Wound healing

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|colspan="5"|Healing progression of a hand abrasion

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| style="border-top:0px;"|Initial injury

| style="border-top:0px;"|3 days

| style="border-top:0px;"|17 days

| style="border-top:0px;"|30 days

Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.

In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier against the external environment. When the barrier is broken, a regulated sequence of biochemical events is set into motion to repair the damage. This process is divided into predictable phases: blood clotting (hemostasis), inflammation, tissue growth (cell proliferation), and tissue remodeling (maturation and cell differentiation). Blood clotting may be considered to be part of the inflammation stage instead of a separate stage.

thumb|Healing progression of a deep laceration wound on the shin with sutures over a five-week period

The wound-healing process is not only complex but fragile, and it is susceptible to interruption or failure leading to the formation of non-healing chronic wounds. Factors that contribute to non-healing chronic wounds are diabetes, venous or arterial disease, infection, and metabolic deficiencies of old age.

Wound care encourages and speeds wound healing via cleaning and protection from reinjury or infection. Depending on each patient's needs, it can range from the simplest first aid to entire nursing specialties such as wound, ostomy, and continence nursing and burn center care.

Stages

Hemostasis (blood clotting): Within the first few minutes of injury, platelets in the blood begin to stick to the injured site. They change into an amorphous shape, more suitable for clotting, and they release chemical signals to promote clotting. This results in the activation of fibrin, which forms a mesh and acts as "glue" to bind platelets to each other. This makes a clot that serves to plug the break in the blood vessel, slowing/preventing further bleeding.
Inflammation: During this phase, damaged and dead cells are cleared out, along with bacteria and other pathogens or debris. This happens through the process of phagocytosis, where white blood cells engulf debris and destroy it. Platelet-derived growth factors are released into the wound that cause the migration and division of cells during the proliferative phase.
Proliferation (growth of new tissue): In this phase, angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound contraction occur. In angiogenesis, vascular endothelial cells form new blood vessels. In fibroplasia and granulation tissue formation, fibroblasts grow and form a new, provisional extracellular matrix (ECM) by excreting collagen and fibronectin. In wound contraction, myofibroblasts decrease the size of the wound by gripping the wound edges and contracting using a mechanism that resembles that in smooth muscle cells. When the cells' roles are close to complete, unneeded cells undergo apoptosis. with faded intervals marking substantial variation, depending mainly on wound size and healing conditions; image does not include major impairments that cause chronic wounds.]]

Timing and re-epithelialization

Timing is important to wound healing. Critically, the timing of wound re-epithelialization can decide the outcome of the healing. If the epithelization of tissue over a denuded area is slow, a scar will form over many weeks, or months;

Early vs cellular phase

right|250px|thumb|A [[Fluorescence microscope|fluorescence micrograph of cells in Drosophila larvae healing after a puncture wound. The arrow points to cells that have fused to form syncytia, and the arrowheads point to cells that are oriented to face the wound.]]

Wound healing is classically divided into hemostasis, inflammation, proliferation, and remodeling. Although a useful construct, this model employs considerable overlapping among individual phases. A complementary model has recently been described Platelets also express sticky glycoproteins on their cell membranes that allow them to aggregate, forming a mass. This fibrin-fibronectin plug is also the main structural support for the wound until collagen is deposited.

Polymorphonuclear neutrophils

Within an hour of wounding, polymorphonuclear neutrophils (PMNs) arrive at the wound site and become the predominant cells in the wound for the first two days after the injury occurs, with especially high numbers on the second day. They are attracted to the site by fibronectin, growth factors, and substances such as kinins. Neutrophils phagocytise debris and kill bacteria by releasing free radicals in what is called a respiratory burst. They also cleanse the wound by secreting proteases that break down damaged tissue. Functional neutrophils at the wound site only have life-spans of around two days, so they usually undergo apoptosis once they have completed their tasks and are engulfed and degraded by macrophages.

Other leukocytes to enter the area include helper T cells, which secrete cytokines to cause more T cells to divide and to increase inflammation and enhance vasodilation and vessel permeability. T cells also increase the activity of macrophages.

Macrophages function in regeneration By secreting these factors, macrophages contribute to pushing the wound healing process into the next phase. They replace PMNs as the predominant cells in the wound by two days after injury.

