text:
|Hand abrasion
|Approximate days since injury
Tissue healing (Wound healing) refers to the body's replacement of destroyed tissue by living tissue. [1] [2]
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. [2] [3] 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. [4]
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. [5]
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.
Timing is important to wound healing. Critically, the timing of wound reepithelialization can decide the outcome of the healing. [12] If the epithelization of tissue over a denuded area is slow, a scar will form over many weeks, or months; [13] [14] If the epithelization of a wounded area is fast, the healing will result in regeneration. [14]
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 [2] 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: [2]
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. [2] Subdivisions of the cellular phase are:
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.
When tissue is first wounded, blood comes in contact with collagen, triggering blood platelets to begin secreting inflammatory factors. [16] Platelets also express sticky glycoproteins on their cell membranes that allow them to aggregate, forming a mass. [8]
Fibrin and fibronectin cross-link together and form a plug that traps proteins and particles and prevents further blood loss. [17] This fibrin-fibronectin plug is also the main structural support for the wound until collagen is deposited. [8] Migratory cells use this plug as a matrix to crawl across, and platelets adhere to it and secrete factors. [8] 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. [16] Growth factors stimulate cells to speed their rate of division. Platelets release other proinflammatory factors like serotonin, bradykinin, prostaglandins, prostacyclins, thromboxane, and histamine, [4] 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.
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. [4] 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. [4] Vasodilation is the end result of factors released by platelets and other cells. The main factor involved in causing vasodilation is histamine. [4] [16] 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. [4] Increased porosity of blood vessels also facilitates the entry of inflammatory cells like leukocytes into the wound site from the bloodstream. [18] [19]
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. [20] 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. [21] [22] 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. [23]
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. [18] [24] T cells also increase the activity of macrophages. [18]
One of the macrophage's roles is to phagocytize other expended phagocytes, [25] bacteria and damaged tissue, [20] and they also debride damaged tissue by releasing proteases. [26]
Macrophages function in regeneration [27] [28] and are essential for wound healing. [20] They are stimulated by the low oxygen content of their surroundings to produce factors that induce and speed angiogenesis [21] and they also stimulate cells that reepithelialize the wound, create granulation tissue, and lay down a new extracellular matrix. [29] 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. [25]
The spleen contains half the body's monocytes in reserve ready to be deployed to injured tissue. [30] [31] 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. [32] Numbers of monocytes in the wound peak one to one and a half days after the injury occurs. [24] 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. [16]
In wound healing that result in incomplete repair, scar contraction occurs, bringing varying gradations of structural imperfections, deformities and problems with flexibility. [33] Macrophages may restrain the contraction phase. [28] 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. [34] [35]
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. [20] These changes indicate that the inflammatory phase is ending and the proliferative phase is underway. [20] 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. [28]
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. [8] 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.
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. [36] 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.
Also called neovascularization, the process of angiogenesis occurs concurrently with fibroblast proliferation when endothelial cells migrate to the area of the wound. [37] 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. [37]
Angiogenesis occurs in overlapping phases in response to inflammation:
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. [21]
Endothelial cells are attracted to the wound area by fibronectin found on the fibrin scab and chemotactically by angiogenic factors released by other cells, [38] 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. [36] 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. [4] [20] Zinc-dependent metalloproteinases digest basement membrane and ECM to allow cell migration, proliferation and angiogenesis. [39]
When macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic acid-filled environment, they stop producing angiogenic factors. [21] 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. [38]
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. [20] By the end of the first week, fibroblasts are the main cells in the wound. [4] 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. [4] 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). [40] 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. [38] Fibroblasts then deposit ground substance into the wound bed, and later collagen, which they can adhere to for migration. [16]
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. [29] Such components include fibronectin, collagen, glycosaminoglycans, elastin, glycoproteins and proteoglycans. [38] Its main components are fibronectin and hyaluronan, which create a very hydrated matrix and facilitate cell migration. [32] 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.
One of fibroblasts' most important duties is the production of collagen. [37]
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. [21] Also, cells involved in inflammation, angiogenesis, and connective tissue construction attach to, grow and differentiate on the collagen matrix laid down by fibroblasts. [41]
Type III collagen and fibronectin generally begin to be produced in appreciable amounts at somewhere between approximately 10 hours [42] and 3 days, [38] depending mainly on wound size. Their deposition peaks at one to three weeks. [29] 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. [21] 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. [43] 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. [4]
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. [38] 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. [43] 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 [44] [45] 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. [45]
Keratinocytes migrate without first proliferating. [46] 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. [47] Thus the time of onset of migration is variable and may occur about one day after wounding. [48] Cells on the wound margins proliferate on the second and third day post-wounding in order to provide more cells for migration. [29]
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. [38] 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. [29] If the wound is very deep, skin appendages may also be ruined and migration can only occur from wound edges. [47]
Migration of keratinocytes over the wound site is stimulated by lack of contact inhibition and by chemicals such as nitric oxide. [49] 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. [24] 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. [24] Thus keratinocytes detach from the basement membrane and are able to enter the wound bed. [36]
Before they begin migrating, keratinocytes change shape, becoming longer and flatter and extending cellular processes like lamellipodia and wide processes that look like ruffles. [32] Actin filaments and pseudopodia form. [36] During migration, integrins on the pseudopod attach to the ECM, and the actin filaments in the projection pull the cell along. [24] The interaction with molecules in the ECM through integrins further promotes the formation of actin filaments, lamellipodia, and filopodia. [24]
Epithelial cells climb over one another in order to migrate. [43] This growing sheet of epithelial cells is often called the epithelial tongue. [46] 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. [46] The more quickly this migration occurs, the less of a scar there will be. [50]
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. [26] [32] [43]
As keratinocytes migrate, they move over granulation tissue but stay underneath the scab, thereby separating the scab from the underlying tissue. [43] [48] 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. [26] [38] [43] [51] To make their way along the tissue, keratinocytes must dissolve the clot, debris, and parts of the ECM in order to get through. [48] [52] They secrete plasminogen activator, which activates plasminogen, turning it into plasmin to dissolve the scab. Cells can only migrate over living tissue, [43] 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. [48] Keratinocytes also dissolve the basement membrane, using instead the new ECM laid down by fibroblasts to crawl across. [24]
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. [26] Proliferation behind migrating keratinocytes normally begins a few days after wounding [47] and occurs at a rate that is 17 times higher in this stage of epithelialization than in normal tissues. [26] Until the entire wound area is resurfaced, the only epithelial cells to proliferate are at the wound edges. [46]
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. [32] When they have finished migrating, the keratinocytes secrete the proteins that form the new basement membrane. [32] 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. [24] 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. [32]
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. [33] 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. [28] [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. [38] Contraction can last for several weeks [47] and continues even after the wound is completely reepithelialized. [4] A large wound can become 40 to 80% smaller after contraction. [32] [43] 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. [38] 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. [33]
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. [26] 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. [33] 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. [4] The contraction stage in proliferation ends as myofibroblasts stop contracting and commit apoptosis. [33] 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. [20] These events signal the onset of the maturation stage of wound healing.
