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Scar free healing is the process by which significant injuries can heal without permanent damage to the tissue the injury has affected. In most healing, scars form due to the fibrosis and wound contraction, however in scar free healing, tissue is completely regenerated. During the 1990s, published research on the subject increased; it is a relatively recent term in the literature. Scar free healing occurs in foetal life but the ability progressively diminishes into adulthood. In other animals such as amphibians, however, tissue regeneration occurs, for example as skin regeneration in the adult axolotl. [1]
Scarring takes place in response to damaged or missing tissue following injury due to biological processes or wounding: it is a process that occurs in order to replace the lost tissue. [2] The process of scarring is complex, it involves the inflammatory response and remodelling amongst other cell activities. Many growth factors and cytokines are also involved in the process, as well as extracellular matrix interactions. [2]
Scarring during healing can create both physical and psychological problems, and is a significant clinical burden. Collagen, for instance, is abnormally organised in scar tissue; collagen in scars is arranged in parallel bundles of collagen fibers, whilst healthy scar free tissue has a "basket weave" structure (Figure 1). [2] The difference in collagen arrangement along with a lack of difference in the dermal tissue when healing has taken place with or without scarring is indicative of regenerative failure of normal skin. [2] Severe scarring resulting from these collagen deposits is known as hypertrophic scarring and is of great concern worldwide with an incidence ranging from 32–72%. [3]
Unlike the limited regeneration seen in adult humans, many animal groups possess an ability to completely regenerate damaged tissue. [4] Full limb regeneration is seen both in invertebrates (e.g. starfish and flatworms which can regenerate fully functioning appendages) and some vertebrates, however in the latter this is almost always confined to the immature members of the species: an example being tadpoles which can regrow their tails and various other body parts, an ability not seen in the mature frogs. [5] The exception to this is the much studied urodele species' of amphibians, also known as salamanders, which carry their ability of complete regeneration into adulthood. [2] These vertebrates possess an exceptional ability to allow regeneration of entire limbs and their tails (as well as a multitude of their internal organs as well, including their spinal cord) [2] through a process known as blastema formation. [6] This involves covering of the wound by a layer of epithelial cells known as the wound cap and subsequent innervation of this area with nerves that give off signals that revert local differentiated cells (such as muscle, cartilage and connective tissue) back to their undifferentiated cell lineage also known as mesenchymal cells. [6] It is this area that is known as the blastema which has the potential to differentiate and proliferate once again allowing regrowth of the limb similar to how it occurs during development. [7] In wound-healing in urodeles it is the quick response of anti-inflammatory macrophages which have been shown to be key to their regeneration capabilities. In one study, it was found that limbs would not regenerate in those urodeles with depleted macrophages and instead would scar with permanent loss of functionality. [8] Knowing how regeneration occurs in animals such as these may have great implications for how wound-healing is tackled in medicine and research has been aimed at this area, as a result.
Reparation of tissue in the mammalian fetus is radically different than the healing mechanisms observed in a healthy adult. During early gestation fetal skin wounds have the remarkable ability to heal rapidly and without scar formation. Wound healing itself is a particularly complex process and the mechanisms by which scarring occurs involves inflammation, fibroplasia, the formation of granulation tissue and finally scar maturation. Since the observation of scar free healing was first reported in the early fetus more than three decades ago, research has focused intently on the underlying mechanisms which separate scarless fetal wound repair from normal adult wound healing.
Scar free healing has been documented in fetuses across the animal kingdom, including mice, rats, monkeys, pigs and humans. It is important to note that the ability of fetuses to heal without scarring is wound size dependent and also age-dependent, whereby after a specific gestational age, usually 24 weeks in humans, typical scar formation will occur. While the exact mechanisms of scar free healing in the fetus remain unknown, research has shown that it is thought to be due to the complex interaction of the components of the extracellular matrix (ECM), the inflammatory response, cellular mediators and the expression of specific growth factors. [9]
Originally, it was thought that the intrauterine environment, the sterile amniotic fluid surrounding the embryo, was responsible for fetal scar free healing. Reasoning that embryonic wounds healed scarlessly because they were not exposed to the same contaminating agents which normal adult wounds were exposed to such as bacteria and viruses. However this theory was discredited by investigating fetal wound healing in the pouch of a young marsupial. These pouches can often be exposed to maternal faeces and urine, a highly different environment to the sterile intrauterine environment seen in eutherian embryos. Despite these differences skin wounds on the marsupial healed without the formation of a scar, proving the irrelevance of the embryonic environment in scar free healing.[ citation needed ]
One of the major differences between embryonic scar-free healing wounds and adult scar-forming wounds is the role played by the cells of the immune system and the inflammatory response.
