Chronic wound

A chronic wound is a wound that does not heal in an orderly set of stages and in a predictable amount of time the way most wounds do; wounds that do not heal within three months are often considered chronic.^[1] 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.^[2]^[3] 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.^[4] 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.^[5]^[6]

Chronic wounds may never heal or may take years to do so. These wounds can cause patients severe emotional and physical stress and create a significant financial burden on patients and the whole healthcare system.^[7]

Acute and chronic wounds are at opposite ends of a spectrum of wound-healing types that progress toward being healed at different rates.^[8]

Signs and symptoms

Chronic wound patients often report pain as dominant in their lives.^[9] It is recommended that healthcare providers handle the pain related to chronic wounds as one of the main priorities in chronic wound management (together with addressing the cause). Six out of ten venous leg ulcer patients experience pain with their ulcer,^[10] and similar trends are observed for other chronic wounds.

Persistent pain (at night, at rest, and with activity) is the main problem for patients with chronic ulcers.^[11] Frustrations regarding ineffective analgesics and plans of care that they were unable to adhere to were also identified.

Cause

In addition to poor circulation, neuropathy, and difficulty moving, factors that contribute to chronic wounds include systemic illnesses, age, and repeated trauma. The genetic skin disorders collectively known as epidermolysis bullosa display skin fragility and a tendency to develop chronic, non-healing wounds.^[12] Comorbid ailments that may contribute to the formation of chronic wounds include vasculitis (an inflammation of blood vessels), immune suppression, pyoderma gangrenosum, and diseases that cause ischemia.^[2] Immune suppression can be caused by illnesses or medical drugs used over a long period, like steroids.^[2] Emotional stress can also negatively affect the healing of a wound, possibly by raising blood pressure and levels of cortisol, which lowers immunity.^[7]

What appears to be a chronic wound may also be a malignancy; for example, cancerous tissue can grow until blood cannot reach the cells and the tissue becomes an ulcer.^[13] Cancer, especially squamous cell carcinoma, may also form as the result of chronic wounds, probably due to repetitive tissue damage that stimulates rapid cell proliferation.^[13]

Another factor that may contribute to chronic wounds is old age.^[14] The skin of older people is more easily damaged, and older cells do not proliferate as fast and may not have an adequate response to stress in terms of gene upregulation of stress-related proteins.^[14] In older cells, stress response genes are overexpressed when the cell is not stressed, but when it is, the expression of these proteins is not upregulated by as much as in younger cells.^[14]

Comorbid factors that can lead to ischemia are especially likely to contribute to chronic wounds. Such factors include chronic fibrosis, edema, sickle cell disease, and peripheral artery disease such as by atherosclerosis.^[2]

Repeated physical trauma plays a role in chronic wound formation by continually initiating the inflammatory cascade. The trauma may occur by accident, for example when a leg is repeatedly bumped against a wheelchair rest, or it may be due to intentional acts. Heroin users who lose venous access may resort to 'skin popping', or injecting the drug subcutaneously, which is highly damaging to tissue and frequently leads to chronic ulcers.^[15] Children who are repeatedly seen for a wound that does not heal are sometimes found to be victims of a parent with Munchausen syndrome by proxy, a disease in which the abuser may repeatedly inflict harm on the child in order to receive attention.^[16]

Periwound skin damage caused by excessive amounts of exudate and other bodily fluids can perpetuate the non-healing status of chronic wounds. Maceration, excoriation, dry (fragile) skin, hyperkeratosis, callus and eczema are frequent problems ^[17] that interfere with the integrity of periwound skin. They can create a gateway for infection as well as cause wound edge deterioration preventing wound closure.

Pathophysiology

Chronic wounds may affect only the epidermis and dermis, or they may affect tissues all the way to the fascia.^[18] They may be formed originally by the same things that cause acute ones, such as surgery or accidental trauma, or they may form as the result of systemic infection, vascular, immune, or nerve insufficiency, or comorbidities such as neoplasias or metabolic disorders.^[18] The reason a wound becomes chronic is that the body's ability to deal with the damage is overwhelmed by factors such as repeated trauma, continued pressure, ischemia, or illness.^[8]^[18]