When the levels of collagen production and degradation equalize, the maturation phase of tissue repair is said to have begun. [21] During maturation, type III collagen, which is prevalent during proliferation, is replaced by type I collagen. [18] Originally disorganized collagen fibers are rearranged, cross-linked, and aligned along tension lines. [32] 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, [29] ranging from approximately 3 days [42] to 3 weeks. [57] The maturation phase can last for a year or longer, similarly depending on wound type. [29]
As the phase progresses, the tensile strength of the wound increases. [29] 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. [21]
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 [8] such as a venous ulcer or pathological scarring such as a keloid scar. [59] [60]
Many factors controlling the efficacy, speed, and manner of wound healing fall under two types: local and systemic factors. [3]
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. [2] 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. [40]
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). [2] Moreover, bone marrow may also contain stem cells that play a major role in cutaneous wound healing. [40]
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. [2] 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. [40] 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. [2]
An injury is an interruption of morphology and/or functionality of a given tissue. After injury, structural tissue heals with incomplete or complete regeneration. [70] [71] 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. [72] Non-injured skin has a continued replacement and regeneration of cells which always results in complete regeneration. [72]
There is a subtle distinction between 'repair' and 'regeneration'. [2] [70] [71] Repair means incomplete regeneration. [70] 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. [70] True tissue regeneration or complete regeneration, [71] refers to the replacement of lost/damaged tissue with an 'exact' copy, such that both morphology and functionality are completely restored. [71] 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. [72]
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. [73] 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. [2] 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. [74]
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. [75] [76] [77]
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. [78] [79]
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; [80] 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). [81] 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. [82]
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. [83] Currently, the principal goals in wound management are to achieve rapid wound closure with a functional tissue that has minimal aesthetic scarring. [84] 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 [85] and complete regeneration is limited to lower vertebrates, such as salamanders, and invertebrates. [86] 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. [85] 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. [87] [88] [89] 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. [87] [88] [89]
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. [90] [91] An example of the importance of the wound healing response within tumors is illustrated in work by Howard Chang, Pat Brown, David Botstein, Ash Alizadeh and colleagues at Stanford University studying Breast cancers [9] .
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. [92] 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. [93] 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. [94]
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). [95] 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. [96]
Successful wound healing is dependent on various cell types, molecular mediators and structural elements. [97]
Primary intention is the healing of a clean wound without tissue loss. [97] 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. [98]
This process is faster than healing by secondary intention. [97] There is also less scarring associated with primary intention, as there are no large tissue losses to be filled with granulation tissue. [97] (Primary intention does require some granulation tissue to form.)
(Delayed primary closure or secondary suture):
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.
Following are the main growth factors involved in wound healing:
|Growth factor
|Main origins
|Epidermal growth factor
|Transforming growth factor-α
|Hepatocyte growth factor
|Vascular endothelial growth factor
|Platelet derived growth factor
|Fibroblast growth factor 1 and 2
|Transforming growth factor-β
|Keratinocyte growth factor
|Unless else specified in boxes, then reference is: [100]
The major complications are many:
Other complications can include Infection and Marjolin's ulcer.
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. [101] 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. [102]
Formation of a thick eschar, slow healing (>1month), Obvious scarring,
Healing in 2 weeks – minimal to no scar; Healing in 3 weeks – minimal to no scar except in high risk scar formers;Healing in 4 weeks or more – hypertrophic in more than 50% of patients
Macrophages are present essentially in all tissues, beginning with embryonic development and, in addition to their role in host defense and in the clearance of apoptotic cells, are being increasingly recognized for their trophic function and role in regeneration.
Researchers have identified a cell that aids limb regrowth in Salamanders. Macrophages are a type of repairing cell that devour dead cells and pathogens, and trigger other immune cells to respond to pathogens.
When the dermis is destroyed, the scars do not regrow hair, nerves or sweat glands, providing additional challenges to body temperature control.
The new tissue is not the same as the tissue that was lost. After the repair process has been completed, there is a loss in the structure or function of the injured tissue. In this type of repair, it is common that granulation tissue (stromal connective tissue) proliferates to fill the defect created by the necrotic cells. The necrotic cells are then replaced by scar tissue.
(1) Complete regeneration: The new tissue is the same as the tissue that was lost. After the repair process has been completed, the structure and function of the injured tissue are completely normal
After the repair process has been completed, the structure and function of the injured tissue are completely normal. This type of regeneration is common in physiological situations. Examples of physiological regeneration are the continual replacement of cells of the skin and repair of the endometrium after menstruation. Complete regeneration can occur in pathological situations in tissues that have good regenerative capacity.
|Wikimedia Commons has media related to Wound healing .
