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Wound healing

Wounds can be caused by a variety of physical and non physical means causing varying degrees of damage to the person involved. The healing of the wound can vary due to the where the trauma occurred. Areas of thick skin, like the foot, heal slower than areas of normal skin density, like the arm, as more tissue is required to rebuild the damaged area (S.Gudo, L.A.DiPietro 2009). The dimension of the wound also affects healing, as a circular wound takes longer to heal than a linear wound due to extra tissue requirement. A wound to the skin results in epithelial cell death and a break in the skins structural and functional integrity. The healing of the wound can occur via two means: primary and secondary intention (Mera, Stephen 1997). Primary intention is the most straight forward type of wound healing and usually occurs after a clean cut of the skin i.e. from a surgical incision (Mera, Stephen 1997). This type of wound healing can heal fairly rapidly as only minimal numbers of epithelium are killed and, provided the wound is brought close together, minimal scaring will take place. Secondary intention occurs when more extensive damage and cell death has occurred i.e. from large surface wounds obtained in a car crash (Mera, Stephen 1997). The healing process follows a similar path to primary intention but, due to the greater extent of tissue loss and damage, healing is prolonged and large amounts of scar tissue are observed after healing. Both methods of wound healing follow a pre programmed course of events which lead to the healing of the affected area, however, there are some differences in the length and magnitude of some stages. The method is considered to be a dynamic process which consists of four continuous and overlapping phases (S.Gudo, L.A.DiPietro 2009). These four phases must take place at the right time with delay, disruption and aberrancies leading to inhibition of this process and the healing of the wound. Below is a table showing the four stages of wound healing: 1.Rapid haemostasis Consists of vascular constriction and the formation of a fibrin clot. The clot and surrounding tissue release inflammatory promoting chemicals, like PDGF ( platelet derived growth factor) and cytokines, which promote inflammation (S.Gudo, L.A.DiPietro 2009) 2.Inflammation Occurs when wound bleeding is controlled and macrophages, neutrophils and lymphocytes arrive at the area. Vasodilatation of the blood vessels allows increased blood flow and vascular permeability in the wound area. The inflammatory cells play individual roles in wound healing (e.g. macrophages engulf debris and act as a control for inflammation, engulfing neutrophils helping to preventing inflammation from turning chronic (S.Gudo, L.A.DiPietro 2009). 3.Cell migration to the wound cite Proliferated macrophages stimulate keratinocytes, fibroblasts and angiogenesis (new blood vessel production) which promotes tissue regeneration. T lymphocytes also migrate to the wound cite. 4.Re-epithelialization and remodelling New capillaries form where the wound took place allowing nutrients and cells to reach the wound site, returning vascular density to normal level. Keratinocytes initiate the re-epithelialization of the wound while ECM remodels to an architecture which represents normal tissue (Komine M et al 2001).

Factors affecting wound healing Messenger molecules play a vital role in many stages of wound healing, for example cytokines secreted from macrophages help induce the inflammatory response which is critical in increasing blood flow and combating infection. Other factors which affect wound healing range from systemic factors such as age, nutrition and obesity to local factors like oxygenation and infection. All these factors contribute to how efficiently wound healing can be carried out, there are also drugs which can aid wound healing in those individuals where healing is lethargic or non existent. Accompanied with the beneficial drugs there are some drugs which inhibit wound healing as a side effect, like some anti cancer treatments, the way these drugs work will also be looked at as a factor which affects wound healing. Messenger molecules Cytokines are one of the most important messenger molecules in the wound healing process, controlling all aspects either directly or indirectly. Many of the cytokines are pro-inflammatory; they help induce an inflammatory response in the area the wound took place. The main pro-inflammatory cytokines are interleukin-1 (IL-1) and interleukin - 6 (IL-6). IL-1 is produced by neutrophils, monocytes, macrophages and keratinocytes while IL- 6 is produced by neutrophils and monocytes. IL-1 is released immediately by keratinocytes upon the wound taking place where it acts in both a paracrine and autocrine fashion on the cells in the surrounding area (Komine M et al 2001). IL-1 also causes migrating keratinocytes to secrete keratin-6 and 16, which induces keratin synthesis crucial for the new tissue formation, and causes fibroblasts to be stimulated and to secrete FGF-7 (Komine M et al 2001). IL-6 has a more permanent role in the wound formation, as it tends to continue to be expressed in old wounds. Upon wounding IL-6 initiates the healing response having both mitogenic and proliferative effects on ketatinocytes whilst being chemoattractive to neutrophils (Komine M et al 2001). The inflammation which is stimulated via IL-1 and IL-6 has to be constantly controlled to prevent chronic inflammation from taking place. To prevent this from occurring cytokines TNF α and IL-1 β have the ability to inhibit inflammation and re-epithelialisation. At high levels TNF α has a detrimental effect on healing , suppressing the extracellular matrix (ECM) proteins and TIMP,s(which inhibit MMP’s) whilst causing increased synthesis of matrix melloproteases (MMP’s) ,which cleave most elements of the extracellular matrix therefore preventing formation and further healing. IL-1β has a similar function to TNF-α and also acts to inhibit wound healing. The exception to this rule is when TNF-α is in very low concentrations as it can often stimulate wound healing and inflammation due to its low numbers greatly reducing its inhibitory ability (Komine M et al 2001). Another exception is in chronic wounds when the levels of TNF-α and IL-1β are high. In these cases inflammation is not reduced and wound healing is not inhibited as it fails to take place due to the persistant inflammation. PDGF, a growth hormone, is released by platelets upon injury. Similar to IL-6, PDGF stimulates chemotaxis and mitogenicity of neutrophils, macrophages, fibroblasts and smooth muscle. This stimulation causes macrophages to release TGF-β. PDGF also promotes angiogenesis by recruiting pericytes which increase the structural integrity of the new capillaries while promoting re-epitheliization by regulating IGF-1 production (Galiano Rd et al 2004). Both of these functions play a crucial role in wound healing and PDGF is used in medicine to enhance wound healing, covered in further detail later in this essay. Systemic factors The systemic factors which affect wound healing are numerous so for the purposes of this essay only age, medication, nutrition and obesity will be covered in detail. Age