The spleen contains half the body's monocytes in reserve ready to be deployed to injured tissue. Attracted to the wound site by growth factors released by platelets and other cells, monocytes from the bloodstream enter the area through blood vessel walls. Numbers of monocytes in the wound peak one to one and a half days after the injury occurs.

Decline of inflammatory phase

As inflammation dies down, fewer inflammatory factors are secreted, existing ones are broken down, and numbers of neutrophils and macrophages are reduced at the wound site.

Because inflammation plays roles in fighting infection, clearing debris and inducing the proliferation phase, it is a necessary part of healing. However, inflammation can lead to tissue damage if it lasts too long. As in the other phases of wound healing, steps in the proliferative phase do not occur in a series but rather partially overlap in time.

Angiogenesis

Also called neovascularization, the process of angiogenesis occurs concurrently with fibroblast proliferation when endothelial cells migrate to the area of the wound. Because the activity of fibroblasts and epithelial cells requires oxygen and nutrients, angiogenesis is imperative for other stages in wound healing, like epidermal and fibroblast migration. The tissue in which angiogenesis has occurred typically looks red (is erythematous) due to the presence of capillaries. e.g. from macrophages and platelets when in a low-oxygen environment. Endothelial growth and proliferation is also directly stimulated by hypoxia, and presence of lactic acid in the wound.

When macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic acid-filled environment, they stop producing angiogenic factors.

Type III collagen and fibronectin generally begin to be produced in appreciable amounts at somewhere between approximately 10 hours and 3 days, At the end of the granulation phase, fibroblasts begin to commit apoptosis, converting granulation tissue from an environment rich in cells to one that consists mainly of collagen.

Keratinocytes migrate without first proliferating. Migration can begin as early as a few hours after wounding. However, epithelial cells require viable tissue to migrate across, so if the wound is deep it must first be filled with granulation tissue. Thus the time of onset of migration is variable and may occur about one day after wounding. Cells on the wound margins proliferate on the second and third day post-wounding in order to provide more cells for migration. Before they begin to migrate, cells must dissolve their desmosomes and hemidesmosomes, which normally anchor the cells by intermediate filaments in their cytoskeleton to other cells and to the ECM.

Fibrin, collagen, and fibronectin in the ECM may further signal cells to divide and migrate. Like fibroblasts, migrating keratinocytes use the fibronectin cross-linked with fibrin that was deposited in inflammation as an attachment site to crawl across. To make their way along the tissue, keratinocytes must dissolve the clot, debris, and parts of the ECM in order to get through. They secrete plasminogen activator, which activates plasminogen, turning it into plasmin to dissolve the scab. Cells can only migrate over living tissue, Growth factors are also important for the innate immune defense of skin wounds by stimulation of the production of antimicrobial peptides and neutrophil chemotactic cytokines in keratinocytes.

Keratinocytes continue migrating across the wound bed until cells from either side meet in the middle, at which point contact inhibition causes them to stop migrating. Thus there is a great interest in understanding the biology of wound contraction, which can be modelled in vitro using the collagen gel contraction assay or the dermal equivalent model.

Contraction commences approximately a week after wounding, when fibroblasts have differentiated into myofibroblasts. In full thickness wounds, contraction peaks at 5 to 15 days post wounding. Later, fibroblasts, stimulated by growth factors, differentiate into myofibroblasts. Myofibroblasts, which are similar to smooth muscle cells, are responsible for contraction. The maturation phase can last for a year or longer, similarly depending on wound type. Since activity at the wound site is reduced, the scar loses its red appearance as blood vessels that are no longer needed are removed by apoptosis.

Factors affecting wound healing

Many factors controlling the efficacy, speed, and manner of wound healing fall under two types: local and systemic factors.

