Understanding Factors Impairing the Healing of Diabetic Foot Ulcers

WHY ARE DIABETIC ULCERS SLOW TO HEAL DESPITE GOOD PEDRIATIC MANAGEMENT

Diabetic foot ulcers result in marked morbidity, impairs a person’s quality of life, puts a person at risk of lower-extremity amputation and makes treatment expensive thus causing high economic losses to an individual. Factors that delay the healing of diabetic wounds are related impaired metabolism of glucose and neurovascular complications. In many cases diabetic ulcers do not heal and readily becomes chronic (Tsourdi et al. 2013).

Wound healing takes place in four phases; these include inflammation, maturation, haemostatis and proliferation. The healing of a diabetic ulcer is coordinated by cells and a series of immune responses involving antibodies found in body fluids. Haemostatis is the first phase of healing of diabetic ulcers and involves vasoconstriction and clotting. The clotting is initiated by platelets which also secret cytokines and growth factors. The second phase is inflammation which is mediated via neutrophil granulocytes. It cleanses the wound from the debris of the cell and prevents contamination of the wound by bacteria through phagocytis. It is also in this phase that provisional extra cellular matrix is formed and it takes 7 days. The third phase is the proliferation phase which is initiated on the second day of the injury and continues to a period of 20 days. This phase mainly involves angiogenesis and tissue granulation. The process of angiogenesis involves various growth factors such as angiotensin, platelet derived growth factor and macrophage angiogenesis. After angiogenesis and the formation of a granulation tissue concomitant epithelialization occurs to cover the ulcer with a cellular barrier. The fourth step is the maturation step which involves the extensive remodeling of tissue and the replacement of the wound matrix by proteoglycan and collagen molecules to form a rigid scar tissue (Tsourdi et al. 2013). The healing of ulcers is impeded by intensive and extensive. The extensive factors are repeated stress on the wound due to its insensitivity and the thickening of capillaries and arterioles basement membranes. Intensive factors relate to the biology of the wound and are factors such as hyperglycemia (Tsourdi et al. 2013). In this essay five factors which impair the healing of diabetic ulcers are discussed. These factors include alcoholism, smoking, biofilms, hyperglycemia and infections

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Hyperglycemia has been related to failure of diabetic ulcers to heal. This is as a result of changes that it induces to the hyaluronan found in the pericellular coat also referred as glycocalyx, of endothelial cells which are found in the small cutaneous blood vessels (Shakya et al. 2015). Hyperglycemia leads to the production of advanced end-products of glycation which bring about the formation of inflammatory molecules which in turn interfere with the synthesis of collagen by disrupting the timing for the synthesis of the extracellular matrix. The inflammatory molecule this high glucose level has been implicated to cause changes in cellular morphology, to decrease proliferation and to cause the keratinocytes to differentiate abnormally thus causing failure of diabetic ulcers to heal. Lower levels of Glycosylated haemoglobin has been found to reduce the healing time for leg and foot ulcers in diabetic patients, thus creating another link between hyperglycemia and healing of diabetic ulcers (Tsourdi et al. 2013). Hyperglycemia causes an increase in the levels of cytokines by elevating the glucose levels in the interstitial fluid. The high levels of cytokines then affect the perivascular area which is made up of pericytes and smooth muscle cells. Under hyperglycemic conditions there is a possibility of generation of reactive oxygen species which damages the glycocalix leading to a reduction in its size. This glycocalix is the reservoir for antithrombotic factors for example antithrombin III which aids in preventing clotting and by thus doing acting as a shield preventing circulating platelets from coming into contact with endothelial cells (Sakya et al. 2015).

Smoking has been found to impact the healing of diabetic ulcers on multiple levels; it leads to prolonged healing time, infection, anastomotic leakage, dehiscence, tissue flap necrosis and a decrease in the tensile strength of the diabetic ulcers. It has been found to affect neutrophils and macrophages cell types which play an important role in the inflammation and killing of bacteria in diabetic ulcers (McDaniel and Browning, 2014). Cigarette smoking causes the oxygen in tissues to be insufficient such that it cannot be able to sustain bodily functions, a condition known as hypoxia. Hypoxia interrupts the wound healing process at any stage since the oxygen pressures in the tissues need to be normal for the entire healing process which involves migration of cells to the site where the ulcer is located, synthesis of collagen and defense from bacteria. It is important to learn that just one cigarette is enough to alter concentration of oxygen in the tissues (Qing, 2017).

