Underlying Factors Formation Keloids And Hypertrophic Scars Biology Essay

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The skin is the largest organ in the body. It is made up of 3 layers, epidermis, dermis and subcutaneous tissue. The epidermis is the outer layer of the skin, made up to five layers. The cells in the epidermis grow from the bottom layer and have become dead cells by the time they reach the surface of the skin. The dermis is made up collagen fibers, elastic tissue and reticular fibers. The dermis is divided into superficial papillary dermis and deep reticular dermis. The superficial layer is made up of a thin layer of collagen, elastic fibers, reticular tissue and capillaries while the deep dermis is thicker and is made up of larger collagen bundles, interwoven elastic fibers and larger blood vessels. The subcutaneous layer contains fat, blood vessels and nerves.

One of the functions of the skin is to protect the body against the external environment. When some types of wounds occur, such as gaping wounds, burns, surgical incision, it causes injury to the epidermal and connective tissue layers of the skin. The skin repairs itself by means of regulatory mechanisms and normal scar formation develops. The regulatory mechanisms are disrupted in keloid and hypertrophic scars. These scars form as a result of excessive deposition of fibrous tissue in the dermal layer after trauma surgery or burns (Jagadeesan et al 2006). These scars are cosmetically disfiguring and affect the quality of life of the individuals affected ( Bock et al 2006 ).

The aim of this essay is to look at the adverse wound healing associated with hypertrophic scars and keloids. First, a review of the phases of normal wound healing will be conducted. Also, a quick review of how the extracellular matrix (ECM) organizes macromolecules and determines the physical properties of tissues will also be conducted. I will also explore how collagen, elastic fibers, growth factors and puberty contribute to these kinds of scarring. The impact on quality of life of these individuals and possible treatments will be assessed.

The stages of normal wound healing

For a tissue to return to normal after damage, the stromal architecture must be maintained or restored (Woolf, N. 2000). Damage to this architecture means that the arrangement of the newly regenerating cells is disturbed and this compromises the function of the tissue. This can be seen in the case of keloids which have been described as "excessive healing" (Enoch, Leaper, 2007). Wound healing is affected by its location on the body, type, size and depth. Infection and age of the individual are also important factors.

Resolution is the process by which the affected area is restored to its original state (Lakhani et al 2009). This can be achieved quickly if the affected tissue retains the basal layer of its cells and are therefore capable of regeneration. On the other hand, if there is extensive damage to the epithelium and dermal layers, then the damaged area will be filled in by scar tissue (Lakhani et al 2009). In the case of keloids, the scar tissues do not stay within the boundaries of the wound (Jagadeesan et al 2006). Hypertrophic scars stay within the boundaries of the wound but appears raised than the surrounding skin (Kose et al 2007).

Below is a description of what happens during the healing of acute wounds. The phases of normal wound healing are carefully regulated and involve overlapping processes. These phases are; haemostasis, inflammation, proliferation, remodeling and maturation (Enoch, Leaper, 2007).

Haemostasis: This phase occurs immediately after injury. The injury causes leakage of blood into tissue space. The blood leakage is controlled by constricting the blood vessels via mediators such as adrenaline and prostaglandin 2-alpha (vasoconstrictors), (Lakhani et al 2009). This results in platelet aggregation and clot formation, limiting further blood loss (Enoch, Leaper, 2007). Degranulation of the platelets occurs resulting in the release of alpha granules which in turn secrete several growth factors, some of which are, PDGF (platelet derived growth factor), and insulin-like growth factor. These proteins attract and activate fibroblasts, marcophages and other cells involved in the wound healing cascade (Enoch, Leaper, 2007).