Mechanical factors
Oedema
Ionizing radiation
Faulty technique of wound closure
Ischemia and necrosis
Foreign bodies. Sharp, small foreign bodies can penetrate the skin leaving little surface wound but causing internal injury and internal bleeding. For a glass foreign body, "frequently, an innocent skin wound disguises the extensive nature of the injuries beneath". First-degree nerve injury requires a few hours to a few weeks to recover. If a foreign body passes by a nerve and causes first-degree nerve injury during entry, then the sensation of the foreign body or pain due to internal wounding may be delayed by a few hours to a few weeks after entry. A sudden increase in pain during the first few weeks of wound healing could be a sign of a recovered nerve reporting internal injuries rather than a newly developed infection.
Low oxygen tension
Perfusion

Systemic factors

Inflammation
Diabetes – Individuals with diabetes demonstrate reduced capability in the healing of acute wounds. Additionally, diabetic individuals are susceptible to developing chronic diabetic foot ulcers, a serious complication of diabetes which affects 15% of people with diabetes and accounts for 84% of all diabetes-related lower leg amputations. The impaired healing abilities of diabetics with diabetic foot ulcers and/or acute wounds involves multiple pathophysiological mechanisms. Nutrients including proteins, carbohydrates, arginine, glutamine, polyunsaturated fatty acids, vitamin A, vitamin C, vitamin E, magnesium, copper, zinc and iron all play significant roles in wound healing. Fats and carbohydrates provide the majority of energy required for wound healing. Glucose is the most prominent source of fuel and it is used to create cellular ATP, providing energy for angiogenesis and the deposition of new tissues.
Age – Increased age (over 60 years) is a risk factor for impaired wound healing. Delayed wound healing in patients of increasing age is associated with altered inflammatory response; for example delayed T-cell infiltration of the wound with alterations in the production of chemokines, and reduced macrophage phagocytic capacity.
Alcohol – Alcohol consumption impairs wound healing and also increases the chances of infection. Alcohol affects the proliferative phase of healing. A single unit of alcohol causes a negative effect on re-epithelialization, wound closure, collagen production and angiogenesis.

Research and development

Up until about 2000, the classic paradigm of wound healing, involving stem cells restricted to organ-specific lineages, had never been seriously challenged. Since then, the notion of adult stem cells having cellular plasticity or the ability to differentiate into non-lineage cells has emerged as an alternative explanation.

Stem cells and cellular plasticity

Multipotent adult stem cells have the capacity to be self-renewing and give rise to different cell types. Stem cells give rise to progenitor cells, which are cells that are not self-renewing, but can generate several types of cells. The extent of stem cell involvement in cutaneous (skin) wound healing is complex and not fully understood. Stem cell injection leads to wound healing primarily through stimulation of angiogenesis.

It is thought that the epidermis and dermis are reconstituted by mitotically active stem cells that reside at the apex of rete ridges (basal stem cells or BSC), the bulge of hair follicles (hair follicular stem cell or HFSC), and the papillary dermis (dermal stem cells). Repair or incomplete regeneration, refers to the physiologic adaptation of an organ after injury in an effort to re-establish continuity without regards to exact replacement of lost/damaged tissue. refers to the replacement of lost/damaged tissue with an 'exact' copy, such that both morphology and functionality are completely restored.

In some instances, after a tissue breakdown, such as in skin, a regeneration closer to complete regeneration may be induced by the use of biodegradable (collagen-glycoaminoglycan) scaffolds. These scaffolds are structurally analogous to extracellular matrix (ECM) found in normal/un-injured dermis. Fundamental conditions required for tissue regeneration often oppose conditions that favor efficient wound repair, including inhibition of (1) platelet activation, (2) inflammatory response, and (3) wound contraction.

A new way of thinking derived from the notion that heparan sulfates are key player in tissue homeostasis: the process that makes the tissue replace dead cells by identical cells. In wound areas, tissue homeostasis is lost as the heparan sulfates are degraded preventing the replacement of dead cells by identical cells. Heparan sulfate analogues cannot be degraded by all known heparanases and glycanases and bind to the free heparin sulfate binding spots on the ECM, therefore preserving the normal tissue homeostasis and preventing scarring.

Repair or regeneration with regards to hypoxia-inducible factor 1-alpha (HIF-1a). In normal circumstances after injury HIF-1a is degraded by prolyl hydroxylases (PHDs). Scientists found that the simple up-regulation of HIF-1a via PHD inhibitors regenerates lost or damaged tissue in mammals that have a repair response; and the continued down-regulation of Hif-1a results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. The act of regulating HIF-1a can either turn off, or turn on the key process of mammalian regeneration.

Scarless wound healing

Scarless wound healing is a concept based on the healing or repair of the skin (or other tissue/organs) after injury with the aim of healing with subjectively and relatively less scar tissue than normally expected. Scarless healing is sometimes mixed up with the concept of scar free healing, which is wound healing that results in absolutely no scar (free of scarring) may occur naturally at some locations of the human body and research in 2025 has decoded molecular players that drive that scarless healing. However, they are different concepts.

