Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.
In undamaged skin, the
epidermis
The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...
(surface,
epithelia
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
l layer) and
dermis
The dermis or corium is a layer of skin between the epidermis (with which it makes up the cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided i ...
(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
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, whi ...
),
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, tissue growth (
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
), and tissue remodeling (maturation and
cell differentiation
Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
). Blood clotting may be considered to be part of the inflammation stage instead of a separate stage.
![Wound Healing](https://upload.wikimedia.org/wikipedia/commons/4/4d/Wound_Healing.jpg)
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 wound 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 on ...
s. Factors that contribute to non-healing chronic wounds are diabetes, venous or arterial disease, infection, and metabolic deficiencies of old age.
[Enoch, S. Price, P. (2004)]
''Cellular, molecular and biochemical differences in the pathophysiology of healing between acute wounds, chronic wounds and wounds in the elderly''
.
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
First aid is the first and immediate assistance given to any person with either a minor or serious illness or injury, with care provided to preserve life, prevent the condition from worsening, or to promote recovery. It includes initial in ...
to entire nursing specialties such as
wound, ostomy, and continence nursing Wound, ostomy, and continence nursing is a nursing specialty involved with the treatment of patients with acute and chronic wounds, patients with an ostomy (those who have had some kind of bowel or bladder diversion), and patients with incontinence ...
and
burn center
A burn center, burn unit, or burns unit is a hospital specializing in the treatment of burns. Burn centers are often used for the treatment and recovery of patients with more severe burns.
Overview
The severity of a burn, and therefore whether ...
care.
Stages
* Hemostasis (blood clotting): Within the first few minutes of injury,
platelets
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
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
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with platele ...
, which forms a mesh and acts as "glue" to bind platelets to each other. This makes a
clot
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of c ...
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
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
, where white blood cells engulf debris and destroy it.
Platelet-derived growth factor
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
s 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
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
,
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
deposition,
granulation tissue
Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size ...
formation, epithelialization, and wound contraction occur.
In angiogenesis, vascular endothelial cells form new blood vessels.
In fibroplasia and granulation tissue formation,
fibroblast
A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
s grow and form a new, provisional
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
(ECM) by excreting collagen and
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
.
Concurrently, re-epithelialization of the epidermis occurs, in which
epithelial cell
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
s proliferate and 'crawl' atop the wound bed, providing cover for the new tissue.
[Garg, H.G. (2000). ''Scarless Wound Healing''. New York Marcel Dekker, Inc. Electronic book.] In wound contraction,
myofibroblast
A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.
Structure
Myofibroblasts are contractile web-like fusiform cells that are identifiable by their expression of α-sm ...
s 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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
* Maturation (remodeling): During maturation and remodeling, collagen is realigned along tension lines, and cells that are no longer needed are removed by programmed cell death, or
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
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;
[ If the epithelization of a wounded area is fast, the healing will result in regeneration.]
Early vs cellular phase
Wound healing is classically divided into hemostasis
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, whi ...
, inflammation, proliferation, and remodeling. Although a useful construct, this model employs considerable overlapping among individual phases. A complementary model has recently been described where the many elements of wound healing are more clearly delineated. The importance of this new model becomes more apparent through its utility in the fields of regenerative medicine
Regenerative medicine deals with the "process of replacing, engineering or regenerating human or animal cells, tissues or organs to restore or establish normal function". This field holds the promise of engineering damaged tissues and organs by st ...
and tissue engineering
Tissue engineering is a biomedical engineering discipline that uses a combination of Cell (biology), cells, engineering, Materials science, materials methods, and suitable biochemistry, biochemical and physicochemical factors to restore, maintai ...
(see Research and development section below). In this construct, the process of wound healing is divided into two major phases: the ''early phase'' and the ''cellular phase'':
The early phase, which begins immediately following skin injury, involves cascading molecular and cellular events leading to hemostasis and formation of an early, makeshift extracellular matrix that provides structural staging
Staging may refer to:
Computing
* Staging (cloud computing), a process used to assemble, test, and review a new solution before it is moved into production and the existing solution is decommissioned
* Staging (data), intermediately storing data ...
for cellular attachment and subsequent cellular proliferation.
The cellular phase involves several types of cells working together to mount an inflammatory response, synthesize granulation tissue, and restore the epithelial layer. Subdivisions of the cellular phase are:
# Macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s and inflammatory components (within 1–2 days)
# Epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
-mesenchymal
Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...
interaction: re-epithelialization (phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
change within hours, migration begins on day 1 or 2)
# Fibroblasts
A fibroblast is a type of biological cell 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 o ...
and myofibroblasts
A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.
Structure
Myofibroblasts are contractile web-like fusiform cells that are identifiable by their expression of α-sm ...
: progressive alignment, collagen production, and matrix contraction (between day 4 and day 14)
# Endothelial cell
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
s and angiogenesis (begins on day 4)
# Dermal matrix: elements of fabrication (begins on day 4, lasting 2 weeks) and alteration/remodeling (begins after week 2, lasting weeks to months—depending on wound size).
Inflammatory phase
Just before the inflammatory phase is initiated, the clotting cascade
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
occurs in order to achieve hemostasis
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, whi ...
, or the stopping of blood loss by way of a fibrin clot. Thereafter, various soluble factors (including chemokines and cytokines) are released to attract cells that phagocytise debris, bacteria, and damaged tissue, in addition to releasing signaling molecules that initiate the proliferative phase of wound healing.
Clotting cascade
When tissue is first wounded, blood comes in contact with collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
, triggering blood platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
s to begin secreting inflammatory factors.[Rosenberg L., de la Torre J. (2006)]
Wound Healing, Growth Factors
. Emedicine.com. Accessed January 20, 2008. Platelets also express sticky glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
s on their cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s that allow them to aggregate
Aggregate or aggregates may refer to:
Computing and mathematics
* collection of objects that are bound together by a root entity, otherwise known as an aggregate root. The aggregate root guarantees the consistency of changes being made within the ...
, forming a mass.
Fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with platele ...
and fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
cross-link together and form a plug that traps protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s and particles and prevents further blood loss. This fibrin-fibronectin plug is also the main structural support for the wound until collagen is deposited. Migratory cells use this plug as a matrix to crawl across, and platelets adhere to it and secrete factors. The clot is eventually lysed and replaced with granulation tissue
Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size ...
and then later with collagen.
Platelets, the cells present in the highest numbers shortly after a wound occurs, release mediators into the blood, including cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s and growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
s. Growth factors stimulate cells to speed their rate of division. Platelets release other proinflammatory factors like serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
, bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and ...
