Healing of Skin Superficial Wound

Healing of Skin Superficial Wound

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How does the body heal a skin wound without bleeding? I had a wound in which thick layer of skin was gone and which was too painful to touch. I could see the wound secreting clear liquid rather than forming a scab like in a blood wound. What is this yellowish thick liquid being secreted and does it form new skin?

Skin is composed of layers, the uppermost being the epidermis. Upper layers of the epidermis (dry, flat cells tightly packed together, and of varying thickness on different parts of the body) can be abraded off, leaving deeper layers of the epidermis (nearer to underlying blood vessels) exposed. Since peripheral nerve endings do exist in this area, the wound is painful. A wound that does not extend into the dermis does not bleed (for example, a second degree burn can lift the upper layers of the epidermis from the deeper layers; no blood will collect in the blister, but the wound is painful. Peel off the top of the blister, and you have an analogous situation.

Because the surface of the skin is no longer present, fluid (as with a blister, not containing red blood cells) leaks from the blood vessels. Initially a transudate, it can also be an exudate. And, no, it does not contain the cells needed to regenerate the upper layers of the skin. It contains many of the proteins found in serum and may contain white blood cells which help to fight off infection.

New cells are generated from the deeper cell layers (the basal cells) which are still intact. They grow from the bottom of the wound up, so to speak. The scab formed by the dried fluid keeps the layer under it moist, providing a good environment for cell growth.

Epidermis and Its Renewal by Stem Cells

Healing of Skin Superficial Wound - Biology

Wound healing is a complex process that is not fully understood. Involved in natural wound healing are many cell types, growth factors, and other proteins, among other influential factors. All tissues undergo some degree of tissue repair/regeneration. The process varies for different tissues, but generally follows a consistent development.
The outcome of wound healing, or tissue repair, is the substitution of viable cells for dead cells. This can occur via regeneration or replacement. In regeneration, the cells are replaced with the same types that were lost and tissue function is generally restored. In replacement, the tissue is eventually replaced with a different type of tissue, namely scar tissue. Most wounds heal through a combination of the two processes the specific combination depending on the type of tissue and the nature and extent of the wound. [1] Ideally, the wound would heal completely by regeneration. Healing in soft epithelial tissue occurs with the concurrent actions of three basic phenomena: wound contraction, formation of granulation tissue, and reepethialization. [2]

Skin repair is similar to wound repair in other tissues, especially epithelialized tissues. One important difference, however is that skin is exposed to air and the external environment. Evolution has likely caused wound repair in the skin to adapt and emphasize survival of the organism via the prevention of infection over functionality of replaced tissue. Scar tissue effectively seals an open wound, but provides poor functionality compared to the original tissue. Cosmetic related concerns provide a desire for improved cutaneos wound healing with less scarring, but perhaps at the expense of prolonged healing time.

After wounding of the skin, a blood clot forms, which may or may not be able to completely close the gap of the wound, depending on its size. An inflammatory response induces vasodilatation and brings increased numbers of blood cells to the area. Neutrophils invade the area and ingest bacteria and tissue debris to help clear the area for repair. Fibroblasts migrate into the clot and produce collagen and other extracellular matrix components. The clot is eventually broken down and replaced by granulation tissue, which consists of fibroblast, collagen, and capillaries. Scar is formed when a large amount of this granulation tissue persists after the healing of the wound. In large wounds, a large amount of granulation tissue forms and wound contraction occurs as a result of the contraction of fibroblasts in the granulation tissue. Wound contraction can lead to large and disfiguring/debilitating scars. [1]
Below are schematics of the healing process for a dermal wound at day 3 and at day 5. Click images for larger views.

Images source: Reference [14]

Using tissue engineering strategies, it may be possible to reduce scar tissue formation and instead promote tissue regeneration over replacement in epidermal and dermal wounds. In conjunction with topical antibiotics to prevent infection, down regulation of fibroblast activity and granulation tissue formation could lead to reduced scar formation. A topical salve that would reduce scar tissue formation and promote regeneration in dermal applications is would have great clinical and surgical applications, as well as use as a self-treatment option for superficial wounds.

Plastic Surgery Key


As the outer barrier to the environment, the skin is the organ most challenged by a range of external stress factors that can lead to cellular damage and barrier disruption. The skin has developed complex mechanisms to protect itself following injuries, including rapidly restoring tissue integrity and function. Over the past two decades, considerable insights have been gained into the cellular and molecular pathways regulating the wound healing response. Multiple strategies have been developed to try to enhance endogenous repair mechanisms, both in experimental systems and by clinical approaches. However, the precise mechanisms that lead to a failure of skin repair and chronic, recalcitrant skin ulcers are still poorly understood. Thus, poor wound healing that can follow trauma and surgical procedures or is associated with chronic disorders (e.g. venous hypertension, atherosclerosis, diabetes mellitus) affects millions of people worldwide. Chronic skin ulcers represent a common diagnostic and therapeutic challenge. In order to offer new effective therapies, we need to better understand the heterogeneity and the complex molecular pathophysiology of chronic wounds.