A scar 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 natural part of the healing process. With the exception of very minor lesions, every wound results in some degree of scarring. An exception to this are animals with complete regeneration, which regrow tissue without scar formation.
Fibronectin is a high-molecular weight (~440kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans.
In biology, the extracellular matrix (ECM) is a three-dimensional network of extracellular macromolecules, such as collagen, enzymes, and glycoproteins, that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.
Healing is the process of the restoration of health from an unbalanced, diseased, damaged or unvitalized organism. The result of healing can be to cure the cause of a health challenge, but one can grow without being cured or heal without "a cure".
Fibrosis, also known as Fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that goes unchecked, leading to considerable tissue remodelling and the formation of permanent scar tissue.
Haptotaxis is the directional motility or outgrowth of cells, e.g. in the case of axonal outgrowth, usually up a gradient of cellular adhesion sites or substrate-bound chemoattractants. These gradients are naturally present in the extracellular matrix (ECM) of the body during processes such as angiogenesis or artificially present in biomaterials where gradients are established by altering the concentration of adhesion sites on a polymer substrate.
Hyaluronic acid, also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans in that it is nonsulfated, forms in the plasma membrane instead of the Golgi apparatus, and can be very large: human synovial HA averages about 7 million Da per molecule, or about twenty thousand disaccharide monomers, while other sources mention 3–4 million Da. As one of the chief components of the extracellular matrix, hyaluronan contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant tumors.
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. Examples of granulation tissue can be seen in pyogenic granulomas and pulp polyps. Its histological appearance is characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries (angiogenesis), infiltrated inflammatory cells in a loose extracellular matrix.
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 one or more of the phases of wound healing. For example, chronic wounds often remain in the inflammatory stage for too long. To overcome that stage and jump-start the healing process a number of factors need to be addressed such as bacterial burden, necrotic tissue, and moisture balance of the whole wound. In acute wounds, there is a precise balance between production and degradation of molecules such as collagen; in chronic wounds this balance is lost and degradation plays too large a role.
A myofibroblast is a cell that is in between a fibroblast and a smooth muscle cell in phenotype.
Glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system.
Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.
Dermatopontin also known as tyrosine-rich acidic matrix protein (TRAMP) is a protein that in humans is encoded by the DPT gene. Dermatopontin is a 22-kDa protein of the noncollagenous extracellular matrix (ECM) estimated to comprise 12 mg/kg of wet dermis weight. To date, homologues have been identified in five different mammals and 12 different invertebrates with multiple functions. In vertebrates, the primary function of dermatopontin is a structural component of the ECM, cell adhesion, modulation of TGF-β activity and cellular quiescence). It also has pathological involvement in heart attacks and decreased expression in leiomyoma and fibrosis. In invertebrate, dermatopontin homologue plays a role in hemagglutination, cell-cell aggregation, and expression during parasite infection.
In medicine, desmoplasia is the growth of fibrous or connective tissue. It is also called desmoplastic reaction to emphasize that it is secondary to an insult. Desmoplasia may occur around a neoplasm, causing dense fibrosis around the tumor, or scar tissue (adhesions) within the abdomen after abdominal surgery.
The dermal equivalent is an in vitro model of the dermal layer of skin. It is constructed by seeding dermal fibroblasts into a collagen gel. This gel may then be allowed to contract as a model of wound contraction. This collagen gel contraction assay may be used to screen for treatments which promote or inhibit contraction and thus affect the development of a scar. Other cell types may be incorporated into the dermal equivalent to increase the complexity of the model. For example, keratinocytes may be seeded on the surface to create a skin equivalent, or macrophages may be incorporated to model the inflammatory phase of wound healing.
Copper peptide GHK-Cu is a naturally occurring copper complex of the tripeptide glycyl-L-histidyl-L-lysine. The tripeptide has strong affinity for copper(II) and was first isolated from human plasma. It can be found also in saliva and urine.
Dermal fibroblasts are cells within the dermis layer of skin which are responsible for generating connective tissue and allowing the skin to recover from injury. Using organelles, dermal fibroblasts generate and maintain the connective tissue which unites separate cell layers. Furthermore, these dermal fibroblasts produce the protein molecules including laminin and fibronectin which comprise the extracellular matrix. By creating the extracellular matrix between the dermis and epidermis, fibroblasts allow the epithelial cells of the epidermis to affix the matrix, thereby allowing the epidermal cells to effectively join together to form the top layer of the skin.
Heparan sulfate analogues are polymers engineered to mimic several properties of heparan sulfates. They can be constituted with a backbone of polysaccharides, such as poly glucose or glucuronates or a polyester such as co polymers of lactic or malic acid to which sulfates, sulfonate or carboxylgroups are added in controlled amounts and location. They have a molecular weight that can range from a few thousands to several hundred thousand Dalton. Heparan sulfates can sequester growth factors (GFs) and cytokines in the extracellular matrix (ECM) thereby protecting them from degradation. This ensures local presence of these signaling proteins to fulfill their function in the ECM which contributes to the preservation of anatomical form and function. Heparan sulfates bind to matrix proteins on specific sites called "heparan sulfate binding sites" on ECM macromolecules like collagen, fibronectin and laminin, to form a scaffold surrounding the cells and to protect ECM proteins and growth factors from proteolytic degradation by steric hindrance. However, at any site of inflammation, so also in wound areas, heparan sulfates are degraded, mainly by heparanases giving free access to protease to degrade the ECM and a subsequent loss of GFs and cytokines that disrupts the normal tissue homeostasis. Heparan sulfate analogues obtain many of the characteristics of heparan sulfates including the ability to sequester GFs and bind and protect matrix proteins. However, heparan sulfate analogues are resistant to enzymatic degradation. This way they strengthen the healing potential of the wound bed by repositioning GFs and cytokines back into the ECM.
Diabetic foot ulcer is a major complication of diabetes mellitus, and probably the major component of the diabetic foot.