Table 1: Summary of the major differences identified between fetal and adult wound healing. [10] [11]
Select Component | Fetal | Adult | Role in Wound Healing | |
Immune System and Inflammation | IL-10 IL-6/8 | High levels Low levels | Low levels High levels | Anti-inflammatory cytokines Pro-inflammatory cytokines |
Extracellular Matrix (ECM) | Hyaluronic acid CD44 (hyaluronic acid receptor Tenascin Fibronectin Decorin Fibromodulin Collagen | High levels High levels High levels High levels Low levels High levels Elevated ratio of type 111 to type 1 | Low levels Low levels Low levels Low levels High levels Low levels Elevated ratio of type 1 to type 111 | Cellular movement, cell-matrix interactions, cell migration Anti-adhesive, anti-proliferative Tissue architecture, cell proliferation/migration, cell matrix interactions Inhibits fibrillogenesis Tissue architecture, ECM remodeling, tensile strength, cell-matrix interactions |
Growth Factors | EGF PDGF FGF TGF-β1 TGF-β2 TGF-β3 VEGF | High levels Low levels Low levels Low levels Low levels High levels Low levels | Decreases with age High levels High levels High levels High levels Low levels High levels | Stimulate fibroblasts to secrete collagen Fibroplasia Matrix deposition, fibroblast migration, angiogenesis Infiltration of neutrophils and macrophages, fibroplasia, scarring, fibrosis Infiltration of neutrophils and macrophages, fibroplasia, scarring, fibrosis Possible role in anti-scarring Angiogenesis |
Wound Closure | Actin cable | Myofibroblasts |
The fetal immune system can be described as 'immunologically immature' due to the marked reduction in neutrophils, macrophages, monocytes, lymphocytes and also inflammatory mediators, compared with adult wounds. [12] Physiologically, adult and fetal neutrophils differ, due to the fact that the concentration of neutrophils is higher in the adult than the fetus, this results in phagocytosis of the wound and the recruitment and release of inflammatory cytokines. Leading to the promotion of a more aggressive inflammatory response in adult wound healing. It is also thought that the time in which this inflammatory response occurs, is much shorter in the fetus thus limiting any damage. [13]
Another difference between the healing of embryonic and adult wounds is due to the role of fibroblast cells. Fibroblasts are responsible for the synthesis of the ECM and collagen. In the fetus, fibroblasts are able to migrate at a faster rate than those found in the adult wound. Fetal fibroblasts can also proliferate and synthesize collagen simultaneously, in comparison to adult fibroblasts where collagen synthesis is delayed. It is this delay in both collagen deposition and migration, which is likely to contribute to formation of a scar in the adult.
Proteins and cell surface receptors found in the ECM differ in fetal and adult wound healing. This is due to the early up regulation of cell adhesion proteins such as fibronectin and tenascin in the fetus. During early gestation in the fetal wounds of rabbits, the production of fibronectin occurs around 4 hours after wounding, much faster than in adult wounds where expression of fibronectin does not occur until 12 hours post wounding. The same pattern can be seen in the deposition of tenascin. It is this ability of the fetal fibroblast to quickly express and deposit fibronectin and tenascin, which ultimately allows cell migration and attachment to occur, resulting in an organised matrix with less scarring. [13]
Another major component of the ECM is hyaluronic acid (HA), a glycosaminoglycan. It is known that fetal skin contains more HA than adult skin due to the expression of more HA receptors. The expression of HA is known to down-regulate the recruitment of inflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-α); since fetal wounds contain a reduced number of pro-inflammatory mediators than adult wounds it is thought that the higher levels of HA in the fetal skin aid in scar free healing.
Analysis using microarrays has also shown that gene expression profiles greatly differ between scar free fetal wounds and postnatal wounds with scar formation. In scarlesss wound healing there is a significant up-regulation in genes associated with cell growth and proliferation, thought to be a major contributing factor to the rapid wound closure seen in the foetus. [9] Whilst wound healing in the fetus has been shown to be completely scarless in an age-dependent manner, adult mammals do not have complete scar free healing but have retained some regenerative properties. Adult regeneration is limited to a number of organs, most notably, the liver.
There are few examples of regeneration in humans continuing after fetal life in to adulthood. Generally, adult wound healing involves fibrotic processes causing wound contraction which may lead to the formation of scar tissue. [14] In regeneration, however, completely new tissue is synthesized. This can lead to scar free healing where the function and structure of the organ is reinstated. [15] However organ regeneration is not yet fully understood.