, prostaglandin
The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
s, prostacyclin
Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.
When used as a drug, it is also known as epoprosteno ...
s, thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.
Thromboxane is named for its ...
, and histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
, which serve several purposes, including increasing cell proliferation and migration to the area and causing blood vessel
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...
s to become dilated and porous
Porosity or void fraction is a measure of the void (i.e. "empty") spaces in a material, and is a fraction of the volume of voids over the total volume, between 0 and 1, or as a percentage between 0% and 100%. Strictly speaking, some tests measure ...
. In many ways, extravasated platelets in trauma perform a similar function to tissue macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s and mast cell
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
s exposed to microbial molecular signatures in infection: they become activated, and secrete molecular mediators – vasoactive amines, eicosanoid
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-c ...
s, and cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s – that initiate the inflammatory process.
Vasoconstriction and vasodilation
Immediately after a blood vessel
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...
is breached, ruptured cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s release inflammatory factors like thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.
Thromboxane is named for its ...
s and prostaglandin
The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
s that cause the vessel to spasm to prevent blood loss and to collect inflammatory cells and factors in the area. This vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vessel ...
lasts five to ten minutes and is followed by vasodilation
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
, a widening of blood vessels, which peaks at about 20 minutes post-wounding. Vasodilation is the result of factors released by platelets and other cells. The main factor involved in causing vasodilation is histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
. Histamine also causes blood vessels to become porous, allowing the tissue to become edema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
tous because proteins from the bloodstream leak into the extravascular space, which increases its osmolar load and draws water into the area. Increased porosity
Porosity or void fraction is a measure of the void (i.e. "empty") spaces in a material, and is a fraction of the volume of voids over the total volume, between 0 and 1, or as a percentage between 0% and 100%. Strictly speaking, some tests measure ...
of blood vessels also facilitates the entry of inflammatory cells like leukocyte
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s into the wound site from the bloodstream
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
.[Dealey C. (1999). ''The care of wounds: A guide for nurses''. Oxford; Malden, Mass. Blackwell Science. Electronic book.]
Polymorphonuclear neutrophils
Within an hour of wounding, polymorphonuclear neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
s (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.[de la Torre J., Sholar A. (2006)]
Wound healing: Chronic wounds
. Emedicine.com. Accessed January 20, 2008. They are attracted to the site by fibronectin, growth factors, and substances such as kinin A kinin is any of various structurally related polypeptides, such as bradykinin and kallidin. They are members of the autacoid family. Kinins are peptides that are cleaved from kininogens by the process of kallikreins. Kallikreins activate kinins wh ...
s. Neutrophils phagocytise debris and kill bacteria by releasing free radical
A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing.
Ageing
Ailments of unknown cause
Biogerontology
Biological processes
Causes of death
Cellular processes
Gerontology
Life extension
Metabo ...
s in what is called a respiratory burst
Respiratory burst (or oxidative burst) is the rapid release of the reactive oxygen species (ROS), superoxide anion () and hydrogen peroxide (), from different cell types.
This is usually utilised for mammalian immunological defence, but also pla ...
. They also cleanse the wound by secreting protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s 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 macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s.
Other leukocytes to enter the area include helper T cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
s, which secrete cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
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
One of the roles of macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
is to phagocytize other expended phagocyte
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...
s, bacteria and damaged tissue, and they also debride damaged tissue by releasing proteases.
Macrophages function in regeneration and are essential for wound healing. They are stimulated by the low oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
content of their surroundings to produce factors that induce and speed angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
and they also stimulate cells that reepithelialize the wound, create granulation tissue, and lay down a new extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
. 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
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . 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, monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...
s 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. Once they are in the wound site, monocytes mature into macrophages. Macrophages also secrete a number of factors such as growth factors and other cytokines, especially during the third and fourth post-wounding days. These factors attract cells involved in the proliferation stage of healing to the area.
In wound healing that result in incomplete repair, scar contraction occurs, bringing varying gradations of structural imperfections, deformities and problems with flexibility. Macrophages may restrain the contraction phase. Scientists have reported that removing the macrophages from a salamander
Salamanders are a group of amphibians typically characterized by their lizard-like appearance, with slender bodies, blunt snouts, short limbs projecting at right angles to the body, and the presence of a tail in both larvae and adults. All ten ...
resulted in failure of a typical regeneration response (limb regeneration), instead bringing on a repair (scarring) response.
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. These changes indicate that the inflammatory phase is ending and the proliferative phase is underway. In vitro evidence, obtained using the dermal equivalent 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 derma ...
model, suggests that the presence of macrophages actually delays wound contraction and thus the disappearance of macrophages from the wound may be essential for subsequent phases to occur.
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. Thus the reduction of inflammation is frequently a goal in therapeutic settings. Inflammation lasts as long as there is debris in the wound. Thus, if the individual's immune system is compromised and is unable to clear the debris from the wound and/or if excessive detritus, devitalized tissue, or microbial biofilm
A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular ...
is present in the wound, these factors may cause a prolonged inflammatory phase and prevent the wound from properly commencing the proliferation phase of healing. This can lead to a chronic wound 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 on ...
.
Proliferative phase
About two or three days after the wound occurs, fibroblasts
A fibroblast is a type of biological cell 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 o ...
begin to enter the wound site, marking the onset of the proliferative phase even before the inflammatory phase has ended.[Falanga V. (2005). Wound Healing. American Academy of Dermatology (AAD).] 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.[Kuwahara R.T. and Rasberry R. 2007.]
Chemical Peels
. Emedicine.com. Accessed September 15, 2007. 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 erythema
Erythema (from the Greek , meaning red) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not assoc ...
tous) due to the presence of capillaries
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
.
Angiogenesis occurs in overlapping phases in response to inflammation:
# Latent period: During the haemostatic and inflammatory phase of the wound healing process, vasodilation and permeabilisation allow leukocyte extravasation and phagocytic debridement and decontamination of the wound area. Tissue swelling aids later angiogenesis by expanding and loosening the existing collagenous extracellular matrix.
# Endothelial activation: As the wound macrophages switches from inflammatory to healing mode, it begins to secrete endothelial chemotactic and growth factors to attract adjacent endothelial cells. Activated endothelial cells respond by retracting and reducing cell junctions, loosening themselves from their embedded endothelium. Characteristically the activated endothelial cells show enlarged nucleoli.
# Degradation of endothelial basement membrane: The wound macrophages, mast cells and the endothelial cells themselves secrete proteases to break down existing vascular basal lamina.
