Issue: Volume 55 - Issue 3 - March, 2009
Abstract
The first wound and wound treatments were described five millennia ago. Since then, various principles of wound care have been passed on from generation to generation. In contrast to large numbers of general technological inventions over the last 100 years, progress beyond ancient wound care practices is a recent phenomenon.
It is essential to know the historical aspects of wound treatment (both successes and failures) in order to continue this progress and provide future direction. A survey of the literature shows that concepts such as “laudable pus” persisted for hundreds of years and that lasting discoveries and meaningful progress did not occur until grand-scale manufacturing and marketing started. Landmarks such as understanding the principles of asepsis/antisepsis, fundamental cellular research findings, knowledge about antibiotics/antimicrobials, moist wound healing, and the chemical and physical processes of wound healing have provided the foundation to guide major developments in wound management, including available evidence-based guidelines. Although research regarding interaction of basic wound management principles remains limited, the combined efforts of global research and clinical groups predict a bright future for improved wound management.
An Ancient Background
Knowledge of the biology of wounds and wound healing, together with inventions and innovations of new wound care products, has proliferated throughout time. The earliest civilizations of Mesopotamia, Arabia, Egypt, and Greece left fascinating records of their medical practice — ie, the clay tablets, Sanskrit documents (2000 BC), Smith papyrus (1650 BC), Eber’s papyrus (1550 BC) and Homer’s writings (800 BC) (see Figure 1). Medical practices of those eras were founded predominantly on empirical beliefs and magic; physicians made decisions based on observation, judgment, and experience. However, wound management during the early Egyptian civilization resembles current approaches. Treatments consisted primarily of wound closure through suturing or open wound therapy in diseased wounds with debridement followed by (though probably not intentionally) antibacterial therapies.1 Ulcerating lesions were bound with figs containing papain.2 Only recently have these agents been found to remove the fibrous slough present on wounds. Wine, vinegar, and hot water were used to cleanse the wounds. After cleansing, dry powders consisting of a mixture of metals (mercury, zinc, silver, and copper) were used to prevent inflammation1 (see Table 1). Copper was found on the island of Cyprus in great amounts and because of its bright blue color, it was used to “paint” ugly wounds.1,3 Interestingly, the reaction of copper with wine and vinegar results in the formation of a strong antibacterial compound (copper acetate).4 Silver was used as an ingredient in plasters to cover open wounds, as well as to purify the drinking water of monarchs of ancient dynasties.5Strips of linen soaked in grease, honey, oil, and lint were used to cover the wound surface.1 A literature review by Aldini et al6notes that it is now known that using lint to pack and fill the wound space might create an oxygen-poor environment that could stimulate angiogenesis; combining the aforementioned products not only prevented the linen from sticking to the wound base (ie, creating a nonadherent dressing), but also was a potential practical solution to diluting the strong osmolytic honey. The Egyptians may have been the first — unknowingly — to employ the “moist wound healing” principle.7 Additionally, treatments included application of natural products such as plants and vegetables (eg, Pistacia terebinthus — antiseptic; Alchemilla vulgaris — tannine, anti-stringent; Symphytum officinale — allantoine, antibacterial)8,9 (see Table 1). Seaweed, which contains iodine, was used for sunburns10 (see Table 1).
Greek medical practice greatly resembled the Egyptian approach with a few key exceptions. An important change was the shift toward promoting pus instead of preventing inflammation. Another change in wound management was introduced by Hippocrates (460 BC–377 BC) who advocated the concept of dry wound therapy11 to promote healing by first intention and emphasized careful observation of the patient, the recuperative powers of nature, and a high standard of ethical conduct as incorporated into the Hippocratic Oath. Although questioned by many great inventors, dry wound therapy and stimulating the formation of “laudable pus” (pus bonum et laudable) remained the therapy of choice far into the 19th century.12
The Roman era produced the first science-based medical manuscript (De Medicina), written by Celsus13 (25 BC–50 AC). He described the four fundamental signs of infection — rubor, calor, dolor, tumor — which are still used today. Furthermore, Celsus addressed the importance of thorough wound cleansing: “Clean the wound of old blood because this can cause infection and change into pus, which inhibits wound healing”. Despite these astute observations, the “laudable pus” and “dry wound” strategy did not change during the following millennium.
