The zebra finch (Taeniopygia guttata)[2] is the most common estrildid finch of Central Australia and ranges over most of the continent, avoiding only the cool moist south and some areas of the tropical far north. It can also be found natively in Indonesia and East Timor. The bird has been introduced to Puerto Rico and Portugal.[1]
Taxonomy and phylogeny
The zebra finch was first collected in 1801 during Nicolas Baudin's expedition to Australia. It was described in 1817 by Louis Jean Pierre Vieillot in his Nouveau Dictionnaire d'Histoire Naturelle, where he gave it the scientific name Fringilla guttata. The Australian subspecies was then described in 1837 by John Gould as Amadina castanotis.[3] Its current genus, Taeniopygia, was described in 1862 by Ludwig Reichenbach.[4] It is placed in the tribe Poephilini,[5] along with the genus Poephila, which it was previously included in;[6] the split between Taeniopygia and Poephila is justified by 1987 study using protein electrophoresis and chromosomal banding.[7]
There are two subspecies of the zebra finch:
Taeniopygia guttata guttata, the Timor zebra finch, extends from Lombok in the Lesser Sunda Islands or Nusa Tenggara in Indonesia to Sermata, in addition to coastal areas around the continent of Australia.
Taeniopygia guttata castanotis is found over the wide range of continental Australia; it is sometimes split as the Australian zebra finch.[8]

The zebra finch likely evolved in Australia, with either northern or southeastern Australia postulated as two places where the genus arose. The present-day distribution of the subspecies T. g. guttata is likely due to a Pleistocene glaciation event where the sea level dropped between about 100 and 150 metres (330 and 490ft), putting the coasts of Timor and Australia closer. This allowed birds swept out to sea by cyclones to see mountains near the west coast of Timor, which prompted them to make landfall on the island.[9]
The morphological differences between the subspecies include differences in size. T. g. guttata is smaller than T. g. castanotis. In addition, the T. g. guttata males do not have the fine barring found on the throat and upper breast and have smaller breast bands.[10]
Habitat and distribution

The zebra finch has the most extensive mainland distribution of the Australian estrilids, being found in about 75% of mainland Australia, as the subspecies Taeniopygia guttata castanotis. This subspecies is generally not found on the coasts, except for the arid western edge.[11] As the subspecies T. g. guttata, it is distributed from the islands Lombok and Sumbawa in the Lesser Sundas east to Luang and Sermata, and south to Sumba, Sawu, Dao, Roti, Semau, and Timor.[10]
The zebra finch (or at the very least, the subspecies T. g. castanotis) is generally found in more arid areas.[8] The areas it chooses to occupy are close to water, and places where rain is concentrated after it falls.[12] However, this is likely more related to the abundance of vegetation than the abundance of water as a resource in itself.[13]. Within these areas, it is found in grasslands with scattered trees and shrubs, and in open or grassy woodlands.[8] It is also found in cultivated areas,[14] such as rice fields[10] It usually stays confined to the low coastal areas of the islands it inhabits, but it can move to elevations up to 2,300 metres (7,500ft) to exploit expanding cultivation and grasslands.[15]
Although zebra finch breeding, for example, is initiated by rainfall,[16] Klaus Immelmann proposed that sustained heavy precipitation is detrimental to the zebra finch. This is supported by the observation that the nest does not shield the chicks or eggs from rain, and rainfall can sometimes result in clutches being abandoned. Furthermore, it is supported by Immelmann's finding that zebra finches left Wyndham after the first heavy rains in November 1959, but returned to breed in April. It is hypothesized that birds in parts of northern Australia migrate inland during the wet season from October to May, and return to the coastal regions during the dryer months.[17]
Life cycle
The life expectancy of a zebra finch is highly variable because of genetic and environmental factors. The zebra finch may reach up to five years in its natural environment. If they are kept caged, they normally live for 5 to 9 years but may live as long as 12 years,[18] with an exceptional case of 14.5 years reported for a caged specimen.[19] The greatest threats to zebra finch survival are predation by cats and loss of natural food.[20]
Song and other vocalizations
Zebra finches are loud and boisterous singers. Their calls can be a loud beep, meep, oi! or a-ha!. Their song is a few small beeps, leading up to a rhythmic song of varying complexity in males. Each male's song is different, although birds of the same bloodline will exhibit similarities, and all finches will overlay their own uniqueness onto a common rhythmic framework. Sons generally learn the song of their fathers with little variation. There is a critical sensitive period during which juvenile males learn their songs by imitating a mature, male tutor.[21] Subsong (early, poorly structured vocalizations) evolve into 'plastic song'. This plastic song is variable between renditions but begins to incorporate some recognizable elements of tutor songs.[21] A study conducted by Nottebohm et al., has shown that birds were able to successfully imitate their tutor’s song after relatively short exposure (40 playbacks of the motifs lasting 30 seconds total) over the duration of their sensitive learning period.[22] These birds eventually form a “template” of what their correct song should sound like. They rely on auditory feedback for both song learning and practice as juveniles and song maintenance as adults. Adult birds maintain their songs by correcting any deviations from their target song template. During adulthood, by around 90 days, the bird's song goes through a crystallization phase where their song template is stable and it no longer changes.[21]
Male zebra finches begin to sing at puberty, while females lack a singing ability.[18] This is due to a developmental difference, where in the embryo, the male zebra finch produces testosterone, which is transformed into estradiol in the brain, which in turn leads to the development of the nervous system for a song system.[23] There are multiple areas of the brain involved in the production of song. When a bird is singing a learned song, the HVC projects to the robust nucleus of the archistriatum (RA), which itself projects to the hypoglossal motoneurons. These motoneurons control the muscles of the trachea and syrinx. When learning a new song, the HVC sends efferents to Area X in the lobus parolfactorius, which connects to the medial nucleus of the dorsolateral thalamus (DLM). This structure connects to the lateral magnocellular nucleus of the anterior neostriatum (LMAN), which projects to the RA, and continues like a normal learned song would. The function of the various areas involved in learning is still being investigated.[24] Area X is likely involved in the acquisition of a new song,[25] whereas the LMAN likely serves a key role in the plasticity necessary for learning.[24] Activation of song behavior later depends on androgens.[26]
Because zebra finch males learn their songs from their surroundings, they are often used as avian model organisms to investigate the neural bases of learning, memory, and sensorimotor integration. For example, studies have investigated the role of FoxP2 in song learning and have found that in young finches both knockdown and overexpression of FoxP2 in the striatal song control nucleus, Area X, prevents accurate song learning and tutor imitation.[27][28] These studies also have implications for human speech. Individuals heterozygous for a point mutation in FOXP2 manifest a speech disorder.[29] Because of similar expression patterns between humans and songbirds, the zebra finch is used as a model to study FoxP2 expression and function.[30] The zebra finch genome was the second bird genome to be sequenced, in 2008, after that of the chicken.[31]
The zebra finch uses an acoustic signal to communicate to embryos. It gives an incubation call to its eggs when the weather is hot—above 26°C (79°F)—and when the end of their incubation period is near. This call alters the growth and behaviour of the chicks, with chicks that were given an incubation call having less mass at the end of the nestling phase when they experienced higher nest temperatures. This contrasts with chicks that were not given an incubation call, which have a higher mass at the end of nestling after being exposed to high nest temperatures. Additionally, the chicks called to as an embryo are more likely to call after experiencing high nest temperatures.[32]
Calling behaviour is used by zebra finches to negotiate parental care duties. In an experiment that delayed the return of the males to the nest, it was found that the resulting duets were shorter and calls were made more often.[33] This is the first species that vocal negotiation over parental care has ever been reported.[34]
Behaviour
Breeding