# Vascular sprouting: With the breakdown of endothelial basement membrane, detached endothelial cells from pre-existing capillaries and post-capillary venules can divide and migrate chemotactically towards the wound, laying down new vessels in the process. Vascular sprouting can be aided by ambient hypoxia and acidosis in the wound environment, as hypoxia stimulates the endothelial transcription factor, hypoxia inducible factor (HIF) to transactivate angiogenic genes such as VEGF and GLUT1. Sprouted vessels can self-organise into luminal morphologies, and fusion of blind channels give rise to new capillary networks.
# Vascular maturation: the endothelium of vessels mature by laying down new endothelial extracellular matrix, followed by basal lamina formation. Lastly the vessel establishes a pericyte layer.
Stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s of endothelial cell
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
s, originating from parts of uninjured blood vessels, develop pseudopod
A pseudopod or pseudopodium (plural: pseudopods or pseudopodia) is a temporary arm-like projection of a eukaryotic cell membrane that is emerged in the direction of movement. Filled with cytoplasm, pseudopodia primarily consist of actin filamen ...
ia and push through the ECM into the wound site to establish new blood vessels.
Endothelial cell
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
s are attracted to the wound area by fibronectin found on the fibrin scab and chemotactically by angiogenic factors released by other cells,[Romo T. and Pearson J.M. 2005.]
Wound Healing, Skin
. Emedicine.com. Accessed December 27, 2006. e.g. from macrophages and platelets when in a low-oxygen environment. Endothelial growth and proliferation is also directly stimulated by hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
, and presence of lactic acid
Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with water. When in the dissolved state, it forms a colorless solution. Production includes both artificial synthesis as well as natu ...
in the wound. For example, hypoxia stimulates the endothelial transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
, hypoxia-inducible factor
Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They are only present in parahoxozoan animals.
Discovery
The HIF transcriptional complex wa ...
(HIF) to transactivate In the context of gene regulation: transactivation is the increased rate of gene expression triggered either by biological processes or by artificial means, through the expression of an intermediate transactivator protein.
In the context of rece ...
a set of proliferative genes including vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
(VEGF) and glucose transporter 1 (GLUT1).
To migrate, endothelial cells need collagenase
Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as ''Clostridium''. They are considered a virulence factor, facilitating the spread of ga ...
s and plasminogen activator Plasminogen activators are serine proteases that catalyze the activation of plasmin via proteolytic cleavage of its zymogen form plasminogen. Plasmin is an important factor in fibrinolysis, the breakdown of fibrin polymers formed during blood clotti ...
to degrade the clot and part of the ECM. Zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
-dependent metalloproteinase
A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogen ...
s digest basement membrane
The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...
and ECM to allow cell migration, proliferation and angiogenesis.
When macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic acid-filled environment, they stop producing angiogenic factors. Thus, when tissue is adequately perfused, migration and proliferation of endothelial cells is reduced. Eventually blood vessels that are no longer needed die by apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
Fibroplasia and granulation tissue formation
Simultaneously with angiogenesis, fibroblast
A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
s begin accumulating in the wound site. Fibroblasts begin entering the wound site two to five days after wounding as the inflammatory phase is ending, and their numbers peak at one to two weeks post-wounding. By the end of the first week, fibroblasts are the main cells in the wound. Fibroplasia ends two to four weeks after wounding.
As a model the mechanism of fibroplasia may be conceptualised as an analogous process to angiogenesis (see above) - only the cell type involved is fibroblasts rather than endothelial cells. Initially there is a latent phase where the wound undergoes plasma exudation, inflammatory decontamination and debridement. Oedema increases the wound histologic accessibility for later fibroplastic migration. Second, as inflammation nears completion, macrophage and mast cells release fibroblast growth and chemotactic factors to activate fibroblasts from adjacent tissue. Fibroblasts at this stage loosen themselves from surrounding cells and ECM. Phagocytes further release proteases that break down the ECM of neighbouring tissue, freeing the activated fibroblasts to proliferate and migrate towards the wound. The difference between vascular sprouting and fibroblast proliferation is that the former is enhanced by hypoxia, whilst the latter is inhibited by hypoxia. The deposited fibroblastic connective tissue matures by secreting ECM into the extracellular space, forming granulation tissue (see below). Lastly collagen is deposited into the ECM.
In the first two or three days after injury, fibroblasts mainly migrate and proliferate, while later, they are the main cells that lay down the collagen matrix in the wound site. Origins of these fibroblasts are thought to be from the adjacent uninjured cutaneous tissue (although new evidence suggests that some are derived from blood-borne, circulating adult stem cells/precursors). Initially fibroblasts utilize the fibrin cross-linking fibers (well-formed by the end of the inflammatory phase) to migrate across the wound, subsequently adhering to fibronectin. Fibroblasts then deposit ground substance Ground substance is an amorphous gel-like substance in the extracellular space that contains all components of the extracellular matrix (ECM) except for fibrous materials such as collagen and elastin. Ground substance is active in the development, m ...
into the wound bed, and later collagen, which they can adhere to for migration.
Granulation tissue
Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size ...
functions as rudimentary tissue, and begins to appear in the wound already during the inflammatory phase, two to five days post wounding, and continues growing until the wound bed is covered. Granulation tissue consists of new blood vessels, fibroblasts, inflammatory cells, endothelial cells, myofibroblasts, and the components of a new, provisional extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
(ECM). The provisional ECM is different in composition from the ECM in normal tissue and its components originate from fibroblasts. Such components include fibronectin, collagen, glycosaminoglycan
Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...
s, elastin
Elastin is a protein that in humans is encoded by the ''ELN'' gene. Elastin is a key component of the extracellular matrix in gnathostomes (jawed vertebrates). It is highly elastic and present in connective tissue allowing many tissues in the bod ...
, glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
s and proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whic ...
s. Its main components are fibronectin and hyaluronan
Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans ...
, which create a very hydrated matrix and facilitate cell migration. Later this provisional matrix is replaced with an ECM that more closely resembles that found in non-injured tissue.
Growth factors (PDGF
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
, TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
) and fibronectin encourage proliferation, migration to the wound bed, and production of ECM molecules by fibroblasts. Fibroblasts also secrete growth factors that attract epithelial cells to the wound site. Hypoxia also contributes to fibroblast proliferation and excretion of growth factors, though too little oxygen will inhibit their growth and deposition of ECM components, and can lead to excessive, fibrotic scar
A scar (or scar tissue) 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 na ...
ring.
Collagen deposition
One of fibroblasts' most important duties is the production of collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
.