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 completely regenerated. Scar improvement, and scar-free healing are an important and relevant area of medicine. During the 1990s, published research on the subject increased; it's a relatively recent term in the literature. Scar free healing is something which takes place in foetal life but the capacity is lost during progression to adulthood. In amphibians, tissue regeneration occurs, for example, as in skin regeneration in the adult axolotl.


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Voiced by Vanessa Marshall. This movie is based on the Flashpoint event which was meant to be the reboot of the DC Universe. After the Barry Allen travels back in time to save his mother, he changes the whole timestream making everything different. Her role in this movie is that she has a war against Aquaman because she killed Mera and it made Aquaman angry, Amazons against Atlanteans. The Amazons has made London ''New Themyscira''. She defeats Aquaman at the end of the movie, but the rest of the world gets destroyed by Captain Atom's energy, Captain Atom was held as a last resort by Aquaman, and Flash manages to revert everything as it was right before the world got consumed.
As Zola defeated Poseidon, the First Born returned to Olympus and ordered the Minotaur to attack Wonder Woman. The Minotaur, however, refused to kill her and the First Born killed him instead. Upon seeing the unmasked Minotaur, Diana discovered her foe was the creature she had spared in the labyrinth.[48] Wonder Woman furiously threw the First Born into the abyss he was originally trapped in while Zola placed Zeke on the throne. Zola revealed herself to be Athena and Zeke to be another iteration of Zeus himself. Both had planned for Wonder Woman to fight the First Born and accept her destiny as a goddess. With the conflict ended, Athena planned to put an end to her human identity and become a goddess once more, but Wonder Woman convinced her to allow Zola and Zeke to live without godly interference.[49]
Dear Justice League, dear justice league comic, Justice League, Michael Northrop, gustavo duarte, middle grade, middle grade comics, middle grade graphic novels, comics for kids, good comics for kids, graphic novels for kids, good graphic novels for kids, young readers, all ages comics, good all ages comics, Batman, Superman, wonder woman, The Flash, Green Lantern, hawkgirl, cyborg, Aquaman, dc zoom, dc kids, ashley v. robinson
The "Diana Prince" identity has been part of Wonder Woman's history since her comics debut in 1941. In the early Golden Age stories, Wonder Woman served as a military secretary during World War II, using Prince as her cover. Later occupations Wonder Woman performed as Prince included translator at the United Nations, Air Force captain and ambassador, and in the '70s TV series, Lynda Carter's Wonder Woman used Prince to serve as an agent of the Inter-Agency Defense Command. In the DC Extended Universe, Prince works as curator for the Department of Antiquities[56] at the extremely prestigious Louvre Museum and is held in very high esteem by the curator of the Gotham City Museum of Antiquities. Her tremendously long life span, accumulation of immense amount of knowledge and exceptional perceptiveness makes Diana Prince the wisest and most emotionally-intelligent member of the Justice League.[57][58]
Development of a live action Wonder Woman film began in 1996, with Ivan Reitman slated to produce and possibly direct. The project floundered in development hell for many years; Jon Cohen, Todd Alcott, and Joss Whedon, among others, were also attached to the project at various points. Warner Bros. announced the film in 2010 and Jenkins signed on to direct in 2015. Inspiration for Wonder Woman was drawn from Wonder Woman creator William Moulton Marston's 1940s stories and George Pérez's 1980s stories about Wonder Woman, as well as the New 52 incarnation of the character. Principal photography began on November 21, 2015, with filming taking place in the United Kingdom, France, and Italy before finishing on May 6, 2016, the 123rd anniversary of Marston's birth. Additional filming took place in November 2016.
Granted by Hermes (God of Messengers), her top speed has never been well documented, but she has entered the speed force under her own power, implying she can accelerate to at least light speed. The Flash has said that Wonder Woman can easily keep up with him and she has been seen keeping up with Flash going faster than hypersonic speed. She has been shown to be on par with some of the fastest characters in the DC Universe such as Jesse Quick. She can disarm human opponents of their weapons instantly and she can immobilize her opponents in the blink of an eye, as she showed when she speedblitzed White Martian and Genocide into space in no time and was able to take down Amazo before he could finish a word. She is such a well trained athlete that in combat, her reflexes even surprise the likes of Superman.
I thought George's one "mistake" in rebooting Wonder Woman was making her only 25 years old when she left Paradise Island. I preferred the idea of a Diana who was thousands of years old (as, if I recall correctly, she was in the TV series). From that angle, I would have liked to have seen Diana having been Wonder Woman in WW2, and be returning to our world in the reboot. Not having that option, I took the next best course, and had Hippolyta fill that role.[81]
The story behind the writing and editing of Wonder Woman can be pieced together from Bender's papers, at Brooklyn College; Frank's papers, at the University of Minnesota; and Marston's editorial correspondence, along with a set of original scripts, housed at the Dibner Library at the Smithsonian Institution Libraries. In his original scripts, Marston described scenes of bondage in careful, intimate detail with utmost precision. For a story about Mars, the God of War, Marston gave Peter elaborate instructions for the panel in which Wonder Woman is taken prisoner:
The New 52 version of the character has been portrayed to be a younger, more headstrong, loving, fierce and willful person.[citation needed] Brian Azzarello stated in a video interview with DC Comics that they're building a very "confident", "impulsive" and "good-hearted" character in her. He referred to her trait of feeling compassion as both her strength and weakness.[75]
Principal photography on the film began on November 21, 2015,[119][120] under the working title Nightingale.[121][122] Among the film sets were Lower Halstow, Kent,[123] and Australia House[124] in England and the Sassi di Matera,[125] Castel del Monte[125] and Camerota[126] in Southern Italy. Matthew Jensen was the director of photography,[127] filming in the United Kingdom, France and Italy.[128] Production in London concluded on March 13, 2016.[129] On March 20, 2016, filming was underway in Italy. In late April, filming took place at the Louvre Museum in Paris, France, where a Wayne Enterprises truck was spotted alongside Gadot.[130] Principal photography finished on May 9, 2016.[131] Patty Jenkins and director of photography Matt Jensen said that the film's look was inspired by painter John Singer Sargent.[132] Reshoots took place in November 2016, while Gadot was five months pregnant. A green cloth was placed over her stomach to edit out her pregnancy during post-production.[133]
The most recent version of the character's origin (since the new 52) has not yet been told in totality, but certain things are known. It has been revealed how the Amazons replenish their numbers (they do so by kidnapping sailors and using them for procreation before killing them) as well as the fact of Wonder Woman's divine lineage. Despite the fact that Zeus is her father it does not necessarily remove other facts about her origin from canon (for instance the blessings of the gods) though it remains to be seen how or if this will be incorporated into the ongoing stories. In the Zero month of the new 52 in which DC was planning to tell the origins of the character from the new 52, the story for Diana focused on the fact that she had been trained by Ares when she was a teenager though she eventually rebelled against him. It is as of yet unclear how this factors into her new origin. When Diana first came to Man's World she encountered a group attacking the Pentagon. Because of this she befriended Barbara Minerva who was working there on ancient antiquities and Barbara helped her acclimatize to Man's World.