Middle Ages until 18th century
Wound debridement (remove a bridle, originally meaning wound incision) was reintroduced around the 16th century.14 After debridement, wounds were treated with red-hot iron pokes, cleaned with boiling oil, and covered with suppuration-provoking substances. Paré (1509–1590) condemned the treatment of wounds with hot oil after serendipitously experiencing the positive effect of a mixture of egg yolk, oil of roses, and turpentine on wound healing.4 Paré also reinvented ligation of vessels and in the battle of St. Quentin (1557) he observed and recorded that maggots frequently infested suppurating wounds; unfortunately, this observation did not result in a new treatment modality. Many of Paré’s published works provide cutting-edge insights regarding nutrition, pain, and debridement, as well as psychological counsel for wounded persons — advanced thoughts, considering the time.15 Silver nitrate was invented and used in the treatment of skin ulcers, compound fractures, and suppurating wounds (draining pus).16 From the 17th and 18th centuries forward, anatomists and scientists offered a number of good ideas; however, they were chastised by their colleagues.
18th Century toward the Present
Cells. The invention of the microscope in the 17th century and the findings of Leeuwenhoek (1632–1723) (protozoa and animalcules) and Malpighi (1628–1694) (epidermal structure) did not facilitate progress in wound healing treatments until a century later when scientists began to focus on the more fundamental cellular level. In 1839, Schleiden and Schwann formulated the so-called “Cell Theory” based on their microscope findings. In 1858, Virchow (1821–1902) discussed his ideas on the formation, proliferation, and regeneration of cells. Understanding of tissue and cell culturing leaped forward when Carrel (among others including Harrison, Jolly, and Burrows), introduced in vitro technology, cultivating adult tissue and organs outside the body.17Reverdin (1842–1929) achieved a clinical breakthrough when small graft islets were placed onto wounds, a process he called “epidermal grafting”.18 Skin grafts became the first widely used form of tissue engineering, progressing from autografts in animal and human subjects to allografting tissue from one person to another.19,20
At the end of the 19th century, the first tissues were cultured using skin placed in a culture medium derived from ascites and preserved at room temperature until re-transplanted several days to months later.21Interestingly, the researcher thought it represented the beginning of over-the-counter products for wound therapy. However, another 100 years elapsed before these ideas were developed further.
Antisepsis/asepsis. In the same period, another group of researchers focused more on the interaction of cells and the animalcules. Semmelweis (1818–1865), Pasteur (1822–1895), and Koch (1843–1910) provided evidence about the relationship between germs and disease. Pasteur’s studies on contamination of wine and beer by airborne yeast clearly stimulated certain investigators to recognize that these “diseases” were due to the invasion of foreign micro-organisms. In England, Lister (1827–1912), impressed by Pasteur’s work, began to systematically sterilize his instruments and bandages and sprayed phenol solutions in his operative field22 (see Table 1). He came upon this idea when a chemist friend explained how he had solved the problem of putrefaction odors of the public water system in Carlisle, Scotland for that city’s local council.23 Mortality rates associated with surgical procedures decreased significantly from 45% to 15% after using carbolic acid as a spray in operating theaters.1,23 However, Lister encountered great resistance and hesitance because a clear connection between micro-organisms and disease had not yet been established.
The demands of war. During wartime, surgeons, once-hesitant to institute the practice, returned to using full-strength phenol to address complications in patients developing gangrene due to invasive infections.12 Use of hydrogen peroxide, another popular antiseptic, declined after reports of air emboli formation; Carrel (1873–1944) introduced a method that required extensive opening of the wound followed by bathing the wounded area with Dakin’s solution (sodium hypochlorite combined with boric acid).24 One month before the introduction of Dakin’s solution, Smith introduced Edinburgh University Solution of Lime (EUSOL), which Dakin criticized as being toxic at any dilution. Iodine, first described by Davis in 1839, was used during the American Civil War (1863) and World War I to treat wounds and scrub hands before surgery.25 Interestingly, iodine had been used during Napoleon’s Egyptian campaign (1798–1801) — soldiers were treated with high concentrations of iodine as found in extracts of seaweed and other marine plants10 (see Table 1).