Though much progress has been accomplished in the study of chronic wounds lately, advances in the study of their healing have lagged behind expectations. This is partly because animal studies are difficult because animals do not get chronic wounds, since they usually have loose skin that quickly contracts, and they normally do not get old enough or have contributing diseases such as neuropathy or chronic debilitating illnesses.^[14] Nonetheless, current researchers now understand some of the major factors that lead to chronic wounds, among which are ischemia, reperfusion injury, and bacterial colonization.^[14]

Ischemia

Ischemia is an important factor in the formation and persistence of wounds, especially when it occurs repetitively (as it usually does) or when combined with a patient's old age.^[14] Ischemia causes tissue to become inflamed and cells to release factors that attract neutrophils such as interleukins, chemokines, leukotrienes, and complement factors.^[14]

While they fight pathogens, neutrophils also release inflammatory cytokines and enzymes that damage cells.^[2]^[14] One of their important jobs is to produce Reactive Oxygen Species (ROS) to kill bacteria, for which they use an enzyme called myeloperoxidase.^[14] The enzymes and ROS produced by neutrophils and other leukocytes damage cells and prevent cell proliferation and wound closure by damaging DNA, lipids, proteins,^[19] the extracellular matrix (ECM), and cytokines that speed healing.^[14] Neutrophils remain in chronic wounds for longer than they do in acute wounds, and contribute to the fact that chronic wounds have higher levels of inflammatory cytokines and ROS.^[3]^[6] Since wound fluid from chronic wounds has an excess of proteases and ROS, the fluid itself can inhibit healing by inhibiting cell growth and breaking down growth factors and proteins in the ECM. This impaired healing response is considered uncoordinated.^[20] However, soluble mediators of the immune system (growth factors), cell-based therapies and therapeutic chemicals can propagate coordinated healing.^[21]

It has been suggested that the three fundamental factors underlying chronic wound pathogenesis are cellular and systemic changes of aging, repeated bouts of ischemia-reperfusion injury, and bacterial colonization with resulting inflammatory host response.^[22]

Bacterial colonization

Since more oxygen in the wound environment allows white blood cells to produce ROS to kill bacteria, patients with inadequate tissue oxygenation, for example those who developed hypothermia during surgery, are at higher risk for infection.^[14] The host's immune response to the presence of bacteria prolongs inflammation, delays healing, and damages tissue.^[14] Infection can lead not only to chronic wounds but also to gangrene, loss of the infected limb, and death of the patient. More recently, an interplay between bacterial colonization and increases in reactive oxygen species leading to formation and production of biofilms has been shown to generate chronic wounds.^[23]

Like ischemia, bacterial colonization and infection damage tissue by causing a greater number of neutrophils to enter the wound site.^[2] In patients with chronic wounds, bacteria with resistances to antibiotics may have time to develop.^[24] In addition, patients that carry drug resistant bacterial strains such as methicillin-resistant Staphylococcus aureus (MRSA) have more chronic wounds.^[24]

Growth factors and proteolytic enzymes

Chronic wounds also differ in makeup from acute wounds in that their levels of proteolytic enzymes such as elastase.^[5] and matrix metalloproteinases (MMPs) are higher, while their concentrations of growth factors such as Platelet-derived growth factor and Keratinocyte Growth Factor are lower.^[6]^[18]

Since growth factors (GFs) are imperative in timely wound healing, inadequate GF levels may be an important factor in chronic wound formation.^[18] In chronic wounds, the formation and release of growth factors may be prevented, the factors may be sequestered and unable to perform their metabolic roles, or degraded in excess by cellular or bacterial proteases.^[18]

Chronic wounds such as diabetic and venous ulcers are also caused by a failure of fibroblasts to produce adequate ECM proteins and by keratinocytes to epithelialize the wound.^[25] Fibroblast gene expression is different in chronic wounds than in acute wounds.^[25]

Though all wounds require a certain level of elastase and proteases for proper healing, too high a concentration is damaging.^[5] Leukocytes in the wound area release elastase, which increases inflammation, destroys tissue, proteoglycans, and collagen,^[26] and damages growth factors, fibronectin, and factors that inhibit proteases.^[5] The activity of elastase is increased by human serum albumin, which is the most abundant protein found in chronic wounds.^[5] However, chronic wounds with inadequate albumin are especially unlikely to heal, so regulating the wound's levels of that protein may in the future prove helpful in healing chronic wounds.^[5]

