflammation:

*Rubor*—the infected region might appear red, *Calor—*the affected region might be warmer than the surrounding tissues, *Dolor*—there might be increased pain and, *Tumour—*or swelling.

A fascinating study by Robson and his team in 1997 [29] exhibited that bacterial counts exceeding 105 organisms per gram of tissue prevent wound closure to the extent that skin-graft replacement or even primary sutures failed to heal the wound. Similarly, presence of beta-haemolytic streptococcus will also inhibit wound healing. This is because endotoxins present in bacteria stimulate phagocytosis and the release of the enzyme collagenase that contributes to collagen degradation and destruction of the priory normal tissue that surrounds the site of injury [29, 30].

#### **5.2 Systemic factors**

Certain factors such as obesity, cardiovascular and respiratory disease etc. might affect an individuals' wound healing capacity and pre-dispose them to wound healing dysfunction [31, 32]. While wound healing is slower with age, it has been observed that those with co-morbidities also exhibit delayed healing which is indistinguishable from the delay caused due to the effects of age alone. This was confirmed with observations of improved healing ability in elderly female patients when they were prescribed/given topical oestrogen supplements [33, 34].

Although it is a prevalent belief that senior patients heal at a slower rate than their younger counterparts, it must also be acknowledged that older patients are more prone to co-morbidities which may interfere with wound healing. Fascinatingly, while longitudinal studies in animal models [35] support this theory, studies in humans have been inconclusive in the sense that dermal collagen deposition is equivalent in patients undergoing skin-grafting irrespective of age, however their re-epithelialisation rates are reduced [36]. While further research is needed to understand the consequences of age in wound repair, it has been speculated that it may be attributed to reduced availability of growth factors.

Some of the known chronic conditions that interfere with wound healing are listed below:

#### *5.2.1 Diabetes mellitus*

Increased serum glucose and hyperglycaemia related deleterious impact has been evidenced in cellular and molecular pathophysiology. For instance, sorbitol, a toxic by-product of glucose metabolism has been found to accumulate in tissues in case of hyperglycaemia and thereby involved in the renal, ocular as well as vascular complications commonly associated with diabetes. Additionally, collagen; which plays a vital role in wound healing mechanisms is more prevalent in its glycosylated form that is comparatively more resistant to enzymatic degradation and less soluble than normal protein product. These defects in collagen maturation led to decreased granulations and reduced collagen in granulation tissue, thereby hampering wound healing [37–39]*.*

### *5.2.2 Hypothyroidism*

Experimental studies have indicated that hypothyroidism leads to decreased collagen production and decreases tensile wound strength. These issues are further complicated by the co-morbidities that are often caused/present in hypothyroidism patients [40, 41].

#### **5.3 Other factors influencing wound healing**

#### *5.3.1 Tissue perfusion*

Tissue perfusion, which may be local due to external compression, or even systemic, when arising from alterations in circulatory volumes may lead to tissue hypoxia; which, as already noted earlier; interferes with wound healing [28].

#### *5.3.2 Hypothermia*

Hypothermia leads to peripheral vasoconstriction which in turn has an impact on cutaneous perfusion, thereby affecting wound healing [42, 43].

#### *5.3.3 Debilitating pain*

The pain stimuli may lead to the diffuse of an adrenergic discharge, which in turn is responsible for cutaneous vasoconstriction. Consequently, it has often been observed that proper pain control leads to improved wound healing [44, 45].

### *5.3.4 Major trauma*

Severe trauma often results in hypo-volemic shock as a consequence of compromised cardiac functionality, thereby enhancing circulating cytokines as well as inflammatory mediators such as TNF- α and leading to anomalies in wound closure such as abnormalities in clotting [46, 47]. Thus, it is essential to maintain normo-volemic conditions as well as body temperature for proper wound management [31, 32, 46–48].