Wound healing is a complex and dynamic biologic process, consisting of three consecutive phases: inflammation, tissue formation, and tissue remodeling

Effective wound healing requires synchronization of cell–cell and cell–matrix interactions as well as an interplay of cytokines

Extracellular matrix proteins are multifunctional molecules that bind directly to cell surface receptors (e.g. integrins) and influence the effects of growth factors on cells (e.g. TGF-β)

In children and adults, the cutaneous wound healing response represents a reparative process that can lead to fibrosis (scar), whereas injured fetal tissue can heal completely without fibrosis, in a process resembling regeneration

A number of medical disorders (e.g. venous hypertension, atherosclerosis, diabetes mellitus) as well as more local factors (e.g. pressure, infection) are associated with chronic non-healing wounds


Restoration of skin integrity and homeostasis following injury is a fundamental process that ensures survival. The primary goal of the wound healing response is to re-establish a functional skin barrier as quickly as possible. Ideally, the wound healing response would lead to complete regeneration of skin tissue and its adnexal structures, with complete restoration of original skin function and morphology. Unfortunately, this is often not the final result of wound repair and the quality of newly formed skin tissue varies considerably.

Regeneration Versus Repair

In children and adults, the wound healing response characteristically leads to fibrosis, i.e. scar formation. In addition, adnexal structures (e.g. hair follicles, sweat and sebaceous glands) as well as components of the dermal extracellular matrix may fail to regenerate, resulting in a loss of normal skin function and impaired morphology. Because it is less than ideal, this type of wound healing is sometimes referred to as a reparative process . In contrast, during embryogenesis injured fetal skin can heal completely without fibrosis. Thus, the process resembles regeneration .

The underlying mechanisms that determine whether tissue regeneration versus tissue repair will occur still remain a mystery. Insights will hopefully come from experimental studies in other multicellular organisms (e.g. amphibians, fish) that retain throughout their adult life the capability to regenerate tissues after injury, as well as from studies of wound repair in fetal skin. In the future, these insights could lead to methods for transforming repair into regeneration and as a result, provide novel therapies that allow wound healing with minimal scarring.

Effect of Immune Response on Wound Healing

The immune system, including both innate and adaptive arms of the immune response, plays a critical role in wound healing. By influencing multiple repair mechanisms (e.g. angiogenesis, connective tissue deposition, epithelialization), inflammation has an impact on all stages of the repair response and ultimately the extent of scarring ( Fig. 141.1 ). In a number of models, there appears to be an inverse correlation between the intensity of the inflammatory immune response and the ability to undergo regeneration, with inappropriate immune reactions leading to tissue damage and impairment of tissue repair. However, this paradigm has recently been challenged by studies in several model organisms in which inflammatory signals were found to be crucial for promoting timely repair and for inducing fundamental processes involved in regeneration . Of note, these novel and unexpected findings emerged from investigations that employed well-established models within the field of tissue regeneration (not immunology).

Mechanisms of Tissue Repair and Regeneration Are Evolutionarily Conserved


Among the vertebrates, amphibians and fish are exceptional in their capacity to regenerate anatomically complete and fully functional tissues and organs during adulthood. In particular, urodele amphibians (newts and salamanders) can regenerate a range of organs and tissues . Cellular and molecular studies have focused primarily on limb regeneration after amputation, and recently such studies in adult salamanders demonstrated that the immediate influx of macrophages after tissue damage (preceding blastema formation) was an essential component of regeneration .


Zebrafish also represent a traditional and valuable model for the study of regeneration. Adult zebrafish maintain regenerative capacity, not only after caudal fin amputation, but also following skin injury . Of interest, in both fin and skin regeneration there is an infiltration of myeloid inflammatory cells, suggesting that in principle regeneration can occur in the presence of inflammatory signals. Thus, by examining skin wound healing in zebrafish it may be possible to distinguish between beneficial and harmful inflammatory mediators and how they influence scar formation.


The effects of inflammation on regeneration and repair have also been studied in mammals, primarily in mice, but also in humans. In addition to transgenic mouse models, refined mouse models that permit inducible and time-restricted depletion of specific immune cells have unraveled specific and critical functions of individual immune cell lineages in skin repair. For example, they provided evidence that, besides their central role in clearing cell detritus and microorganisms, macrophages exert distinct functions during the various phases of repair . Notably, macrophages recruited immediately after injury are essential for the induction of vascular sprouts and angiogenesis . Also, as the wound begins to contract, there is activation of focal adhesion kinase/extracellular signal-regulated kinase (FAK-ERK) within fibroblasts which leads to release of chemokine ligand 2 (CCL2), one of the prime chemokines known to drive monocyte/macrophage recruitment . Thus, an intimate interaction between macrophages and fibroblasts is envisioned.

In the presence of a functional immune system, higher vertebrates, including rodents and humans, can undergo post-amputation fingertip regeneration . Previously it was thought that the blastema, an undifferentiated pluripotent cell population presumably derived from mature cells via dedifferentiation, was responsible for mouse distal digit regeneration. However, recent genetic fate mapping and clonal analysis of individual cells revealed that a wide range of lineage-restricted tissue stem/progenitor cells contributed to restoration of the mouse distal digit, rather than pluripotent blastema cells . In humans, conservatively managed amputation injuries in children (but not adults) can be followed by restoration of the contour, fingerprints, and normal sensation and function of the digit, with minimal scarring . While the molecular mechanisms underlying this phenomenon are not yet understood, investigation of conserved mechanisms in more easily trackable non-human models will hopefully allow extrapolation to humans.