Excess matrix metalloproteinases, which are released by leukocytes, may also cause wounds to become chronic. MMPs break down ECM molecules, growth factors, and protease inhibitors, and thus increase degradation while reducing construction, throwing the delicate compromise between production and degradation out of balance.^[6]^[27]

Diagnosis

Infection

If a chronic wound becomes more painful this is a good indication that it is infected.^[28] A lack of pain however does not mean that it is not infected.^[28] Other methods of determination are less effective.^[28]

Classification

The vast majority of chronic wounds can be classified into three categories: venous ulcers, diabetic, and pressure ulcers.^[8]^[14] A small number of wounds that do not fall into these categories may be due to causes such as radiation poisoning or ischemia.^[14]

Venous and arterial ulcers

Venous ulcers, which usually occur in the legs, account for about 70% to 90% of chronic wounds^[2] and mostly affect the elderly. They are thought to be due to venous hypertension caused by improper function of valves that exist in the veins to prevent blood from flowing backward. Ischemia results from the dysfunction and, combined with reperfusion injury, causes the tissue damage that leads to the wounds.

Diabetic ulcers

Another major cause of chronic wounds, diabetes, is increasing in prevalence.^[29] Diabetics have a 15% higher risk for amputation than the general population^[2] due to chronic ulcers. Diabetes causes neuropathy, which inhibits nociception and the perception of pain.^[2] Thus patients may not initially notice small wounds to legs and feet, and may therefore fail to prevent infection or repeated injury.^[8] Further, diabetes causes immune compromise and damage to small blood vessels, preventing adequate oxygenation of tissue, which can cause chronic wounds.^[8] Pressure also plays a role in the formation of diabetic ulcers.^[14]

Pressure ulcers

Another leading type of chronic wounds is pressure ulcers,^[30] which usually occur in people with conditions such as paralysis that inhibit movement of body parts that are commonly subjected to pressure such as the heels, shoulder blades, and sacrum.^[31]^[32] Pressure ulcers are caused by ischemia that occurs when pressure on the tissue is greater than the pressure in capillaries, and thus restricts blood flow into the area.^[30] Muscle tissue, which needs more oxygen and nutrients than skin does, shows the worst effects from prolonged pressure.^[32] As in other chronic ulcers, reperfusion injury damages tissue.

Treatment

Though treatment of the different chronic wound types varies slightly, appropriate treatment seeks to address the problems at the root of chronic wounds, including ischemia, bacterial load, and imbalance of proteases.^[14] Periwound skin issues should be assessed and their abatement included in a proposed treatment plan.^[17] Various methods exist to ameliorate these problems, including antibiotic and antibacterial use, debridement, irrigation, vacuum-assisted closure, warming, oxygenation, moist wound healing (the term pioneered by George D. Winter), removing mechanical stress, and adding cells or other materials to secrete or enhance levels of healing factors.^[29]

It is uncertain whether intravenous metronidazole is useful in reducing foul smelling from malignant wounds.^[33] There is insufficient evidence to use silver-containing dressings or topical agents for the treatment of infected or contaminated chronic wounds.^[34] For infected wounds, the following antibiotics are often used (if organisms are susceptible) as oral therapy due to their high bioavailability and good penetration into soft tissues: ciprofloxacin, clindamycin, minocycline, linezolid, moxifloxacin, and trimethoprim-sulfamethoxazole.^[35]

The challenge of any treatment is to address as many adverse factors as possible simultaneously, so each of them receives equal attention and does not continue to impede healing as the treatment progresses.^[36]^[37]

Preventing and treating infection

To lower the bacterial count in wounds, therapists may use topical antibiotics, which kill bacteria and can also help by keeping the wound environment moist,^[38]^[39] which is important for speeding the healing of chronic wounds.^[3]^[31] Some researchers have experimented with the use of tea tree oil, an antibacterial agent which also has anti-inflammatory effects.^[24] Disinfectants are contraindicated because they damage tissues and delay wound contraction.^[39] Further, they are rendered ineffective by organic matter in wounds like blood and exudate and are thus not useful in open wounds.^[39]

A greater amount of exudate and necrotic tissue in a wound increases likelihood of infection by serving as a medium for bacterial growth away from the host's defenses.^[14] Since bacteria thrive on dead tissue, wounds are often surgically debrided to remove the devitalized tissue.^[38] Debridement and drainage of wound fluid are an especially important part of the treatment for diabetic ulcers, which may create the need for amputation if infection gets out of control. Mechanical removal of bacteria and devitalized tissue is also the idea behind wound irrigation, which is accomplished using pulsed lavage.^[14]

Removing necrotic or devitalized tissue is also the aim of maggot therapy, the intentional introduction by a health care practitioner of live, disinfected maggots into non-healing wounds. Maggots dissolve only necrotic, infected tissue; disinfect the wound by killing bacteria; and stimulate wound healing. Maggot therapy has been shown to accelerate debridement of necrotic wounds and reduce the bacterial load of the wound, leading to earlier healing, reduced wound odor and less pain. The combination and interactions of these actions make maggots an extremely potent tool in chronic wound care.