At the turn of the century, Halsted (1852–1922) advocated the use of silver foil dressings as an antiseptic for infected wounds.26These dressings were used extensively until just after World War II.16,27 Chlorhexidine was discovered in 1946 and introduced into clinical practice in 1954, predominately as an antiseptic for washing hands and as a surgical scrub.28 However, its application in wounds has been limited largely to irrigation. Acetic acid was used in wounds infected with Gram-positive and Gram-negative bacteria (eg, Pseudomonas aeruginosa),24 a remnant of the ancient wine-and-vinegar cleansing strategy. Additional antiseptics used included boric acid, alcohol, hexachlorophene, thimerosal, gentian violet, and permanganate (see Table 1). Concern regarding the possible side effects was tempered by the sheer number of wounded soldiers. After the war, medical personnel heeded the in vitro research that indicated these agents were cytotoxic to human cells and many appeared to have an adverse effect on wound healing — thus, clinicians were increasingly reluctant to use many of these antiseptics.29-31 The discussion on the toxicity of these agents, started in 1914 by Fleming, still continues today, almost 100 years later.
Antibiotics/antimicrobials. Fleming’s discovery of penicillin (1928) and the development of oral antibiotics (1940) that provided potent and pathogen-specific antimicrobial agents revolutionized clinical therapy and marked the demise of many former remedies. Topical application of antibiotic ointments increased, especially in burn care. However, after the emergence of antibiotic-resistant strains of pathogens, alternative treatments became imperative.32 In 1949, iodophores (povidone iodine and cadexomer iodine, also known as slow-release antiseptics) were developed and proved to be safer and less painful to use than the early iodine products that caused irritation and skin discoloration, as well as pain.10,24,33 In 1968, Fox34 introduced another slow-release antiseptic, silver sulfadiazine (SSD), which combines the antiseptic properties of silver and sulfonamide to provide a broader-spectrum and safer antibiotic. Initially, silver nitrate was used. Although complications such as discoloration and irritation of the skin and possible toxicity reduced silver’s popularity, SSD and silver-releasing dressings remained in use.4 Various and emerging silver-coated dressings use metallic silver, inorganic silver compounds, or organic complexes as their source of silver combined with dressing components such as polyurethane, alginates, carboxymethyl cellulose, knitted fabrics, and activated charcoal5 (see Table 1).
The age-old use of honey, sugar, and maggots was re-introduced. All were popular throughout the centuries but remained in the background after the introduction of antibiotics. Several studies reported the three-fold benefits of honey on wounds: antibacterial (and deodorizing), debriding, and promotion of wound healing. The enzymatic action of glucose-oxidase on glucose and molecular oxygen leads to the production of hydrogen peroxide and gluconolacton, which have an antibacterial effect35-42(see Table 1). The effectiveness of honey as an antimicrobial agent varies according to factors such as floral origin, viscosity, and geographic location. Currently, various wound treatments are commercially available in tubes, impregnated dressings, or as components in innovative dressings (honey and alginate). Sugar in powder form is used in traditional medicine in Brazil where sugar production is high43; several case studies describe the use of sugar in modern medicine.44 However, until today, sugar has not received a place in the standard wound management.
In 1829, Napoleon’s surgeon-in-chief, Baron Larrey, reported that when maggots were found in battle injuries, they prevented the development of infection and accelerated healing.45 Zacharias, a confederate medical officer (surgeon) during the American civil war (1861–1865) was the first Western physician to intentionally introduce maggots into wounds.46 The benefits of maggot therapy on wounds have been found to be three-fold: debridement (elimination) of necrotic tissue, microbial killing, and stimulation of granulation tissue46-50 (see Table 1). Today, the bio-industry is flourishing and produces sterile larvae, primarily of the common green bottle fly Lucilia sericata.
Moist wound healing. Understanding of asepsis and antisepsis was an important step in wound healing. However, the paradigm of dry wound healing or exposing the wound to air remained part of many treatments. One exception was reported in the early 19th century, when good healing results in burns were achieved by immersing the wound in water. However, this concept was not accepted as a standard of care. Little progress was made in this area (with the exception of the invention of tulle gras and paraffin-impregnated gauze in 1914) until the 1960s when studies compared dry and moist wound healing. Winter’s historical study51 (1962) demonstrated that partial-thickness wounds in domestic pigs re-epithelialized more rapidly under occlusive dressings; the same result was reported in vivo in humans 1 year later.52 The basic concept behind moist wound healing is that the presence of exudate (ex + sudare, to sweat) in a wound will provide an environment that stimulates healing through the delivery to the wound of a range of cells and cytokines necessary for wound repair. These findings eventually led to the development of three generations of occlusive dressings.51 The first generation comprised impermeable foils without adhesive layer, described in a study by Garb53 in 1960; such dressings allow exudate to accumulate beneath the dressing, causing the foil to swim off the wound. The second generation of foils, semi-permeable polyurethane films with an adhesive layer, were introduced in the 1970s (see Table 1). The third-generation foils (hydrophilic polyurethane films, polyether urethane) had an even higher permeability so the adhesive layer, which could destroy the newly formed epithelium, became redundant.54
Hydrocolloids, initially manufactured for the preservation of fruits (reducing moisture loss and surface wounding), were introduced into clinical practice in the 1980s.55 According to product descriptions and the experience of wound care providers, hydrocolloids are designed for use in partial- and full-thickness wounds with or without necrotic tissue and have been found to be especially useful on areas such as heels and sacral ulcers that require contouring (see Table 1).