Collagen deposition is important because it increases the strength of the wound; before it is laid down, the only thing holding the wound closed is the fibrin-fibronectin clot, which does not provide much resistance to traumatic injury
An injury is any physiological damage to living tissue caused by immediate physical stress. An injury can occur intentionally or unintentionally and may be caused by blunt trauma, penetrating trauma, burning, toxic exposure, asphyxiation, or o ...
. Also, cells involved in inflammation, angiogenesis, and connective tissue construction attach to, grow and differentiate on the collagen matrix laid down by fibroblasts.
Type III collagen
Type III Collagen is a homotrimer, or a protein composed of three identical peptide chains (monomers), each called an alpha 1 chain of type III collagen. Formally, the monomers are called collagen type III, alpha-1 chain and in humans are encoded ...
and fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
generally begin to be produced in appreciable amounts at somewhere between approximately 10 hours[Fig. 9-1. The cellular, biochemical, and mechanical phases of wound healing. ] and 3 days, depending mainly on wound size. Their deposition peaks at one to three weeks. They are the predominating tensile substances until the later phase of maturation, in which they are replaced by the stronger type I collagen
Type I collagen is the most abundant collagen of the human body. It forms large, eosinophilic fibers known as collagen fibers.
It is present in scar tissue, the end product when tissue heals by repair, as well as tendons, ligaments, the endomys ...
.
Even as fibroblasts are producing new collagen, collagenases and other factors degrade it. Shortly after wounding, synthesis exceeds degradation so collagen levels in the wound rise, but later production and degradation become equal so there is no net collagen gain. This homeostasis signals the onset of the later maturation phase. Granulation gradually ceases and fibroblasts decrease in number in the wound once their work is done. 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.
Epithelialization
The formation of granulation tissue into an open wound allows the reepithelialization phase to take place, as epithelial cells migrate across the new tissue to form a barrier between the wound and the environment. Basal keratinocyte
Keratinocytes are the primary type of Cell (biology), cell found in the epidermis (skin), epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.
Basal cells in the stratum basale, basal layer (''str ...
s from the wound edges and dermal appendage
The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between ho ...
s such as hair follicle
The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between h ...
s, sweat glands
Sweat glands, also known as sudoriferous or sudoriparous glands, , are small tubular structures of the skin that produce sweat. Sweat glands are a type of exocrine gland, which are glands that produce and secrete substances onto an epithelial sur ...
and sebacious (oil) glands are the main cells responsible for the epithelialization phase of wound healing. They advance in a sheet across the wound site and proliferate at its edges, ceasing movement when they meet in the middle. In healing that results in a scar, sweat glands, hair follicles[ and nerves do not form. With the lack of hair follicles, nerves and sweat glands, the wound, and the resulting healing scar, provide a challenge to the body with regards to temperature control.]
Keratinocyte
Keratinocytes are the primary type of Cell (biology), cell found in the epidermis (skin), epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.
Basal cells in the stratum basale, basal layer (''str ...
s 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.[Mulvaney M. and Harrington A. 1994.]
Chapter 7: Cutaneous trauma and its treatment
In, ''Textbook of Military Medicine: Military Dermatology''. Office of the Surgeon General, Department of the Army. Virtual Naval Hospital Project. Accessed through web archive on September 15, 2007. Thus the time of onset of migration is variable and may occur about one day after wounding.[Larjava H., Koivisto L., and Hakkinen L. 2002. Chapter 3: Keratinocyte Interactions with Fibronectin During Wound Healing. In, Heino, J. and Kahari, V.M. ''Cell Invasion''. Medical Intelligence Unit; 33. Georgetown, Tex., Austin, Tex Landes Bioscience, Inc. Electronic book.] Cells on the wound margins proliferate on the second and third day post-wounding in order to provide more cells for migration.
If the basement membrane
The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...
is not breached, epithelial cells are replaced within three days by division and upward migration of cells in the stratum basale
The ''stratum basale'' (basal layer, sometimes referred to as ''stratum germinativum'') is the deepest layer of the five layers of the epidermis, the external covering of skin in mammals.
The ''stratum basale'' is a single layer of columnar or ...
in the same fashion that occurs in uninjured skin. However, if the basement membrane is ruined at the wound site, reepithelization must occur from the wound margins and from skin appendages such as hair follicles and sweat and oil glands that enter the dermis
The dermis or corium is a layer of skin between the epidermis (with which it makes up the cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided i ...
that are lined with viable keratinocytes. If the wound is very deep, skin appendages may also be ruined and migration can only occur from wound edges.
Migration of keratinocytes over the wound site is stimulated by lack of contact inhibition In cell biology, contact inhibition refers to two different but closely related phenomena: contact inhibition of locomotion (CIL) and contact inhibition of proliferation (CIP). CIL refers to the avoidance behavior exhibited by fibroblast-like cells ...
and by chemicals such as nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
. Before they begin to migrate, cells must dissolve their desmosomes
A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adh ...
and hemidesmosomes
Hemidesmosomes are very small stud-like structures found in keratinocytes of the epidermis of skin that attach to the extracellular matrix. They are similar in form to desmosomes when visualized by electron microscopy, however, desmosomes attach t ...
, which normally anchor the cells by intermediate filaments
Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate ''Branchiostoma''.
Intermedia ...
in their cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
to other cells and to the ECM. Transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s called integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
s, which are made of glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
s and normally anchor the cell to the basement membrane by its cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
, are released from the cell's intermediate filaments and relocate to actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
filaments to serve as attachments to the ECM for pseudopod
A pseudopod or pseudopodium (plural: pseudopods or pseudopodia) is a temporary arm-like projection of a eukaryotic cell membrane that is emerged in the direction of movement. Filled with cytoplasm, pseudopodia primarily consist of actin filamen ...
ia during migration. Thus keratinocytes detach from the basement membrane and are able to enter the wound bed.
Before they begin migrating, keratinocytes change shape, becoming longer and flatter and extending cellular processes like lamellipodia
The lamellipodium (plural lamellipodia) (from Latin ''lamella'', related to ', "thin sheet", and the Greek radical ''pod-'', "foot") is a cytoskeletal protein actin projection on the leading edge of the cell. It contains a quasi-two-dimensional ...
and wide processes that look like ruffles. Actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
filaments and pseudopod
A pseudopod or pseudopodium (plural: pseudopods or pseudopodia) is a temporary arm-like projection of a eukaryotic cell membrane that is emerged in the direction of movement. Filled with cytoplasm, pseudopodia primarily consist of actin filamen ...
ia form. During migration, integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
s on the pseudopod attach to the ECM, and the actin filaments in the projection pull the cell along. The interaction with molecules in the ECM through integrins further promotes the formation of actin filaments, lamellipodia, and filopodia
Filopodia (singular filopodium) are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. Within the lamellipodium, actin ribs are known as ''microspikes'', and when they extend beyond the lame ...