Research findings have reported that there are about 4000 compounds in a cigarette smoke. Three of these which are carbon monoxide, hydrogen cyanide and nicotine have been reported to reduce the healing of ulcers in diabetic patients. Nicotine causes vasoconstriction leading to reduced blood flow and thus limiting oxygen supply to tissues (Guo and DiPietro, 2010). Nicotine stimulates the release of catecholamines from the sympathetic nervous system. The catecholamine triggers peripheral vasoconstriction and reduces tissue perforation rates thus causing harm to the skin and subcutaneous tissue. Carbon monoxide binds to hemoglobin which is responsible for the transportation of oxygen. This causes tissue hypoxia thus delaying the healing of diabetic ulcers. Hydrogen cyanide inhibits the metabolic process which is responsible for cellular oxygen metabolism. Smoking of cigarettes has been associated with a reduction in the proliferation of erythrocytes, fibroblasts and white blood cells. Low numbers of erythrocytes cause hypoxia. Reduced numbers of white blood cells which are responsible for phagocytosis of tissue debris, apoptotic neutrophils and bacteria during the inflammatory stage of ulcer healing in diabetes reduces diabetic ulcers healing substantially (McDaniel and Browning, 2014).

A biofilm refers to a large group of bacteria adhering to a particular surface. These bacteria then produce complex exopolymers which contain polysaccharides, nucleic acids and carbohydrates and these enable their survival on the surface and bring them close to one another. The biofilms are three dimensional in shape and are found in the surface glycocalix which has water scattered among themselves. These biofilms play many beneficial functions for human beings such as providing resistance as a result of colonization in the large intestines, improving the quality of water; global cycling of nutrients and ensuring the organic compounds are degraded. They however have proved a great menace to industrial settings as well as clinical settings (Hess, 2011). This is due to the fact that these microbial, communities are extremely hard to eliminate using antimicrobial agents and are also a host of immune responses. The biofilms found in chronic wounds are protected from the inflammatory process by the exopolymer. This slows down wound healing (Anderson and Hamm, 2012). The exopolymers produced by biofilms depresses the lymph proliferative response blocks the activation of compliments and prevents phagocytes from detecting the opsonins which are found on the cell wall of the bacteria, this reduction in phagocytic response slows down the wound healing process in diabetic ulcers (Omar et al. 2017).

The exopolymer has been found to also reduce the leucocytes ability to enter the biofilm and to subsequently hamper the movement of any leukocytes who enter the biofilm within the biofilm. The exopolymer also reduces the ability of the leukocytes to degrade in order to produce reactive oxygen species and is therefore a barrier to the phagocytis of bacteria (Seth et al. 2013). Through these processes healing of diabetic wounds is slowed down by biofilms. When the biofilms are exposed to antibiotic concentrations which do not completely inhibit them or to completely wrong antibiotics leads to the production of mucoid phenotypes which in turn generates biofilms which are thicker and have additional components in their matrix (Metcalf and Bowler, 2013). This makes them even harder to eliminate and thus increases their effect on slowing down wound healing (Falanga, 2005). Other mechanisms that have been proposed to explain how biofilms resist treatment therapies are and therefore slow down the healing of wounds and ulcers are; their physiological heterogeneity, their ability to repopulate themselves as a result of the presence of cells which persist, the bacteria found in biofilms have low metabolic rates and this affects the mechanism of action of antibiotics which are commonly used, overexpression of the open reading frames of the efflux pump, limitations to drug diffusion caused by the exopolymer and the predominance of genes which are resistant to drugs, which are easily transferrable to other organisms found within a biofilm (Omar et al. 2016).