If there is any part of the story that stands out, it's the "oh $%" cliffhanger. I've read plenty of stories with such cliffhangers, but this one is a real gut-punch. Not because it's shocking for this arc, but when you realize next issue is the finale for Robinson's run for the time being. From the moment Diana sought out Jason, it built to this moment. It got me excited for next time, despite its failures this issue.
Wonder Woman's origin story relates that she was sculpted from clay by her mother Queen Hippolyta and was given a life to live as an Amazon, along with superhuman powers as gifts by the Greek gods. In recent years, DC changed her background with the retcon that she is the daughter of Zeus and Hippolyta, jointly raised by her mother and her aunts Antiope and Menalippe. The character has changed in depiction over the decades, including briefly losing her powers entirely in the late 1960s; by the 1980s, artist George Perez gave her an atheltic look and emphasized her Amazonian heritage.[11][12] She possesses an arsenal of advanced technology, including the Lasso of Truth, a pair of indestructible bracelets, a tiara which serves as a projectile, and, in older stories, a range of devices based on Amazon technology.
When Diana returns she takes on the persona of Diana Prince, now a secret agent and member of the Department of Metahuman Affairs. She is partnered with Nemesis and the two report to Sarge Steel. Her first assignment is to retrieve her sister Donna Troy, who has been kidnapped by several of her most persistent enemies; their powers have been augmented by Circe. After this is accomplished, Diana takes back the title of Wonder Woman.[9]
As Themyscira's emissary to Man's World, Diana has made it her duty to lead by example, even if the differences between her birthplace and new home sometimes present hurdles for her to jump. She has come to represent the possibility and potential of life without war, hate or violence, and she is a beacon of hope to all who find themselves in need. She stands as an equal among the most powerful Super Heroes, with a sense of purpose to protect the world from injustice in all forms.
William Marston's earliest works were notorious for containing subversive "bondage and sapphic-undertones" subtext. Among Wonder Women's infamous catchphrases, "Suffering Sappho", was a direct reference to lesbianism. Fredric Wertham's Seduction of the Innocent referred to her as the "lesbian counterpart to Batman" (whom he also identified as a homosexual). After Marston's death in 1947, DC Comics downplayed her sexuality and feminist origin. Wonder Women, without Marston's creative direction, become more "traditional" superhero fair; the lesbian relationships and sexual imagery disappeared from the "Wonder Woman" comic, along with Wonder Woman's super powers. During the Comics Code Authority-decades since, Wonder Woman's subversiveness had been gradually stripped away; subsequent comic book writers and artists either didn't know know what do with her or barely hinted at Wonder Woman's erotic legacy.[10] Similar to whitewashing, Wonder Woman's queerness and feminist identity throughout the latter half of the 20th century was never discussed and rendered "invisible" in adaptations in favor of the dominant sexism portrayal of women in comic books.[26]
During 1942 to 1947, images of bound and gagged women frequently graced the covers of both Sensation Comics and Wonder Woman. An early example includes a scene in Wonder Woman #3 (Feb.-March 1943), Wonder Woman herself ties up several women, dresses them in deer costumes and chases them through the forest. Later she rebinds them and displays them on a platter.[3][4]
"As to the 'advanced femininity,' what are the activities in comic books which women 'indulge in on an equal footing with men'? They do not work. They are not homemakers. They do not bring up a family. Mother-love is entirely absent. Even when Wonder Woman adopts a girl there are Lesbian overtones," he said. At the Senate hearings, Bender testified, too. If anything in American popular culture was bad for girls, she said, it wasn't Wonder Woman; it was Walt Disney. "The mothers are always killed or sent to the insane asylums in Walt Disney movies," she said. This argument fell on deaf ears.
Artemis Wonder Woman #3 (February–March 1943) Artemis is the Goddess of the Moon, Hunting, Archery, Forest, and Animals, and the older twin sister to Apollo who is based on the goddess of the same name. Post-Crisis, she was one of Wonder Woman's patron goddesses. In the New 52, Artemis was more antagonistic, often teaming up with her brother to battle the amazon. Post-Rebirth, Artemis took the form of a deer and aided Wonder Woman with several other gods..
