have a repair response; and the continued down-regulation of hif-1a results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. the act of regulating hif-1a can either turn off, or turn on the key process of mammalian regeneration. scarless wound healing scarless wound healing is a concept based on the healing or repair of the skin (or other tissue/organs) after injury with the aim of healing with subjectively and relatively less scar tissue than normally expected. scarless healing is sometimes mixed up with the concept of scar free healing, which is wound healing 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; however, this is generally not the case in the modern western society, in which many patients are turning to plastic surgery clinics with unrealistic expectations. depending on scar type, treatment may be invasive (intralesional steroid injections, surgery) and/or conservative (compression therapy, topical silicone gel, brachytherapy, photodynamic therapy). clinical judgment is necessary to successfully balance the potential benefits of the various treatments available against the likelihood of a poor response and possible complications resulting from these treatments. many of these treatments may only have a placebo effect, and the evidence base for the use of many current treatments is poor. since the 1960s, comprehension of the basic biologic processes involved in wound repair and tissue regeneration have expanded due to advances in cellular and molecular biology. currently, the principal goals in wound management are to achieve rapid wound closure with a functional tissue that has minimal aesthetic scarring. however, the ultimate goal of wound healing biology is to induce a more perfect reconstruction of the wound area. scarless wound healing only occurs in mammalian foetal tissues and complete regeneration is limited to lower vertebrates, such as salamanders, and invertebrates. in adult humans, injured tissue are repaired by collagen deposition, collagen remodelling and eventual scar formation, where fetal wound healing is believed to be more of a regenerative process with minimal or no scar formation. therefore, foetal wound healing can be used to provide an accessible mammalian model of an optimal healing response in adult human tissues. clues as to how this might be achieved come from studies of wound healing in embryos, where repair is fast and efficient and results in essentially perfect regeneration of any lost tissue. the etymology of the term scarless wound healing has a long history. in print the antiquated concept of scarless healing was brought up the early 20th century and appeared in a paper published in the london lancet. this process involved cutting in a surgical slant, instead of a right angle...; it was described in various newspapers. cancer after inflammation, restoration of normal tissue integrity and function is preserved by feedback interactions between diverse cell types mediated by adhesion molecules and secreted cytokines. disruption of normal feedback mechanisms in cancer threatens tissue integrity and enables a malignant tumor to escape the immune system. an example of the importance of the wound healing response within tumors is illustrated in work by howard chang and colleagues at stanford university studying breast cancers. oral collagen supplements preliminary results are promising for the short and long-term use of oral collagen supplements for wound healing and skin aging. oral collagen supplements also increase skin elasticity, hydration, and dermal collagen density. collagen supplementation is generally safe with no reported adverse events. further studies are needed to elucidate medical use in skin barrier diseases such as atopic dermatitis and to determine optimal dosing regimens. wound dressings modern wound dressing to aid in wound repair have undergone considerable research and development in recent years. scientists aim to develop wound dressings which have the following characteristics: provide wound protection remove excess exudate antimicrobial properties maintain a humid environment have high permeability to oxygen easily removed from a wound site non-anaphylactic characteristics cotton gauze dressings have been the standard of care, despite their dry properties that can adhere to wound surfaces and cause discomfort upon removal. recent research has set out to improve cotton gauze dressings to bring them closer in line to achieve modern wound dressing properties, by coating cotton gauze wound dressing with a chitosan/ag/zno nanocomposite. these updated dressing provide increase water absorbency and improved antibacterial efficacy. wound cleansing dirt or dust on the surface of the wound, bacteria, tissue that has died, and fluid from the wound may be cleaned. the evidence supporting the most effective technique is not clear and there is insufficient evidence to conclude whether cleaning wounds is beneficial for promoting healing or whether wound cleaning solutions (polyhexamethylene biguanide, aqueous oxygen peroxide, etc.) are better than sterile water or saline solutions to help venous leg ulcers heal. it is uncertain whether the choice of cleaning solution or method of application makes any difference to venous leg ulcer healing. simulating wound healing from a growth perspective considerable effort has been devoted to understanding the physical relationships governing wound healing and subsequent scarring, with mathematical models and simulations developed to elucidate these relationships. the growth of tissue around the wound site is a result of the migration of cells and collagen deposition by these cells. the alignment of collagen describes the degree of scarring; basket-weave orientation of collagen is characteristic of normal skin, whereas aligned collagen fibers lead to significant scarring. it has been shown that the growth of tissue and extent of scar formation can be controlled by modulating the stress at a wound site. the growth of tissue can be simulated using the aforementioned relationships from a biochemical and biomechanical point of view. the biologically active chemicals that play an important role in wound healing are modeled with fickian diffusion to generate concentration profiles. the balance equation for open systems when modeling wound