Inflammation: Enoch & Leaper (2007) stated that this phase can be divided into early and late depending on the type of inflammatory cells involved ranging between 1-3 days. During this phase, vasodilatation (widening of blood vessels) occurs 5 -10 minutes after vasoconstriction (Lakhani et al 2009). Vasodilatation occurs due to the local release of histamine by mast cells. This process allows protein filled fluid from the plasma into the tissues. As a result of this, swelling occurs. Polymorphonuclear leukocytes such as neutrophils are attracted to the wound site by chemoattractants such as transforming growth factor beta etc. These neutrophils infiltrate the wound site and destroy bacterial and any other foreign particles by phagocytosis. In the later stages, marcophages replace the neutrophils and continue with the destruction and phagocytosis of pathogens that may have infiltrated the tissue. The marcophages also function as the primary producers of growth factors important in attracting fibroblasts which are important in the proliferation phase of wound repair. Fibroblasts are connective tissue cells that secrete collagen fibers and other macromolecules of the extracellular matrix. In the late stages of inflammation, collagen fibers can be seen vertically oriented at the incision margins of the wound (Enoch, Leaper, 2007).

Proliferation: Events during this phase include fibroblast migration, extra cellular matrix (ECM) deposits, formation of granulation tissue and epithelialization. Fibroblasts are attracted to the area by growth factors such as transforming growth factor beta (TGF β). An increase in the level of production of this growth factor has been linked to an increase in scar tissue (Jagadeesan et al 2006). An isoform of transforming growth factor beta, TGF β1, has been linked to keloids and hypertrophic scars (Jagadeesan et al 2006). The fibroblasts proliferate and produce extracellular matrix proteins such as fibronectin, collagen and other proteins crucial to wound repair (Enoch, Leaper, 2007).

Granulation tissue is made up of proliferating fibroblasts and capillaries enclosed in extracellular matrix (Enoch, Leaper, 2007). Granulation tissue secretes chemicals which degrade the existing clot. Growth factors such as platelet derived growth factor and transforming growth factor beta, induce angiogenesis (this is the formation of new blood vessels). The new blood vessels together with the old clot form a microvascular network which diminishes because collagen accumulates to form scars (Enoch, Leaper, 2007). In normal tissue surplus collagen is removed by collagenases secreted by cells such as fibroblasts and marcophages (Lakhani et al 2009). Verhaegen et al (2009) found an abundance of collagen in hypertrophic and keloid scars. Older collagen is continuously degraded so that new collagen may be deposited. It is believed that this is where the balance goes wrong in hypertrophic and keloidal scars, i.e collagen synthesis exceeds collagen degradation. Collagen gives tensile strength, therefore, faults in its production and orientation give rise to fibrotic scars. (Woolf, N. 2000).

Mitts et al (2010) suggested that by treating keloid fibroblast fibers with the combination of Aldosterone (a steroid hormone), and spironolactone or eplerenone, (both mineralocorticoid antagonist) will inhibit newly synthesized collagen fibers and help in the degradation of existing collagen.

Epitilialization occur after formation of granulation tissue. This process is the migration of a single layer of epidermal cells coming together to form a sheet over the wound. The wound size determines the progression of these cells.

I have included a review of the ECM below so that the importance of its constituents can be appreciated.

Extracellular Matrix (ECM) is produced by fibroblasts in connective tissue. The major constituents of the matrix are glycoaminoglycans (GAGs), structural carbohydrates which form large proteogylcans (Naish et al 2009), fibrous proteins (such as collagen and elastin which play a vital role in keloids and hypertrophic scars) and adhesive proteins. The ECM regulates the growth, movement and proliferation of the cells within it. The GAGs and proteoglycans give the matrix its hydrated gel like structure known as the ground substance (Alberts et al 2008). They are made up of recurring disaccharide chains, one of the sugars being a sulfated amino sugar and the other uronic acid. GAGs are negatively charged and thereby attract positively charged cations such as sodium by osmosis. As a result, water is drawn into the matrix giving it tugor qualities, which allow the matrix to oppose compressive forces from tissues (Alberts et al 2008). Types of GAGs are hyaluronan; chondroitin sulfate and dermatan sulfate; heparin sulfate and keratin sulfate.

Hyaluronic acid is the largest GAG. Unlike the rest of the GAGs, it is not synthesized within the cells but directly from the cell surface. It is also not sulfated or covalently bonded to protein. Hyaluronic acid polymers are quite large; they can displace a large volume of water making them excellent lubricators and shock absorbers (King, M W 2010). They are produced in large quantities during wound healing (Alberts et al 2008).