.
Epithelial cells climb over one another in order to migrate. This growing sheet of epithelial cells is often called the epithelial tongue. The first cells to attach to the basement membrane
The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...
form the stratum basale
The ''stratum basale'' (basal layer, sometimes referred to as ''stratum germinativum'') is the deepest layer of the five layers of the epidermis, the external covering of skin in mammals.
The ''stratum basale'' is a single layer of columnar or ...
. These basal cells continue to migrate across the wound bed, and epithelial cells above them slide along as well. The more quickly this migration occurs, the less of a scar there will be.
Fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with platele ...
, 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.
As keratinocytes migrate, they move over granulation tissue but stay underneath the scab, thereby separating the scab from the underlying tissue. Epithelial cells have the ability to phagocytize debris such as dead tissue and bacterial matter that would otherwise obstruct their path. Because they must dissolve any scab that forms, keratinocyte migration is best enhanced by a moist environment, since a dry one leads to formation of a bigger, tougher scab. 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 Plasminogen activators are serine proteases that catalyze the activation of plasmin via proteolytic cleavage of its zymogen form plasminogen. Plasmin is an important factor in fibrinolysis, the breakdown of fibrin polymers formed during blood clotti ...
, which activates plasminogen
Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encode ...
, turning it into plasmin
Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encoded ...
to dissolve the scab. Cells can only migrate over living tissue, so they must excrete collagenases and proteases like matrix metalloproteinases
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...
(MMPs) to dissolve damaged parts of the ECM in their way, particularly at the front of the migrating sheet. Keratinocytes also dissolve the basement membrane, using instead the new ECM laid down by fibroblasts to crawl across.
As keratinocytes continue migrating, new epithelial cells must be formed at the wound edges to replace them and to provide more cells for the advancing sheet. Proliferation behind migrating keratinocytes normally begins a few days after wounding and occurs at a rate that is 17 times higher in this stage of epithelialization than in normal tissues. Until the entire wound area is resurfaced, the only epithelial cells to proliferate are at the wound edges.
Growth factors, stimulated by integrins and MMPs, cause cells to proliferate at the wound edges. Keratinocytes themselves also produce and secrete factors, including growth factors and basement membrane proteins, which aid both in epithelialization and in other phases of healing. 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 In cell biology, contact inhibition refers to two different but closely related phenomena: contact inhibition of locomotion (CIL) and contact inhibition of proliferation (CIP). CIL refers to the avoidance behavior exhibited by fibroblast-like cells ...
causes them to stop migrating. When they have finished migrating, the keratinocytes secrete the proteins that form the new basement membrane. Cells reverse the morphological changes they underwent in order to begin migrating; they reestablish desmosome
A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adh ...
s and hemidesmosome
Hemidesmosomes are very small stud-like structures found in keratinocytes of the epidermis of skin that attach to the extracellular matrix. They are similar in form to desmosomes when visualized by electron microscopy, however, desmosomes attach to ...
s and become anchored once again to the basement membrane. Basal cells
The ''stratum basale'' (basal layer, sometimes referred to as ''stratum germinativum'') is the deepest layer of the five layers of the epidermis, the external covering of skin in mammals.
The ''stratum basale'' is a single layer of columnar or ...
begin to divide and differentiate in the same manner as they do in normal skin to reestablish the strata found in reepithelialized skin.
Contraction
Contraction is a key phase of wound healing with repair. If contraction continues for too long, it can lead to disfigurement and loss of function. 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
The collagen gel contraction assay is a type of wound contraction. It is performed using the dermal equivalent model, which consists of dermal fibroblasts seeded into a collagen gel.
References
Skin physiology
{{med-stub ...
or the dermal equivalent 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 derma ...
model.
Contraction commences approximately a week after wounding, when fibroblasts have differentiated into myofibroblast
A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.
Structure
Myofibroblasts are contractile web-like fusiform cells that are identifiable by their expression of α-sm ...
s. In full thickness wounds, contraction peaks at 5 to 15 days post wounding. Contraction can last for several weeks and continues even after the wound is completely reepithelialized. A large wound can become 40 to 80% smaller after contraction. Wounds can contract at a speed of up to 0.75 mm per day, depending on how loose the tissue in the wounded area is. Contraction usually does not occur symmetrically; rather most wounds have an 'axis of contraction' which allows for greater organization and alignment of cells with collagen.
At first, contraction occurs without myofibroblast involvement. Later, fibroblasts, stimulated by growth factors, differentiate into myofibroblasts. Myofibroblasts, which are similar to smooth muscle cells, are responsible for contraction. Myofibroblasts contain the same kind of actin as that found in smooth muscle
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
cells.
Myofibroblasts are attracted by fibronectin and growth factors and they move along fibronectin linked to fibrin in the provisional ECM in order to reach the wound edges. They form connections to the ECM at the wound edges, and they attach to each other and to the wound edges by desmosomes
A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adh ...
. Also, at an adhesion called the fibronexus, actin in the myofibroblast is linked across the cell membrane to molecules in the extracellular matrix like fibronectin and collagen. Myofibroblasts have many such adhesions, which allow them to pull the ECM when they contract, reducing the wound size. In this part of contraction, closure occurs more quickly than in the first, myofibroblast-independent part.
As the actin in myofibroblasts contracts, the wound edges are pulled together. Fibroblasts lay down collagen to reinforce the wound as myofibroblasts contract. The contraction stage in proliferation ends as myofibroblasts stop contracting and commit apoptosis. The breakdown of the provisional matrix leads to a decrease in hyaluronic acid and an increase in chondroitin sulfate, which gradually triggers fibroblasts to stop migrating and proliferating. These events signal the onset of the maturation stage of wound healing.
Maturation and remodeling
When the levels of collagen production and degradation equalize, the maturation phase of tissue repair is said to have begun. During maturation, type III collagen
Type III Collagen is a homotrimer, or a protein composed of three identical peptide chains (monomers), each called an alpha 1 chain of type III collagen. Formally, the monomers are called collagen type III, alpha-1 chain and in humans are encoded ...
, which is prevalent during proliferation, is replaced by type I collagen. Originally disorganized collagen fibers are rearranged, cross-linked, and aligned along tension lines
Langer's lines, Langer lines of skin tension, or sometimes called cleavage lines, are topological lines drawn on a map of the human body. They are parallel to the natural orientation of collagen fibers in the dermis, and generally perpendicular to ...
