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Strategies for prevention of scars: what can we learn from fetal skin?

Strategies for prevention of scars: what can we learn fromfetal skin? Mohammad Reza Namazi1, MD, Mohammad Kazem Fallahzadeh2, MD, andRobert A. Schwartz3, MD, MPH Fetal wound healing occurs rapidly and without scar formation early in gestation.
Studying the mechanisms of scarless repair can lead to novel scar-preventive approaches. In fetal wounds, collagen is deposited early and is fine and reticular with less cross-linking. Several important differences of fetal vs. postgestational wound-healing response have been determined, such as the presence of less inflammation, higher hyaluronic acid concentration and a greater ratio of collagen type III to type I. Compared with typical wounds, there are also altered ratios of signaling molecules, such as higher ratios of transforming growth factor (TGF)-b3 to TGF-b1 and -b2, and matrix metallo- proteinases to tissue inhibitors of metalloproteinases. Furthermore, fetal fibroblasts do not exhibit TGF-b1-induced collagen production compared with their mature counterparts.
Patterning genes (homeobox genes) involved in organogenesis are more active in the fetal period and are believed to be the ‘‘first domino’’ in the fetal cutaneous wound repair regulatory cascade. The recommended scar-preventive agents, such as Scarguard MDâ, silicone gel and sheet, Seprafilmâ Bioresorbable Membrane, topical hyaluro- nan, onion extract, oral tamoxifen and 585-nm pulsed dye laser are reviewed in this study. Despite the lack of supporting evidence, there is a widespread false presumption that the acceleration of healing with the widely assumed scar-preventive commercial agents is associated with decreased scar formation. Humans are erroneously inclined to make a negative correlation between the healing rate and the degree of scar formation, while such a correlation does not exist in reality. Despite the importance of scar preven- tion, no FDA-approved therapy for this purpose is available in the 21st century, which reflects the important challenges, such as the presence of redundant pathways, that and diffuse fasciitis. The principles of anti-scarring therapy based on modulation of pro-scarring vs. anti-scarring fac- Scar formation is a major clinical problem resulting in tors appear to be promising for all the above-mentioned adverse cosmesis, loss of function, especially if over joints, conditions, indicating that studies in the skin could have a and hindrance of growth in children. Scars also have a dra- matic impact on the patient’s quality of life, and have beenassociated with anxiety, social avoidance, and depression.1 Therefore, prevention of scar formation has long beenimportant. Scar reduction is not only important to derma- Scar and fibrosis are the end result of surgical and non- tologists, but is also salient in many other conditions, such surgical skin injury. Aggressive wound healing may have as adhesions and strictures resulting from surgical proce- once offered an evolutionary advantage for survival at the dures in abdominal and pelvic cavities, spinal cord rup- expense of scar formation. Amazingly, fetal cutaneous tures, scarification of hand tendons after injury, corneal wounds, especially in the first 6 months of gestation, heal abrasions, glomerulonephritis, cirrhosis, human vascular without scar formation.2 Many clinicians hope that restenosis lesions, myocardial infarction, systemic sclerosis, understanding the remarkable reparative capabilities of ª 2011 The International Society of Dermatology International Journal of Dermatology 2011, 50, 85–93 the fetus may lead to the development of new wound- better influx of fibroblasts.12 By the nature of its hygro- healing therapies that reduce or prevent scar formation scopic properties, HA can occupy 10,000 times its own volume. Thus, HA allows proliferating cells to avoid Fetal monkey lip incisional wounds heal with restora- inhibitory contacts.13 Hyaluronic acid synthesis precedes tion of normal appendage and dermal collagen architec- mitosis and dissociates the dividing cell from its substra- ture in midgestation. At the start of the third trimester, these wounds do not restore appendage (hair follicle and Fetal fibroblasts have more surface receptors for HA sebaceous gland) architecture, but still heal with a normal than adult fibroblasts, enhancing fibroblast migration.2 collagen pattern. Thus, a ‘‘transition wound’’ phenotype Experimental tympanic membrane perforations in rats occurs. By the mid-third trimester, the wounds heal with treated with HA not only close faster but also heal with a typical scar pattern, i.e. no appendages and collagen much less scar tissue than the untreated controls.12 scar.3 The transition point in a human fetal skin modelalso occurs after the second trimester of gestation.4 It is notable that not all fetal tissues share the anti-scar- ring properties of fetal skin; fetal wounds in the dia- phragm and the gastrointestinal tract heal by fibrosis and Transforming growth factor-b is secreted by most cells contraction, as in the adults.5,6 Fetal cutaneous wound involved in wound healing, including neutrophils, lym- healing is not only scarless but also rapid. The rapid epi- phocytes, macrophages, keratinocytes, and fibroblasts.