Two types of regeneration in human adults are currently recognised; spontaneous and induced. [2]
Spontaneous regeneration occurs in the human body naturally. The most recognised example of this is the regeneration of the liver, [16] which can regenerate up to two thirds of its mass when injured by surgical removal, ischaemia or after exposure to harmful toxins. [16] (Figure 2)
Through this mechanism the liver can be restored to its original state, scar-free. However, despite nearly 80 years of research on liver regeneration much debate still surrounds the exact mechanisms by which the process occurs. [16]
Another example of spontaneous regeneration endometrial lining of the uterus after menses during reproductive years. Endometrial glands from a basal layer of the uterine wall can regenerate the functional layer without fibrosis or scarring. [17]
Most recently, the kidney has been found to have the ability to regenerate. Following removal or incapacitation of one kidney the other may double in size in order to counteract the loss of the other kidney. This is known a compensatory growth. [18]
Induced regeneration stimulated by an outside source of a "non-regenerative" organ. [2] In humans is for therapeutic use. Induced regeneration is currently being trialled to replace organ transplants as issues such as rejection, lack of donors and scarring would be eliminated. [19]
The table below details some of the tissues in which induced regeneration has been attempted;
Tissue | Type of Regeneration | Mechanisms of Regeneration and current research tools |
Heart Muscle | Induced | Using differentiation of somatic stem cells into cardiomyocytes. [20] |
Thymus | Induced | Up regulating FOXN1, which causes increased expression of thymic epithelial cell specific receptor, which regenerates an aged thymus. [21] |
Vagina | Induced | Reconstruction of vaginal muscle and epithelial cells using biodegradable scaffolds. [22] |
Skin | Induced | Use of a regeneratively active collagen scaffold to prevent wound contraction. [2] |
Peripheral Nerve | Induced | Use of a regeneratively active collagen scaffold to prevent wound contraction. [2] |
Following injury or surgery, a doctor's key aim is to restore full function in a patient and help ensure they return to as close to their original state before their skin trauma or surgery. [23] Ensuring patients return as closely to their original appearance and original function is challenging in the context of scarring. Scar-free healing is yet to be observed in healthy post gestational humans, despite being seen in human embryos. Currently, it is only possible to reduce scar visibility, and the NHS suggests a number of different methods of doing this including corticosteroid injections, skin creams, silicone gels, pressure dressings, dermal fillers, radiotherapy and laser therapy. [24] Although these methods do reduce a scars visible appearance, they do not result in a scar free appearance. Billions of pounds are spent on wound maintenance and healing on the NHS every year. Between 2014 and 2015 in England and Wales, 19,239 people sustained a burn injury which required hospital care. [25] In addition to the significant financial cost, the cost of scars is immense to the patients too. One study into the quality of life of patients with scars found that over half of the participants felt stigmatised by their scars and felt their personal relationships deteriorated. In addition to this, 68% tried to hide their scars, whilst reporting their work life, self-confidence and ability to communicate with others had been negatively affected. [26] Future research and advances in scar-free healing could lessen the cost to the NHS whilst also improving the quality of life to many people affected.
In humans, the vocal cords, also known as vocal folds, are folds of throat tissues that are key in creating sounds through vocalization. The length of the vocal cords affects the pitch of voice, similar to a violin string. Open when breathing and vibrating for speech or singing, the folds are controlled via the recurrent laryngeal branch of the vagus nerve. They are composed of twin infoldings of mucous membrane stretched horizontally, from back to front, across the larynx. They vibrate, modulating the flow of air being expelled from the lungs during phonation.
A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of connective tissue in animals.
A scar is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound results in some degree of scarring. An exception to this are animals with complete regeneration, which regrow tissue without scar formation.
A tendon or sinew is a tough band of dense fibrous connective tissue that connects muscle to bone. It sends the mechanical forces of muscle contraction to the skeletal system, while withstanding tension.
With physical trauma or disease suffered by an organism, healing involves the repairing of damaged tissue(s), organs and the biological system as a whole and resumption of (normal) functioning. Medicine includes the process by which the cells in the body regenerate and repair to reduce the size of a damaged or necrotic area and replace it with new living tissue. The replacement can happen in two ways: by regeneration in which the necrotic cells are replaced by new cells that form "like" tissue as was originally there; or by repair in which injured tissue is replaced with scar tissue. Most organs will heal using a mixture of both mechanisms.
Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.