Clinical Implications

The underlying etiology of chronic, non-healing ulcers is multifactorial (see Ch. 105 ). It includes hypoxia due to vascular disease or sustained pressure, infection, and persistent inflammation . How the latter impairs the healing response is still not well understood, but increased protease activity (e.g. metalloproteinases [MMPs], serine proteinases) and generation of reactive oxygen species are thought to play a major role. Unravelling the underlying molecular pathophysiology of chronic wounds in humans will clearly involve studies of both regeneration and repair.

Impact of Wound Depth on Wound Healing

Skin wounds are often categorized according to their depth ( Fig. 141.2 ). Defects that affect only the epidermis (or a portion of the epidermis) are referred to as erosions . When the wound extends into the dermis, it is termed an ulceration . In “partial-thickness” wounds, the epidermis and a portion of the dermis are missing, with the ulcer extending into the mid dermis, but the adnexal structures remain. Full-thickness wounds, on the other hand, involve the entire dermis and extend into the subcutaneous fat. As a result, adnexal structures are lost as a source of keratinocytes for re-epithelialization.

The depth of a skin injury clearly affects the capacity of the skin to repair or regenerate. When erosions heal, there is regeneration of the entire epidermis, without scarring (see Fig. 141.2 ). Ulcerations, however, heal via a reparative process and are associated with scar formation. In partial-thickness wounds, the preserved adnexal structures serve as a source of epithelial cells to repopulate the epidermis. Epithelia from these structures, as well as from the wound edge, migrate across the wound surface to provide coverage. In contrast, because adnexal structures are lost in full-thickness wounds (see above), re-epithelialization can only occur from the wound edges.

Healing of full-thickness wounds includes, to some extent, contraction. While there is minimal contraction in partial-thickness wounds, the reason for this difference is not clear. Contraction may be mediated by mechanical or biologic factors, e.g. the differentiation of fibroblasts into myofibroblasts. Recent studies in mice suggest that the contributions of different stem cell sources for wound fibroblasts may determine the outcome of the repair response. These include a superficial population critical for hair development and a deeper population that forms the lower dermis and early on may provide a source of locally-derived wound fibroblasts that can develop into myofibroblasts .

During contraction, the wound area decreases via centripetal movement of pre-existing tissue, not the formation of new tissue. Unfortunately, contraction of wounds may result in cosmetically disfiguring contractures. However, the contraction of wounds occurs in predictable directions (in relation to “skin tension lines”), and in order to direct the contracture, surgical incisions should be placed, if possible, parallel to these skin tension lines. Also, an argument in favor of the use of full-thickness skin grafts is to prevent wound contraction and subsequent contracture (see Ch. 148 ).

Primary Versus Second Intention Healing

When an acute wound, such as one resulting from a surgical excision, is allowed to heal on its own, this is termed second (secondary) intention healing (see Ch. 146 ). In primary intention healing, closure of the wound is accomplished by approximating the wound edges the latter includes side-to-side closures, flaps, and grafts. Both primary and second intention forms of wound healing proceed through the three phases of healing.

In second intention healing, the time interval until complete re-epithelialization depends upon several factors. These include wound depth, anatomic location (e.g. facial wounds heal faster than acral wounds), any secondary infection, vascular supply, and geometric shape (for a given area, a more narrow diameter will heal faster). For smaller wounds, especially those that are partial-thickness, primary and second intention healing can produce similar cosmetic results. Once wounds have a diameter >8 mm, primary intention healing leads to better cosmetic results. Tertiary intention healing refers to wounds that are closed with the goal of primary intention healing, but dehiscence occurs and the wound is then allowed to heal by second intention.

The decision to choose primary versus second intention wound healing depends on a number of variables, including a patient’s overall medical status and cosmetic concerns, as well as the anatomic location, depth and size of the wound, and whether it is located on a convex or concave surface. In addition to comorbidities such as atherosclerosis, venous hypertension and diabetes mellitus, the risk of infection (which may be increased in open wounds) and the patient’s preference also influence the decision.

Skin Repair – Cellular and Molecular Aspects

In most mammalian organ systems, the repair response involves a complex and dynamic interplay of numerous cell types, including cells that reside within the tissue (e.g. keratinocytes, endothelial cells, fibroblasts) and hematopoietic cells recruited to the site of tissue damage. Three sequential phases of wound repair have been delineated – inflammatory, proliferative, and remodeling (maturation) . This section discusses the associated cellular and molecular events.

Three Phases of Wound Healing

Tissue injury causes leakage of blood constituents into the wound site and release of vasoactive factors ( Table 141.1 ), resulting in the activation of the clotting cascade. Clotted blood provides a matrix that allows for cell adhesion and migration. Not only do platelets trapped within the clot play an important role in hemostasis, they also represent a rich source of growth factors (e.g. PDGF) and proinflammatory cytokines that mediate the recruitment of inflammatory cells and fibroblasts into the wound site ( Fig. 141.3 ). The early inflammatory phase of repair is characterized by local activation of innate immune functions and chemoattraction, both of which lead to an early influx of polymorphonuclear leukocytes (PMNs neutrophils). This is followed by invasion of blood monocytes, which differentiate into tissue macrophages .