thelialization of fetal wounds may occur in part because Transforming growth factor-b is first released from of early deposition of tenascin and fibronectin, which are degranulating platelets.14 Interestingly, TGF-b upregulates thought to be necessary for migration and cell anchoring, its own production in an autocrine pattern, leading to respectively.7 As discussed below, overexpression of vas- TGF-b overproduction and scar formation.14 Transform- cular endothelial growth factor (VEGF) may be another ing growth factor-b is a potent chemoattractant of macro- reason for rapid healing of fetal wounds. How is scarless wound healing different than the scarring wound healing? extracellular matrix synthesis and prevents its degradation In scarless wounds, collagen is rapidly deposited in a fine by upregulating the expression of tissue inhibitors of me- reticular pattern indistinguishable from uninjured skin. In talloproteinases (TIMPs) and downregulating the expres- contrast, adult scarring wounds have disorganized and sion of proteases. Three highly homologous TGF-b genes thick collagen bundles with more collagen cross-linking.7 in mammals, designated TGF-b1, -b2 and -b3, have been Interestingly, amniotic fluid is neither essential nor suf- identified.14 Shah et al.15 treated adult rodent wounds ficient for scarless repair. Fetal marsupials develop outside with isoform-specific neutralizing antibodies either alone the uterus in a maternal pouch and heal cutaneous or in combination. Exogenous addition of neutralizing wounds without scar.8 Adult sheep skin transplanted onto antibody to TGF-b1 alone resulted in some reduction in the backs of fetal sheep bathed in the amniotic fluid of the inflammatory and angiogenic responses, as well as the intrauterine environment heal with scarring of inci- reduction of extracellular matrix deposition in the early stages with a marginal reduction in cutaneous scarring.
By contrast, neutralizing antibody to TGF-b2 alone hadlittle effect on the inflammatory or angiogenic responses, and no effect on the resultant scar. However, when neu- Several structural and molecular differences between adult tralizing antibodies to TGF-b1 and TGF-b2 were adminis- tered together, the synergistic effect resulted in a dramaticamelioration of scar formation. Surprisingly, exogenous addition of TGF-b3 to cutaneous wounds in adult rodents Type I collagen is the predominant collagen of both adult also produced the same effects. Wounds treated with and fetal extracellular matrix. However, fetal skin has a TGF-b3 showed a marked reduction in the immunoreac- higher ratio of type III to type I collagen; with maturation, tivity for TGF-b1 and TGF-b2 on Days 5 and 7 post- the relative amount of type III collagen decreases.10,11 wounding compared with untreated control wounds.
TGF-b3 is thus believed to downregulate TGF-b1 and A glycoprotein called HA-stimulating activity (HASA) is Fetal wounds have higher ratios of TGF-b3 to TGF-b1 found in fetal skin and is absent in adult wounds. This and TGF-b2, favoring less scar formation.16,17 glycoprotein is suggested to be responsible for an increase Additionally, in a recent study by Rolfe et al.18 it has in HA and the resulting enhanced fluidity, which allows been shown that fetal fibroblasts, in comparison with International Journal of Dermatology 2011, 50, 85–93 ª 2011 The International Society of Dermatology mature fibroblasts, respond differently to TGF-b1 stimu- lation and fail to demonstrate the TGF-b1-induced pro- The fetal skin is relatively hypoxic. Midgestational fetal duction of collagen (mRNA and protein). This different lamb tissue pO2 is about 16 mmHg, whereas adult tissue response is due to a comparatively short-lived or rapid pO2 ranges from 45 to 60 mmHg. TGF-b1 production by phosphorylation of several components of the TGF-b1 fetal fibroblasts may be blunted in hypoxemic condi- tions.14 Physiologically low oxygen concentrations in fetal Interestingly, healing of oral mucosal wounds produces skin upregulate hypoxia-inducible factor 1, which is a less scarring compared with skin. Expression of Integrin potent transcriptional regulator of oxygen-dependent avb6 is increased in oral mucosal epithelium during genes such as VEGF and TGF-b3.21 Vascular endothelial wound healing; this protein enhances the secretion of growth factor, a mitogen for endothelial cells, increases both TGF-b1 and TGF-b3. In a recent study by Eslami twofold in scarless wounds, while its expression remains et al., expression of TGF-b molecules and b6 integrin was unchanged in scarring fetal wounds. Interestingly, one assessed in experimental human gingival wounds, and the novel, non-protein angiogenic factor is nicotine, which gingiva and skin of red Duroc pigs by means of real-time acts through nicotinic acetylcholine receptors to stimu- polymerase chain reaction, gene microarrays, and immu- late angiogenesis. The use of nicotine accelerates angio- nostaining.17 As with human wounds, b6 integrin expres- genesis and wound healing in the diabetic mouse model.20 On the other hand, it is shown that endostatin, postwounding, and remained enhanced for more than an angiogenesis inhibitor, minimizes scarring of mouse 49 days. The expression levels of b6 integrin and TGF-b3 wounds.20 It is difficult to interpret these results given were markedly higher in the pig gingival wounds com- that VEGF is expressed more in scarless healing. There- pared with cutaneous wounds. It was concluded that the fore, the role of VEGF in scarless healing needs more prolonged expression of Integrin avb6 resulting in a higher concentration of activated TGF-b3 protected gingi-val wound epithelium from scar formation.
