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] 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.[4][5]

Chronic wounds may never heal or may take years to do so. These wounds cause patients severe emotional and physical stress and create a significant financial burden on patients and the whole healthcare system.[6]

Acute and chronic wounds are at opposite ends of a spectrum of wound healing types that progress toward being healed at different rates.[7]

Signs and symptoms

Chronic wound patients often report pain as dominant in their lives.[8] 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,[9] 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.[10] 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. 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, for example 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.[6]

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.[11] 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.[11]

Another factor that may contribute to chronic wounds is old age.[12] 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.[12] 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.[12]

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.[13] 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.[14]

Pathophysiology

Chronic wounds may affect only the epidermis and dermis, or they may affect tissues all the way to the fascia.[15] 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.[15] 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.[7][15]

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.[12] Nonetheless, current researchers now understand some of the major factors that lead to chronic wounds, among which are ischemia, reperfusion injury, and bacterial colonization.[12]

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.[12] Ischemia causes tissue to become inflamed and cells to release factors that attract neutrophils such as interleukins, chemokines, leukotrienes, and complement factors.[12]

While they fight pathogens, neutrophils also release inflammatory cytokines and enzymes that damage cells.[2][12] One of their important jobs is to produce Reactive Oxygen Species (ROS) to kill bacteria, for which they use an enzyme called myeloperoxidase.[12] The enzymes and ROS produced by neutrophils and other leukocytes damage cells and prevent cell proliferation and wound closure by damaging DNA, lipids, proteins,[16] the extracellular matrix (ECM), and cytokines that speed healing.[12] 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][5] 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.[17] However, soluble mediators of the immune system (growth factors), cell-based therapies and therapeutic chemicals can propagate coordinated healing.[18]

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.[19]

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 suffered hypothermia during surgery, are at higher risk for infection.[12] The host’s immune response to the presence of bacteria prolongs inflammation, delays healing, and damages tissue.[12] 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 the generate chronic wounds.[20]

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.[21] In addition, patients that carry drug resistant bacterial strains such as methicillin-resistant Staphylococcus aureus (MRSA) have more chronic wounds.[21]

Growth factors and proteolytic enzymes

Chronic wounds also differ in makeup from acute wounds in that their levels of proteolytic enzymes such as elastase.[4] and matrix metalloproteinases (MMPs) are higher, while their concentrations of growth factors such as Platelet-derived growth factor and Keratinocyte Growth Factor are lower.[5][15]

Since growth factors (GFs) are imperative in timely wound healing, inadequate GF levels may be an important factor in chronic wound formation.[15] 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.[15]

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.[22] Fibroblast gene expression is different in chronic wounds than in acute wounds.[22]

Though all wounds require a certain level of elastase and proteases for proper healing, too high a concentration is damaging.[4] Leukocytes in the wound area release elastase, which increases inflammation, destroys tissue, proteoglycans, and collagen,[23] and damages growth factors, fibronectin, and factors that inhibit proteases.[4] The activity of elastase is increased by human serum albumin, which is the most abundant protein found in chronic wounds.[4] 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.[4]

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.[5][24]

Diagnosis

Infection

If a chronic wound becomes more painful this is a good indication that it is infected.[25] A lack of pain however does not mean that it is not infected.[25] Other methods of determination are less effective.[25]

Classification

The vast majority of chronic wounds can be classified into three categories: venous ulcers, diabetic, and pressure ulcers.[7][12] A small number of wounds that do not fall into these categories may be due to causes such as radiation poisoning or ischemia.[12]

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

Main article: Diabetic foot ulcer

Another major cause of chronic wounds, diabetes, is increasing in prevalence.[26] 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.[7] Further, diabetes causes immune compromise and damage to small blood vessels, preventing adequate oxygenation of tissue, which can cause chronic wounds.[7] Pressure also plays a role in the formation of diabetic ulcers.[12]

Pressure ulcers

Another leading type of chronic wounds is pressure ulcers,[27] 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.[28][29] 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.[27] Muscle tissue, which needs more oxygen and nutrients than skin does, shows the worst effects from prolonged pressure.[29] 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.[12] Various methods exist to ameliorate these problems, including antibiotic and antibacterial use, debridement, irrigation, vacuum-assisted closure, warming, oxygenation, moist wound healing, removing mechanical stress, and adding cells or other materials to secrete or enhance levels of healing factors.[26]

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,[30][31] which is important for speeding the healing of chronic wounds.[3][28] Some researchers have experimented with the use of tea tree oil, an antibacterial agent which also has anti-inflammatory effects.[21] Disinfectants are contraindicated because they damage tissues and delay wound contraction.[31] Further, they are rendered ineffective by organic matter in wounds like blood and exudate and are thus not useful in open wounds.[31]

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.[12] Since bacteria thrive on dead tissue, wounds are often surgically debrided to remove the devitalized tissue.[30] 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.[12]

Removing necrotic or devitalzed 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.[7][12] 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.[7] 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][7]

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 suffer from chronic wounds for many years.[32] 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.[33] 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 during weartime.