Chemical mediator Action
Histamine Increased vascular permeability
Serotonin Stimulation of fibroblast proliferation
Cross-linking of collagen molecules
Kinins Increased vascular permeability
Prostaglandins Increased vascular permeability
Sensitize pain receptors
Increased synthesis of GAGs
Complement Increased vascular permeability
Increased phagocytosis
Enhanced bacterial lysis
Mast cell and basophil activation

While one function of the inflammatory infiltrate is to combat invading microbes, another equally important function is the release of cytokines and growth factors (e.g. IL-1, IL-6, vascular endothelial growth factor [VEGF], tumor necrosis factor [TNF], TGF-β Table 141.2 ), which are critical for the initiation of the second proliferative phase of skin repair (see Fig. 141.3 ). During this phase of tissue formation, newly formed granulation tissue, consisting primarily of invading macrophages and fibroblasts as well as endothelial cells (as vessel precursors), covers and fills the wound area. Fibrin, fibronectin, vitronectin, type III collagen, and tenascin are components of the provisional extracellular wound matrix which facilitate cell adhesion, migration and proliferation. At the wound edge, epidermal–mesenchymal interactions stimulate keratinocyte proliferation and migration, leading to re-epithelialization .

Growth factor Abbreviation Source Functions
Platelet-derived growth factor PDGF Platelets, keratinocytes, fibroblasts, endothelial cells, perivascular cells Fibroblast proliferation, chemotaxis & collagen metabolism angiogenesis
Transforming growth factor-β TGF-β Platelets, keratinocytes, fibroblasts, endothelial cells, macrophages Fibroblast proliferation, chemotaxis & collagen metabolism angiogenesis immunomodulation
Transforming growth factor-α TGF-α Platelets, keratinocytes Keratinocyte proliferation & migration
Epidermal growth factor EGF Platelets Keratinocyte proliferation & migration
Interleukins IL-1, IL-10 Leukocytes, keratinocytes Fibroblast proliferation proinflammatory (IL-1) anti-inflammatory (IL-10)
Tumor necrosis factor TNF Leukocytes, keratinocytes Promotes inflammation
Connective tissue growth factor CTGF Fibroblasts, endothelial cells Fibroblast proliferation, chemotaxis & collagen metabolism
Fibroblast growth factor FGF Keratinocytes, macrophages Fibroblast & epithelial cell proliferation matrix deposition, wound contraction angiogenesis
Keratinocyte growth factor KGF Fibroblasts Keratinocyte proliferation
Insulin-like growth factor 1 IGF-1 Fibroblasts Keratinocyte proliferation & differentiation
Hepatocyte growth factor HGF Fibroblasts, macrophages Keratinocyte proliferation
Vascular endothelial growth factor VEGF Platelets, keratinocytes, macrophages, neutrophils Angiogenesis vascular permeability macrophage chemotaxis

Upon completion of epithelialization, cell proliferation and neovascularization cease, scar tissue forms and the wound enters the remodeling ( maturation ) phase, which lasts for several months. This last phase is characterized by a balance between the synthesis of new components of the scar matrix and their degradation by proteases. This balance determines whether there is normal versus abnormal scar formation (e.g. atrophic scars, hypertrophic scars, keloids). The mechanisms underlying granulation tissue regression and its transformation into scar tissue during this phase are largely unknown. Typically, there is also regression of vascular structures, transformation of fibroblasts into myofibroblasts, substitution of provisional extracellular matrix (ECM) with a permanent collagenous matrix, and a final resolution of the inflammatory response. However, if the inflammatory response persists, a disturbed healing response may result, leading to chronic skin ulcers (see Fig. 141.3 ). The mechanisms that direct resolution of the inflammatory response are not precisely understood, but most likely involve increased production of anti-inflammatory mediators, active suppression of proinflammatory factors, normalization of microvascular permeability, induction of apoptosis of inflammatory cells, and epithelialization.

Cellular Components


Within hours after injury, keratinocytes at the wound edge are activated and undergo marked phenotypic and functional alterations, a fundamental change required for re-epithelialization of the wound bed ( Fig. 141.4 ). In order to initiate migration, keratinocytes need to undergo significant alteration of their junctions and adhesion molecules this includes detachment of hemidesmosomes and replacement of their collagen-binding receptors with new integrins that allow the keratinocytes to adhere to the newly formed provisional wound matrix. In addition, these keratinocytes begin to proliferate as they reduce production of proteins normally expressed by differentiated stratified epidermis, in particular specific keratins (see Ch. 56 ). During wound healing, one classic marker of activated keratinocytes is the expression of keratins associated with proliferation, keratins 6 (K6) and K16.

It has been proposed that the cytoskeletal changes associated with activation, including the expression of these particular keratin filaments, provide plasticity and flexibility, while still maintaining resilience of the intracellular scaffold that is important for migration . Many of the growth factors active during wound healing, such as keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), are potential regulators of these processes. These growth factors can be synthesized either by activated keratinocytes (and act in an autocrine loop) or by cells present in the dermis, in particular fibroblasts, and then act in a paracrine fashion .