Negative pressure wound therapy (NPWT) is a treatment that improves ischemic tissues and removes wound fluid used by bacteria.^[8]^[14] This therapy, also known as vacuum-assisted closure, reduces swelling in tissues, which brings more blood and nutrients to the area, as does the negative pressure itself.^[8] The treatment also decompresses tissues and alters the shape of cells, causes them to express different mRNAs and to proliferate and produce ECM molecules.^[2]^[8]

Recent technological advancements produced novel approaches such as self-adaptive wound dressings^[40] that rely on properties of smart polymers sensitive to changes in humidity levels. The dressing delivers absorption or hydration as needed over each independent wound area and aids in the natural process of autolytic debridement. It effectively removes liquefied slough and necrotic tissue, disintegrated bacterial biofilm as well as harmful exudate components, known to slow the healing process.^[41] The treatment also reduces bacterial load by effective evacuation and immobilization of microorganisms from the wound bed, and subsequent chemical binding of available water that is necessary for their replication.^[42] Self-adaptive dressings protect periwound skin from extrinsic factors and infection while regulating moisture balance over vulnerable skin around the wound.

Treating trauma and painful wounds

Persistent chronic pain associated with non-healing wounds is caused by tissue (nociceptive) or nerve (neuropathic) damage and is influenced by dressing changes and chronic inflammation. Chronic wounds take a long time to heal and patients can experience chronic wounds for many years.^[43] Chronic wound healing may be compromised by coexisting underlying conditions, such as venous valve backflow, peripheral vascular disease, uncontrolled edema and diabetes mellitus.

If wound pain is not assessed and documented it may be ignored and/or not addressed properly. It is important to remember that increased wound pain may be an indicator of wound complications that need treatment, and therefore practitioners must constantly reassess the wound as well as the associated pain.

Optimal management of wounds requires holistic assessment. Documentation of the patient's pain experience is critical and may range from the use of a patient diary, (which should be patient driven), to recording pain entirely by the healthcare professional or caregiver.^[44] Effective communication between the patient and the healthcare team is fundamental to this holistic approach. The more frequently healthcare professionals measure pain, the greater the likelihood of introducing or changing pain management practices.

At present there are few local options for the treatment of persistent pain, whilst managing the exudate levels present in many chronic wounds. Important properties of such local options are that they provide an optimal wound healing environment, while providing a constant local low dose release of ibuprofen while worn.

If local treatment does not provide adequate pain reduction, it may be necessary for patients with chronic painful wounds to be prescribed additional systemic treatment for the physical component of their pain. Clinicians should consult with their prescribing colleagues referring to the WHO pain relief ladder of systemic treatment options for guidance. For every pharmacological intervention there are possible benefits and adverse events that the prescribing clinician will need to consider in conjunction with the wound care treatment team.

Ischemia and hypoxia

Blood vessels constrict in tissue that becomes cold and dilate in warm tissue, altering blood flow to the area. Thus keeping the tissues warm is probably necessary to fight both infection and ischemia.^[31] Some healthcare professionals use 'radiant bandages' to keep the area warm, and care must be taken during surgery to prevent hypothermia, which increases rates of post-surgical infection.^[14]

Underlying ischemia may also be treated surgically by arterial revascularization, for example in diabetic ulcers, and patients with venous ulcers may undergo surgery to correct vein dysfunction.

Diabetics that are not candidates for surgery (and others) may also have their tissue oxygenation increased by Hyperbaric Oxygen Therapy, or HBOT, which may provide a short-term improvement in healing by improving the oxygenated blood supply to the wound.^[19]^[45] In addition to killing bacteria, higher oxygen content in tissues speeds growth factor production, fibroblast growth, and angiogenesis.^[2]^[19] However, increased oxygen levels also means increased production of ROS.^[19] Antioxidants, molecules that can lose an electron to free radicals without themselves becoming radicals, can lower levels of oxidants in the body and have been used with some success in wound healing.^[6]

Low level laser therapy has been repeatedly shown to significantly reduce the size and severity of diabetic ulcers as well as other pressure ulcers.