Proteoglycans are made up of a protein core with GAG side chains attached. Their sizes vary from a single GAG chain to 100 chains. The varying side chains form different pore sizes and charge densities in the matrix. Proteoglycans control the action of signaling molecules (e.g growth factors) by binding to them. This results in the localization of the molecules and in the control of their actions by either stimulating or inhibiting them.

The fibrous proteins of the ECM, such as collagen and elastin, give strength and resilience respectively.

Collagens are of two types, fibrillar and non-fibrillar. Collagens are the most abundant protein making up 25% of total protein mass in mammals (Alberts et al 2008).

Collagen together with GAG's, provide the skin with mechanical and hydration properties (Mitts et al 2010). Collagen has a helical structure made up to 3 alpha collagen polypeptide chains woven together to form a superhelical triple-helix. The alpha chains are repeats of (Gly-X-Y) glycine, X and Y can be any amino acid but are usually proline and hydroxyproline (Alberts et al 2008).

Proline stabilizes the structure of the helix due to its ring structure, and the hydroxyl group help stabilize the alpha chains by forming hydrogen bonds, while the glycine residues allow the alpha chains to pack tightly together due to its small structure of one hydrogen atom as its side chain. The triple helices cross link to form a fibril, the fibril then combine to form a collagen fiber. Keloids and hypertrophic scars have been described as excessive fibroblast proliferation and overabundance of collagen deposition (Rossiello et al 2008).

Verhaegen et al (2009) measured the differences in the collagen architecture of normal skin, normotrophic, hypertrophic and keloidal scars. They found that collagen bundles were organized in a parallel orientation in all the three scars compared to that of normal skin, which was more haphazard in its orientation. Secondly, when the other specimens were compared to keloid specimen, they found that collagen bundles were significantly thinner in the others. Thirdly, they compared four different layers of keloidal tissue, they found differences in the collagen architecture. Collagen bundle distance was highest and most randomly packed in the dermal layer (Verhaegen et al 2009).

The group mentioned the importance of collagen regeneration in wound healing and also concluded that collagen does not regenerate to its original architecture after wounds. In particular, they found the architecture to be disrupted in keloid and hypertrophic scars (Verhaegen et al 2009). They suggested that future research could look into "regeneration of collagen networks" as a treatment of scar formation and repair.

Verhaegen et al 2009

Fig 1> Collagen architecture in normal skin and different scars by confocal microscopy. (A) Normal skin, (B) normotrophic scar, (C) hypertrophic scar, and (D) keloidal scar. The scale bar in (A) represents 100 mm and is also applicable to (B-D). Verhaegen et al 2009

Elastic System

Whilst collagen gives tissues the required strength, elastic fibers provide the tissue with elasticity and resilience, these fibers allow the tissues to passively recoil without generating energy after a temporary stretch enabling tissues to function properly (Amadeu et al 2004). To prevent excessive stretching, long inelastic collagen fibrils are interwoven with the elastic fibres. (Alberts et al 2008)

The elastic system in the skin are made up of three different fibers oxytalan, elaunin and elastic fibers. These fibers are made up of two major components fibrillin rich microfibrils and elastin (Amadeu et al 2004). Fibrillin is a large glycoprotein that binds to elastin, and is important for the integrity of the elastic fibers (Alberts et al 2008)

Oxytalan are fibrillin rich microfibrils with very little elastin. They are mainly found in the superficial dermis (Amadeu et al 2004).

Elaunin are fibrillin rich microfibrils with a little more elastin than oxytalan. They connects oxytalan with elastic fibers (Amadeu et al 2004)..

Elastic fibers have highly hydrophobic cross linked elastin as its major component within its core surrounded, by fibrillin rich microfibrils(Amadeu et al 2004). .

In normal skin, elastic fibers interconnect throughout the dermis and have particularly thick fibers within the deep dermis (Albert et al 2008).

Amadeu et al (2004) found a difference in the distribution of the elastic system components (elastin and fibrillin-1) in keloid and hypertrophic scars. They analyzed the superficial and deep dermis of normal skin, normal scars, keloids and hypertrophic scars.