The zebra finch generally breeds in loose colonies of up to 50 nests (although the number of individuals in a colony can be up to about 230 when breeding, and around 350 when not), but it may nest solitarily.[14] It often does not breed in the colony it was born; of the ringed birds that bred in the Danaher breeding colony () from 1985 to 1989, 24% of them were hatched from the colony or in the immediate vicinity. Additionally, natal dispersal is not sex-biased, unlike in most passerines. However, males between 36 and 50 days of age are more likely to disperse than females, although after this age, more females disperse than males.[35] Predation is likely a major factor in coloniality; nests in the main colony suffer less predation than nests further away. Pairs with preyed-upon nests are significantly more likely to nest in a bush more than 20 metres (66ft) away from their previous nesting plant.[36] Another large factor is where others nest: individuals are more likely to nest closer to conspecifics. In addition, reproductive success of conspecifics may play a role in where individuals nest; a study published in 2012 found that this finch was more likely to breed near nests with chicks older than six days (used as a proxy for reproductive success because they fledge about 87% of the time).[37] The zebra finch usually places its nest in a thorny shrub or tree, although it will nest in other structures, natural and artificial.[14] Often, there are multiple nests in one shrub.[8]
The zebra finch builds both a roosting and breeding nest. The former is dome-shaped and has a large entrance on the side. This contrasts with the small entrance that conceals the inside of the latter nest. The breeding nest is also lined with soft material, such as wool and feathers.[38] Both sites are defended during the day; however, while a desperate bird is sometimes let in to the roosting nest during the night, the breeding nest is always guarded.[39]
The zebra finch is an opportunistic breeder, initiating reproductive behaviour about one to three months after water becomes available. This is so that the young hatch when semi-ripe and ripe seeds (their primary food) become available. This finding is in line with the food quality hypothesis of zebra finch breeding, which states that dry grass seed is inadequate as a food source for nestlings, and that higher quality food (like ripening seeds) is needed to sustain them.[16] Thus, in captivity, it can breed year round when provided with sufficient water,[40] and it may attempt to breed several times per breeding season.[41] Zebra finches form socially monogamous pair bonds that remain stable for at least the duration of raising a clutch, but can last for up to several years. Extra-pair copulation, mating with individuals other than one's mate, occurs occasionally, with females usually soliciting it.[42] Extra-pair parentage is relatively rare in the wild, accounting for about 2% of young.[43][44] Attempts at forced extra-pair copulations by males occur frequently (about 43.8% of the time in one study); but, females can always successfully resist forced copulations if they so choose.[45]

There are multiple hypotheses as to why extra-pair copulation might have evolved.[46] One theory is the good genes theory, which states that a female chooses extra-pair copulation if the extra-pair male grants its offspring direct benefits as a result of the male's alleles.[47] There are results that seem to support this; a 1992 study found a correlation between the song rate of a male and the attractiveness of it (measured on the basis of how much time the female spent with the male).[42] However, a 2007 study found that the responsiveness of a female (measured by behaviours indicating an intent to copulate or rejection) was not significantly related to the male's beak colour or its song rate. Song rate was instead hypothesized to draw female's attention to males. According to the author, this meant that the validity of the conclusions of the 1992 experiment needed to be reexamined.[45] Combined with the lack of influence that certain morphological traits have, the large control of females over copulation could indicate chase-away sexual selection,[48] where an exaggerated trait is evolved to counter increased resistance by the female to that feature.[49] An additional theory as to why extra-pair copulation might evolve is the between-sex genetic correlation theory. This theory is based on the lack of definite female benefits in extra-pair copulations, and the benefits that males have by being promiscuous. It states that extra-pair mating behaviour could arise from the same set of loci, and thus that strong selection for extra-pair mating behaviour would indirectly select for promiscuous behaviour in females.[46]