Pressure wounds are often the result of local ischemia from the increased pressure. Increased pressure also plays a roles in many diabetic foot ulcerations as changes due to the disease causes the foot to have limited joint mobility and creates pressure points on the bottom of the foot. Effective measures to treat this includes a surgical procedure called the gastrocnemius recession in which the calf muscle is lengthened to decrease the fulcrum created by this muscle and resulting in a decrease in plantar forefoot pressure.^[46]

Growth factors and hormones

Since chronic wounds underexpress growth factors necessary for healing tissue, chronic wound healing may be speeded by replacing or stimulating those factors and by preventing the excessive formation of proteases like elastase that break them down.^[5]^[6]

One way to increase growth factor concentrations in wounds is to apply the growth factors directly. This generally takes many repetitions and requires large amounts of the factors, although biomaterials are being developed that control the delivery of growth factors over time.^[47] Another way is to spread onto the wound a gel of the patient's own blood platelets, which then secrete growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor 1–2 (IGF), PDGF, transforming growth factor-β (TGF-β), and epidermal growth factor (EGF).^[18] Other treatments include implanting cultured keratinocytes into the wound to reepithelialize it and culturing and implanting fibroblasts into wounds.^[29]^[38] Some patients are treated with artificial skin substitutes that have fibroblasts and keratinocytes in a matrix of collagen to replicate skin and release growth factors.

In other cases, skin from cadavers is grafted onto wounds, providing a cover to keep out bacteria and preventing the buildup of too much granulation tissue, which can lead to excessive scarring. Though the allograft (skin transplanted from a member of the same species) is replaced by granulation tissue and is not actually incorporated into the healing wound, it encourages cellular proliferation and provides a structure for epithelial cells to crawl across.^[2] On the most difficult chronic wounds, allografts may not work, requiring skin grafts from elsewhere on the patient, which can cause pain and further stress on the patient's system.^[3]

Collagen dressings are another way to provide the matrix for cellular proliferation and migration, while also keeping the wound moist and absorbing exudate.^[6] Additionally Collagen has been shown to be chemotactic to human blood monocytes, which can enter the wound site and transform into beneficial wound-healing cells.^[48]

Since levels of protease inhibitors are lowered in chronic wounds, some researchers are seeking ways to heal tissues by replacing these inhibitors in them.^[27] Secretory leukocyte protease inhibitor (SLPI), which inhibits not only proteases but also inflammation and microorganisms like viruses, bacteria, and fungi, may prove to be an effective treatment.^[27]

Research into hormones and wound healing has shown estrogen to speed wound healing in elderly humans and in animals that have had their ovaries removed, possibly by preventing excess neutrophils from entering the wound and releasing elastase.^[26] Thus the use of estrogen is a future possibility for treating chronic wounds.

Epidemiology

Chronic wounds mostly affect people over the age of 60.^[14] The incidence is 0.78% of the population and the prevalence ranges from 0.18 to 0.32%.^[18] As the population ages, the number of chronic wounds is expected to rise.^[30] Ulcers that heal within 12 weeks are usually classified as acute, and longer-lasting ones as chronic.

