stop migrating. when they have finished migrating, the keratinocytes secrete the proteins that form the new basement membrane. cells reverse the morphological changes they underwent in order to begin migrating; they reestablish desmosomes and hemidesmosomes and become anchored once again to the basement membrane. 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. contraction contraction is a key phase of wound healing with repair. if contraction continues for too long, it can lead to disfigurement and loss of function. thus there is a great interest in understanding the biology of wound contraction, which can be modelled in vitro using the collagen gel contraction assay or the dermal equivalent model. contraction commences approximately a week after wounding, when fibroblasts have differentiated into myofibroblasts. in full thickness wounds, contraction peaks at 5 to 15 days post wounding. contraction can last for several weeks and continues even after the wound is completely reepithelialized. a large wound can become 40 to 80% smaller after contraction. wounds can contract at a speed of up to 0.75 mm per day, depending on how loose the tissue in the wounded area is. contraction usually does not occur symmetrically; rather most wounds have an 'axis of contraction' which allows for greater organization and alignment of cells with collagen. at first, contraction occurs without myofibroblast involvement. later, fibroblasts, stimulated by growth factors, differentiate into myofibroblasts. myofibroblasts, which are similar to smooth muscle cells, are responsible for contraction. myofibroblasts contain the same kind of actin as that found in smooth muscle cells. myofibroblasts are attracted by fibronectin and growth factors and they move along fibronectin linked to fibrin in the provisional ecm in order to reach the wound edges. they form connections to the ecm at the wound edges, and they attach to each other and to the wound edges by desmosomes. also, at an adhesion called the fibronexus, actin in the myofibroblast is linked across the cell membrane to molecules in the extracellular matrix like fibronectin and collagen. myofibroblasts have many such adhesions, which allow them to pull the ecm when they contract, reducing the wound size. in this part of contraction, closure occurs more quickly than in the first, myofibroblast-independent part. as the actin in myofibroblasts contracts, the wound edges are pulled together. fibroblasts lay down collagen to reinforce the wound as myofibroblasts contract. the contraction stage in proliferation ends as myofibroblasts stop contracting and commit apoptosis. the breakdown of the provisional matrix leads to a decrease in hyaluronic acid and an increase in chondroitin sulfate, which gradually triggers fibroblasts to stop migrating and proliferating. these events signal the onset of the maturation stage of wound healing. maturation and remodeling when the levels of collagen production and degradation equalize, the maturation phase of tissue repair is said to have begun. during maturation, type iii collagen, which is prevalent during proliferation, is replaced by type i collagen. originally disorganized collagen fibers are rearranged, cross-linked, and aligned along tension lines. the onset of the maturation phase may vary extensively, depending on the size of the wound and whether it was initially closed or left open, ranging from approximately three days to three weeks. the maturation phase can last for a year or longer, similarly depending on wound type. as the phase progresses, the tensile strength of the wound increases. collagen will reach approximately 20% of its tensile strength after three weeks, increasing to 80% by the 12th week. the maximum scar strength is 80% of that of unwounded skin. since activity at the wound site is reduced, the scar loses its red appearance as blood vessels that are no longer needed are removed by apoptosis. 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 such as a venous ulcer or pathological scarring such as a keloid scar. factors affecting wound healing many factors controlling the efficacy, speed, and manner of wound healing fall under two types: local and systemic factors. local factors moisture; keeping a wound moist rather than dry makes wound healing more rapid and with less pain and less scarring mechanical factors oedema ionizing radiation faulty technique of wound closure ischemia and necrosis foreign bodies. sharp, small foreign bodies can penetrate the skin leaving little surface wound but causing internal injury and internal bleeding. for a glass foreign body, "frequently, an innocent skin wound disguises the extensive nature of the injuries beneath". first-degree nerve injury requires a few hours to a few weeks to recover. if a foreign body passes by a nerve and causes first-degree nerve injury during entry, then the sensation of the foreign body or pain due to internal wounding may be delayed by a few hours to a few weeks after entry. a sudden increase in pain during the first few weeks of wound healing could be a sign of a recovered nerve reporting internal injuries rather than a newly developed infection. low oxygen tension perfusion systemic factors inflammation diabetes – individuals with diabetes demonstrate reduced capability in the healing of acute wounds. additionally, diabetic individuals are susceptible to developing chronic diabetic foot ulcers, a serious complication of diabetes which affects 15% of people with diabetes and accounts for 84% of all diabetes-related lower leg amputations. the impaired healing abilities of diabetics with diabetic foot ulcers and/or acute wounds involves multiple pathophysiological mechanisms. 