There are several traits correlated with increased extra-pair copulations. Spending time with a mate is important; even more important than the attractiveness of a male (as judged by other females; attractiveness as judged by one female was positively correlated with the judgements of other females).[45] Symmetry of both plumage, like chest bands, and artificial features, like leg bands, are preferred by the female, as measured by how often the male is displayed to.[50] Because of the prevalence of extra-pair paternity, males have evolved various mechanisms to try and assure their paternity of a clutch. The male guards its mate by following it and stopping extra-pair copulation attempts. Sperm competition, where two or more males attempt to inseminate a single egg, also occurs. This is indicated by the male in a pair copulating with its mate more often the day before egg-starts. This is because the last male to copulate with a female before the next egg has a 70% to 80% chance of fertilizing the egg in question.[51] Another adaptation to sperm competition is the male ejaculating up to seven times more sperm in extra-pair copulations. The increased amount of sperm occurs because of the combination of ejaculate size being controlled by the time between previous copulations, and the fact that extra-pair copulations occur in the male after its period of within-pair copulation period is complete.[52]
The number of eggs ranges from two to eight eggs per clutch, with five being the most common number.[53] These eggs are white or pale greyish blue in colour, and have a size of about 16 by 10 millimetres (0.63 by 0.39in). They are incubated for 14 to 16 days.[40] From about 5%[43] to 11% of offspring are the result of intraspecific brood parasitism, and in cases of parasitism, there is usually only one parasitic egg per nest. Additionally, parasitized nests often have one more egg than non-parasitized nests.[44] The female may follow a mixed strategy with relation to brood parasitism (being parasitic in addition to incubating its own clutch). From about 32% to 58% of females do this, and almost all (about 96%) lay parasitic eggs before incubating their clutch. Unpaired females sometimes lay parasitic eggs, but paired females do not rely solely on parasitism. A female that parasitized a nest in the past is more likely to do so in the future. Most of these eggs are unsuccessful; that is, the host abandons its otherwise empty nest after a parasitic egg is laid. Additionally, successful parasites are more likely to have future success from parasitism.[41] At least during late incubation, the female zebra finch can distinguish its own eggs on the basis of odour. This method of distinction arises from the visual similarity between parasitic and non-parasitic eggs, and the cost associated with raising an egg other than one's own.[54] When a bird is parasitized during a nesting attempt, it is less likely to be parasitized again during that season and, at the very least, during the next season (although this could be statistical noise).[41]
Young zebra finches fledge about 17 to 18 days after hatching.[8] They feed themselves by around 35 days after hatching, although they are still socially dependent on their parents during this time; the young become socially dependent between 36 and 50 days after hatching. They also develop sexually dimorphic plumage during this period. Birds first attempt to form pair bonds and breed when they get close to 80 days in age. 80 days after hatching, most birds can breed.[35]
Males and females are very similar in size, but are easily distinguished from one another after reaching maturity, as the males usually have bright orange cheek feathers, red beaks (as opposed to the orange beaks of females), and generally more striking black and white patterns.[20]
Inbreeding
Inbreeding causes early death (inbreeding depression) in the zebra finch, although it does not seem to affect fertility. Embryos have a much lower survival rate, with a study finding fertile eggs from sibling pairs had only about a 25% survival rate, compared to about 41% for unrelated pairs. This early difference in survival eventually becomes null after fledging, with about equal survival rates for offspring from both sibling and unrelated pairs.[55] Inbreeding depression mostly arises due to the expression of deleterious recessive alleles.[56]
Diet
The zebra finch is primarily eats grass seeds,[10] feeding mostly on semi-ripe and ripe seeds (although it also takes dry seeds[16]). The seeds are all dehusked,[57] and are found on stems and the ground, with most being taken, at least in the nominate subspecies, from the latter.[8] The grasses they are taken from are commonly between about 1 and 2.6 millimetres (0.039 and 0.102in) in length,[58] and larger and easily dehusked seeds are preferred.[59] It supplements its diet with insects[8] (mainly ants and termites) caught in short flights from lookout perches,[60] in addition to flowers of the genus Chenopodium.[58] The nestlings diet consists almost entirely of half-ripe[8] and ripe seeds, in addition to green plant material.[16] There are two main reasons why grass seeds are the dietary staple of the zebra finch: they are an abundant and relatively stable food source in this finch's preferred climate, and they are convenient to, for example, dehusk.[61] In some areas, such as the eastern arid zone in Australia, the seeds taken are consistent, whereas in others, like northern Victoria, there are annual changes in the diet, as different species become abundant.[60] The diet of this finch is generally low in species diversity; at Sandringham, Queensland 74% of the seeds eaten over a 15 month period were from Panicum decompositum, for example.[62]
The zebra finch generally forages for seeds on the ground, taking them individually. But, it also eats seeds on the heads of standing grass. To do this, it either flies and pecks out seeds one at a time, or it perches on a nearby branch. It may also take the head to the ground by jumping up and seizing it with its bill or feet. In times of scarcity, the zebra finch can use its bill to dig into the ground to find buried seed.[63] These seeds are generally taken from patches which have fewer husks (when compared to the number of whole seeds) and are larger and more dense. A seed patch may be checked for many months after its supply of seed is depleted. Additionally, colonial roosting and nesting and foraging in flocks can help birds discover new patches of seed.[64]
This bird commonly forages in flocks, although it sometimes forages in pairs or by itself.[10] In the breeding season, small or medium sized flocks are common, but in the non-breeding season, flocks of up to about 500 birds may be formed. It occasionally forms mixed-species flocks with other estrildids.[8] A feeding flock can be formed by individuals joining those already feeding, or by individuals landing on the ground together. Birds that arrive in this flock later are more likely to rely on scrounging, or taking food from competitors, whereas early arrivals are more likely to find food for themselves. Individuals that tend to explore more may be more dominant (measured by factors such as in what order individuals accessed a food source[65]), at least in a study that had relatively low food availability and a single source where food could be taken from. These individuals may also be less successful in a scramble competition, where there are multiple points where food can be found. The reason for the latter is hypothesized to be a result of a trade-off between faster speed in sampling an area and lower accuracy in detecting seeds.[66]
Foraging activity in the zebra finch peaks in the first hour after sunrise and the second to last hour before sunset. In the first instance, the increase foraging is generally achieved through many short bouts of foraging, whereas the latter comes from a few long bouts.[67] When food becomes less available, like from August to September in northern Victoria, there is more feeding in the afternoon, less time spent on patches of food before leaving, and the distance between places where food is available is longer.[60] There are generally two groups of individuals based on foraging behaviour. In the first group, the probability of starting or stopping a feeding bout is constant through time, and short meals are more usual. Most birds in this group have longer bouts when the gap between the previous bout is longer. In the second group (which may consist of more birds), the longer a gap is, the more likely the individual is to start feeding again. Additionally, for most birds in this group, the same is true of the stopping of a bout; the longer it is, the more likely it is to be stopped. Feeding is also usually cyclical for the second group.[67]
Drinking and bathing
The zebra finch generally consumes about 24% to 28% of its body weight (or about 3 millilitres (0.11impfloz; 0.10USfloz)) in water per day at a temperature of 22 to 23°C (72 to 73°F). When at a higher temperature of 40°C (104°F), it may drink from 6 to 12 millilitres (0.21 to 0.42impfloz; 0.20 to 0.41USfloz) of water per day. The zebra finch also extracts water from seeds, and can get water from metabolizing its food. This metabolic water consumption can equal the amount of water that is lost when temperatures are below 23°C (73°F), although only for birds that are gradually dehydrated. Suddenly dehydrated birds must be in temperatures below 12°C (54°F) before the water lost is equal to that produced by the metabolism. This finch can survive periods of low water consumption; one study that gradually reduced the amount of water given over a period of a few months to just 0.5 to 1 millilitre (0.018 to 0.035impfloz; 0.017 to 0.034USfloz) per week at temperatures from 22 to 24°C (72 to 75°F) found that the zebra finch could survive these conditions. Additionally, more than half of birds survived in a total water deprivation experiment that ran 513 days long.[13]
When water is close, the zebra finch drinks regularly during the day; if it is over about 5 kilometres (3.1mi) away, visits generally peak at midday. It prefers to drink from small puddles or other collections of water, especially those with gently sloped banks. Additionally, exposed drinking areas are preferred to more enclosed ones. It can also drink from dew on the tip of leaves. Due to the danger of predation, the zebra finch gathers in flocks in a bush or tree near a waterhole, only going to drink after the group is large enough. It then only drinks for a few seconds. After drinking, the zebra finch generally bathes for around a minute. Then, it dries off and re-oils its plumage in a warm sheltered spot.[13]
The zebra finch only needs an average of 3.6 seconds to drink 1.5 millilitres (0.053impfloz; 0.051USfloz) of water. This short amount of time per bout is achieved by this finch's drinking method. It swallows the water it gets while its bill tip is still submerged, unlike most birds that bring their bill tip up to swallow. This unique action is accomplished by having the tongue scoop water into the pharynx. Then, the front of the larynx forces the water into the oesophagus, which, through peristalsis, takes the fluid to the crop. This method could have evolved because the adaptations necessary were already there because of the need to quickly dehusk and swallow seeds. It allows for water to be drunk faster and taken from more diverse sources, such as drops of dew[68][69] and cattle troughs; the latter requires the bird to drink upside down.[69]
Temperature regulation
The body temperature (as measured from the cloaca) of the zebra finch may vary from 38 to 44°C (100 to 111°F), rising with increasing air temperatures. Body temperatures over 45°C (113°F) can cause death within an hour. This finch first cools itself by covering its plumage with water, not moving, and holding its wings out to allow more thinly feathered regions to be exposed.[70] It also has a large capacity for evaporative cooling through the lungs and skin, with measurements of heat lost through evaporative cooling over heat produced being as high as 1.37 at 43.4°C (110.1°F).[71] This can occur as a result of panting, which starts to occur when body temperatures reach 42 to 43°C (108 to 109°F) (although this may start when the air temperature is as low as 32°C (90°F)). This can cause dehydration and may put birds into a lethargic state.[70] Additionally, the zebra finch's simple rete mirabile ophthalmicum (found in the head) makes it unable to cool the brain as effectively as other birds, like the common kestrel. This lacking ability to cool the brain, in combination with dehydration, may cause the mass die-offs found during prolonged periods of high temperatures.[72] For example, in January 1932, temperatures were between 47 and 52°C (117 and 126°F) for 16 days in northern Southern Australia, causing upwards of tens of thousands of this bird to die, with many being found in dams.[70]
Predators
Nest predators of the zebra finch include the tiger snake, brown snake, dragon lizard, pygmy mulga monitor, singing honeyeater, grey-crowned babbler, yellow-throated miner, little crow, Torresian crow, black rat, and house mouse. Canivorous marsupials are also nest predators, and barn owls take roosting adult zebra finches.[36]