Fibroblasts and myofibroblastsFibroblasts are major players in wound healing after developmental maturity; by gaining contractile proteins Decorin is a proteoglycan component of connective tissue.
such as a-smooth muscle actin they transform into myofi- It binds to type I collagen fibrils and plays a role in broblasts. These cells have certain clinical features of matrix assembly. Decorin’s name is a derivative of the smooth muscle cell, and contribute to scar formation and fact that it ‘‘decorates’’ collagen. Fibromodulin is a small contraction; however, their presence during fetal wound interstitial proteoglycan, which may participate in the healing is controversial. Some studies have shown their assembly of the extracellular matrix as it interacts with absence22 while others, such as Cass et al.,23 have shown type I and type II collagen fibrils and inhibits fibrillogene- their presence. In the above-mentioned study by Rolfe sis in vitro. It may also downregulate TGF-b activities by et al.,18 fetal fibroblasts exposed to TGF-b1 have been sequestering TGF-b in the extracellular matrix. Decorin is found to be capable of maturation into myofibroblasts; downregulated in fetal wounds, while fibromodulin is however, this differentiation was found to be quicker and more transitory compared with mature fibroblasts with Lysyl oxidase levels also increase during fetal skin development, perhaps resulting in higher collagen cross- The contractile forces generated by myofibroblasts may alter the orientation of collagen fibrils and contribute toscarring. Adult fibroblasts need to proliferate first before Matrix metalloproteinases (MMP) and TIMPs being able to lay down collagen, while fetal fibroblasts Scarless wounds have a higher ratio of MMP to TIMP, are capable of proliferating simultaneously while making favoring remodeling and less accumulation of colla- collagen. As a result, collagen deposition is delayed in gen.2,19 This may be due to decreased expression of TGF- adult wound healing, contributing to scar formation.7,12 b1, as it decreases MMP and increases TIMP expression, Additionally, fetal fibroblasts at early gestation express a favoring collagen accumulation and scarring.20 lower level of TGF-b receptor II than fetal cells later ingestation. It is also demonstrated that receptor tyrosine Platelet-derived growth factor (PDGF) and fibroblast kinases express differentially between fetal and adult rat fibroblasts, suggesting that further elucidation of the Scarring wounds have higher levels of the profibrotic TGF-b receptor signaling process in fetal fibroblasts may cytokines PDGF and FGF. Platelet-derived growth factor help to understand how fetal cells respond to TGF-b is a potent mitogen and chemoattractant for fibroblasts.2 differently from adult cells.24 Moreover, as mentioned ª 2011 The International Society of Dermatology International Journal of Dermatology 2011, 50, 85–93 earlier, fetal fibroblasts have more HA receptors than such as fibrinogen and other proteins. Steric hindrance by the HA matrix may alter the chemotactic gradient, andthereby influence the magnitude and nature of the inflam- matory response. Hyaluronic acid also serves as a high- Recently, Kong et al.25 identified a novel, previously capacity free radical scavenger. It is suggested that the unidentified group of E-cadherin-positive cells in the presence of HA has a physical effect on the fibrin matrix blood of fetal and adult mice, and named them ‘‘Dot that forms. Hyaluronic acid also limits fibrin formation cells’’. Dot cells have a tiny dot shape with a diameter through binding to the fibrinogen molecule, with the between 1 and 7 lm. It is suggested that Dot cells are resultant prevention of excessive collagen deposition.13 relatively primitive cells or stem cells because of their The balance of cytokines in the fetus favors HA expres- unusually small size and expression of stem cell markers sion. Proinflammatory cytokines, such as IL-1 and tumor such as E-cadherin, integrin b1 and CD34 by these cells.