The opposite of scarless wound healing is scarification (wound healing to scar more). Historically, certain cultures consider scarification attractive; however, this is generally not the case in the modern western society, in which many patients are turning to plastic surgery clinics with unrealistic expectations. Depending on scar type, treatment may be invasive (intralesional steroid injections, surgery) and/or conservative (compression therapy, topical silicone gel, brachytherapy, photodynamic therapy). Clinical judgment is necessary to successfully balance the potential benefits of the various treatments available against the likelihood of a poor response and possible complications resulting from these treatments. Many of these treatments may only have a placebo effect, and the evidence base for the use of many current treatments is poor.

Since the 1960s, comprehension of the basic biologic processes involved in wound repair and tissue regeneration have expanded due to advances in cellular and molecular biology. Currently, the principal goals in wound management are to achieve rapid wound closure with a functional tissue that has minimal aesthetic scarring. However, the ultimate goal of wound healing biology is to induce a more perfect reconstruction of the wound area. Scarless wound healing only occurs in mammalian foetal tissues In adult humans, injured tissue are repaired by collagen deposition, collagen remodelling and eventual scar formation, where fetal wound healing is believed to be more of a regenerative process with minimal or no scar formation. Therefore, foetal wound healing can be used to provide an accessible mammalian model of an optimal healing response in adult human tissues. Clues as to how this might be achieved come from studies of wound healing in embryos, where repair is fast and efficient and results in essentially perfect regeneration of any lost tissue.

The etymology of the term scarless wound healing has a long history.

Cancer

After inflammation, restoration of normal tissue integrity and function is preserved by feedback interactions between diverse cell types mediated by adhesion molecules and secreted cytokines. Disruption of normal feedback mechanisms in cancer threatens tissue integrity and enables a malignant tumor to escape the immune system. An example of the importance of the wound healing response within tumors is illustrated in work by Howard Chang and colleagues at Stanford University studying breast cancers.

Wound dressings

Modern wound dressing to aid in wound repair has undergone considerable research and development in recent years. Scientists aim to develop wound dressings which have the following characteristics:

Provide wound protection
Remove excess exudate
Possess antimicrobial properties
Maintain a humid environment
Have high permeability to oxygen
Are easily removed from a wound site
Possess non-anaphylactic characteristics

Cotton gauze dressings have been the standard of care, despite their dry properties that can adhere to wound surfaces and cause discomfort upon removal. Recent research has set out to improve cotton gauze dressings to bring them closer in line to achieve modern wound dressing properties, by coating cotton gauze wound dressing with a chitosan/Ag/ZnO nanocomposite. These updated dressing provide increase water absorbency and improved antibacterial efficacy. It is uncertain whether the choice of cleaning solution or method of application makes any difference to venous leg ulcer healing. The growth of tissue around the wound site is a result of the migration of cells and collagen deposition by these cells. The alignment of collagen describes the degree of scarring; basket-weave orientation of collagen is characteristic of normal skin, whereas aligned collagen fibers lead to significant scarring. It has been shown that the growth of tissue and extent of scar formation can be controlled by modulating the stress at a wound site.

The growth of tissue can be simulated using the aforementioned relationships from a biochemical and biomechanical point of view. The biologically active chemicals that play an important role in wound healing are modeled with Fickian diffusion to generate concentration profiles. The balance equation for open systems when modeling wound healing incorporates mass growth due to cell migration and proliferation. Here the following equation is used:

Dtρ0 = Div (R) + R0,

where ρ represents mass density, R represents a mass flux (from cell migration), and R0 represents a mass source (from cell proliferation, division, or enlargement). Relationships like these can be incorporated into an agent-based models, where the sensitivity to single parameters such as initial collagen alignment, cytokine properties, and cell proliferation rates can be tested.

Wound closure intentions

Successful wound healing is dependent on various cell types, molecular mediators and structural elements.

Primary intention

Primary intention is the healing of a clean wound without tissue loss.

This process is faster than healing by secondary intention.