As the stratified epithelium consists of keratinocytes committed to multiple stages of differentiation, it is important to know which keratinocytes can be activated for regeneration. Experimental data from mice expressing a transgene within defined keratinocyte subpopulations revealed that interfollicular epidermal stem cells, transient amplifying cells, and early differentiated cells have the ability to form a fully differentiated epidermis . These data suggest that primarily skin stem cells and transient amplifying cells contribute to wound healing and that keratinocytes become irreversibly committed to the differentiation process fairly rapidly and then respond poorly to activating signals. Once keratinocytes process profilaggrin into filaggrin, they undergo specific changes that mark late terminal differentiation, which seemingly demarcates the final “line of regenerative potency” within the differentiating keratinocyte population (see Fig. 141.4 ) .


The development of molecular biology and other new biotechnologies helps us to recognize the wound healing and non-healing wound of skin in the past 30 years. This review mainly focuses on the molecular biology of many cytokines (including growth factors) and other molecular factors such as extracellular matrix (ECM) on wound healing. The molecular biology in cell movement such as epidermal cells in wound healing was also discussed. Moreover many common chronic wounds such as pressure ulcers, leg ulcers, diabetic foot wounds, venous stasis ulcers, etc. usually deteriorate into non-healing wounds. Therefore the molecular biology such as advanced glycation end products (AGEs) and other molecular factors in diabetes non-healing wounds were also reviewed.

Healing of Skin Superficial Wound - Biology

The role of bacteria in the pathogenesis of chronic, nonhealing wounds is unclear. All wounds are colonized with bacteria, but differentiating colonizers from invading organisms is difficult, if not impossible, at the present time. Furthermore, robust new molecular genomic techniques have shown that only 1% of bacteria can be grown in culture anaerobes are especially difficult to identify using standard culture methods. Recent studies utilizing microbial genomic methods have demonstrated that chronic wounds are host to a wide range of microorganisms. New techniques also show that microorganisms are capable of forming highly organized biofilms within the wound that differ dramatically in gene expression and phenotype from bacteria that are typically seen in planktonic conditions. The aim of this review is to present a concise description of infectious agents as defined by new molecular techniques and to summarize what is known about the microbiology of chronic wounds in order to relate them to the pathophysiology and therapy of chronic wounds.

What to know about types of wound healing

Wound healing is the process that the skin goes through as it repairs damage from wounds. There are three main types of wound healing, depending on treatment and wound type. These are called primary, secondary, and tertiary wound healing.

Every wound goes through various stages of healing, depending on the type of wound and its severity. Understanding these categories, as well as the steps of the wound healing process, can help people understand how best to care for a wound.

Keep reading to learn more about the stages of wound healing , the different types of wound healing, and some treatment options.

Primary wound healing, or primary intention wound healing, refers to when doctors close a wound using staples, stitches, glues, or other forms of wound-closing processes.

Closing a wound in this way reduces the tissue lost and allows the body to focus on closing and healing a smaller-area wound rather than the larger initial wound.

For example, a doctor might stitch up a large cut rather than allow the body to heal over the entire cut.

Secondary wound healing, or secondary intention wound healing, occurs when a wound that cannot be stitched causes a large amount of tissue loss. Doctors will leave the wound to heal naturally in these cases.

This may be more common for wounds that have a rounder edge, cover uneven surfaces, or are on surfaces of the body where movement makes stitches or other closure methods impossible.

Secondary wound healing relies on the body’s own healing mechanisms. This process takes longer, which may be due to increased wound size, the risk of infection and contamination, and other factors, such as the use of certain medications.

Tertiary wound healing, or healing by delayed primary closure, occurs when there is a need to delay the wound-closing process.

This could be necessary if a doctor fears that they may trap infectious germs in a wound by closing it. In these cases, they may allow the wound to drain or wait for the effects of other therapies to take place before closing the wound.

There are several types of wounds, depending on factors such as the source of the wound and any underlying issues that may lead to it. The type may alter how doctors treat the wound or other factors in the healing process.

Wounds are typically open or closed. A closed wound is an injury that does not break the surface of the skin but causes damage to the underlying tissues. A bruise is a common example of this. On the other hand, open wounds break the surface of the skin and may also damage underlying tissues.

Some types of open wounds include:

  • Abrasions: These form as a result of rubbing or scraping the skin against a hard surface.
  • Lacerations: These are deeper cuts caused by sharp objects, such as a knife, or sharp edges.
  • Punctures: These are small yet deep holes caused by a long, pointed object, such as a nail.
  • Burns: These result from contact with an open flame, a strong heat source, severe cold, certain chemicals, or electricity.
  • Avulsions: This refers to the partial or complete tearing away of skin and tissues.

Chronic wounds may also cause breakages in the skin that need to heal. These include bedsores, other pressure injuries, and diabetes-related ulcers.

All wounds go through different healing processes, ranging from the initial wound reaction to the later stages of creating new skin.

Simple wounds, such as those without extensive tissue damage or infection, take about 4–6 weeks to heal. This does not include scar tissue, however, which takes longer to form and heal.

Scar tissue will never return to 100% strength, but it will reach about 80% strength around 11–14 weeks after sustaining the initial wound.

The following sections describe the wound healing process in more detail.

Hemostasis phase

The hemostasis phase occurs as the injury happens and is the first response from the body. The wound causes blood and other fluids to leave the body. The body responds by trying to stop this flow of blood.