Originally signed for three feature films, with Wonder Woman and Justice League being her second and third films, Gadot signed an extension to her contract for additional films.[313] Jenkins initially signed for only one film,[314] but in an interview with Variety, Geoff Johns revealed that he and Jenkins were writing the treatment for a Wonder Woman sequel and that he has a "cool idea for the second one". At the 2017 San Diego Comic Con, Warner Bros. officially announced a sequel would be released on December 13, 2019, and would be titled Wonder Woman 2; the date was later moved up to November 1, 2019, to avoid competition with Star Wars: The Rise of Skywalker.[315][316][317] Later, Jenkins was officially signed to return as director, with confirmation that Gadot will be returning as the titular role.[318] Days later, the studio hired Dave Callaham to co-write the film's script with Jenkins and Johns.[319] On March 9, 2018, Kristen Wiig was confirmed to play Cheetah, the villain of the film.[320] Later that month, it was announced that Pedro Pascal would have a key role in the film.[321] In May 2018, long-time DCEU producer Zack Snyder confirmed on social media platform Vero that he, along with wife Deborah Snyder, will serve as producers on the Wonder Woman sequel.[322] In June 2018, the title of the film was announced to be Wonder Woman 1984.[323] A third film was announced in January 2019 to be taking place in the present.[324]
On November 3, 2016, Rupert Gregson-Williams was hired to write and compose the film's music.[138][139] He was joined by Evan Jolly, Tom Howe,[140] Paul Mounsey,[141] and Andrew Kawczynski,[142] who provided additional music. The soundtrack was released on CD, digital, and vinyl the same day as the film.[143] Australian musician Sia sang a song for the film, titled "To Be Human", featuring English musician Labrinth. Written by Florence Welch and Rick Nowels, the track is also featured on the soundtrack.[144] The soundtrack also features samples from Wonder Woman's theme "Is She with You" from the Batman v Superman: Dawn of Justice soundtrack composed by Hans Zimmer and Junkie XL.
After taking Despero to the authorities, Wonder Woman and Superman came across the mysterious Pandora, someone Wonder Woman was familiar with. She believed Superman could use her box to trap the evil she unleashed in ancient times; but when Superman touched it, he was overwhelmed by its power. While Pandora took the box and left, the two heroes received news that a new superhuman, Shazam, was entering the borders of Kahndaq. Their confrontation with Shazam turned violent until the rest of the Justice League and the Justice League of America intervened to defuse the situation. Suddenly, Dr. Light lost control of his powers and began absorbing Superman's solar energy, unleashing an energy beam at Wonder Woman. In a fit of anger, Superman killed Dr. Light with his heat vision, an action that caused a fight between the two Leagues.[65]
Wonder Woman's powers are a result of the blessings she received from the gods (or presumably in the modern version by her divine ancestry), but originally came from her "brain energy" training. Her abilities in large part come from her upbringing in the martial society of the Amazons. She is one of the most powerful superheroes in the DC universe.
Starting in Wonder Woman vol. 2 #51, the Amazons, who had revealed their presence to the world in Wonder Woman vol. 2 #50, are blamed for a series of murders and for the theft of various artifacts. The Amazons are then taken into custody, Queen Hippolyta is nowhere to be found and Steve Trevor is forced by General Yedziniak to attack Themyscira. These events lead to the "War of the Gods" occurring. The culprit of the murders, thefts and the framing of the Amazons is revealed to be the witch Circe, who "kills" Diana by reverting her form back into the clay she was born from. Later, Wonder Woman is brought back to life and together with Donna Troy, battles Circe and ultimately defeats her.[103][104][105][106] Circe would later return by unknown means.
The debate continued with the release of Jenkins's 2017 film, Wonder Woman, which according to the BBC had "some thinking it's too feminist and others thinking it's not feminist enough".[235] Kyle Killian found an inherent contradiction in the construction of Wonder Woman as "a warrior" who, she states, is also highly sexualized. Killian thus suggests that these elements "should not be the focus of a kickass heroine—her beauty, bone structure, and sexiness—if she is to be a feminist icon".[236] Theresa Harold concurred, comparing Wonder Woman to Katniss Everdeen (of The Hunger Games), who "didn't have to wear a teenager's wet dream of a costume to fight in".[237] Christina Cauterucci also felt that Wonder Woman's ability to be considered a "feminist antidote" was undermined by her "sex appeal".[238] Other critics refer to the construction of Wonder Woman in the film as "an implausible post-feminist hero".[227][239]
Marston was a man of a thousand lives and a thousand lies. "Olive Richard" was the pen name of Olive Byrne, and she hadn't gone to visit Marston—she lived with him. She was also the niece of Margaret Sanger, one of the most important feminists of the 20th century. In 1916, Sanger and her sister, Ethel Byrne, Olive Byrne's mother, had opened the first birth-control clinic in the United States. They were both arrested for the illegal distribution of contraception. In jail in 1917, Ethel Byrne went on a hunger strike and nearly died.
When Diana returns she takes on the persona of Diana Prince, now a secret agent and member of the Department of Metahuman Affairs. She is partnered with Nemesis and the two report to Sarge Steel. Her first assignment is to retrieve her sister Donna Troy, who has been kidnapped by several of her most persistent enemies; their powers have been augmented by Circe. After this is accomplished, Diana takes back the title of Wonder Woman.[9]
Gaines decided he needed another expert. He turned to Lauretta Bender, an associate professor of psychiatry at New York University's medical school and a senior psychiatrist at Bellevue Hospital, where she was director of the children's ward, an expert on aggression. She'd long been interested in comics but her interest had grown in 1940, after her husband, Paul Schilder, was killed by a car while walking home from visiting Bender and their 8-day-old daughter in the hospital. Bender, left with three children under the age of 3, soon became painfully interested in studying how children cope with trauma. In 1940, she conducted a study with Reginald Lourie, a medical resident under her supervision, investigating the effect of comics on four children brought to Bellevue Hospital for behavioral problems. Tessie, 12, had witnessed her father, a convicted murderer, kill himself. She insisted on calling herself Shiera, after a comic-book girl who is always rescued at the last minute by the Flash. Kenneth, 11, had been raped. He was frantic unless medicated or "wearing a Superman cape." He felt safe in it—he could fly away if he wanted to—and "he felt that the cape protected him from an assault." Bender and Lourie concluded the comic books were "the folklore of this age," and worked, culturally, the same way fables and fairy tales did.