Regeneration in biology is the process of renewal, restoration, and tissue growth that makes genomes, cells, organisms, and ecosystems resilient to natural fluctuations or events that cause disturbance or damage. Every species is capable of regeneration, from bacteria to humans. Regeneration can either be complete where the new tissue is the same as the lost tissue, or incomplete after which the necrotic tissue becomes fibrotic.
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of permanent scar tissue.
In cell biology, an effector cell is any of various types of cell that actively responds to a stimulus and effects some change.
Tendinitis/tendonitis is inflammation of a tendon, often involving torn collagen fibers. A bowed tendon is a horseman's term for a tendon after a horse has sustained an injury that causes swelling in one or more tendons creating a "bowed" appearance.
A chronic wound is a wound that does not heal in an orderly set of stages and in a predictable amount of time the way most wounds do; wounds that do not heal within three months are often considered chronic. Chronic wounds seem to be detained in one or more of the phases of wound healing. For example, chronic wounds often remain in the inflammatory stage for too long. To overcome that stage and jump-start the healing process, a number of factors need to be addressed such as bacterial burden, necrotic tissue, and moisture balance of the whole wound. In acute wounds, there is a precise balance between production and degradation of molecules such as collagen; in chronic wounds this balance is lost and degradation plays too large a role.
A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.
Paired mesoderm homeobox protein 2 is a protein that in humans is encoded by the PRRX2 gene.
Artificial skin is a collagen scaffold that induces regeneration of skin in mammals such as humans. The term was used in the late 1970s and early 1980s to describe a new treatment for massive burns. It was later discovered that treatment of deep skin wounds in adult animals and humans with this scaffold induces regeneration of the dermis. It has been developed commercially under the name Integra and is used in massively burned patients, during plastic surgery of the skin, and in treatment of chronic skin wounds.
In medicine, desmoplasia is the growth of fibrous connective tissue. It is also called a desmoplastic reaction to emphasize that it is secondary to an insult. Desmoplasia may occur around a neoplasm, causing dense fibrosis around the tumor, or scar tissue (adhesions) within the abdomen after abdominal surgery.
Acellular dermis is a type of biomaterial derived from processing human or animal tissues to remove cells and retain portions of the extracellular matrix (ECM). These materials are typically cell-free, distinguishing them from classical allografts and xenografts, can be integrated or incorporated into the body, and have been FDA approved for human use for more than 10 years in a wide range of clinical indications.
The dermal equivalent, also known as dermal replacement or neodermis, is an in vitro model of the dermal layer of skin. There is no specific way of forming a dermal equivalent, however the first dermal equivalent was constructed by seeding dermal fibroblasts into a collagen gel. This gel may then be allowed to contract as a model of wound contraction. This collagen gel contraction assay may be used to screen for treatments which promote or inhibit contraction and thus affect the development of a scar. Other cell types may be incorporated into the dermal equivalent to increase the complexity of the model. For example, keratinocytes may be seeded on the surface to create a skin equivalent, or macrophages may be incorporated to model the inflammatory phase of wound healing.
Dermal fibroblasts are cells within the dermis layer of skin which are responsible for generating connective tissue and allowing the skin to recover from injury. Using organelles, dermal fibroblasts generate and maintain the connective tissue which unites separate cell layers. Furthermore, these dermal fibroblasts produce the protein molecules including laminin and fibronectin which comprise the extracellular matrix. By creating the extracellular matrix between the dermis and epidermis, fibroblasts allow the epithelial cells of the epidermis to affix the matrix, thereby allowing the epidermal cells to effectively join together to form the top layer of the skin.
Diabetic foot ulcer is a breakdown of the skin and sometimes deeper tissues of the foot that leads to sore formation. It may occur due to a variety of mechanisms. It is thought to occur due to abnormal pressure or mechanical stress chronically applied to the foot, usually with concomitant predisposing conditions such as peripheral sensory neuropathy, peripheral motor neuropathy, autonomic neuropathy or peripheral arterial disease. It is a major complication of diabetes mellitus, and it is a type of diabetic foot disease. Secondary complications to the ulcer, such as infection of the skin or subcutaneous tissue, bone infection, gangrene or sepsis are possible, often leading to amputation.
Regeneration in humans is the regrowth of lost tissues or organs in response to injury. This is in contrast to wound healing, or partial regeneration, which involves closing up the injury site with some gradation of scar tissue. Some tissues such as skin, the vas deferens, and large organs including the liver can regrow quite readily, while others have been thought to have little or no capacity for regeneration following an injury.