. The onset of the maturation phase may vary extensively, depending on the size of the wound and whether it was initially closed or left open, ranging from approximately three days[ to three weeks. The maturation phase can last for a year or longer, similarly depending on wound type.]
As the phase progresses, the tensile strength
Ultimate tensile strength (UTS), often shortened to tensile strength (TS), ultimate strength, or F_\text within equations, is the maximum stress that a material can withstand while being stretched or pulled before breaking. In brittle materials t ...
of the wound increases. Collagen will reach approximately 20% of its tensile strength after three weeks, increasing to 80% by the 12th week. The maximum scar strength is 80% of that of unwounded skin. Since activity at the wound site is reduced, the scar loses its red appearance as blood vessel
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...
s that are no longer needed are removed by apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
The phases of wound healing normally progress in a predictable, timely manner; if they do not, healing may progress inappropriately to either a chronic wound 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 on ...
such as a venous ulcer
Venous ulcer is defined by the American Venous Forum as "a full-thickness defect of skin, most frequently in the ankle region, that fails to heal spontaneously and is sustained by chronic venous disease, based on venous duplex ultrasound testing." ...
or pathological scarring such as a keloid scar
Keloid, also known as keloid disorder and keloidal scar,
is the formation of a type of scar which, depending on its maturity, is composed mainly of either type III (early) or type I (late) collagen. It is a result of an overgrowth of granulation t ...
.
Factors affecting wound healing
Many factors controlling the efficacy, speed, and manner of wound healing fall under two types: local and systemic factors.
Local factors
* Moisture; keeping a wound moist rather than dry makes wound healing more rapid and with less pain and less scarring
* Mechanical factors
* Oedema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...
* Ionizing radiation
Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...
* Faulty technique of wound closure
* Ischemia
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
and necrosis
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
* 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
Blood gas tension refers to the partial pressure of gases in blood. There are several significant purposes for measuring gas tension. The most common gas tensions measured are oxygen tension (PxO2), carbon dioxide tension (PxCO2) and carbon monoxi ...
* Perfusion
Systemic factors
* Inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
* Diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
– 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. This impaired healing involves hypoxia, fibroblast and epidermal cell dysfunction, impaired angiogenesis and neovascularization, high levels of metalloproteases, damage from reactive oxygen species and AGEs (advanced glycation end-products), decreased host immune resistance, and neuropathy.
* Nutrient
A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
s – Malnutrition or nutritional deficiencies have a recognizable impact on wound healing post trauma or surgical intervention. 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. As the nutritional needs of each patient and their associated wound are complex, it is suggested that tailored nutritional support would benefit both acute and chronic wound healing.
* Metabolic disease
A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...
s
* Immunosuppression
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...
* Connective tissue
Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...
disorders
* Smoking – Smoking causes a delay in the speed of wound repair notably in the proliferative and inflammatory phases. It also increases the likelihood of certain complications such as wound rupture, wound and flap necrosis, decrease in wound tensile strength and infection. Passive smoking
Passive smoking is the inhalation of tobacco smoke, called secondhand smoke (SHS), or environmental tobacco smoke (ETS), by persons other than the intended "active" smoker. It occurs when tobacco smoke enters an environment, causing its inhalat ...
also impairs a proper wound healing process.
* Age – Increased age (over 60 years) is a risk factor for impaired wound healing. It is recognized that, in older adults of otherwise overall good health, the effects of aging causes a temporal delay in healing, but no major impairment with regard to the quality of 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
Units of alcohol are used in the United Kingdom (UK) as a measure to quantify the actual alcoholic content within a given volume of an alcoholic beverage, in order to provide guidance on total alcohol consumption.
A number of other countries (in ...
causes a negative effect on re-epithelialization, wound closure, collagen production and angiogenesis.
In the 2000s there arose the first Mathematical models of the healing process, based on simplified assumptions and on a system of differential equations
In mathematics, a system of differential equations is a finite set of differential equations. Such a system can be either linear or non-linear. Also, such a system can be either a system of ordinary differential equations or a system of partial dif ...
solved through MATLAB
MATLAB (an abbreviation of "MATrix LABoratory") is a proprietary multi-paradigm programming language and numeric computing environment developed by MathWorks. MATLAB allows matrix manipulations, plotting of functions and data, implementation ...
. The models show that the "rate of the healing process" appears to be "highly influenced by the activity and size of the injury itself as well as the activity of the healing agent."
Research and development
Up until about 2000, the classic paradigm of wound healing, involving stem cells
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
restricted to organ-specific lineages, had never been seriously challenged. Since then, the notion of adult stem cells
Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from Greek σωματικóς, m ...
having cellular ''plasticity'' or the ability to differentiate into non-lineage cells has emerged as an alternative explanation. To be more specific, hematopoietic
Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...
progenitor cells
In genealogy, the progenitor (rarer: primogenitor; german: Stammvater or ''Ahnherr'') is the – sometimes legendary – founder of a family, line of descent, clan or tribe, noble house, or ethnic group..
Ebenda''Ahnherr:''"Stammvater eines G ...
(that give rise to mature cells in the blood) may have the ability ''de-differentiate'' back into hematopoietic stem cells and/or ''transdifferentiate'' into non-lineage cells, such as fibroblasts.
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
Rete pegs (also known as rete processes or rete ridges) are the epithelial extensions that project into the underlying connective tissue in both skin and mucous membranes.
In the epithelium of the mouth, the attached gingiva exhibit rete pegs, wh ...
(basal stem cells or BSC), the bulge of hair follicle
The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between h ...
s (hair follicular stem cell or HFSC), and the papillary dermis (dermal stem cells). Moreover, bone marrow may also contain stem cells that play a major role in cutaneous wound healing.
In rare circumstances, such as extensive cutaneous injury, self-renewal subpopulations in the bone marrow are induced to participate in the healing process, whereby they give rise to collagen-secreting cells that seem to play a role during wound repair. These two self-renewal subpopulations are (1) bone marrow-derived mesenchymal stem cells
Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage ce ...
(MSC) and (2) hematopoietic stem cells
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
(HSC). Bone marrow also harbors a progenitor subpopulation (endothelial
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
progenitor cells or EPC) that, in the same type of setting, are mobilized to aid in the reconstruction of blood vessels. Moreover, it is thought that extensive injury to skin also promotes the early trafficking of a unique subclass of leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
(circulating fibrocyte
A fibrocyte is an inactive mesenchymal cell, that is, a cell showing minimal cytoplasm, limited amounts of rough endoplasmic reticulum and lacks biochemical evidence of protein synthesis.