In normal skin, they found thin fibrillin-1fibers in a "candlestick- like" arrangement in the superficial dermis. In the deep dermis, the fibrillin-1fibers were found mainly around cutaneous appendages and vessels (Amadeu et al (2004)

Small amount of elastin was found in the superficial dermis, with thicker elastin fibers found in the deep dermis.

In normal scars, they found fibrillin-1 fibers thickened in superficial dermis sometimes arranged in a "candlestick- like" arrangement. In deep dermis found fibrillin-1 in long fibers arranged parallel to the epidermis and also like in normal skin found around appendages and vessels (Amadeu et al 2004)..

Elastin was rare in superficial dermis and present in long fibers arranged parallel to the epidermis in the deep dermis (Amadeu et al 2004).

In hypertrophic scars, they found fiibrillin-1in long thin fibers in the superficial dermis without the "candlestick-like" arrangement. In the deep dermis, fibrillin-1fibers were broken up into fragments and found (unconnected to each other) deposited around nodules (Amadeu et al 2004).

In the deep dermis elastin fibers were found unconnected to each other and deposited around nodules but with very little deposition within the nodules themselves (Amadeu et al 2004).

In keloids, they found a reduction of fibrillin-1 and elastin fibers in the superficial dermis. The fibrillin-1 fibers were thin without the "candlestick-like" arrangement. In the deep dermis they found decreased level of fibrillin-1 in very thin fibers.

Elastin was decreased in the superficial dermis, but showed an increased level in the deep dermis arranged parallel to collagen fibers (Amadeu et al 2004).

Amadeu et al (2004) suggested that the increase in elastin coupled with the decrease of fibrillin-1in the deep dermis suggests changes in the composition of myofibrils during development of excessive scarring such as hypertrophic and keloid scars.

In summary, the researchers found that volume density of fibrillin-1in the superficial and deep dermis was higher in normal skin when compared to keloids and hypertrophic scars. The volume density for the elastin fibers in the superficial dermis of normal skin was higher when compared to the rest of the scars. Their figures indicated that there was more elastin in keloids in the superficial dermis when compared to hypertrophic scars (elastin in normal skin was higher by 50.5% in hypertrophic scars and by 36% in keloids) (Amadeu et al 2004). In the deep dermis, volume density of elastin in keloids compared with normal skin was 40% higher. 24.8% higher compared with normal scars and 33.4% higher compared with hypertrophic scars.

The adhesive proteins such as fibronectin and laminin act to connect the fibrous proteins to the cells.

The ECM and its components are essential in wound healing as they provide the framework the cells need to fulfill their proper functions.

The matrix fulfils its differing roles by varying the amount and organization of the macromolecules components, thereby determining the tissue's physical properties (Alberts et al 2008).

Maturation / Remodelling phase: The repairs that were made during the proliferation phase are made even stronger. The original collagen (type III) is replaced with the stronger type I collagen (Lakhani et al 2009). The collagen bundles are arranged in a parallel orientation. In normal skin, collagen is arranged hapharzadly (Verhaegen et al 2009). The wound continue to contract. By the end of the maturation phase, the wound is now permanently replaced with collagen rich scar tissue.

Keloids

Keloids are the result of the deposition of excessive scar tissue during wound healing. During the proliferation phase of wound healing, the constituents of the extracellular matrix are deposited into the dermis (Enoch, Leaper, 2007). The excessive fibroproliferation is mainly due to the excessive deposition of thick hyalinised eosimophilic collagen (Jagadeesan et al 2006). In the past, keloids were classified into two subgroups; true and false (cicatrix) keloids. The true keloids are the ones that occur spontaneously without any trauma to the skin while the false keloids occur after surgery or burns (Sullivan et al 1996). Individuals inflicted with keloids are left with devastating physical and psychological scars (Bock et al 2006).