Foam dressings were developed during the 1980s as an alternative to hydrocolloids and are designed to protect and to absorb fluid without product breakdown but they require fixation. Foam dressings may be impregnated or layered in combination with other materials and are indicated for partial- and full-thickness wounds (see Table 1). Around the same period, hydrogels (amorphous formulations of water, polymers and other ingredients) were introduced. They are designed to provide moisture to a dry wound and are indicated for partial- and full-thickness wounds, wounds with necrosis, minor burns, and radiation tissue damage. The high moisture content serves to re-hydrate wound tissue (see Table 1).
Alginates, the next innovation in the treatment of exuding wounds, were designed to absorb exudate and provide calcium to the wound area. When alginates come in contact with wound exudate, they form a biocompatible gel that provides a moist healing environment (see Table 1). Although the products may be relatively new, the idea and basics behind alginates have a long history. In 1881, Stanford, a chemist working on brown algae, discovered alginic acid, a new group of seaweed-derived chemicals.56 After World War II, Blaine, an army major, investigated tissue reactions to alginates. He discovered that alginates had the above-mentioned properties. More recently (2007), a review57 of the literature on the efficacy of modern dressings in healing chronic and acute wounds by secondary intention was conducted. The review included 99 studies — 89 randomized controlled trials (RCTs), three meta-analyses (one came from one of the selected systematic reviews), seven systematic reviews, and one cost-effectiveness study. The authors concluded that hydrocolloid dressings are superior to saline gauze or paraffin gauze dressings for the complete healing of chronic wounds and that alginates were better than other modern dressings for debriding necrotic wounds. Hydrofiber and foam dressings, when compared with other traditional dressings or a silver-coated dressing respectively, reduced time to healing in acute wounds.57,58
Present and Future
Recently, more than a century after the first description of the fundamental cellular world, tremendous progress has been made in exploring the cellular and molecular mechanisms responsible for wound healing. Research on chronic wounds emphasized that not one but numerous factors (ie, deficiencies in local and systemic growth factors, changes in extracellular matrix [ECM], diminished fibroblast function, decreased antimicrobial activity of leukocytes, biofilms, and disturbance of macro- and microcirculation) are responsible for slowing down healing in chronic wounds.59,60 These findings triggered the pharmaceutical industry to develop products that tackle specific aspects of these processes; thereby, narrowing their therapeutic spectrum.
Growth factors. Topical gels containing growth factors were introduced in the early 1980s after clinical studies demonstrated a possible beneficial effect of autologous platelet-derived growth factors (PDGF).61 Further development of these gels resulted in the first commercially available product containing recombinant human PDGF (rhPDGF) in 1997.62 US Food and Drug Administration (FDA) approval was based on several RCTs63-65 in which rhPGDF healed more wounds by week 20 of care than the placebo gel/standard care. Currently, the FDA notes evidence of an increased risk of death from cancer in patients who had repeated treatments but because of known risks associated with diabetic foot and leg ulcers that do not heal, potential risk should be weighed against benefit for each individual patient.66
Gene therapy using adenoviral vectors that transiently express PDGF also were tested as a therapeutic modality for treating difficult-to-heal wounds.67 Because high doses of growth factors were necessary to achieve minor healing effect, it was assumed that endogenous proteolytic enzymes probably degrade exogenously applied growth factors.
This led to the development of matrix metalloproteinase (MMP)-modulating products that reduce proteolytic enzymes by physically entrapping and mechanically inhibiting their activity. Although these modern categories cannot be seen as a panacea, positive results with rhPDGF were reported in neuropathic diabetic ulcers68 and in venous leg ulcers with an ECM-modulating product.69 However, it must be noted that efficacy of these treatments was measured by specialized wound care personnel under tightly controlled conditions. The conditions for their use are often not ideal when these therapies are used in routine practice.