Bibliography

 Media related to Taeniopygia guttata at Wikimedia Commons

 on the Internet Bird Collection

View the  in Ensembl
View the  genome assembly in the UCSC Genome Browser.
 Housing and husbandry for zebra finches


In mainstream Nicene Christianity, there is no restriction on kinds of animals that can be eaten.[1][2] This practice stems from Peter's vision of a sheet with animals, described in the Book of Acts, Chapter 10, in which Saint Peter "sees a sheet containing animals of every description lowered from the sky."[3]  Nonetheless, the New Testament does give a few guidelines about the consumption of meat, practiced by the Christian Church today; one of these is not consuming food knowingly offered to pagan idols,[4] a conviction that the early Church Fathers, such as Clement of Alexandria and Origen preached.[5] In addition, Christians traditionally bless any food before eating it with a mealtime prayer (grace), as a sign of thanking God for the meal they have.
Slaughtering animals for food is  often done without the trinitarian formula,[6][7] although the Armenian Apostolic Church, among other Orthodox Christians, have rituals that "display obvious links with shechitah, Jewish kosher slaughter."[8] The Bible, states Norman Geisler, stipulates one to "abstain from food sacrificed to idols, from blood, from meat of strangled animals".[9]
In the New Testament, Paul of Tarsus notes that some devout Christians may wish to abstain from consuming meat if it causes "my brother to stumble" in his faith with God (cf. 1 Corinthians 8:13).[10] As such, some Christian monks, such as the Trappists, have adopted a policy of Christian vegetarianism.[11] In addition, Christians of the Seventh-day Adventist tradition generally "avoid eating meat and highly spiced food".[12] Christians in the Anglican, Catholic, Lutheran, Methodist, and Orthodox denominations traditionally observe a meat-free day, especially during the liturgical season of Lent.[13][14][15][16]
With reference to medieval times, Jillian Williams states that "unlike the Jewish and Muslims methods of animal slaughter, which requires the draining of the animal's blood, Christian slaughter practices did not usually specify the method of slaughter". In actual practice, states Williams, European Christians have flexibly practiced both the method of draining the blood, and wringing the animal's neck to retain its blood as valuable food.[17] According to Basheer Ahmad Masri, the "Jewish and the Christian methods of slaughter fulfill the Islamic condition of bleeding the animal".[18] In contrast, David Grumett and Rachel Muers state that the Orthodox Christian Shechitah and Jewish Kosher methods of slaughter differ from the Muslim Halal (Dabh) method in that they require the cut to "sever trachea, oesophagus and the jugular veins" as this method is believed to produce meat with minimal suffering to the animal.
Some Christian denominations condone the moderate drinking of alcohol (moderationism), such as Anglicans, Catholics, Lutherans, and the Orthodox,[19] although others, such as  Seventh-day Adventists, Baptists, Methodists, and Pentecostals either abstain from or prohibit the consumption of alcohol (abstentionism and prohibitionism).[20] However, all Christian Churches, in view of the Biblical position on the issue, universally condemn drunkenness as sinful.[21][22]
See also

Bible Diet
Christian vegetarianism
Christian views on alcohol
Fasting and abstinence in the Catholic Church
Kashrut (Jewish dietary laws)
Kutha meat
Islamic dietary laws
Pescetarianism
Seventh-Day Adventist Church, Health and Diet
Word of Wisdom

Does Catholicism have any dietary restrictions?