Keloids may develop after minor skin irritation or incision such as acne and insect bites. There are varying time lapse between the wound and keloid formation (Kose et al 2007). The average tends to be within the year of the wound. By the second and third month of keloid formation, its surface become irritable, round and smooth giving it a nodular appearance (Kose et al 2007). Keloids extend beyond the confines of the original wound showing "clawlike" extensions into the normal neighbouring skin (Rossiello et al 2008). The scar does not regress with time as in the case with hypertrophic scar. It has the unattractive quality of being strongly adverse to treatment, and comes back with a vengeance to the same anatomical place if it is removed by surgery. Some researchers believe that keloids have phases of enlargement and reactivation (Brissett et al 2001). Below, are images of the devastating disfigurement of keloid scars taken from the Bayat et al (2005)

Bayat et al (2005)

Clinical presentation

Locations such as the presternal areas, deltoid, ears, chest, upper back, and posterior neck are more susceptible to keloid formation. Other areas of the body have also been identified, such as the pubic area (Bayat et al 2005). Patients complain of burning, pruritus (itching) and pain in the areas affected. (Kose et al 2007). These types of discomfort were also described by the individuals interviewed by Brown et al (2008).

Epidemiology

Keloids occur only in humans and affect both genders equally (Bayat et al 2005). Keloids affect all races, but predominantly higher in pigmented individuals (such as blacks and Asians) with a genetic predisposition. Albinos and Caucasians are rarely affected (Rossiello et al 2008). Keloid scars can appear in single or multiple anatomical sites. Bayat et al (2005) stated that multiple keloid scars were commonly found on individuals with positive familial history of keloids than with individuals with negative family history of keloids.

Kose et al 2007 stated that symptoms of keloids and hypertrophic scars disappear in women after menopause but may be stimulated during pregnancy, indicating a link with the hormone oestrogen? It rarely affects babies and the elderly but it is more predominant in the second decade of life. Bayat et al (2005) suggested that this is probably due to a higher degree of skin tension in younger people when compared to that of older individuals.

Histopathology

Keloids occur due to the excessive deposit of collagen which grows beyond the borders of the original wound. They are known not to regress with time. Collagen and Elastic properties as above.

Molecular and cellular pathology

Collagen deposition

Keloids are known to have increased levels of the extracellular matrix (ECM). Lee et al (1991) stated that keloid fibroblasts have a significant increase in the levels of type I procollagen mRNA. They also found a moderate increase in type III procollagen mRNA and elastin when compared to that of normal skin. In the maturation phase of wound healing, type III collagen is replaced by the stronger type I collagen (Lakhani et al 2009).

Increase in collagen synthesis can also be attributed to an elevated level in Propyl-4 hydroxylase activity (Jagadeesan et al 2006). Propyl-4 hydroxylase is an enzyme which catalyzes peptide bound proline residues to 4- hydroxyproline during the formation of procollagens. The hydroxylation process is an important step to forming a stable triple helix in procollagens, without this step, the unhydroxylated procollagens are unable to form triple helix and undergo degradation. Sakaida et al (1995) proposed that the use of propyl-4 hydroxylase inhibitors might be useful to dampen down collagen synthesis.

Another factor contributing to excessive collagen is an increase in the synthesis of fibronectin (Pedro et al 2008). Fibronectin is a multiadhesive matrix protein (Lodish et al 2008). These proteins help influence cell movement, shape and organization of the cell cytoskeleton by binding to fibrous collagen and other factors such as integrins (cell surface adhesive receptors) (Lodish et al 2008). With the help of the fibronectin the cells modify the extra cellular matrix (ECM) to suit their environments. They play an important factor in wound healing where they act to promote the migration of immune cells such as marcophages into the wound.

Growth factors

In normal wound healing, growth factors such as interleukins, transforming growth factor beta (TGF β) and insulin like growth factors (IGF) play an important role.

Interleukins are part of the cytokines family which help regulate cell growth, cell movement and cell differentiation. They also help stimulate inflammation which is a natural process in wound healing (Jagadeesan et al 2006)

Transforming growth factor beta (TGF β) as suggested by Jagadeesan et al (2006) plays a key role in the initiation and termination of tissue repair and regeneration. They also suggested that the increase in the level of production of this growth factor lead to increased level of extracellular matrix constituents such as fibronectin and collagen, leading to increased scar tissue as in the case of keloids and hypertrophic scars.