Tissue engineering/skin substitutes. The term tissue engineering was coined at a National Science Foundation meeting in 1987.70 It had taken a long route from the late 19th century. Skin substitutes can be categorized into three groups: temporary, semipermanent, and permanent. Temporary skin substitutes are placed on either a partial- or full-thickness wound and remain until the wound is healed. Semipermanent material remains attached to an excised wound and is eventually replaced by autologous skin grafts. Permanent skin substitutes incorporate an epidermal or dermal component, are designed to replace autologous skin grafts, and can be categorized as acellular/synthetic bilaminates, collagen-based composites, and culture-derived tissue. In 1998, the first tissue-engineered skin consisting of a bilayered construct of neonatal foreskin fibroblasts, keratinocytes, and bovine collagen gained FDA approval70,71 and was shown to improve healing of venous stasis, diabetic, 72 and arterial insufficiency wounds73 in studies comparing its use with local wound care consisting of gauze with saline solution. No comparison has been made between the use of tissue-engineered and autologous skin graft treatment. Recent research74 has examined genetically modified epidermal cells that can be used to engineer three-dimensional skin substitutes, which when transplanted, can act as in vivo “bioreactors” for local or systemic delivery of therapeutical proteins.
Stem cells. Research also is investigating the differential capacities of stem cells and how to influence and enhance their capabilities. This is facilitating development of scaffolds and stem cell markers.75
Wound bed preparation. In 2000, renewed interest in wound debridement led to introduction of wound bed preparation, a term coined at a meeting of the European Tissue Repair Society.76 Wound bed preparation infers a more prolonged maintenance debridement phase along with the correction of the biological micro-environment77 — the focus shifting from application of sophisticated dressings. Many agents can be used to facilitate debridement — from saline soaks to maggots and dressings that enhance wound autolysis (see Table 1). However, surgical debridement should be performed first if possible.78 Unfortunately, the lack of suitable equipment and fear of removing healthy tissue are common reasons for abandoning this technique and turning to alternative methods. Also, sharp debridement can be performed only by physicians or specially trained registered nurses (of whom there are few). The initial debridement of a chronic wound often temporarily speeds up wound healing but may be followed by a healing arrest, eventually returning the wound to its poor pre-therapy state.79 Explanations for this negative spiral address the phenotypically abnormal fibroblasts that seem to exist in chronic wounds,80 the degenerative wound fluid that blocks or slows down the proliferation of cells, and biofilms of organized bacterial communities that thwart successful healing if not eliminated. In order to heal the wound, repeated removal of detrimental factors (after addressing and correcting underlying pathology) should precede implementation of improved wound care products and/or devices. To date, terms such as wound bed preparation and their affiliated meanings remain untested concepts/theories.
Biophysical stimulation. Other newer technologies thought to support biological pathways involved in tissue repair comprise biophysical stimulation such as vacuum-assisted wound closure, hyperbaric oxygen (HBO), and pulsed electromagnetic fields81-83 (see Table 1).
Negative pressure. Draining wounds after surgery is a long-established surgical practice made more feasible with the introduction of suction drainage and later the evacuation glass bottle.84 A series of five articles, the “Kremlin papers,”85 was published in the Russian literature in the 1980s. Negative pressure (-75 mm Hg to -80 mm Hg) was used in combination with aggressive debridement to significantly reduce bacterial counts in purulent wounds.86 In 1989, Chariker et al87 discussed their experience utilizing topical negative pressure (TNP) in seven patients with incisional or cutaneous fistulae. A moist gauze was placed over the wound surface and a flat drain placed over the gauze and covered with a bio-occlusive dressing. The drain was connected to an existing vacuum line such as a standard hospital wall suction source with continuous pressure set at approximately -60 mm Hg to -80 mm Hg. This method became known as the Chariker-Jeter technique. In the early 1990s, suction drainage using Redon-drainage tubes combined with foam dressings as the interface was proposed as a new therapeutic concept to achieve wound healing.88-90 In 1993, a commercially available vacuum-assisted closure device (the V.A.C.® Therapy System, KCI, San Antonio, TX) was introduced by Argenta and Morykwas; its efficacy was validated through several animal models using -125 mm Hg pressure.82,83 Additional medical manufacturers/suppliers provided TNP systems, including the patented Versatile 1™ Wound Vacuum System using the Chariker-Jeter® approach (Blue Sky Medical Group Inc, Carlsbad, CA). The most important difference between the two negative pressure systems is in the interface used (polyurethane/-and polyvinylalcohol foam versus gauze, respectively).