Affected blood vessels constrict to reduce blood flow. As some research notes, platelets and thrombocytes in the blood start to clump together near the open wound, forming a fibrin network. This thickens the blood in the immediate area to help stop the bleeding.

This newly formed clot also prevents germs from getting into the body. This restores the skin’s function as a barrier against dirt and other potentially infectious agents so that healing can begin.

The platelets release chemicals that alert the surrounding cells to start the next process and heal the wound.

Inflammatory phase

During the inflammatory phase, the cleaning and healing of the area begin.

There is generally some inflammation in the area, as the immune cells rush to the damaged tissue. White blood cells enter the area to start cleaning out the wound and move any waste away from the site and out of the body.

Proliferative phase

The proliferative phase of wound healing occurs when the wound is stable. The body’s focus during this stage is to close the wound, create new tissue, and repair any damaged blood vessels in the area.

This occurs over the course of four different processes:

  • Epithelialization: This is the process of creating new skin tissue in the various layers of damaged skin.
  • Angiogenesis: This is the creation of new blood vessels in the area of the wound healing.
  • Collagen formation: This is the building up of strength in the tissue of the wound.
  • Contraction: This is the reduction and eventual closing of the wound size and area.

The combined connective tissue and blood vessels is called granulation tissue. This granulation tissue starts to form around 4 days into a wound’s healing process.

Remodeling phase

During the remodeling phase, the internal wound is mostly healed. The process switches to creating strong skin to replace the temporary tissue in the area.

Some research notes that this process occurs around 2 or 3 weeks after the injury and can last for 1 year or longer. This is the active scar tissue phase of healing.

The body replaces the temporary granular tissue from the early wound with stronger scar tissue. As time goes on, the scar tissue has an increased concentration of collagen, which makes it stronger.

Treatment and home care options for a wound will vary greatly based on a number of factors, such as the location of the wound, the type of wound, and any additional treatments that are necessary.

Treatments may include any closures needed, antibiotics to protect the wound, and dressings, in addition to other forms of therapy.

Doctors will give people regular instructions on caring for their wound as it heals, as well as regular dates for check-ups to help monitor the healing process.

Anyone who is uncertain about the severity or type of wound or the need for treatment should contact a doctor.

Minor wounds, such as scrapes and small cuts, may not require a visit to the doctor. However, anyone who experiences a larger wound or a wound that does not stop bleeding after the application of gentle pressure should contact a doctor for a full diagnosis and treatment.

Wounds that cover larger areas of the skin, such as road rash, may also require professional medical attention. These require proper cleaning to prevent contamination and infection.

Anyone who notices symptoms of infection — such as itching, pain, and redness around the wound — should also contact a doctor.

Wound healing is a complex process with many stages, from the moment the initial wound occurs, through the various initial reactions of the body, to the process of healing itself.

The three main types of wound healing are primary, secondary, and tertiary.

Minor wounds go through the stages of wound healing fairly quickly. More severe wounds will take longer to heal.

Any symptoms of infection, as well as any major injuries, should prompt a visit to a doctor for a full diagnosis and treatment. Anyone who is unsure about their wound healing should also contact a doctor.

Human skin transcriptome during superficial cutaneous wound healing

Dr. E. Kankuri, Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, PO Box 63, Haartmaninkatu 8, 00290 Helsinki, Finland.

Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, Helsinki, Finland

Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, Helsinki, Finland

Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, Helsinki, Finland

Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, Helsinki, Finland

Slovak Academy of Sciences, Cancer Research Institute, Laboratory of Tumor Cell Biology, Bratislava, Slovakia

Department of Plastic Surgery, Tampere University Hospital, Tampere, Finland

Department of Plastic Surgery, Tampere University Hospital, Tampere, Finland

Department of Surgery, Satakunta Central Hospital, Pori, Finland

Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, Helsinki, Finland

Department of Cardiothoracic Surgery, Helsinki University Meilahti Hospital, Helsinki, Finland

Department of Surgery, Satakunta Central Hospital, Pori, Finland

Helsinki Burn Center, Töölö Hospital, Helsinki University Central Hospital, Helsinki, Finland

Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, Helsinki, Finland

Dr. E. Kankuri, Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, PO Box 63, Haartmaninkatu 8, 00290 Helsinki, Finland.


Healing of the epidermis is a crucial process for maintaining the skin's defense integrity and its resistance to environmental threats. Compromised wound healing renders the individual readily vulnerable to infections and loss of body homeostasis. To clarify the human response of reepithelialization, we biopsied split-thickness skin graft donor site wounds immediately before and after harvesting, as well as during the healing process 3 and 7 days thereafter. In all, 25 biopsies from eight patients qualified for the study. All samples were analyzed by genome-wide microarrays. Here, we identified the genes associated with normal skin reepithelialization over time and organized them by similarities according to their induction or suppression patterns during wound healing. Our results provide the first elaborate insight into the transcriptome during normal human epidermal wound healing. The data not only reveal novel genes associated with epidermal wound healing but also provide a fundamental basis for the translational interpretation of data acquired from experimental models.

Table S1. Gene lists of different comparisons. The list is arranged in the order from largest expression change to the smallest. In each comparison is listed the Affymetrix probe set ID, gene expression fold-change, gene symbol, and statistical significance (1 means p-value <0.05 0 means p-value >0.05). Only genes with the altered expression of twofold or more are listed in the table.