Wound healing is a complex process in which the skin, and the tissues under it, repair themselves after injury.[1]  In this article, wound healing is depicted in a discrete timeline of physical attributes (phases) constituting the post-trauma repairing process. In undamaged skin, the epidermis (surface layer) and dermis (deeper 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.[1][2] This process is divided into predictable phases: blood clotting (hemostasis), inflammation, tissue growth (proliferation), and tissue remodeling (maturation). Blood clotting may be considered to be part of the inflammation stage instead of a separate stage.[3]
The wound healing process is not only complex but also fragile, and it is susceptible to interruption or failure leading to the formation of non-healing chronic wounds. Factors that contribute to non-healing chronic wounds are diabetes, venous or arterial disease, infection, and metabolic deficiencies of old age.[4]
Wound care encourages and speeds wound healing via cleaning and protection from reinjury or infection. Depending on each patient's needs, it can range from the simplest first aid to entire nursing specialties such as wound, ostomy, and continence nursing and burn center care.
Stages
Hemostasis (blood clotting): Within the first few minutes of injury, platelets in the blood begin to stick to the injured site. This activates the platelets, causing a few things to happen. They change into an amorphous shape, more suitable for clotting, and they release chemical signals to promote clotting. This results in the activation of fibrin, which forms a mesh and acts as "glue" to bind platelets to each other. This makes a clot that serves to plug the break in the blood vessel, slowing/preventing further bleeding.[5][6]
Inflammation: During this phase, damaged and dead cells are cleared out, along with bacteria and other pathogens or debris. This happens through the process of phagocytosis, where white blood cells "eat" debris by engulfing it. Platelet-derived growth factors are released into the wound that cause the migration and division of cells during the proliferative phase.
Proliferation (growth of new tissue): In this phase, angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound contraction occur.[7] In angiogenesis, vascular endothelial cells form new blood vessels.[8] In fibroplasia and granulation tissue formation, fibroblasts grow and form a new, provisional extracellular matrix (ECM) by excreting collagen and fibronectin.[7]  Concurrently, re-epithelialization of the epidermis occurs, in which epithelial cells proliferate and 'crawl' atop the wound bed, providing cover for the new tissue.[9] In wound contraction, myofibroblasts decrease the size of the wound by gripping the wound edges and contracting using a mechanism that resembles that in smooth muscle cells. When the cells' roles are close to complete, unneeded cells undergo apoptosis.[7]
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.

Timing and reepithelialization
Timing is important to wound healing. Critically, the timing of wound reepithelialization can decide the outcome of the healing.[11] If the epithelization of tissue over a denuded area is slow, a scar will form over many weeks, or months;[12][13] If the epithelization of a wounded area is fast, the healing will result in regeneration.[13]
Early vs cellular phase