References

^ Mustoe T (March 17–18, 2005). "Dermal ulcer healing: Advances in understanding" (PDF). Tissue repair and ulcer/wound healing: molecular mechanisms, therapeutic targets and future directions. Paris, France: EUROCONFERENCES. Archived from the original (PDF) on October 27, 2005.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l Snyder RJ (2005). "Treatment of nonhealing ulcers with allografts". Clinics in Dermatology. 23 (4): 388–95. doi:10.1016/j.clindermatol.2004.07.020. PMID 16023934.
^ ^a ^b ^c ^d Taylor JE, Laity PR, Hicks J, Wong SS, Norris K, Khunkamchoo P, et al. (October 2005). "Extent of iron pick-up in deforoxamine-coupled polyurethane materials for therapy of chronic wounds". Biomaterials. 26 (30): 6024–33. doi:10.1016/j.biomaterials.2005.03.015. PMID 15885771.
^ Gist S, Tio-Matos I, Falzgraf S, Cameron S, Beebe M (June 2009). "Wound care in the geriatric client". Clinical Interventions in Aging. 4: 269–87. doi:10.2147/CIA.S4726. PMC 2697592. PMID 19554098.
^ ^a ^b ^c ^d ^e ^f ^g Edwards JV, Howley P, Cohen IK (October 2004). "In vitro inhibition of human neutrophil elastase by oleic acid albumin formulations from derivatized cotton wound dressings". International Journal of Pharmaceutics. 284 (1–2): 1–12. doi:10.1016/j.ijpharm.2004.06.003. PMID 15454291.^{[permanent dead link‍]}
^ ^a ^b ^c ^d ^e ^f ^g Schönfelder U, Abel M, Wiegand C, Klemm D, Elsner P, Hipler UC (November 2005). "Influence of selected wound dressings on PMN elastase in chronic wound fluid and their antioxidative potential in vitro". Biomaterials. 26 (33): 6664–73. doi:10.1016/j.biomaterials.2005.04.030. PMID 15978664.
^ ^a ^b Augustin M, Maier K (2003). "Psychosomatic aspects of chronic wounds". Dermatology and Psychosomatics/Dermatologie und Psychosomatik. 4 (1): 5–13. doi:10.1159/000070529. S2CID 72066898.
^ ^a ^b ^c ^d ^e ^f ^g ^h Moreo K (2005). "Understanding and overcoming the challenges of effective case management for patients with chronic wounds". The Case Manager. 16 (2): 62–3, 67. doi:10.1016/j.casemgr.2005.01.014. PMID 15818347.
^ Krasner D (May 1998). "Painful venous ulcers: themes and stories about living with the pain and suffering". Journal of Wound, Ostomy, and Continence Nursing. 25 (3): 158–68. doi:10.1097/00152192-199805000-00008. PMID 9678007.
^ Hofman D, Ryan TJ, Arnold F, Cherry GW, Lindholm C, Bjellerup M, Glynn C (May 1997). "Pain in venous leg ulcers". Journal of Wound Care. 6 (5): 222–4. doi:10.12968/jowc.1997.6.5.222. PMID 9256727.
^ Walshe C (December 1995). "Living with a venous leg ulcer: a descriptive study of patients' experiences". Journal of Advanced Nursing. 22 (6): 1092–100. doi:10.1111/j.1365-2648.1995.tb03110.x. PMID 8675863.
^ Bardhan, Ajoy; Bruckner-Tuderman, Leena; Chapple, Iain L. C.; Fine, Jo-David; Harper, Natasha; Has, Cristina; Magin, Thomas M.; Marinkovich, M. Peter; Marshall, John F.; McGrath, John A.; Mellerio, Jemima E. (2020-09-24). "Epidermolysis bullosa". Nature Reviews Disease Primers. 6 (1): 78. doi:10.1038/s41572-020-0210-0. ISSN 2056-676X. PMID 32973163. S2CID 221861310.
^ ^a ^b Trent, JT. 2003. Wounds and malignancy. Archived 2016-01-13 at the Wayback Machine Advances in Skin & Wound Care. Accessed January 1, 2007.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u Mustoe T (May 2004). "Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy". American Journal of Surgery. 187 (5A): 65S–70S. doi:10.1016/S0002-9610(03)00306-4. PMID 15147994.
^ Williams AM, Southern SJ (October 2005). "Conflicts in the treatment of chronic ulcers in drug addicts--case series and discussion". British Journal of Plastic Surgery. 58 (7): 997–9. doi:10.1016/j.bjps.2005.04.024. PMID 16040018.