Table S2. Top 20 genes of each expression pattern. up-regulated (u), down-regulated (d), or unchanged (–).

Table S3. K-Means Clusters. A graphical presentation of each cluster. The genes belonging to the clusters are listed in the Supporting Information Table S4.

Table S4. K-Means clustering. In alphabetical order genes of the 21 clusters. A graphical presentation of each cluster is shown in the Supporting Information Table S3.

Table S5. Quantitative Real-Time PCR validation. The gene expression fold-change differences in the comparison between seventh POD sample and intact skin sample.

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

New study reveals how skin cells prepare to heal wounds

Spatially choreographed gene expression in a healing skin wound, with insets showing the predicted differentiation trajectories of epidermal cells in unwounded and wounded skin. Credit: UCI School of Medicine

A team of University of California, Irvine researchers have published the first comprehensive overview of the major changes that occur in mammalian skin cells as they prepare to heal wounds. Results from the study provide a blueprint for future investigation into pathological conditions associated with poor wound healing, such as in diabetic patients.

"This study is the first comprehensive dissection of the major changes in cellular heterogeneity from a normal state to wound healing in skin," said Xing Dai, Ph.D., a professor of biological chemistry and dermatology in the UCI School of Medicine, and senior author. "This work also showcases the collaborative efforts between biologists, mathematician and physicists at UCI, with support from the National Institute of Arthritis & Musculoskeletal & Skin Diseases-funded UCI Skin Biology Resource-based Center and the NSF-Simons Center for Multiscale Cell Fate Research.

The study, titled, "Defining epidermal basal cell states during skin homeostasis and wound healing using single-cell transcriptomics," was published this week in Cell Reports.

"Our research uncovered at least four distinct transcriptional states in the epidermal basal layer as part of a 'hierarchical-lineage' model of the epidermal homeostasis, or stable state of the skin, clarifying a long-term debate in the skin stem cell field," said Dai.

Using single-cell RNA sequencing coupled with RNAScope and fluorescence lifetime imaging, the team identified three non-proliferative and one proliferative basal cell state in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization, which is the process by which the skin and mucous membranes replace superficial epithelial cells damaged or lost in a wound.

Epithelial tissue maintenance is driven by resident stem cells, the proliferation and differentiation dynamics of which need to be tailored to the tissue's homeostatic and regenerative needs. However, our understanding of tissue-specific cellular dynamics in vivo at single-cell and tissue scales is often very limited.

"Our study lays a foundation for future investigation into the adult epidermis, specifically how the skin is maintained and how it can robustly regenerate itself upon injury," said Dai.

Ready-made cellular plugs heal skin wounds

Mark C. Coles is at the Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK.

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Christopher D. Buckley is at the Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK, and at the Institute for Inflammation and Ageing, University of Birmingham, Birmingham, UK.

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Skin consists of an outer epidermal layer (the epidermis) and an inner dermal layer (the dermis). If you pinch your skin, you can lift it because these two cellular layers move freely above a membranous sheet called the fascia, which contains cells and extracellular-matrix material. This gelatinous tissue creates a frictionless interface between the skin and the more rigid structures beneath it, such as muscle and bone. However, it now seems that the fascia has roles beyond providing a non-stick surface. Writing in Nature, Correa-Gallegos et al. 1 report that the fascia contains a movable sealant that patches up deep injuries to enable rapid wound repair.

Read the paper: Fascia is a repository of mobile scar tissue

The scar tissue of a healing skin wound contains fibroblast cells, which make and modify extracellular-matrix proteins. These fibroblasts can be identified by their expression of a protein called Engrailed-1, and are termed Engrailed-positive fibroblasts (EPFs). The idea that the fascia might be a repository of cellular components involved in wound healing and scar formation came from a previous study 2 , which reported that EPFs reside not only in the skin, as expected, but also in the fascia.

To investigate wound healing in mice, Correa-Gallegos and colleagues grafted fascia that contained cells engineered to express green fluorescent protein onto skin cells expressing red fluorescent protein. The authors then wounded this dual-coloured ‘fluorescent sandwich’ and transplanted it into a healthy mouse. Comparison of the percentages of green and red cells revealed that 80% of cells in the healing wound came from the fascia. Furthermore, the vast majority of many cell types found in the healing injury originated from the fascia, including contractile fibroblasts (or myofibroblasts), blood-vessel cells, macrophages of the immune system and nerve cells.

To confirm that their observations were not due to any peculiarities of this artificial grafted structure, the authors injected a dye into the fascia of mice, and then gave the mice a deep wound that penetrated the animals’ skin and fascia. The authors mapped the dye-labelled cells that populated the healing wound and the surrounding scar tissue. More than half of the cells in the healed wound were labelled with the dye, confirming that the fascia is a major source of scar-forming tissue after deep injury.

Deep wounds lead to scars that are larger and harder to heal than those arising from superficial wounds that do not penetrate the fascia 3 . The authors used two-photon microscopy to analyse deep skin wounds in mice engineered 4 to express fluorescent proteins, which can be used to trace scar-forming EPFs. They found that a cellular plug in the fascia, consisting of extracellular matrix, macrophages, blood vessels and nerves, moved upwards into the damaged skin to form a scar. This healing process did not require cell division, indicating that the plug was prefabricated. Importantly, the authors found that key proteins that have been reported to define the types of fibroblast found in scars 5 are expressed at higher levels on fascial than on dermal fibroblasts, consistent with a model in which fascial EPFs are a major source of fibroblasts in healing deep wounds (Fig. 1).