healing incorporates mass growth due to cell migration and proliferation. here the following equation is used: dtρ0 = div (r) + r0, where ρ represents mass density, r represents a mass flux (from cell migration), and r0 represents a mass source (from cell proliferation, division, or enlargement). relationships like these can be incorporated into an agent-based models, where the sensitivity to single parameters such as initial collagen alignment, cytokine properties, and cell proliferation rates can be tested. wound closure intentions successful wound healing is dependent on various cell types, molecular mediators and structural elements. primary intention primary intention is the healing of a clean wound without tissue loss. in this process, wound edges are brought together, so that they are adjacent to each other (re-approximated). wound closure is performed with sutures (stitches), staples, or adhesive tape or glue. primary intention can only be implemented when the wound is precise and there is minimal disruption to the local tissue and the epithelial basement membrane, e.g. surgical incisions. this process is faster than healing by secondary intention. there is also less scarring associated with primary intention, as there are no large tissue losses to be filled with granulation tissue, though some granulation tissue will form. examples of primary intention include: well-repaired lacerations, well reduced bone fractures, healing after flap surgery. early removal of dressings from clean or clean-contaminated wounds does affect primary healing of wounds. secondary intention secondary intention is implemented when primary intention is not possible because of significant tissue damage or loss, usually due to the wound having been created by major trauma. the wound is allowed to granulate. surgeon may pack the wound with a gauze or use a drainage system. granulation results in a broader scar. healing process can be slow due to presence of drainage from infection. wound care must be performed daily to encourage wound debris removal to allow for granulation tissue formation. using antibiotics or antiseptics for the surgical wound healing by secondary intention is controversial. examples: gingivectomy, gingivoplasty, tooth extraction sockets, poorly reduced fractures, burns, severe lacerations, pressure ulcers. there is insufficient evidence that the choice of dressings or topical agents affects the secondary healing of wounds. there is lack of evidence for the effectiveness of negative pressure wound therapy in wound healing by secondary intention. tertiary intention (delayed primary closure): the wound is initially cleaned, debrided and observed, typically 4 or 5 days before closure. the wound is purposely left open. examples: healing of wounds by use of tissue grafts. if the wound edges are not reapproximated immediately, delayed primary wound healing transpires. this type of healing may be desired in the case of contaminated wounds. by the fourth day, phagocytosis of contaminated tissues is well underway, and the processes of epithelization, collagen deposition, and maturation are occurring. foreign materials are walled off by macrophages that may metamorphose into epithelioid cells, which are encircled by mononuclear leukocytes, forming granulomas. usually the wound is closed surgically at this juncture, and if the "cleansing" of the wound is incomplete, chronic inflammation can ensue, resulting in prominent scarring. overview of involved growth factors following are the main growth factors involved in wound healing: growth factorabbreviationmain originseffects epidermal growth factor egf activated macrophages salivary glands keratinocytes keratinocyte and fibroblast mitogen keratinocyte migration granulation tissue formation transforming growth factor-α tgf-α activated macrophages t-lymphocytes keratinocytes hepatocyte and epithelial cell proliferation expression of antimicrobial peptides expression of chemotactic cytokines hepatocyte growth factor hgf mesenchymal cells epithelial and endothelial cell proliferation hepatocyte motility vascular endothelial growth factor vegf mesenchymal cells vascular permeability endothelial cell proliferation platelet derived growth factor pdgf platelets macrophages endothelial cells smooth muscle cells keratinocytes granulocyte, macrophage, fibroblast and smooth muscle cell chemotaxis granulocyte, macrophage and fibroblast activation fibroblast, endothelial cell and smooth muscle cell proliferation matrix metalloproteinase, fibronectin and hyaluronan production angiogenesis wound remodeling integrin expression regulation fibroblast growth factor 1 and 2 fgf-1, −2 macrophages mast cells t-lymphocytes endothelial cells fibroblasts fibroblast chemotaxis fibroblast and keratinocyte proliferation keratinocyte migration angiogenesis wound contraction matrix (collagen fibers) deposition transforming growth factor-β tgf-β platelets t-lymphocytes macrophages endothelial cells keratinocytes smooth muscle cells fibroblasts granulocyte, macrophage, lymphocyte, fibroblast and smooth muscle cell chemotaxis timp synthesis angiogenesis fibroplasia matrix metalloproteinase production inhibition keratinocyte proliferation keratinocyte growth factor kgf keratinocytes keratinocyte migration, proliferation and differentiation unless else specified in boxes, then reference is: complications of wound healing the major complications are many: deficient scar formation: results in wound dehiscence or rupture of the wound due to inadequate formation of granulation tissue. excessive scar formation: hypertrophic scar, keloid, desmoid. exuberant granulation (proud flesh). deficient contraction (in skin grafts) or excessive contraction (in burns). others: dystrophic calcification, pigmentary changes, painful scars, incisional hernia other complications can include infection and marjolin's ulcer. biologics, skin substitutes, biomembranes and scaffolds advancements in the clinical understanding of wounds and their pathophysiology have commanded significant biomedical innovations in the treatment of acute, chronic, and other types of wounds. many biologics, skin substitutes, biomembranes and scaffolds have been developed to facilitate wound healing through various mechanisms. 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.