The term ''fibrocyte'' contrasts with the term ''fibrobla ...
s) to the injured region, where they perform various functions related to wound healing. I mesenchymal stromal cell therapy alone does not lead to the complete restoration of ulcerated skin.
Wound repair versus regeneration
An injury is an interruption of morphology and/or functionality of a given tissue. After injury, structural tissue heals with incomplete or complete regeneration.[ Tissue without an interruption to the morphology almost always completely regenerates. An example of complete regeneration without an interruption of the morphology is non-injured tissue, such as skin.][ Non-injured skin has a continued replacement and regeneration of cells which always results in complete regeneration.][
There is a subtle distinction between 'repair' and 'regeneration'.][ ''Repair'' means ''incomplete regeneration''.] 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.[
''True tissue regeneration'' or ''complete regeneration'',] refers to the replacement of lost/damaged tissue with an 'exact' copy, such that both morphology and functionality are completely restored.[ Though after injury mammals can completely regenerate spontaneously, they usually do not completely regenerate. An example of a tissue regenerating completely after an interruption of morphology is the ]endometrium
The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional laye ...
; the endometrium after the process of breakdown via the menstruation cycle heals with complete regeneration.
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
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
-glycoaminoglycan
Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case o ...
) scaffolds. These scaffolds are structurally analogous to extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
(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. In addition to providing support for fibroblast and endothelial cell attachment, biodegradable scaffolds inhibit wound contraction, thereby allowing the healing process to proceed towards a more-regenerative/less-scarring pathway. Pharmaceutical agents have been investigated which may be able to turn off myofibroblast
A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.
Structure
Myofibroblasts are contractile web-like fusiform cells that are identifiable by their expression of α-sm ...
differentiation.
A new way of thinking derived from the notion that heparan sulfate
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
s 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.[Van Neck et al, Heparan sulfate proteoglycan mimetics thrive tissue regeneration: an overview. In Intech book under the working title "Tissue Regeneration", is scheduled for on line publication on Nov 26, 2011"]
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.[Zhang Y, Strehin I, Bedelbaeva K, Gourevitch D, Clark L, Leferovich J, Messersmith PB, Heber-Katz E. Drug-induced regeneration in adult mice. Sci Transl Med. 2015;290.]
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
A scar (or scar tissue) 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 na ...
tissue than normally expected. Scarless healing is sometimes mixed up with the concept of ''scar free healing
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 ...
,'' which is wound healing which results in absolutely no scar (''free'' of scarring). However they are different concepts.
A reverse to scarless wound healing is scarification
Scarification involves scratching, etching, burning/branding, or superficially cutting designs, pictures, or words into the skin as a permanent body modification or body art. The body modification can take roughly 6–12 months to heal. In the p ...
(wound healing to scar more). Historically, certain cultures consider scarification attractive;[Rush, J. (2005). Spiritual tattoo: a cultural history of tattooing, piercing, scarification, branding, and implants, Frog Ltd.] however, this is generally not the case in the modern western society, in which many patients are turning to plastic surgery
Plastic surgery is a surgical specialty involving the restoration, reconstruction or alteration of the human body. It can be divided into two main categories: reconstructive surgery and cosmetic surgery. Reconstructive surgery includes craniofa ...
clinics with unrealistic expectations. Depending on scar
A scar (or scar tissue) 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 na ...
type, treatment may be invasive (intralesional steroid injections, surgery) and/or conservative ( compression therapy, topical silicone gel
A silicone or polysiloxane is a polymer made up of siloxane (−R2Si−O−SiR2−, where R = organic group). They are typically colorless oils or rubber-like substances. Silicones are used in sealants, adhesives, lubricants, medicine, cooking ...
, brachytherapy
Brachytherapy is a form of radiation therapy where a sealed radiation source is placed inside or next to the area requiring treatment. ''Brachy'' is Greek for short. Brachytherapy is commonly used as an effective treatment for cervical, prosta ...
, photodynamic therapy
Photodynamic therapy (PDT) is a form of phototherapy involving light and a photosensitizing chemical substance, used in conjunction with molecular oxygen to elicit cell death (phototoxicity).
PDT is popularly used in treating acne. It is used cl ...
). 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
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
, 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
In biology, regeneration 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 rege ...
have expanded due to advances in cellular and molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
.[Clark, R. (1996). The molecular and cellular biology of wound repair, Springer Us.] 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 and complete regeneration
Regeneration may refer to:
Science and technology
* Regeneration (biology), the ability to recreate lost or damaged cells, tissues, organs and limbs
* Regeneration (ecology), the ability of ecosystems to regenerate biomass, using photosynthesis
...
is limited to lower vertebrates, such as salamanders
Salamanders are a group of amphibians typically characterized by their lizard-like appearance, with slender bodies, blunt snouts, short limbs projecting at right angles to the body, and the presence of a tail in both larvae and adults. All ten ...
, and invertebrates
Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...
. In adult humans, injured tissue are repaired by collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
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.[ In print the antiquated concept of scarless healing was brought up the early 20th century and appeared in a paper published in the London Lancet. This process involved cutting in a surgical slant, instead of a right angle...; it was described in various Newspapers.]
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
Stanford University, officially Leland Stanford Junior University, is a private research university in Stanford, California. The campus occupies , among the largest in the United States, and enrolls over 17,000 students. Stanford is consider ...
studying Breast cancers.
Oral collagen supplements
Preliminary results are promising for th
short and long-term use of oral collagen supplements for wound healing
and skin aging. Oral collagen supplements also increase skin elasticity, hydration, and dermal collagen density. Collagen supplementation is generally safe with no reported adverse events. Further studies are needed to elucidate medical use in skin barrier diseases such as atopic dermatitis and to determine optimal dosing regimens.
Wound Dressings
Modern wound dressing to aid in wound repair have 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
An exudate is a fluid emitted by an organism through pores or a wound, a process known as exuding or exudation.
''Exudate'' is derived from ''exude'' 'to ooze' from Latin ''exsūdāre'' 'to (ooze out) sweat' (''ex-'' 'out' and ''sūdāre'' 'to ...
* Antimicrobial
An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals ar ...
properties
* Maintain a humid environment
* Have high permeability to oxygen
* Easily removed from a wound site
* Non-anaphylactic
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
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
Chitosan is a linear polysaccharide composed of randomly distributed β-(1→4)-linked Glucosamine, D-glucosamine (deacetylated unit) and N-Acetylglucosamine, ''N''-acetyl-D-glucosamine (acetylated unit). It is made by treating the chitin shell ...
/ Ag/ ZnO nanocomposite
Nanocomposite is a multiphase solid material where one of the phases has one, two or three dimensions of less than 100 nanometers (nm) or structures having nano-scale repeat distances between the different phases that make up the material.