Wound healing is classically divided into hemostasis, inflammation, proliferation, and remodeling. Although a useful construct, this model employs considerable overlapping among individual phases. A complementary model has recently been described[1] 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 and tissue engineering (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:[1]
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 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.[1] Subdivisions of the cellular phase are:  [1] Macrophages and inflammatory components (within 1–2 days), [2] Epithelial-mesenchymal interaction: re-epithelialization (phenotype change within hours, migration begins on day 1 or 2), [3] Fibroblasts and myofibroblasts: progressive alignment, collagen production, and matrix contraction (between day 4 and day 14), [4] Endothelial cells and angiogenesis (begins on day 4), [5] 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).[1]
Inflammatory phase
Just before the inflammatory phase is initiated, the clotting cascade occurs in order to achieve hemostasis, or stop 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, triggering blood platelets to begin secreting inflammatory factors.[15]  Platelets also express sticky glycoproteins on their cell membranes that allow them to aggregate, forming a mass.[7]
Fibrin and fibronectin cross-link together and form a plug that traps proteins and particles and prevents further blood loss.[16]  This fibrin-fibronectin plug is also the main structural support for the wound until collagen is deposited.[7] Migratory cells use this plug as a matrix to crawl across, and platelets adhere to it and secrete factors.[7] The clot is eventually lysed and replaced with granulation tissue and then later with collagen.
Platelets, the cells present in the highest numbers shortly after a wound occurs, release mediators into the blood, including cytokines and growth factors.[15]  Growth factors stimulate cells to speed their rate of division. Platelets release other proinflammatory factors like serotonin, bradykinin, prostaglandins, prostacyclins, thromboxane, and histamine,[3] which serve several purposes, including increasing cell proliferation and migration to the area and causing blood vessels to become dilated and porous. In many ways, extravasated platelets in trauma perform a similar function to tissue macrophages and mast cells exposed to microbial molecular signatures in infection: they become activated, and secrete molecular mediators – vasoactive amines, eicosanoids, and cytokines  – that initiate the inflammatory process.
Vasoconstriction and vasodilation
Immediately after a blood vessel is breached, ruptured cell membranes release inflammatory factors like thromboxanes and prostaglandins that cause the vessel to spasm to prevent blood loss and to collect inflammatory cells and factors in the area.[3] This vasoconstriction lasts five to ten minutes and is followed by vasodilation, a widening of blood vessels, which peaks at about 20 minutes post-wounding.[3] Vasodilation is the end result of factors released by platelets and other cells. The main factor involved in causing vasodilation is histamine.[3][15] Histamine also causes blood vessels to become porous, allowing the tissue to become edematous because proteins from the bloodstream leak into the extravascular space, which increases its osmolar load and draws water into the area.[3] Increased porosity of blood vessels also facilitates the entry of inflammatory cells like leukocytes into the wound site from the bloodstream.[17][18]
Polymorphonuclear neutrophils
Within an hour of wounding, polymorphonuclear neutrophils (PMNs) arrive at the wound site and become the predominant cells in the wound for the first two days after the injury occurs, with especially high numbers on the second day.[19] They are attracted to the site by fibronectin, growth factors, and substances such as kinins. Neutrophils phagocytise debris and kill bacteria by releasing free radicals in what is called a 'respiratory burst.[20][21] They also cleanse the wound by secreting proteases that break down damaged tissue. Functional neutrophils at the wound site only have life-spans of around 2 days, so they usually undergo apoptosis once they have completed their tasks and are engulfed and degraded by macrophages.[22]
Other leukocytes to enter the area include helper T cells, which secrete cytokines to cause more T cells to divide and to increase inflammation and enhance vasodilation and vessel permeability.[17][23] T cells also increase the activity of macrophages.[17]
Macrophages
One of the macrophage's roles is to phagocytize other expended phagocytes,[24] bacteria and damaged tissue,[19] and they also debride damaged tissue by releasing proteases.[25]
Macrophages function in regeneration[26][27]  and are essential for wound healing.[19] They are stimulated by the low oxygen content of their surroundings to produce factors that induce and speed angiogenesis[20] and they also stimulate cells that reepithelialize the wound, create granulation tissue, and lay down a new extracellular matrix.[28] 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.[24]
The spleen contains half the body's monocytes in reserve ready to be deployed to injured tissue.[29][30] Attracted to the wound site by growth factors released by platelets and other cells, monocytes from the bloodstream enter the area through blood vessel walls.[31] Numbers of monocytes in the wound peak one to one and a half days after the injury occurs.[23] 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.[15]
In wound healing that result in incomplete repair, scar contraction occurs, bringing varying gradations of structural imperfections, deformities and problems with flexibility.[32] Macrophages may restrain the contraction phase.[27] Scientists have reported that removing the macrophages from a salamander resulted in failure of a typical regeneration response (limb regeneration), instead bringing on a repair (scarring) response.[33][34]
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.[19]  These changes indicate that the inflammatory phase is ending and the proliferative phase is underway.[19] In vitro evidence, obtained using the dermal equivalent 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.[27]
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.[7] 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 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.
Proliferative phase
About two or three days after the wound occurs, fibroblasts begin to enter the wound site, marking the onset of the proliferative phase even before the inflammatory phase has ended.[35] 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.[36] Because the activity of fibroblasts and epithelial cells requires oxygen and nutrients, angiogenesis is imperative for other stages in wound healing, like epidermal and fibroblast migration. The tissue in which angiogenesis has occurred typically looks red (is erythematous) due to the presence of capillaries.[36]
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 cells of endothelial cells, originating from parts of uninjured blood vessels, develop pseudopodia and push through the ECM into the wound site to establish new blood vessels.[20]
Endothelial cells are attracted to the wound area by fibronectin found on the fibrin scab and chemotactically by angiogenic factors released by other cells,[37] e.g. from macrophages and platelets when in a low-oxygen environment. Endothelial growth and proliferation is also directly stimulated by hypoxia, and presence of lactic acid in the wound.[35] For example, hypoxia stimulates the endothelial transcription factor, hypoxia-inducible factor (HIF) to transactivate a set of proliferative genes including vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1).
To migrate, endothelial cells need collagenases and plasminogen activator to degrade the clot and part of the ECM.[3][19] Zinc-dependent metalloproteinases digest basement membrane and ECM to allow cell migration, proliferation and angiogenesis.[38]
When macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic acid-filled environment, they stop producing angiogenic factors.[20] 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.[37]
Fibroplasia and granulation tissue formation
Simultaneously with angiogenesis, fibroblasts 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.[19] By the end of the first week, fibroblasts are the main cells in the wound.[3] 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.[3] 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).[39] 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.[37]   Fibroblasts then deposit ground substance into the wound bed, and later collagen, which they can adhere to for migration.[15]
Granulation tissue 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 (ECM). The provisional ECM is different in composition from the ECM in normal tissue and its components originate from fibroblasts.[28] Such components include fibronectin, collagen, glycosaminoglycans, elastin, glycoproteins and proteoglycans.[37] Its main components are fibronectin and hyaluronan, which create a very hydrated matrix and facilitate cell migration.[31] Later this provisional matrix is replaced with an ECM that more closely resembles that found in non-injured tissue.
Growth factors (PDGF, TGF-β) 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 scarring.
Collagen deposition
One of fibroblasts' most important duties is the production of collagen.[36]
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.[20] Also, cells involved in inflammation, angiogenesis, and connective tissue construction attach to, grow and differentiate on the collagen matrix laid down by fibroblasts.[40]
Type III collagen and fibronectin generally begin to be produced in appreciable amounts at somewhere between approximately 10 hours[41] and 3 days,[37] depending mainly on wound size. Their deposition peaks at one to three weeks.[28] They are the predominating tensile substances until the later phase of maturation, in which they are replaced by the stronger type I collagen.
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.[20] 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.[42] 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.[3]
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.[37] Basal keratinocytes from the wound edges and dermal appendages such as hair follicles, sweat glands and sebacious (oil) glands are the main cells responsible for the epithelialization phase of wound healing.[42] 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[43][44] 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.[44]
Keratinocytes migrate without first proliferating.[45] 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.[46] Thus the time of onset of migration is variable and may occur about one day after wounding.[47] Cells on the wound margins proliferate on the second and third day post-wounding in order to provide more cells for migration.[28]
If the basement membrane is not breached, epithelial cells are replaced within three days by division and upward migration of cells in the stratum basale in the same fashion that occurs in uninjured skin.[37] 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 that are lined with viable keratinocytes.[28] If the wound is very deep, skin appendages may also be ruined and migration can only occur from wound edges.[46]
Migration of keratinocytes over the wound site is stimulated by lack of contact inhibition and by chemicals such as nitric oxide.[48] Before they begin to migrate, cells must dissolve their desmosomes and hemidesmosomes, which normally anchor the cells by intermediate filaments in their cytoskeleton to other cells and to the ECM.[23] Transmembrane receptor proteins called integrins, which are made of glycoproteins and normally anchor the cell to the basement membrane by its cytoskeleton, are released from the cell's intermediate filaments and relocate to actin filaments to serve as attachments to the ECM for pseudopodia during migration.[23] Thus keratinocytes detach from the basement membrane and are able to enter the wound bed.[35]
Before they begin migrating, keratinocytes change shape, becoming longer and flatter and extending cellular processes like lamellipodia and wide processes that look like ruffles.[31] Actin filaments and pseudopodia form.[35] During migration, integrins on the pseudopod attach to the ECM, and the actin filaments in the projection pull the cell along.[23] The interaction with molecules in the ECM through integrins further promotes the formation of actin filaments, lamellipodia, and filopodia.[23]
Epithelial cells climb over one another in order to migrate.[42] This growing sheet of epithelial cells is often called the epithelial tongue.[45] The first cells to attach to the basement membrane form the stratum basale. These basal cells continue to migrate across the wound bed, and epithelial cells above them slide along as well.[45] The more quickly this migration occurs, the less of a scar there will be.[49]
Fibrin, collagen, and fibronectin in the ECM may further signal cells to divide and migrate.  Like fibroblasts, migrating keratinocytes use the fibronectin cross-linked with fibrin that was deposited in inflammation as an attachment site to crawl across.[25][31][42]