Secondary intention

Secondary intention is implemented when primary intention is not possible because of significant tissue damage or loss, usually due to the wound having been created by major trauma.
Examples: gingivectomy, gingivoplasty, tooth extraction sockets, poorly reduced fractures, burns, severe lacerations, pressure ulcers.
There is insufficient evidence that the choice of dressings or topical agents affects the secondary healing of wounds.
There is lack of evidence for the effectiveness of negative pressure wound therapy in wound healing by secondary intention.

Tertiary intention

(Delayed primary closure):

The wound is initially cleaned, debrided and observed, typically 4 or 5 days before closure.
The wound is purposely left open.
Examples: healing of wounds by use of tissue grafts.

If the wound edges are not reapproximated immediately, delayed primary wound healing transpires. This type of healing may be desired in the case of contaminated wounds. By the fourth day, phagocytosis of contaminated tissues is well underway, and the processes of epithelization, collagen deposition, and maturation are occurring. Foreign materials are walled off by macrophages that may metamorphose into epithelioid cells, which are encircled by mononuclear leukocytes, forming granulomas. Usually the wound is closed surgically at this juncture, or the scab is eaten, and if the "cleansing" of the wound is incomplete, chronic inflammation can ensue, resulting in prominent scarring.

Overview of involved growth factors

Following are the main growth factors involved in wound healing:

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! Growth factor !! Abbreviation !! Main origins !! Effects

! Epidermal growth factor

| EGF

Activated macrophages
Salivary glands
Keratinocytes

Keratinocyte and fibroblast mitogen
Keratinocyte migration
Granulation tissue formation

! Transforming growth factor-α

| TGF-α

Activated macrophages
T-lymphocytes
Keratinocytes

Hepatocyte and epithelial cell proliferation
Expression of antimicrobial peptides
Expression of chemotactic cytokines

! Hepatocyte growth factor

| HGF

Mesenchymal cells

Epithelial and endothelial cell proliferation
Hepatocyte motility

! Vascular endothelial growth factor

| VEGF

Mesenchymal cells

Vascular permeability
Endothelial cell proliferation

! Platelet derived growth factor

| PDGF

Platelets
Macrophages
Endothelial cells
Smooth muscle cells
Keratinocytes

Granulocyte, macrophage, fibroblast and smooth muscle cell chemotaxis
Granulocyte, macrophage and fibroblast activation
Fibroblast, endothelial cell and smooth muscle cell proliferation
Matrix metalloproteinase, fibronectin and hyaluronan production
Angiogenesis
Wound remodeling
Integrin expression regulation

! Fibroblast growth factor 1 and 2

| FGF-1, −2

Macrophages
Mast cells
T-lymphocytes
Endothelial cells
Fibroblasts

Fibroblast chemotaxis
Fibroblast and keratinocyte proliferation
Keratinocyte migration
Angiogenesis
Wound contraction
Matrix (collagen fibers) deposition

! Transforming growth factor-β

| TGF-β

Platelets
T-lymphocytes
Macrophages
Endothelial cells
Keratinocytes
Smooth muscle cells
Fibroblasts

Granulocyte, macrophage, lymphocyte, fibroblast and smooth muscle cell chemotaxis
TIMP synthesis
Angiogenesis
Fibroplasia
Matrix metalloproteinase production inhibition
Keratinocyte proliferation

! Keratinocyte growth factor

| KGF

Keratinocytes

Keratinocyte migration, proliferation and differentiation

|colspan=4| Unless else specified in boxes, then reference is:

Complications of wound healing

The major complications are many:

Deficient scar formation: Results in wound dehiscence or rupture of the wound due to inadequate formation of granulation tissue.
Excessive scar formation: Hypertrophic scar, keloid, desmoid.
Exuberant granulation (proud flesh).
Deficient contraction (in skin grafts) or excessive contraction (in burns).
Pigmentary changes such as Postinflammatory hyperpigmentation
Others: Dystrophic calcification, painful scars, incisional hernia

Other complications can include infection and Marjolin's ulcer.

Biologics, skin substitutes, biomembranes and scaffolds

Advancements in the clinical understanding of wounds and their pathophysiology have commanded significant biomedical innovations in the treatment of acute, chronic, and other types of wounds. Many biologics, skin substitutes, biomembranes and scaffolds have been developed to facilitate wound healing through various mechanisms. This includes a number of products under the trade names such as Epicel, Laserskin, Transcyte, Dermagraft, AlloDerm/Strattice, Biobrane, Integra, Apligraf, OrCel, GraftJacket and PermaDerm.