Figure 1 | The healing of deep skin wounds. The skin consists of an outer layer called the epidermis and an inner layer, the dermis. Superficial wounds no deeper than skin level can be repaired by cells called Engrailed-positive fibroblasts (EPFs) in the dermis, which make extracellular-matrix material. Working with mice, Correa-Gallegos et al. 1 investigated the healing of deep wounds that penetrated below the skin into a layer known as the fascia. The fascia contains EPFs, extracellular matrix, blood vessels, nerves and immune cells called macrophages. The authors report that a prefabricated plug of material from the fascia moves upwards, steered by fascial EPFs, to seal the wound. (Image based on Fig. 6 of ref. 1.)

Given that fibroblasts regulate the extracellular matrix, the authors used microscopy to visualize physical features of fibres of the protein collagen, which is a component of the extracellular matrix. Collagen in the fascia was more coiled and immature than were the stretched and interwoven collagen fibres in the dermis. Furthermore, when a fluorescent dye was used to tag collagen in an injured animal, this revealed that the extracellular matrix of the fascia moved upwards like a pliable gel into the damaged tissue, to plug and then repair the wound. By contrast, dermal collagen remained immobile.

The authors then tested whether EPFs from the fascia drive the movement of the prefabricated plug. They inserted non-adhesive membranes in mice to separate the fascia from the dermis, which resulted in delayed repair and non-healing wounds that remained open. Animals in which these membranes were not inserted did not show these effects. The removal of fascial EPFs by a genetic approach also resulted in the plug not entering wounds and in poor healing. These findings indicate that fascial EPFs do indeed steer the plug that seals deep wounds.

Macrophages form a protective cellular barrier in joints

Although this study has potential relevance for human disease, most of the work was carried out in an artificial mouse model. Moreover, mice have a type of muscle called the panniculus carnosus, which lies between the fascia and the skin and is used to twitch the skin 6 . However, humans lack this twitching ability and have only a small remnant of this muscle. Therefore, the authors needed to determine whether scar formation occurs in a similar manner in humans and mice despite such differences.

The team analysed fascial fibroblasts in human skin and investigated a type of human raised scar called a keloid, which grows bigger than the original injury and can be profoundly itchy, inflamed and painful 7 . Many of the proteins that characterize the mouse fascia were also highly expressed in human fascia and keloid scars. This similarity suggests that the same processes are involved in wound healing and scar formation in both species. However, it is not yet clear whether these findings in mice reveal general principles that are relevant to human skin disease.

The authors’ findings provide satisfying potential explanations for some unsolved clinical conundrums. Nerves, blood vessels and macrophages in the prefabricated plug are dragged into the mouse wound if the same phenomenon occurs in humans, this could explain why keloids itch and are painful. Keloid formation is more common at sites of thicker fasciae (such as the chest, back and thighs) than at sites where the fascia is thinner (for example, the feet), which is consistent with a model in which the fascia drives keloid formation.

Could these discoveries about the skin shed light on other clinically relevant fibrotic diseases (conditions associated with the accumulation of extracellular matrix) that affect organs in which the fascia is not present, such as the lungs and liver? Perhaps the mechanisms uncovered in mice might have relevance for the processes underlying skin damage in the leg ulcers that can develop in people who have diabetes. In any case, it is clear that advances made in understanding the biology of the fascia might reveal new targets for treating scarring diseases of the skin.

Nature 576, 215-216 (2019)

Essential oil compound may speed the healing of wounds

Although essential oils are typically associated with aromatherapy, new research indicates that medicines based on them could also help to heal skin wounds when applied topically. It all comes down to a certain substance in some of the oils, that reduces inflammation.

The chemical compound in question is known as beta-carophyllene – it's found in the oils of lavender, rosemary and ylang ylang, among other sources. In a study conducted at Indiana University, beta-carophyllene extracted from these plants was applied to superficial wounds on mice.

It was observed that doing so increased cell growth and cell migration to the wound site, causing the injuries to heal faster than similar untreated wounds. Additionally, the scientists noted increased gene expression of hair follicle stem cells in the treated injuries. This suggests that there would ultimately be less scarring.

Based on previous research, it was already known that beta-carophyllene activates a receptor in the body, which in turn produces an anti-inflammatory response. It is this response that is likely the key.

"In the wound healing process, there are several stages, starting from the inflammatory phase, followed by the cell proliferation stage and the remodelling stage," says the lead scientist, Assoc. Prof. Sachiko Koyama. "I thought maybe wound healing would be accelerated if inflammation was suppressed, stimulating an earlier switch from the inflammatory stage to the next stage."

That said, Koyama believes that there may be additional factors at work, which further research should hopefully reveal. She also advises against simply applying essential oils to wounds, as the beta-carophyllene used in the study was of a known purity, and was diluted in a specific concentration.

"There are many things to test before we can start using it clinically, but our results are very promising and exciting," she says. "Someday in the near future we may be able to develop a drug, and drug delivery methods, using the chemical compounds found in essential oils."

A paper on the research was published this week in the journal PLOS ONE.