A ho-hum end to James Robinson's ho-hum run on Wonder Woman. Most things to come out of Dark Nights: Metal have been crap and that trend continues with these Dark Gods. They are so damn generic, with titles like Mob God, and God with No Name. James Robinson used to be one of my favorite comic book writers in the 90's but he's really shit the bed the last several years. The only good thing to come of this run is that Jason's story line is finally over. That tool is pretty much useless. I'm also g ...more
The New 52 version of the character has been portrayed to be a younger, more headstrong, loving, fierce and willful person.[citation needed] Brian Azzarello stated in a video interview with DC Comics that they're building a very "confident", "impulsive" and "good-hearted" character in her. He referred to her trait of feeling compassion as both her strength and weakness.[75]
Her outfit did not receive any prominent change until after the 2005–2006 Infinite Crisis storyline. Similar to her chestplate, her glowing belt was also shaped into a "W".[194] This outfit continued until issue #600 – J. Michael Straczynski's run of Wonder Woman's altered timeline changed her outfit drastically. Her outfit was redesigned by Jim Lee and included a redesigned emblem, a golden and red top, black pants, and a later discontinued blue-black jacket.[194]
Not long after this, Athena sensed a dark destiny for the gods amidst the cosmic mechanations of Alexander Luthor Jr.. In the crisis created by his chaos, Diana was forced to kill Maxwell Lord, and incurred the ire of the world's public.[34] The U.S. government responded by mobilizing against Themyscira, and Diana realized that as long as she was a target, the Amazons would never be safe. Diana prayed to the gods to take the Amazons to safety, but got more than she bargained for.[35] On Olympus, she pleaded against Athena's decision to remove the gods from Earth's affairs. Regardless, the gods departed, leaving Diana bereft of family and faith.[36]
After Jimenez, Walt Simonson wrote a six-issue homage to the I Ching era, in which Diana temporarily loses her powers and adopts an all-white costume (Wonder Woman vol. 2, #189–194). Greg Rucka became writer with issue #195. His initial story arc centered upon Diana's authorship of a controversial book and included a political subtext. Rucka introduced a new recurring villain, ruthless businesswoman Veronica Cale, who uses media manipulation to try to discredit Diana. Rucka modernized the Greek and Egyptian gods, updating the toga-wearing deities to provide them with briefcases, laptop computers, designer clothing, and modern hairstyles. Rucka dethroned Zeus and Hades, who were unable to move with the times as the other gods had, replacing them with Athena and Ares as new rulers of the gods and the underworld. Athena selected Diana to be her personal champion.[9]
Wonder Woman's costume has come under heavy criticism throughout the years. Many find that as an example of a character that is supposed to represent female empowerment that by wearing a costume which reveals a gratuitous amount of skin that the character is being contradictory. Numerous attempts have been made to make her costume more realistic, however in terms of the character's history there are few problems with it. Despite that it offers little protection, Wonder Woman does not require very much protection, either from harm or from the elements. The costume is also sometimes criticized for its symbolism closely related to American themes, that despite the fact that she is meant to be an emissary of peace to the whole planet, that her costume looks very American This is explained as one of the motivations for her role in Man's World world. The costume is a breastplate inspired by the colors and symbols of a downed World War II airplane being flown by Steve Trevor's mother . As an American pilot, it is therefore not surprising that stars (on the lower part of her breastplate) and stripes (one her boots) are evident parts of the design. In the summer of 2011 it was announced that DC Comics would reboot its entire lineup and create the new 52. Debate immediately surfaced as the head creative force behind the reboot (Jim Lee) decided that all female characters should be drawn with "pants" or full leg covering as part of their costume. This was in line with the redrawn Wonder Woman after issue #600 in volume 3. However, as the summer progressed images began to appear with Diana in a costume which appeared to be a synthesis of her traditional one and the reimagined one. With the actual reboot this is the costume that was decided on, essentially with the breastplate in the general shape of the traditional costume, and the theme being more in line with the redesign of the previous year. She additionally has added aspects of her uniform which didn't exist before such as a braided armband.

subset: commoncrawl


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Explore Gallery of Long Chestnut Brown Shag Hairstyles
Showing Photo About 60 Lovely Long Shag Haircuts For Effortless Stylish Looks Regarding Recent Long Chestnut Brown Shag Hairstyles
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Mar 28 | 3 Nisan |
Torah Portion
Aish HaTorah Israel Programs
A Holocaust Survivor in Quarantine
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When God Means Business
Dating in the Age of Corona
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One Rabbi's Dream to Close All Shuls
Coronavirus: A Time for Kindness
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Jtube: Shark Tank: Swimply
How Israel Looks Without Tourists
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This is the story of a family. Even though they already had a little girl, their family felt incomplete, so they adopted a gorgeous little red head.
The daughters share playtimes and birthdays together. From the outside looking in, their home life appears joyful – that is, until the adopted daughter starts making mistakes. Her mistakes aren't extraordinary, and they certainly aren't out of the ordinary mistakes for a little girl, but mom is downright furious. She screams at her new daughter and she starts questioning her decision to adopt in the first place. How could her adopted daughter not know better?
It's too much time to raise her!
The mistakes don't stop. The adopted daughter keeps causing problems. She's doesn't do anything as extreme as this tot who brought a cow into her home, but she's not behaving up to her parent's expectations. When she makes a big mess in a bedroom, that's the last straw.
The family decides to get rid of her for good.
This is a fictional account of what one family does to their adopted daughter, but it's something that happens to adopted non-human members of our families year after year. For our four-legged family members, nothing about abandonment is illegal. This beautiful film is by Zsofia Zsemberi, and was made with the intention of showing people just how cruel it is to get rid of a pet when you're "tired" of it!
Please SHARE this powerful message about life and loving pets with all of your family and friends. All animals deserve love. Let's work together to help end the socially accepted practice of abandoning pets!
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Believe it or not, it's one of our best sellers--check it out here!Sign up to receive more surprising Texas-tradition inspired recipes!