As keratinocytes migrate, they move over granulation tissue but stay underneath the scab, thereby separating the scab from the underlying tissue.[42][47] Scabs are formed on locations that are exposed to harmful UVR and the main biological function of
human wound scabs is to inhibit the exposure to UVR, thus protecting otherwise exposed cells in a wound from UVR-induced DNA damage.[50] 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.[25][37][42][51] To make their way along the tissue, keratinocytes must dissolve the clot, debris, and parts of the ECM in order to get through.[47][52] They secrete plasminogen activator, which activates plasminogen, turning it into plasmin to dissolve the scab.  Cells can only migrate over living tissue,[42] so they must excrete collagenases and proteases like matrix metalloproteinases (MMPs) to dissolve damaged parts of the ECM in their way, particularly at the front of the migrating sheet.[47] Keratinocytes also dissolve the basement membrane, using instead the new ECM laid down by fibroblasts to crawl across.[23]
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.[25] Proliferation behind migrating keratinocytes normally begins a few days after wounding[46] and occurs at a rate that is 17 times higher in this stage of epithelialization than in normal tissues.[25] Until the entire wound area is resurfaced, the only epithelial cells to proliferate are at the wound edges.[45]
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.[53] Growth factors are also important for the innate immune defense of skin wounds by stimulation of the production of antimicrobial peptides and neutrophil chemotactic cytokines in keratinocytes.
Keratinocytes continue migrating across the wound bed until cells from either side meet in the middle, at which point contact inhibition causes them to stop migrating.[31]  When they have finished migrating, the keratinocytes secrete the proteins that form the new basement membrane.[31]  Cells reverse the morphological changes they underwent in order to begin migrating; they reestablish desmosomes and hemidesmosomes and become anchored once again to the basement membrane.[23] Basal cells begin to divide and differentiate in the same manner as they do in normal skin to reestablish the strata found in reepithelialized skin.[31]
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.[32] Thus there is a great interest in understanding the biology of wound contraction, which can be modelled in vitro using the collagen gel contraction assay or the dermal equivalent model.[27][54]
Contraction commences approximately a week after wounding, when fibroblasts have differentiated into myofibroblasts.[55]  In full thickness wounds, contraction peaks at 5 to 15 days post wounding.[37] Contraction can last for several weeks[46] and continues even after the wound is completely reepithelialized.[3] A large wound can become 40 to 80% smaller after contraction.[31][42]  Wounds can contract at a speed of up to 0.75mm per day, depending on how loose the tissue in the wounded area is.[37]  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.[55]
At first, contraction occurs without myofibroblast involvement.[56]  Later, fibroblasts, stimulated by growth factors, differentiate into myofibroblasts.  Myofibroblasts, which are similar to smooth muscle cells, are responsible for contraction.[56]  Myofibroblasts contain the same kind of actin as that found in smooth muscle cells.[32]
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.[25]  They form connections to the ECM at the wound edges, and they attach to each other and to the wound edges by desmosomes.  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.[56]  Myofibroblasts have many such adhesions, which allow them to pull the ECM when they contract, reducing the wound size.[32]  In this part of contraction, closure occurs more quickly than in the first, myofibroblast-independent part.[56]
As the actin in myofibroblasts contracts, the wound edges are pulled together.  Fibroblasts lay down collagen to reinforce the wound as myofibroblasts contract.[3] The contraction stage in proliferation ends as myofibroblasts stop contracting and commit apoptosis.[32]  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.[19]  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.[20] During maturation, type III collagen, which is prevalent during proliferation, is replaced by type I collagen.[17] Originally disorganized collagen fibers are rearranged, cross-linked, and aligned along tension lines.[31] 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,[28] ranging from approximately 3 days[41] to 3 weeks.[57] The maturation phase can last for a year or longer, similarly depending on wound type.[28]
As the phase progresses, the tensile strength of the wound increases.[28] Collagen will reach approximately 20% of its tensile strength after 3 weeks, increasing to 80% by 12th week. The maximum scar strength is 80% of that of unwounded skin.[58] Since activity at the wound site is reduced, the scar loses its red appearance as blood vessels that are no longer needed are removed by apoptosis.[20]
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[7] such as a venous ulcer or pathological scarring such as a keloid scar.[59][60]
Factors affecting wound healing
Many factors controlling the efficacy, speed, and manner of wound healing fall under two types: local and systemic factors.[2]
Local factors
Moisture; keeping a wound moist rather than dry makes wound healing more rapid and with less pain and less scarring[61]
Mechanical factors
Edema
Ionizing radiation
Faculty technique of wound closure
Ischemia and necrosis
Foreign bodies. Sharp, small foreign bodies can penetrate the skin leaving little surface wound but causing internal injury and internal bleeding. For a glass foreign body, "frequently, an innocent skin wound disguises the extensive nature of the injuries beneath".[62] First-degree nerve injury requires a few hours to a few weeks to recover.[63] If a foreign body passes by a nerve and causes first-degree nerve injury during entry, then the sensation of the foreign body or pain due to internal wounding may be delayed by a few hours to a few weeks after entry. A sudden increase in pain during the first few weeks of wound healing could be a sign of a recovered nerve reporting internal injuries rather than a newly developed infection.
Low oxygen tension
Perfusion
Systemic factors
Inflammation
Diabetes – Individuals with diabetes demonstrate reduced capability in the healing of acute wounds. Additionally, diabetic individuals are susceptible to developing chronic diabetic foot ulcers, a serious complication of diabetes which affects 15% of people with diabetes and accounts for 84% of all diabetes-related lower leg amputations.[64] The impaired healing abilities of diabetics with diabetic foot ulcers and/or acute wounds involves multiple pathophysiological mechanisms.[65] 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.[65]
Nutrients – Malnutrition or nutritional deficiencies have a recognizable impact on wound healing post trauma or surgical intervention.[66] 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.[65] 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.[65] 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.[65]
Metabolic diseases
Immunosuppression
Connective tissue 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.[65]
Age – Increased age (over 60 years) is a risk factor for impaired wound healing.[65] 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.[67] 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.[68]
Alcohol – Alcohol consumption impairs wound healing and also increases the chances of infection. Alcohol affects the proliferative phase of healing. A single unit of alcohol causes a negative effect on re-epithelialization, wound closure, collagen production and angiogenesis.[65]
Research and development
Up until about 2000, the classic paradigm of wound healing, involving stem cells restricted to organ-specific lineages, had never been seriously challenged. Since then, the notion of adult stem cells having cellular plasticity or the ability to differentiate into non-lineage cells has emerged as an alternative explanation.[1] To be more specific, hematopoietic progenitor cells (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.[39]
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.