^ Vennemann B, Perdekamp MG, Weinmann W, Faller-Marquardt M, Pollak S, Brandis M (May 2006). "A case of Munchausen syndrome by proxy with subsequent suicide of the mother". Forensic Science International. 158 (2–3): 195–9. doi:10.1016/j.forsciint.2005.07.014. PMID 16169176.
^ ^a ^b Dowsett C, Gronemann MN, Harding K (2015). "Taking wound assessment beyond the edge". Wounds International. 6 (1). Archived from the original on 2018-05-04. Retrieved 2017-03-31.
^ ^a ^b ^c ^d ^e ^f ^g ^h Crovetti G, Martinelli G, Issi M, Barone M, Guizzardi M, Campanati B, et al. (April 2004). "Platelet gel for healing cutaneous chronic wounds". Transfusion and Apheresis Science. 30 (2): 145–51. doi:10.1016/j.transci.2004.01.004. PMID 15062754.
^ ^a ^b ^c ^d Alleva R, Nasole E, Di Donato F, Borghi B, Neuzil J, Tomasetti M (July 2005). "alpha-Lipoic acid supplementation inhibits oxidative damage, accelerating chronic wound healing in patients undergoing hyperbaric oxygen therapy". Biochemical and Biophysical Research Communications. 333 (2): 404–10. doi:10.1016/j.bbrc.2005.05.119. PMC 2136431. PMID 15950945.
^ Krishnaswamy VR, Manikandan M, Munirajan AK, Vijayaraghavan D, Korrapati PS (December 2014). "Expression and integrity of dermatopontin in chronic cutaneous wounds: a crucial factor in impaired wound healing". Cell and Tissue Research. 358 (3): 833–41. doi:10.1007/s00441-014-2000-z. PMID 25260909. S2CID 16355532.
^ Lasagni L, Sagrinati C, Ronconi E, Angelotti ML, Parente E, Ballerini L, et al. (2010). "Novel strategies of regenerative medicine using chemical compounds". Current Medicinal Chemistry. 17 (34): 4134–49. doi:10.2174/092986710793348590. PMID 20939819.
^ Mustoe T (May 2004). "Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy". American Journal of Surgery (review). 187 (5A): 65S–70S. doi:10.1016/S0002-9610(03)00306-4. PMID 15147994.
^ Dhall S, Do D, Garcia M, Wijesinghe DS, Brandon A, Kim J, et al. (2014). "A novel model of chronic wounds: importance of redox imbalance and biofilm-forming bacteria for establishment of chronicity". PLOS ONE. 9 (10): e109848. Bibcode:2014PLoSO...9j9848D. doi:10.1371/journal.pone.0109848. PMC 4196950. PMID 25313558.
^ ^a ^b ^c Halcón L, Milkus K (November 2004). "Staphylococcus aureus and wounds: a review of tea tree oil as a promising antimicrobial". American Journal of Infection Control. 32 (7): 402–8. doi:10.1016/j.ajic.2003.12.008. PMID 15525915.
^ ^a ^b Foy Y, Li J, Kirsner R, Eaglstein W (2004). "Analysis of fibroblast defects in extracellular matrix production in chronic wounds". Journal of the American Academy of Dermatology. 50 (3): P168. doi:10.1016/j.jaad.2003.10.595.
^ ^a ^b Kanda N, Watanabe S (April 2005). "Regulatory roles of sex hormones in cutaneous biology and immunology". Journal of Dermatological Science. 38 (1): 1–7. doi:10.1016/j.jdermsci.2004.10.011. PMID 15795118.
^ ^a ^b ^c Lai JY, Borson ND, Strausbauch MA, Pittelkow MR (April 2004). "Mitosis increases levels of secretory leukocyte protease inhibitor in keratinocytes". Biochemical and Biophysical Research Communications. 316 (2): 407–10. doi:10.1016/j.bbrc.2004.02.065. PMID 15020232.
^ ^a ^b ^c Reddy M, Gill SS, Wu W, Kalkar SR, Rochon PA (February 2012). "Does this patient have an infection of a chronic wound?". JAMA. 307 (6): 605–11. doi:10.1001/jama.2012.98. PMID 22318282.
^ ^a ^b ^c Velander PE, Theopold C, Gheerardyn R, Bleiziffer O, Yao F, Eriksson E (2004). "Autologous cultured keratinocytes suspensions accelerate re-epithelialization in the diabetic pig". Journal of the American College of Surgeons. 199 (3): 58. doi:10.1016/j.jamcollsurg.2004.05.119.
^ ^a ^b ^c Supp DM, Boyce ST (2005). "Engineered skin substitutes: practices and potentials". Clinics in Dermatology. 23 (4): 403–12. doi:10.1016/j.clindermatol.2004.07.023. PMID 16023936.