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.[28] 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.[12]

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 can compensate for limitations of blood supply and correct hypoxia.[16][34][35] In addition to killing bacteria, higher oxygen content in tissues speeds growth factor production, fibroblast growth, and angiogenesis.[2][16] However, increased oxygen levels also means increased production of ROS.[16] 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.[5]

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 suffer 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.[36]

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.[4][5]

One way to increase growth factor concentrations in wounds is to apply the growth factors directly, though this takes many repetitions and requires large amounts of the factors.[5] 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).[15] Other treatments include implanting cultured keratinocytes into the wound to reepithelialize it and culturing and implanting fibroblasts into wounds.[26][30] 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.[5] 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.[37]

Since levels of protease inhibitors are lowered in chronic wounds, some researchers are seeking ways to heal tissues by replacing these inhibitors in them.[24] 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.[24]

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.[23] Thus the use of estrogen is a future possibility for treating chronic wounds.

Epidemiology/Other

Chronic wounds mostly affect people over the age of 60.[12] The incidence is 0.78% of the population and the prevalence ranges from 0.18 to 0.32%.[15] As the population ages, the number of chronic wounds is expected to rise.[27]Ulcers that heal within 12 weeks are usually classified as acute, and longer-lasting ones as chronic.

References

  1. ↑ 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.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 Snyder, Robert J. (2005). "Treatment of nonhealing ulcers with allografts". Clinics in Dermatology. 23 (4): 388–95. doi:10.1016/j.clindermatol.2004.07.020. PMID 16023934.
  3. 1 2 3 4 Taylor, Jennifer E.; Laity, Peter R.; Hicks, John; Wong, Steven S.; Norris, Keith; Khunkamchoo, Peck; Johnson, Anthony F.; Cameron, Ruth E. (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.
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  13. ↑ Williams, A.M.; Southern, S.J. (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.
  14. ↑ Vennemann, B.; Perdekamp, M. Große; Weinmann, W.; Faller-Marquardt, M.; Pollak, S.; Brandis, M. (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.
  15. 1 2 3 4 5 6 7 8 Crovetti, Giovanni; Martinelli, Giovanna; Issi, Marwan; Barone, Marilde; Guizzardi, Marco; Campanati, Barbara; Moroni, Marco; Carabelli, Angelo (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.
  16. 1 2 3 4 Alleva, Renata; Nasole, Emanuele; Donato, Ferruccio Di; Borghi, Battista; Neuzil, Jiri; Tomasetti, Marco (2005). "Α-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. PMID 15950945.
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  18. ↑ Lasagni L, Sagrinati C, Ronconi E, Angelotti ML, Parente E, Ballerini L, Peired A, Romagnani P (2010). "Novel strategies of regenerative medicine using chemical compounds". Curr. Med. Chem. 17 (34): 4134–49. doi:10.2174/092986710793348590. PMID 20939819.
  19. ↑ 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.
  20. ↑ Dhall, S (2014). "A Novel Model of Chronic Wounds: Importance of Redox Imbalance and Biofilm-Forming Bacteria for Establishment of Chronicity". PLOS ONE. 9 (10): 1–17. doi:10.1371/journal.pone.0109848. PMC 4196950Freely accessible. PMID 25313558.
  21. 1 2 3 Halcon, L; Milkus, K (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.
  22. 1 2 Foy, Yvonne; Li, Jie; Kirsner, Robert; Eaglstein, William (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.
  23. 1 2 Kanda, Naoko; Watanabe, Shinichi (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.
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  26. 1 2 3 Velander, Patrik E.; Theopold, Christoph; Gheerardyn, Raphael; Bleiziffer, Oliver; Yao, Feng; Eriksson, Elof (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.
  27. 1 2 3 Supp, Dorothy M.; Boyce, Steven T. (2005). "Engineered skin substitutes: Practices and potentials". Clinics in Dermatology. 23 (4): 403–12. doi:10.1016/j.clindermatol.2004.07.023. PMID 16023936.
  28. 1 2 3 Thomas, David R.; Diebold, Marilyn R.; Eggemeyer, Linda M. (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.
  29. 1 2 Pressure ulcers: Surgical treatment and principles at eMedicine
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  31. 1 2 3 Patel CV, Powell L, Wilson SE (2000). "Surgical wound infections". Current Treatment Options in Infectious Diseases. 2: 147–53. ISSN 1523-3820.
  32. ↑ 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
  33. ↑ Osterbrink J (2003). "Der Deutsche Schmerzstandard und seine Auswirkungen auf die Pflege". Die Schwester, der Pfleger. 42: 758–64.
  34. ↑ Kranke, Peter; Bennett, Michael H; Debus, Sebastian E; Roeckl-Wiedmann, Irmgard; Schnabel, Alexander (2004). Kranke, Peter, ed. "Cochrane Database of Systematic Reviews". Cochrane Database Syst. Rev. (2): CD004123. doi:10.1002/14651858.CD004123.pub2. PMID 15106239. |chapter= ignored (help)
  35. ↑ Zamboni WA, Wong HP, Stephenson LL, Pfeifer MA (September 1997). "Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study". Undersea Hyperb. Med. 24 (3): 175–9. PMID 9308140. Retrieved 2008-05-16.
  36. ↑ Greenhagen, Robert M.; Johnson, Adam R.; Peterson, Matthew C.; Rogers, Lee C.; Bevilacqua, Nicholas J. (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". Journal of Foot and Ankle Surgery. 49 (2): 159.e9–13. doi:10.1053/j.jfas.2009.07.002. PMID 20137982.
  37. ↑ Postlethwaite, A. E.; Kang, AH (1976). "Collagen-and collagen peptide-induced chemotaxis of human blood monocytes". Journal of Experimental Medicine. 143 (6): 1299–307. doi:10.1084/jem.143.6.1299. PMC 2190221Freely accessible. PMID 1271012.

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