Topical negative pressure therapy removes wound exudate by active suction, changes the bacterial environment,81 and indirectly manages the micro- and macro environment of the wound by increasing circulation/oxygenation. Experimental studies, clinical experience, and the latest RCTs have shown enhanced granulation tissue formation91 and wound bed preparation92; increased wound area reduction81,91; increased cell division, possibly induced by increased tension93; decreased local and interstitial tissue edema and increased perfusion of the (peri-) wound area94; and a significant modulation of bacterial species. 81At the recent Third World Union of Wound Healing Societies’95 (WUWHS) meeting, a consensus document of best practice was presented for use of vacuum-assisted wound closure. This document, prepared by a working group of experts, included recommendations based on several large retrospective and cohort studies and seven RCTs, as well as several smaller studies.
Positive pressure. Wound environment also may be changed by positive pressure (HBO). Generally, wounds with increased oxygen tension at the wound site following HBO may benefit from this therapy; however, it is still debated if evidence is sufficient to support HBO use in larger populations.96,97 Further research is needed to clarify the exact mechanism of this treatment98,99(see Table 1).
Other adjunctive therapies. Findings of transcutaneous voltage differences between skin surface and deeper skin layers100have resulted in the development and use of several devices that manipulate current to stimulate wound healing. Direct current, low-frequency pulsed current, high-voltage pulsed current, bio-electrical stimulation,101 and pulsed electromagnetic fields102 have been used with varying degree of success. Other adjunctive devices still under evaluation include infrared heat lamps, noncontact radiant therapy, radiant therapy, laser photostimulation, light therapy, ultrasound,103 and intermittent pneumatic compression.
Summary. Despite recent advances in wound care, the challenge of managing chronic wounds remains compounded by a lack of consensus on clearly defined wound care principles. Many organizations have developed guidelines for the assessment and treatment of wounds (see Table 2). These groups often examine the available literature and compile the findings into a set of guidelines. Because few guidelines have been validated, not every hospital follows the same protocol. Each patient must be comprehensively assessed and treatment plans must be individualized.
Conclusion
In the last two decades, enhanced understanding of the biology of wound healing and technological improvements have led to numerous improvements in wound care. Although clinicians have outgrown the ancient way of decision-making that was based on empirical and magical beliefs, old habits never die — they just fade away. Many healthcare professionals continue to treat and dress wounds according to age-old practices, despite the fact that new research shows this may not be the best treatment modality for the patient. The choice of therapy still depends largely on high-quality marketing, expert opinion, and gut feeling rather than on scientific evidence.
Because evidence-based medicine has become the new paradigm, the number of international guidelines for the assessment and treatment of wounds has slowly increased. Some of the components of these guidelines are somewhat limited by lack of Level A support but this situation should improve as more rigorous studies are conducted to address existing research gaps. Evidence-based medicine represents the integration of best research results with clinical expertise and patient values. In other words, without diminishing the importance of the opinion of experts in the field, more solid and large RCTs comparing old to new standards of care are needed. In addition, healthcare workers must be aware of the persuasive power of their industrial partners and products. More training on product specifications, proper use, and the need for a broad biopsychosocial patient approach is warranted. The medical doctor and his companion in battle — the qualified, registered wound nurse — should be alert to withstand the Siren’s song of industry and address the patient’s interest first.
Acknowledgment
The authors thank Professor Dr. Eddy Houwaert, Department of Medical History, Free University of Amsterdam, for his kindness in critically reading and commenting on this paper. The chair at this University Centre was first occupied by the late Professor Dr. Gerrit Arie Lindeboom, medical encyclopedist (1905–1986). The authors also thank Mr. Bob Tank for checking the English text.
Dr. Mouës is a resident, Department of Plastic and Reconstructive Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands. Dr. Heule is a senior staff member, Department of Dermatology, Erasmus University Medical Centre. Mr. Legerstee is the Professional Education Manager, Systagenix Wound Management, The Netherlands. Dr. Hovius is Head, Department of Plastic and Reconstructive Surgery, Erasmus University Medical Centre. Please address correspondence to: Chantal M. Mouës, MD, Resident, Plastic and Reconstructive Surgery, Erasmus University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands: email: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 or 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。.
