Scar free healing

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]

Figure 1: A) Collagen fibres in normal skin 'basket weave'. B) Parallel collagen fibres in scar tissue.

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]

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)

Figure 2: Mechanism of liver regeneration in adult humans

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;

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 is 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.

• Kishi, K.; Okabe, K.; Shimizu, R.; Kubota, Y. (2012). "Fetal Skin Posses the Ability to Regenerate Completely: Complete Regeneration of Skin". The Keio Journal of Medicine. 61 (4): 101–108. doi:10.2302/kjm.2011-0002-ir. PMID 23324304.