TGF β interacts and signal via four types of transmembrane receptors in order to act on its target cells (Jagadeesan et al 2006). Types I and II are the main ones that are involved directly with signal transduction while the other two receptors act in accessory roles by presenting types I and II with ligands (Jagadeesan et al 2006).

The type I receptor interacts with intracellular SMAD proteins (proteins which stimulate gene transcription by transducing signals from the cell surface to the nucleus (Brown et al 2008).

The TGF β1 isoform has been linked with keloids and hypertrophic scars (Jagadeesan et al 2006). Jagadeesan et al (2006) suggested that during the proliferative phase of wound healing, modifications to the regulatory pathway stimulates the TGF β1 receptor to accelerate the synthesis of fibronectin production leading to an elevated rate of collagen synthesis in keloid fibroblasts.

Brown et al 2008, stated that Single nucleotide polymorphisms (SNPs; variations in DNA when a single nucleotide in the genome is altered creating a unique pattern) which affect the SMAD proteins may prove to be significant in the development of keloids. The researchers initial analysis found that some SNPs may be linked with predisposition to keloids but later found this to be untrue after corrective measurement were put into place. However they did indicate that their findings might be inconclusive because of the well documented disorders of the SMAD genes in fibrotic diseases. They indicated that, for future research, SNPs located in regulatory regions on SMAD genes and also involved in gene splicing should be looked at. For the understanding of treatments, they indicated that spontaneous keloids might have a different aetiology to trauma induced keloids, and that the understanding of these differences would help with clinical classification and treatment regimes (Brown et al 2008)

Hormonal factors

Some researchers have reported the increase in the incidence of keloids in females whilst some say that it equally affect both male and female (refs?). Oestrogen and androgens have been implicated by researchers because of the decreased incidence in older individuals and the rarity of keloids in babies (ref). Gilliver et al (2007), reported on the impact of hormonal regulation of wound healing in the elderly. It was reported that the decrease of oestrogen in postmenopausal women led to delayed wound healing and decreased collagen deposition.

In normal wound healing oestrogen accelerates reepithelialization by modulating cytokine expression, extracellular matrix (ECM) deposition, stimulation of angiogenesis and wound contraction and also the regulation of proteolysis (Gulliver et al 2007). Most importantly, oestrogen increases the expression of TGF β1 (a factor that induces and inhibits the synthesis and degradation of extracellular matrix, respectively). This factor has been linked to keloids in the past because modification to its regulatory pathway has been found to accelerate the synthesis of fibronectin production leading to the increased synthesis of collagen (Jagadeesan et al 2006).

It was difficult for me to find research linking androgens and oestrogen directly to keloids, but I did find a lot of researchers speculating that there might be a link between the two (refs). I therefore propose that maybe this should be a research area in the future because I believe that there is enough evidence, (as I have displayed above) for further research.

Hypertrophic scars

These are known to have the highest incidence especially after burns but they can occur following trauma and surgical procedures. It is believed that during the proliferative phase of wound healing, collagen deposition is exceeds collagen lysis.

O'Sullivan et al 1996 states that after the proliferative period, collagen synthesis and lysis reach a temporary equilibrium within three to four weeks after injury in normal scars. In the case of keloids and hypertrophic scars, this temporary equilibrium is defective and never reached where collagen synthesis continue to exceed collagen lysis.

Clinical presentation

Like keloids, hypertrophic scars are characterized by excessive fibroblast proliferation and increased deposition of collagen. Unlike keloids, hypertrophic scars remain confined to the area of original tissue injury (Rossiello et al 2008). They grow by extending tissue margin but not by invasion as in the case with keloids. Hypertrophic scars are recognizable by the difference in the colour to the surrounding skin, they are raised, but they rarely elevate more than 4mm above skin surface (Kose et al 2007). Hypertrophic scars develop within one to three months after the wound (Bloeman et al 2008).

Also, like keloids, patients present with pain and itching with the scar appearing stiff with a rough texture, making mobility, in the area affected, a challenge to the sufferers. Like keloids, they can present with serious deformities and cosmetic problems and may also slowly regress, fade and whiten with time (Van der Veer et al 2008)

Hypertrophic scars present in joint areas of the body and are common in the extensor surfaces such as knees and elbows (Kose et al 2007)

Epidemiology

Epidemiological factors have been very difficult to find. I have read varying information from different researchers. The general information being, that this type of scar is more common than keloids, affects people of different races and more common after burns injury.