It is thought that the epidermis and dermis are reconstituted by mitotically active stem cells that reside at the apex of rete ridges (basal stem cells or BSC), the bulge of hair follicles (hair follicular stem cell or HFSC), and the papillary dermis (dermal stem cells).[1] Moreover, bone marrow may also contain stem cells that play a major role in cutaneous wound healing.[39]
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.[1] These two self-renewal subpopulations are (1) bone marrow-derived mesenchymal stem cells (MSC) and (2) hematopoietic stem cells (HSC). Bone marrow also harbors a progenitor subpopulation (endothelial progenitor cells or EPC) that, in the same type of setting, are mobilized to aid in the reconstruction of blood vessels.[39] Moreover, it thought that, extensive injury to skin also promotes the early trafficking of a unique subclass of leukocytes (circulating fibrocytes) to the injured region, where they perform various  functions related to wound healing.[1]
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.[69][70] Whereas, 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.[71] Non-injured skin has a continued replacement and regeneration of cells which always results in complete regeneration.[71]
There is a subtle distinction between 'repair' and 'regeneration'.[1][69][70] Repair means incomplete regeneration.[69] 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.[69]
True tissue regeneration or complete regeneration,[70] refers to the replacement of lost/damaged tissue with an ‘exact’ copy, such that both morphology and functionality are completely restored.[70]  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 after the process of breakdown via the menstruation cycle heals with complete regeneration.[71]
In some instances, after a tissue breakdown, such as in skin, a regeneration closer to complete regeneration may be induced by the use of biodegradable (collagen-glycoaminoglycan) scaffolds. These scaffolds are structurally analogous to extracellular matrix (ECM) found in normal/un-injured dermis.[72] 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.[1] 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 differentiation.[73]
A new way of thinking derived from the notion that heparan sulfates are key player in tissue homeostasis:  the process that makes the tissue replace dead cells by identical cells. In wound areas, tissue homeostasis is lost as the heparan sulfates are degraded preventing the replacement of dead cells by identical cells. Heparan sulfate analogues cannot be degraded by all know heparanases and glycanases and bind to the free heparin sulfate binding spots on the ECM, therefore preserving the normal tissue homeostasis and preventing scarring.[74][75][76]
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.[77][78]
Scarless wound healing
Scarless wound healing is a concept based on the healing or repair of the skin (or other tissue/organs) after injury with the aim of healing with subjectively and relatively less scar tissue than normally expected. Scarless healing is sometimes mixed up with the concept of scar free healing, which is wound healing which results in absolutely no scar (free of scarring). However they are different concepts.
A reverse to scarless wound healing is scarification (wound healing to scar more). Historically, certain cultures consider scarification attractive;[79] however, this is generally not the case in the modern western society, in which many patients are turning to plastic surgery clinics with unrealistic expectations. Depending on scar type, treatment may be invasive (intralesional steroid injections, surgery) and/or conservative (compression therapy, topical silicone gel, brachytherapy, photodynamic therapy).[80] Clinical judgment is necessary to successfully balance the potential benefits of the various treatments available against the likelihood of a poor response and possible complications resulting from these treatments. Many of these treatments may only have a placebo effect, and the evidence base for the use of many current treatments is poor.[81]
Since the 1960s, comprehension of the basic biologic processes involved in wound repair and tissue regeneration have expanded due to advances in cellular and molecular biology.[82] Currently, the principal goals in wound management are to achieve rapid wound closure with a functional tissue that has minimal aesthetic scarring.[83] 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[84] and complete regeneration is limited to lower vertebrates, such as salamanders, and invertebrates.[85] In adult humans, injured tissue are repaired by collagen deposition, collagen remodelling and eventual scar formation, where fetal wound healing is believed to be more of a regenerative process with minimal or no scar formation.[84] 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.[86][87][88] 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.[86][87][88]
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.[89][90]
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.[91]  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.[92]  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.[93]
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).[94] Relationships like these can be incorporated into an agent-based models, where the sensitivity to single parameters such as initial collagen alignment, cytokine properties, and cell proliferation rates can be tested.[95]
Wound closure intentions
Successful wound healing is dependent on various cell types, molecular mediators and structural elements.[96]
Primary intention
Primary intention is the healing of a clean wound without tissue loss.[96] 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.[97]
This process is faster than healing by secondary intention.[96] There is also less scarring associated with primary intention, as there are no large tissue losses to be filled with granulation tissue.[96] (Primary intention does require some granulation tissue to form.)
Examples of primary intention include: well-repaired lacerations, well reduced bone fractures, healing after flap surgery.
Secondary intention
Secondary intention is implemented when primary intention is not possible.
This is due to wounds being created by major trauma in which there has been a significant loss in tissue or tissue damage.[97]
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.[98]
Examples: gingivectomy, gingivoplasty, tooth extraction sockets, poorly reduced fractures, burns, severe lacerations, pressure ulcers.
Tertiary intention
(Delayed primary closure or secondary suture):
The wound is initially cleaned, debrided and observed, typically 4 or 5 days before closure.
The wound is purposely left open.
Examples: healing of wounds by use of tissue grafts.
If the wound edges are not reapproximated immediately, delayed primary wound healing transpires. This type of healing may be desired in the case of contaminated wounds. By the fourth day, phagocytosis of contaminated tissues is well underway, and the processes of epithelization, collagen deposition, and maturation are occurring. Foreign materials are walled off by macrophages that may metamorphose into epithelioid cells, which are encircled by mononuclear leukocytes, forming granulomas. Usually the wound is closed surgically at this juncture, and if the "cleansing" of the wound is incomplete, chronic inflammation can ensue, resulting in prominent scarring.
Overview of involved growth factors
Following are the main growth factors involved in wound healing:

Complications of wound healing
The major complications are many:
Deficient scar formation: Results in wound dehiscence or rupture of the wound due to inadequate formation of granulation tissue.
Excessive scar formation: Hypertrophic scar, keloid, desmoid.
Exuberant granulation (proud flesh).
Deficient contraction (in skin grafts) or excessive contraction (in burns).
Others: Dystrophic calcification, pigmentary changes, painful scars, incisional hernia
Other complications can include Infection and Marjolin's ulcer.
Biologics, skin substitutes, biomembranes and scaffolds
Advancements in the clinical understanding of wounds and their pathophysiology have commanded significant biomedical innovations in the treatment of acute, chronic, and other types of wounds. Many biologics, skin substitutes, biomembranes and scaffolds have been developed to facilitate wound healing through various mechanisms.[100] 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.[101]
See also

Collective cell migration
Dressing (medical)
History of wound care
Regeneration in humans
Wound bed preparation
Wound licking
Scar free healing

Notes and references

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