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. nutrients – malnutrition or nutritional deficiencies have a recognizable impact on wound healing post trauma or surgical intervention. nutrients including proteins, carbohydrates, arginine, glutamine, polyunsaturated fatty acids, vitamin a, vitamin c, vitamin e, magnesium, copper, zinc and iron all play significant roles in wound healing. fats and carbohydrates provide the majority of energy required for wound healing. glucose is the most prominent source of fuel and it is used to create cellular atp, providing energy for angiogenesis and the deposition of new tissues. as the nutritional needs of each patient and their associated wound are complex, it is suggested that tailored nutritional support would benefit both acute and chronic wound healing. metabolic 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. passive smoking also impairs a proper wound healing process. age – increased age (over 60 years) is a risk factor for impaired wound healing. it is recognized that, in older adults of otherwise overall good health, the effects of aging causes a temporal delay in healing, but no major impairment with regard to the quality of healing. delayed wound healing in patients of increasing age is associated with altered inflammatory response; for example delayed t-cell infiltration of the wound with alterations in the production of chemokines, and reduced macrophage phagocytic capacity. alcohol – alcohol consumption impairs wound healing and also increases the chances of infection. alcohol affects the proliferative phase of healing. a single unit of alcohol causes a negative effect on re-epithelialization, wound closure, collagen production and angiogenesis. in the 2000s there arose the first mathematical models of the healing process, based on simplified assumptions and on a system of differential equations solved through matlab. the models show that the "rate of the healing process" appears to be "highly influenced by the activity and size of the injury itself as well as the activity of the healing agent." research and development up until about 2000, the classic paradigm of wound healing, involving stem cells 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. 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. stem cells and cellular plasticity multipotent adult stem cells have the capacity to be self-renewing and give rise to different cell types. stem cells give rise to progenitor cells, which are cells that are not self-renewing, but can generate several types of cells. the extent of stem cell involvement in cutaneous (skin) wound healing is complex and not fully understood. stem cell injection leads to wound healing primarily through stimulation of angiogenesis. it is thought that the epidermis and dermis are reconstituted by mitotically active stem cells that reside at the apex of rete ridges (basal stem cells or bsc), the bulge of hair follicles (hair follicular stem cell or hfsc), and the papillary dermis (dermal stem cells). moreover, bone marrow may also contain stem cells that play a major role in cutaneous wound healing. in rare circumstances, such as extensive cutaneous injury, self-renewal subpopulations in the bone marrow are induced to participate in the healing process, whereby they give rise to collagen-secreting cells that seem to play a role during wound repair. these two self-renewal subpopulations are (1) bone marrow-derived mesenchymal stem cells (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. moreover, it is 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. wound repair versus regeneration an injury is an interruption of morphology and/or functionality of a given tissue. after injury, structural tissue heals with incomplete or complete regeneration. tissue without an interruption to the morphology almost always completely regenerates. an example of complete regeneration without an interruption of the morphology is non-injured tissue, such as skin. non-injured skin has a continued replacement and regeneration of cells which always results in complete regeneration. there is a subtle distinction between 'repair' and 'regeneration'. repair means incomplete regeneration. repair or incomplete regeneration, refers to the physiologic adaptation of an organ after injury in an effort to re-establish continuity without regards to exact replacement of lost/damaged tissue. true tissue regeneration or complete regeneration, refers to the replacement of lost/damaged tissue with an 'exact' copy, such that both morphology and functionality are completely restored. though after injury mammals can completely regenerate spontaneously, they usually do not completely regenerate. an example of a tissue regenerating completely after an interruption of morphology is the endometrium; the endometrium after the process of breakdown via the menstruation cycle heals with complete regeneration. in some instances, after a tissue breakdown, such as in skin, a regeneration closer to complete regeneration may be induced by the use of biodegradable (collagen-glycoaminoglycan) scaffolds. these scaffolds are structurally analogous to extracellular matrix (ecm) found in normal/un-injured dermis. fundamental conditions required for tissue regeneration often oppose conditions that favor efficient wound repair, including inhibition of (1) platelet activation, (2) inflammatory response, and (3) wound contraction. 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. a new way of thinking derived from the notion that heparan sulfates are key player in tissue homeostasis: the process that makes the tissue replace dead cells by identical cells. in wound areas, tissue homeostasis is lost as the heparan sulfates are degraded preventing the replacement of dead cells by identical cells. heparan sulfate analogues cannot be degraded by all known heparanases and glycanases and bind to the free heparin sulfate binding spots on the ecm, therefore preserving the normal tissue homeostasis and preventing scarring. repair or regeneration with regards to hypoxia-inducible factor 1-alpha (hif-1a). in normal circumstances after injury hif-1a is degraded by prolyl hydroxylases (phds). scientists found that the simple up-regulation of hif-1a via phd inhibitors regenerates lost or damaged tissue in mammals that