^ ^a ^b ^c Thomas DR, Diebold MR, Eggemeyer LM (2005). "A controlled, randomized, comparative study of a radiant heat bandage on the healing of stage 3-4 pressure ulcers: a pilot study". Journal of the American Medical Directors Association. 6 (1): 46–9. doi:10.1016/j.jamda.2004.12.007. PMID 15871870.
^ ^a ^b Pressure ulcers: Surgical treatment and principles at eMedicine
^ Ramasubbu DA, Smith V, Hayden F, Cronin P, et al. (Cochrane Wounds Group) (August 2017). "Systemic antibiotics for treating malignant wounds". The Cochrane Database of Systematic Reviews. 2017 (8): CD011609. doi:10.1002/14651858.CD011609.pub2. PMC 6483739. PMID 28837757.
^ Vermeulen, Hester; van Hattem, Jarne M; Storm-Versloot, Marja N; Ubbink, Dirk T; Westerbos, Stijn Joël (2007-01-24). Cochrane Wounds Group (ed.). "Topical silver for treating infected wounds". Cochrane Database of Systematic Reviews (1): CD005486. doi:10.1002/14651858.CD005486.pub2. PMID 17253557.
^ "Anti-infective management of infected skin ulcers" (PDF). Infezioni in Medicina. 32 (2). 2024-06-01. doi:10.53854/liim-3202-3. PMC 11142418. PMID 38827836.
^ Jones V, Grey JE, Harding KG (April 2006). "Wound dressings". BMJ. 332 (7544): 777–80. doi:10.1136/bmj.332.7544.777. PMC 1420733. PMID 16575081.
^ Cutting K (May 2010). "Wound dressings: 21st century performance requirements". Journal of Wound Care. 19(Sup 1): 4–9. doi:10.12968/jowc.2010.19.Sup1.48258.
^ ^a ^b ^c Brem H, Kirsner RS, Falanga V (July 2004). "Protocol for the successful treatment of venous ulcers". American Journal of Surgery. 188 (1A Suppl): 1–8. doi:10.1016/S0002-9610(03)00284-8. PMID 15223495.
^ ^a ^b ^c Patel CV, Powell L, Wilson SE (2000). "Surgical wound infections". Current Treatment Options in Infectious Diseases. 2: 147–53. ISSN 1523-3820.
^ Wolcott R, Fischenich RN (April 2014). "Ultimate Standardization of First-Line Wound Dressings to a Single Type". Today's Wound Clinic. 8 (3).
^ Reyzelman AM, Vartivarian M (August 2015). "Evidence of Intensive Autolytic Debridement With a Self-Adaptive Wound Dressing". Wounds. 27 (8): 229–35. PMID 26284377.
^ Newman GR, Walker M, Hobot JA, Bowler PG (March 2006). "Visualisation of bacterial sequestration and bactericidal activity within hydrating Hydrofiber wound dressings". Biomaterials. 27 (7): 1129–39. doi:10.1016/j.biomaterials.2005.07.046. PMID 16120458.
^ Flanagan M, Vogensen H, and Haase L. 2006. Case series investigating the experience of pain in patients with chronic venous leg ulcers treated with a foam dressing releasing ibuprofen. World Wide Wounds. 2006
^ Osterbrink J (2003). "Der Deutsche Schmerzstandard und seine Auswirkungen auf die Pflege". Die Schwester, der Pfleger. 42: 758–64.
^ Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE, Weibel S (June 2015). "Hyperbaric oxygen therapy for chronic wounds" (PDF). The Cochrane Database of Systematic Reviews. 2015 (6): CD004123. doi:10.1002/14651858.CD004123.pub4. PMC 7055586. PMID 26106870.
^ Greenhagen RM, Johnson AR, Peterson MC, Rogers LC, Bevilacqua NJ (2010). "Gastrocnemius recession as an alternative to tendoAchillis lengthening for relief of forefoot pressure in a patient with peripheral neuropathy: a case report and description of a technical modification". The Journal of Foot and Ankle Surgery. 49 (2): 159.e9–13. doi:10.1053/j.jfas.2009.07.002. PMID 20137982.
^ Pop MA, Almquist BD (September 2017). "Biomaterials: A potential pathway to healing chronic wounds?". Experimental Dermatology. 26 (9): 760–763. doi:10.1111/exd.13290. PMC 5500184. PMID 28094868.
^ Postlethwaite AE, Kang AH (June 1976). "Collagen-and collagen peptide-induced chemotaxis of human blood monocytes". The Journal of Experimental Medicine. 143 (6): 1299–307. doi:10.1084/jem.143.6.1299. PMC 2190221. PMID 1271012.