It has been demonstrated in both clinical and animal studies that the use of alcohol reduces the healing of wounds and ulcers and also increases wound infection. Persons exposed to alcohol tend to be more careless when it comes to protecting the ulcer from further injury. Exposure to alcohol reduces the resistance of the host and when one is injured when intoxicated then they the ulcer becomes more prone to infection. The effect of alcohol on the healing of a diabetic wound depends on whether the exposure is acute or chronic. A short term acute exposure to alcohol has been linked to affect the defense of the host by suppressing the release of pro-inflammatory cytokines during an inflammatory challenge. Acute exposure to alcohol also been related to decreased recruitment of neutrophils and reduced phagocytic function. Acute exposure to alcohol therefore has a potential to slow down the healing of diabetic wounds. Ethanol exposure has also be alluded to have possible effects on the proliferation phase of the healing of diabetic foot ulcers. An alcohol level of 100 mg/dL in the blood alters re-epithelialization, production of collagen, angiogenesis and closure of the wound. Angiogenesis is reduced by 61% and this is such a marked decrease for just a single exposure to ethanol and can substantially slow down the process of healing of diabetic ulcers. The reduction of angiogenesis is as a result of reduced expression of VEGF receptors and decreased expression of the nucleus HIF-1alpha found in the cells of the endothelium. Ethanol mediates a decrease in the vascularity of a wound causing oxidative stress and results into hypoxia. Exposure to ethanol influences the restoration of connective tissues and results in a decrease in the production of collagen and an alteration I the balance of protease at the site of the wound (Guo and DiPietro, 2010).

Wound infection is the most prevalent factors that prevent wounds from healing even though it can be prevented. It is a normal occurrence of bacteria to be in wounds as they are part of the normal flora of the skin (Penhallow, 2005). However when the bacterial population gets to a threshold of 10^5 they become a clinically relevant infection and they can substantially delay wound healing. In the determination of bacterial cause of infections it is important that true pathogens be distinguished from positive culture (Falanga, 2005). When injury occurs the underlying tissues are exposed to microbes which normally reside on the skin surface infection results. The wound is thus classified as contaminated, colonized, local infection or invasive spreading infection depending on the nature of infection and the status of replication of the microorganisms. The presence of bacteria and endotoxins leads to the prolonged elevation of the levels of pro-inflammatory cytokines like interleukin-1 (IL-1) and TNF-α thus leading to the elongation of inflammatoryphase. The elongation of thee inflammatory phase causes the diabetic ulcer to enter a chronicstage which causes it to fail to heal. Prolonged inflammation causes an increase in the levels of a family of protease called matrix metalloproteases (MMPs) which degrade extra cellular matrix thus slowing down the healing of diabetic ulcers. The increased protease levels causes a decrease in the levels of protease inhibitors this causes the growth factors in wounds to undergo rapid degradation (Guo and DiPietro, 2010).

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References

Anderson, K. and Hamm, R.L., 2012. Factors that impair wound healing. Journal of the American College of Clinical Wound Specialists, 4(4), pp.84-91.

Falanga, V., 2005. Wound healing and its impairment in the diabetic foot. The Lancet, 366(9498), pp.1736-1743.

Guo, S.A. and DiPietro, L.A., 2010. Factors affecting wound healing. Journal of dental research, 89(3), pp.219-229.

Hess, C.T., 2011. Checklist for factors affecting wound healing. Advances in skin & wound care, 24(4), p.192.

McDaniel, J.C. and Browning, K.K., 2014. Smoking, chronic wound healing, and implications for evidence-based practice. Journal of wound, ostomy, and continence nursing: official publication of The Wound, Ostomy and Continence Nurses Society/WOCN, 41(5), p.415.

Metcalf, D.G. and Bowler, P.G., 2013. Biofilm delays wound healing: A review of the evidence. Burns & Trauma, 1(1), p.5.

Omar, A., Wright, J., Schultz, G., Burrell, R. and Nadworny, P., 2017. Microbial biofilms and chronic wounds. Microorganisms, 5(1), p.9.

Penhallow, K., 2005. A review of studies that examine the impact of infection on the normal wound-healing process. Journal of wound care, 14(3), pp.123-126.

Qing, C., 2017. The molecular biology in wound healing & non-healing wound. Chinese Journal of Traumatology, 20(4), pp.189-193.

Seth, A.K., Geringer, M.R., Nguyen, K.T., Agnew, S.P., Dumanian, Z., Galiano, R.D., Leung, K.P., Mustoe, T.A. and Hong, S.J., 2013. Bacteriophage therapy for Staphylococcus aureus biofilm–infected wounds: a new approach to chronic wound care. Plastic and reconstructive surgery, 131(2), pp.225-234.

Shakya, S., Wang, Y., Mack, J.A. and Maytin, E.V., 2015. Hyperglycemia-induced changes in hyaluronan contribute to impaired skin wound healing in diabetes: review and perspective. International journal of cell biology, 2015.

Tsourdi, E., Barthel, A., Rietzsch, H., Reichel, A. and Bornstein, S.R., 2013. Current aspects in the pathophysiology and treatment of chronic wounds in diabetes mellitus. BioMed research international, 2013.

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