Histopathology

Collagen structure

Elastin structure

Molecular and cellular pathology

In normal wounds, the expression of fibronectin, one of the factors that affect heamostasis decreases shortly after the closing of the wound. Together with fibrin, they facilitate the migration of dermal fibroblast and endothelial cells. Van der Veer et al 2008, stated that these decrease in fibronectin expression do not occur in the case of hypertrophic scars. It is believed that the expression continues at a higher level months to years following the wound which may eventually have an effect on fibroblast density.

With the belief that hypertrophic scars occurs mostly after burns (Bloemen et al 2008), this would have an exaggerated effect on inflammation leading to a high concentration level of cytokines such as platelet derived growth factor, interleukin and TGF β1, factors which have been linked to keloids and hypertrophic scars.

All the above factors together with others such as lengthy reepithelialization, decreased apoptosis and increase in granulation tissues influence the modification pathways and result in an increased extracellular matrix which eventually lead to increase in collagen making the wound become hypertrophic.

The quality of life of keloid and hypertrophic individuals

Regarding the quality of life of individuals suffering from keloids and hypertrophic scars, Bock et al (2006) measured the psychological and physical impairments felt by 100 patients. They found that the patients suffered from feelings of worthlessness and that they lacked physical or sexual desirability (Bock et al 2006). Most of the patients felt and experienced stigmatization. Brown et al (2008) also stated that 56% of their research subjects felt that other people judged them as being criminals based on their appearance. Brown et al (2008) and Bock et al (2006) mentioned that rejection and loss of self confidence are common amongst these patients. The location of the scar is important because mobility of the affected area might be restricted if the scar crosses a joint (Brown et al 2008). Bock et al (2006) suggested that the quality of life of these patients can be compared with that of people suffering from psoriasis. Rapp et al (1999) stated that people suffering from psoriasis suffered the same reduced quality of life as those people with severe heart failure.

Treatment of Keloids and hypertrophic scars

Many researchers have agreed that the one of the most important factor for treatment is the correct diagnosis of these scars. Proper diagnosis leads to proper specialized treatment. Also, many of them have agreed that prevention is better than cure. Mostly, this prevention is aimed at people who have had previous scars and are predisposed to genetic factors. Advise has been given to the type of surgery, if any for both scars. The best treatments are the ones that the patients would adhere to, as it would be difficult for the physician to manage these scars without their help.

Preventive treatment

Hypertrophic scars mostly happen after burns, immediate topical treatment is needed to control inflammation and help with accelerated wound closure (Bloemen et al 2008) One such treatment is silicone, it is topical, painless, non-invasive and can be applied as a gel. To get the best advantage, it is advised that it should be applied and worn 12 - 24 hours a day from about 2 weeks to the 3rd month post operatively (Bloemen et al 2008).

Another preventive treatment is pressure therapy where compression garments are used. These are recommended immediately after wound healing and the patient can bear the pressure of the compression. Bloemen et at 2008 stated that it had an effect on the collagen remodeling phase of wound healing. Kerckhove et al 2005 measured the significance of using two different pressure garments on scar wounds. They used compression garments with a mean of 15mmHg and 10mmHg respectively. They recommended the 15mmHg pressure garment as a preventive measure. They believed it accelerates scar maturation and also a significant decrease scar thickness was recorded up to one month of use. However, no significant difference was measured after this period.

Curative treatment

Corticosteroids, have anti-inflammatory characteristics and inhibit collagen synthesis. Bloemen et al 2008 suggested that Triamcinolone acetonide 10-40mg/ml could be administered intralesionally by injection. The group recommended that total dosage should not exceed 30-40mg making it unsuitable for use on extensive burn scars. They also mentioned that topically administered steroids may only have an effect on superficial burns only due to poor tissue absorption.