The id ...
. These updated dressing provide increase water absorbency and improved antibacterial efficacy
Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a pragmatic clinical trial#Efficacy versu ...
.
Wound cleansing
Dirt or dust on the surface of the wound, bacteria, tissue that has died, and fluid from the wound may be cleaned. The evidence supporting the most effective technique is not clear and there is insufficient evidence to conclude whether cleaning wounds is beneficial for promoting healing or whether wound cleaning solutions (polyhexamethylene biguanide, aqueous oxygen peroxide, etc.) are better than sterile water or saline solutions to help venous leg ulcers heal. It is uncertain whether the choice of cleaning solution or method of application makes any difference to venous leg ulcer healing.
Simulating wound healing from a growth perspective
Considerable effort has been devoted to understanding the physical relationships governing wound healing and subsequent scarring, with mathematical models and simulations developed to elucidate these relationships. 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 model
An agent-based model (ABM) is a computational model for simulating the actions and interactions of autonomous agents (both individual or collective entities such as organizations or groups) in order to understand the behavior of a system and wha ...
s, 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. In this process, wound edges are brought together, so that they are adjacent to each other (re-approximated). Wound closure is performed with sutures (stitches), staples, or adhesive tape or glue.
Primary intention can only be implemented when the wound is precise and there is minimal disruption to the local tissue and the epithelial basement membrane, e.g. surgical incisions.
This process is faster than healing by secondary intention. There is also less scarring associated with primary intention, as there are no large tissue losses to be filled with granulation tissue, though some granulation tissue will form.
* Examples of primary intention include: well-repaired laceration
A wound is a rapid onset of injury that involves lacerated or punctured skin (an ''open'' wound), or a contusion (a ''closed'' wound) from blunt force trauma or compression. In pathology, a ''wound'' is an acute injury that damages the epiderm ...
s, well reduced bone fracture
A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a '' ...
s, healing after flap surgery
Flap surgery is a technique in plastic and reconstructive surgery where any type of tissue is lifted from a donor site and moved to a recipient site with an intact blood supply. This is distinct from a graft, which does not have an intact blood ...
.
* Early removal of dressings from clean or clean-contaminated wounds does affect primary healing of wounds.
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.
* The wound is allowed to granulate.
* Surgeon may pack the wound with a gauze or use a drainage system.
* Granulation results in a broader scar.
* Healing process can be slow due to presence of drainage from infection.
* Wound care must be performed daily to encourage wound debris removal to allow for granulation tissue formation.
* Using antibiotics or antiseptics for the surgical wound healing by secondary intention is controversial.
* Examples: gingivectomy
Gingivectomy is a dental procedure in which a dentist or oral surgeon cuts away part of the gums in the mouth (the '' gingiva'').
It is the oldest surgical approach in periodontal therapy and is usually done for improvement of aesthetics or p ...
, gingivoplasty, tooth extraction
A dental extraction (also referred to as tooth extraction, exodontia, exodontics, or informally, tooth pulling) is the removal of teeth from the dental alveolus (socket) in the alveolar bone. Extractions are performed for a wide variety of reason ...
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 graft
Grafting refers to a surgical procedure to move tissue from one site to another on the body, or from another creature, without bringing its own blood supply with it. Instead, a new blood supply grows in after it is placed. A similar technique ...
s.
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, 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
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
involved in wound healing:
Complications of wound healing
The major complications are many:
# Deficient scar formation: Results in wound dehiscence
Wound dehiscence is a surgical complication in which a wound ruptures along a surgical incision. Risk factors include age, collagen disorder such as Ehlers–Danlos syndrome, diabetes, obesity, poor knotting or grabbing of stitches, and trauma ...
or rupture of the wound due to inadequate formation of granulation tissue.
# Excessive scar formation: Hypertrophic scar
A hypertrophic scar is a cutaneous condition characterized by deposits of excessive amounts of collagen which gives rise to a raised scar, but not to the degree observed with keloids. Like keloids, they form most often at the sites of pimples, body ...
, keloid
Keloid, also known as keloid disorder and keloidal scar,
is the formation of a type of scar which, depending on its maturity, is composed mainly of either type III (early) or type I (late) collagen. It is a result of an overgrowth of granulation t ...
, desmoid
Aggressive fibromatosis or desmoid tumor is a rare condition. Desmoid tumors arise from cells called fibroblasts, which are found throughout the body and provide structural support, protection to the vital organs, and play a critical role in wou ...
.
# Exuberant granulation (proud flesh
Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size ...
).
# Deficient contraction (in skin grafts) or excessive contraction (in burns).
# Others: Dystrophic calcification
Dystrophic calcification (DC) is the calcification occurring in degenerated or necrotic tissue, as in hyalinized scars, degenerated foci in leiomyomas, and caseous nodules. This occurs as a reaction to tissue damage, including as a consequence o ...
, pigmentary changes, painful scars, incisional hernia
An incisional hernia is a type of hernia caused by an incompletely-healed surgical wound. Since median incisions in the abdomen are frequent for abdominal exploratory surgery, ventral incisional hernias are often also classified as ventral herni ...
Other complications can include infection and Marjolin's ulcer
Marjolin's ulcer refers to an aggressive ulcerating squamous cell carcinoma presenting in an area of previously traumatized, chronically inflamed, or scarred skin.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed ...
.
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.''[Vyas KS, Vasconez HC]
Wound Healing: Biologics, Skin Substitutes, Biomembranes and Scaffolds
. Healthcare. 2014; 2(3):356-400.
See also
* Collective cell migration Collective cell migration describes the movements of group of cells and the emergence of collective behavior from cell-environment interactions and cell-cell communication. Collective cell migration is an essential process in the lives of multicellu ...
* Dressing (medical)
A dressing is a sterile pad or compress applied to a wound to promote healing and protect the wound from further harm. A dressing is designed to be in direct contact with the wound, as distinguished from a bandage, which is most often used to hold ...
* History of wound care
The history of wound care spans from prehistory to modern medicine. Wounds naturally heal by themselves, but hunter-gatherers would have noticed several factors and certain herbal remedies would speed up or assist the process, especially if it was ...
* Regeneration in humans
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 a ...
* Wound bed preparation
* Wound licking
Wound licking is an instinctive response in humans and many other animals to cover an injury with saliva. Dogs, cats, small rodents, horses, and primates all lick wounds. Saliva contains tissue factor which promotes the blood clotting mech ...
* Scar free healing
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 ...
Notes and references
External links
{{Authority control
Healing
Skin physiology
Physiology
Trauma surgery