Age related inhibition of wound healing is of vital concern to the population as the elderly, aged 60 or over, is the fastest growing age group in the world. In the elderly wound healing tends to only be prolonged rather then prevented altogether. There are several causes for the increase in time taken for a wound to heal in the elderly over a younger person, these include, an altered inflammatory response as T-cell infiltration to the wound area is decreased along with the capacity for macrophages to phagocytose debris and microorganisms (S.Gudo, L.A.DiPietro 2009. These symptoms are accompanied with decreased secretion of growth factors, delayed re-epithelization, delayed angiogenesis, delayed collagen deposition and decreased wound strength all of which lead to decreased wound healing capacity and greater chance of reopening of old wounds. Some research has shown that exercising in the elderly has a high concordance rate with increased ability to heal w compared to those elderly people who don’t exercise. It is suggested that this is due to exercise induced anti inflammatory response decreasing pro-inflammatory cytokines in the wound area allowing a faster proliferation and remodelling of the wound (Emery et al 2005).
Medication

Some medication given to patients can lead to a decrease in wound healing function via a range of methods. Glucocorticoid steroids, used to treat autoimmune diseases, inhibit wound healing by causing global inhibition of inflammation and inhibition of cellular responses, like fibroblast proliferation and collages synthesis. Cancer drugs such as angiogenesis inhibitors like bevacizumab , an anti body fragment that neutralises VEGF, limits blood flow to the cancerous tumour and the area where the wound has taken place, decreasing angiogenesis and inhibiting the wound healing (Scappaticci et al 2005). The only problem with this claim is that most patients on Bevacizuab are also undergoing other chemotherapeutics which makes it difficult to differentiate which is causing the inhibition, however, as age related factors highlight angiogenesis is crucial to wound repair and a reduction decreases healing. PDGF is the only wound healing ‘drug’ to have been FDA approved to treat chronic wounds (Galiano Rd et al 2004). Becaplermin (human variant PDGF-BB) has been successfully applied to diabetic patients and, due to its angiogenesis and re-epitheliization properties, has shown success in improving wound healing (Galiano Rd et al 2004) . Recently Adenovirus-PDGF-BB has been initiated for persons with diabetic ulcers, also showing improvements in healing. These advances in growth factor therapy may enable many experimental wound accelerators to be effective in patients in the near future (Galiano Rd et al 2004).