Aonther intralesional injection is 5-Fluorouracil. This has been found to affect collagen remodeling phase (reduces fibroblast proliferation). Has an effect on the reduction of the scar and complete flattening can be achieved with the administration of 5-10 injections (Mutalik, S. 2005) It was mentioned that the treatment can be quite painful but it could be alleviated by giving a field block anaesthetic or triamcinolone acetonide (Mutalik, S. 2005)

Interferons, are a class of inherent proteins secreted by the immune system. Interferons boost the immune system and regulate growth factors thereby giving them antiproliferative properties. Administration of interferon alpha 2b has been reported as successful with some researchers claiming a significant improvement in patients as reviewed by Bloemen et al 2008. However, Davidson et al 2006 compared this treatment with triamcinolone when they treated some patients with interferone alpha 2-b and the others with triamcinolone. They found a 54% recurrence rate with in interferone patients compared with a 15% recurrence rate in patients treated with triamcinolone.

Cyrotherapy, is administered in a15-30 seconds cycle of thawing and freezing using liquid nitrogen (Mutalik, S. 2005). It is also thought to influence the collagen remodeling phase. It can be used on its own for hypertrophic scars or with intralesional corticosteroid treatments in keloids. Also, it can be sprayed on the scars or intralesionally as in the case with deep nodular keloids. Other researchers have reported a good response to the treatment without recurrence in patients with hypertrophic scars. with the administration of this treatment.

Surgical intervention, this is not a favorite treatment with physicians because of recurrence rates. The surgeon takes a lot of factors into consideration together with patient expectation before commencing. These factors include, the age of the scar, the position of the scar anatomically, the scar's surface area, failed prior treatments and the cause of the scar (Bloemen et al 2008).

Also, for optimal success, surgery should be coupled with other treatments such as steroid injections to limit the recurrent rate of 45% - 100% (review by Robles et al 2007). It is also claimed that when surgery is coupled with other treatments such as steroid injection, the recurrence decreases to less than 50% in keloid patients (Mustoe et al 2002).

Laser therapy, Robels et al 2007, suggested that the 585-nm pulsed dye laser has shown the most effective results. They stated that combining this treatment with intralesional steroid injection may make the scars softer. This increases the chances of the steroids having an effect on fibroblast proliferation.

Conclusion

Before embarking on this research, I had no idea what hypertrophic scars were. I labeled every such scar as a keloid. Having seen the horrific pictures of keloids, I can only have empathy for these people. I now feel that I should make the heroic attempt of finding a cure in the future. I can only hope!

Bock et al 2006, commented on the feelings of hopelessness that these patients suffer from because of the non responsiveness of their scars to treatments. Several researchers have made attempts and I think it is showing a more promising prognosis.

My essay focused more on collagen and elastin deposition, therefore, I have included below, the recommendations that other researchers who have looked into the cause and effect of collagen in keloid and hypertrophic scars.

Suggested research areas for future treatment

Suggestions to block TGF β1 receptor was raised by Jagadeesan et al 2006 as a way to reduce collagen synthesis. They also mentioned the acceleration of the degeneration of type I and III collagen (which are abundant in keloids) could be an effective way of future treatment.

Mitts et al 2010 findings indicated that the ECM of the keloid explant treated with Aldosterone (a steroid hormone), when coupled with spironolactone or eplerenone, (both mineralocorticoid antagonist) showed active matrix remodeling by inducing formation of newly synthesized elastin in the cultured fibres of hypertrophic and keloid scars. In addition to this findings they noticed that, keloid fibroblasts, when treated with the combination of these two, not only increase levels of newly synthesized elastic fibers but also inhibit newly synthesized collagen fibers and help in the degradation of existing collagen fibers (Mitts et al 2010)

The researchers therefore proposed the intralesion injection of aldosterone and eplerenone (the more specific mineralocorticoid inhibitor) as a possible treatment for keloids and hypertrophic scars.

For hypertrophic scars, Mitts et al 2010 found that by combining aldosterone and spironolactone , produced more elastic fibers in both superficical and deep layers of dermal scars.

The other area that I did not research is the melanocytes, I would like to see research done in this area because of the higher incidence rates of keloids in dark pigmented individuals.

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