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These glasses are laser engraved with the Lubbock map, as well as its GPS coordinates. Truly unique and stunning, these glasses are sure to make your next entertaining event stand out as something special!Perfect for wedding events, graduation gifts, stocking stuffers, or any time you're needing a unique gift that will be cherished forever.
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Projects per year
Fingerprint Dive into the research topics where Donald J Newport is active. These topic labels come from the works of this person. Together they form a unique fingerprint.
- 16 Similar Profiles
Recent external collaboration on country level. Dive into details by clicking on the dots.
- 3 Finished
Perinatal Stress and Gene Influences: Pathways to Infant Vulnerability
Newport, D. J., Cubells, J. F., Ritchie, J. C., Stowe, Z., Owens, M. J. & Goodman, S. H.
9/1/07 → 7/31/12
Project: Research project
Bipolar Disorder in Pregnancy: Predictors of Morbibity
8/12/05 → 7/31/11
Project: Research project
Development Psychopharmacology
7/1/01 → 6/30/07
Project: Research project
Research Output
Research Output per year
Correction to: The Role of Oxytocin in Early Life Adversity and Later Psychopathology: a Review of Preclinical and Clinical Studies (Current Treatment Options in Psychiatry, (2018), 5, 4, (401-415), 10.1007/s40501-018-0158-9)Londono Tobon, A., Newport, D. J. & Nemeroff, C., Mar 15 2019, In : Current Treatment Options in Psychiatry. 6, 1, 1 p.
Research output: Contribution to journal › Comment/debate
Open Access
Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safetythe National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG) Study Group, Jan 1 2019, In : Alcoholism: Clinical and Experimental Research. 43, 1, p. 158-169 12 p.
Research output: Contribution to journal › Article
Patterns of positivity: Positive affect trajectories among infants of mothers with a history of depressionDavis, M., Goodman, S. H., Lavner, J. A., Maier, M. S., Stowe, Z. N., Newport, D. J. & Knight, B., Nov 1 2019, In : Infancy. 24, 6, p. 911-932 22 p.
Research output: Contribution to journal › Article
School-age social behavior and pragmatic language ability in children with prenatal serotonin reuptake inhibitor exposureSmearman, E. L., Hendrix, C. L., Winiarski, D. A., Johnson, K. C., Smith, A. K., Ousley, O. Y., Stowe, Z. N., Newport, D. J. & Brennan, P. A., Jan 1 2019, In : Development and Psychopathology.
Research output: Contribution to journal › Article
An exploratory study of whether pregnancy outcomes influence maternal self-reported history of child maltreatmentCammack, A. L., Hogue, C. J., Drews-Botsch, C. D., Kramer, M. R., Pearce, B. D., Knight, B., Stowe, Z. N. & Newport, D. J., Jan 1 2018, (Accepted/In press) In : Child Abuse and Neglect.
Research output: Contribution to journal › Article


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100% of consumers (3 of 3) said they would recommend this vehicle to a friend.
by Weasel from Helena, MT | March 23, 2020
I fell in love with the Seltos online. Seeing and driving the Seltos in person removed any doubts. I have now owned my Seltos for a month. I have driven in snow and dry roads with no problems at all. The all wheel drive is awesome. When I need a little performance the Seltos does not disappoint either.
by DavidUnboxed from Pensacola, Fl | March 04, 2020
I'm very pleased! Car and Driver was correct when they said if you test drove Kia 5 years ago - you owe it to yourself to give it a reconsideration now - as its not the same low quality seen at that time. Highway Driving Assist /w Auto Hold is completely awesome. Auto-headlights, excellent. Traction control and pep for the Turbo, fantastic for the fuel economy and enough to make me feel I can get out of the way quickly if needed. Very roomy interior. Road-trip worthy. If I have to give it negatives - it's louder than a luxury car on the road. It's a SUV crossover - so I expected that. My old Dodge Neon was worse. I wish auto-hold and HDA had the option to be 'on at startup'. I guess they don't want to confuse drivers without familiarity. Living in flat Florida, I enable these every time I start the car. These 'semi-autonomous features (my words not Kia) - require a 'keep hands on wheel feature'. The detection method for that triggers sometimes when I drive I-10 in a straight stretch for a few miles. When it does, I can dismiss the warning with the slightest movement of my hands. If you need to tow, make sure you can get a hitch. Kia has it in 'down under' but not here yet -- and the aftermarket has not picked it up yet.
by Victor from Roseville | February 25, 2020
This car is a perfect fit. Plenty of room for us. Love the cargo space and plenty of room to fit grandchildren in rear seat. Gas mileage is good. Has all the bells and whistles.
The 2021 Kia Seltos is an all-new compact SUV with clean, yet rugged styling. Standard features include an 8-inch touchscreen display, rear back-up camera, remote keyless entry, and Apple CarPlay/Android Auto smartphone compatibility. Maximum cargo capacity is 62.8 cubic feet with the rear seat folded down.
Five trims are available: LX, S, EX, S Turbo, and SX Turbo.
It is powered by a 141-hp 2.0-liter four-cylinder engine mated to continuously variable transmission and all-wheel drive. Fuel economy for the Seltos is an EPA-estimated rating of 27/31 mpg city/highway. A more powerful 175-hp, turbocharged 1.6-liter four-cylinder is also available. The turbocharge Seltos models have a slightly lower fuel economy rating of 25/30 mpg.
*MSRP and Invoice prices displayed are for educational purposes only, do not reflect the actual selling price of a particular vehicle, and do not include applicable gas taxes or destination charges.


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"Hope has a name. His name is Jesus." This song sings like a modern hymn, but also boasts an epic, soaring chorus. The simplicity of the musical arrangement makes ample…
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Greg LaFollette
Greg LaFollette is a musician and producer in Nashville,TN. He is the resident artist at a local church plant, Grace Story Church, and serves as their director of arts and liturgy.


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