Nutrition and Obesity Like some drugs, malnutrition can have a massive impact on the ability of a wound to heal. Common in many 3rd world countries malnutrition affects wound healing in a variety of ways. Lack of proteins, carbohydrates and fats in the diet leads to impaired ATP production which leads to decreased angiogenesis and new tissue disposition (S.Gudo, L.A.DiPietro 2009). This causes similar affects to patients on anti cancer drugs, impairing wound healing as blood flow to the new tissue is not increased. Vitamins also play a vital role in the healing of wounds. Vitamins A and E play an inflammatory role, so like TNF α and IL-1 β messenger molecules help inhibit inflammation and allow the remodelling phase of healing to occur. With out these vitamins chronic inflammation could result from a localised immune response. Vitamin C also plays a vital role in wound healing, lack of which results in decreased collagen synthesis, fibroblast proliferation and impaired healing. Obesity, which affects 30% of American adults, can also lead to wound healing complications. Increased chance of infection and decreased healing rate are both observed, due to compromised immune systems and decreased oxygen to the wound area as a result of increased wound tension (S.Gudo, L.A.DiPietro 2009). The reduction in wound healing capacity is one reason why many obese patients are advised to lose large amounts of weight before surgical procedures are carried out. Local factors As looked at above infection and oxygenation are both vital factors which help or inhibit wound healing in patients. Oxygenation is essential for cell metabolism and ATP production, critical for all wound healing. In the initial stages of the wound oxygen levels in the damaged tissue tend to be fairly hypoxic as a result of vascular disruption. Hypoxia in acute wounds helps to stimulate wound healing via the release of cytokines and growth factors, as looked at above, causing an immune response (Rodriguez et al 2008). Oxygen’s role in the immune response doesn’t end at stimulating inflammation it also forms superoxide which acts to promote angiogenesis and cytokine action in the wound. Microorganisms, often the body’s normal flora, invade the body via the break in the skin and become an opportunistic infection. To combat this many molecules, most of which have been covered in this essay, promote inflammation and lead to the phagocytosis of any foreign material and organisms in the wound area. Inflammation is affected by most of the factors which have been covered in this essay, such as age and nutrition, and is probably the most important method the body uses to rid itself of foreign organisms. Wound healing is a very complex and important biological process, dependant on millions of molecules and cells coordinating and communicating together. Of all the factors looked at in this essay the cytokines, and there role in eliciting an inflammatory response, have the most important role in wound healing. This is due to the importance of the inflammatory response in removing harmful microorganisms and increasing blood flow to the wound area allowing cells like fibroblasts to proliferate.. Although the factors which affect the body’s ability to heal are vast there are many things humans can do to insure that wound healing is optimized. A balanced diet, regular exercise and lack of obesity would go a long way to allowing affective wound healing to take place in a large proportion of the population. For those individuals who are unable to effectively heal, due to malnutrition or age, wound healing can be aided by medicine’s, like low dosage corticosteroids, allowing these individuals to heal more effectively (S.Gudo, L.A.DiPietro 2009). Most importantly with improving food sources in 3rd world countries and improvements in medicine, like omega 3 studies (S.Gudo, L.A.DiPietro 2009) and advances in PDGF, occurring all the time many wound healing aliments could be a thing of the past.

References • Barrientos, S., Stojadinovic, O., Golinko, M. S., Brem, H. and Tomic-Canic, M. (2008), PERSPECTIVE ARTICLE: Growth factors and cytokines in wound healing. Wound Repair and Regeneration, 16: 585–601. doi: 10.1111/j.1524-475X.2008.00410.x

• Komine M, Rao LS, Freedberg IM, Simon M, Milisavljevic V, Blumenberg M. J Invest Dermatol. 2001 Feb;116(2):330-8. Interleukin-1 induces transcription of keratin K6 in human epidermal keratinocytes

• Swift ME, Burns AL, Grey KL, DipietroLA(2001). Age related alterations in the inflammatory response to dermal injury. J Invest Dermatol 117:1027-1035 • Mera, Stephen L Published Cheltenham : Stanley Thornes 1997, Understanding disease: pathology and prevention

• Gregory S Schultz, Glenn Ladwig and Annette Wysocki - in turn adapted from Asmussen PD, Sollner B. Mechanism of wound healing. In: Wound Care. Tutorial Medical Series. Stuttgart: Hippokrates Verlag, 1993, worldwidewounds.com > Figure 3 - The time relationship between the different processes of wound healing.

• S.Gudo, L.A.DiPietro 2009 – factors affecting wound healing, centre for wound healing and tissue regeneration IL60612

• Emery Cf, Kiecolt-Glaser JK, Glaser R, Malarkey WB, Frid DJ (2005)exercise accelerates wound healing among health older adults: a preliminary investigation

• Scappaticci FA, Fehrenbacher L, Cartwright T, Hainsworth JD, Heim W, Berlin Jet al(2005) Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab

• Rodriguez PG, Felix FN, Woodley DT, Shim EK (2008) the role of oxygen in wound healing: a review of the literature Dermatol surg

• Galiano RD, Tepper OM, Pelo CR, Bhatt KA, Callaghan M, Bastidas N et al. (2004) Topical vascular endotelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow derived cells