necrosis factor-alpha, which downregulate HA expres- The percentage of Dot cells in fetal mice blood is more sion, are underexpressed in the fetal wounds, whereas in than 20 times higher compared with adult blood. Dot adults there is upregulation of these cytokines in response cells migrate to wounds and differentiate into dermal to wound healing. As mentioned previously, HASA also cells, which release less interstitial collagen and reduce contributes to the higher production of HA in fetal skin.
scarring. Transplantation of Dot cells to adult mice healsskin wounds with less scarring due to reduced smooth muscle actin and collagen expression in the repair tissue.
Recent studies indicate that upregulated ACE may partici- These results infer that Dot cells are a previously uniden- pate in cutaneous pathological scar formation,30 suggest- tified component in scarless wound healing.
ing that ACE inhibitors may exert an anti-scar effect.
Moreover, ACE inhibitors also retard Smad3 function, which plays an important role in the TGF-b-induced Scarless fetal wounds have less inflammatory infiltrate, which may lead to improvement in the final wound-heal-ing process. Decreased inflammation may be partly due to decreased fetal platelet degranulation and aggregation Homeobox genes are transcription factors that are impli- with the resultant lower levels of the chemoattractants cated in the patterning and cell type specification events TGF-b and PDGF.2 Moreover, fetal neutrophils may not during development. Human homeobox genes MSX-1, possess the chemotactic ability of adult neutrophils.25 MSX-2, and MOX-1 are differentially expressed in skin Both interleukin (IL)-6 and IL-8, which are important in development. Moreover, fetal scarless repair is associated chemotaxis and activation of inflammatory cells, are sig- with decreased expression of HOXB13 and increased nificantly lower in early fetal fibroblasts. Treating adult PRX-2 expression.2 This implies that PRX-2 activation is mouse wounds with IL-10, which has an anti-inflamma- an important stimulant to dermal generation. Conversely, tory effect through decreased production of IL-6 and HOX-B13, which is strongly expressed in normal second IL-8, reduces inflammation and helps produce scarless trimester fetal skin, is markedly downregulated in healing. This may have therapeutic implications in human response to wounding. Thus, HOX-B13 may be an inhib- itor of dermal proliferation, and its constant expression Insomnia, through increasing IL-6 levels,29 might pre- may be involved in maintaining a static dermal architec- dispose patients to scar formation. If proven by controlled ture rather than promoting dermal growth.32 studies, this concept can have therapeutic implications, Hox genes, another subgroup of homeobox genes, especially after myocardial infarction, severe burns and encode for a family of transcription factors that are major regulators of tissue migration and cell differentiation dur- High levels of HA may also contribute to decreased ing embryogenesis. In a recent study, Jain et al.33 inflammation of fetal wounds. In in vitro systems, the reported the increased expression of Hox gene Hoxd8 in chemotactic and random migration of white blood cells excisional wounds of mid-gestational mice compared with can be inhibited by HA. The phagocytic activity of mono- the normal skin samples of mid-gestational mice and exci- nuclear phagocytes is also inhibited by even a relatively sional wounds of late-gestational mice; therefore, it is low concentration of HA (£0.05 mg/ml). Therefore, HA proposed that this gene may have anti-scarring effects in exerts biomechanical regulation over processes such as fetal wound healing. Conversely, expression of another inflammation through its ability to modify the activity of Hox gene Hoxd3 was found to be increased in both exci- cells involved in the inflammatory response.13 The HA sional wounds and normal skin samples of mid-gesta- molecular network is able to exclude large molecules, tional mice compared with late-gestational mice; hence, International Journal of Dermatology 2011, 50, 85–93 ª 2011 The International Society of Dermatology this gene is considered to be expressed constitutively in Table 1 Comparison of fetal vs. adult wound healing It is likely that fetal mammals have the ability to heal large skin defects made early in gestation because tran-scription factor patterning genes, such as homeobox genes, are more active in the fetal environment. As a result, researchers have hypothesized that transcription factors, like homeobox genes, may be the ‘‘first domino’’ in the fetal cutaneous wound repair regulatory cascade.32 How these homeobox genes may coordinate scarless fetal wound repair is currently under investigation. Sev- eral possible targets have been identified, including the promoter regions of members of the TGF-b superfamily, various cellular adhesion molecules, and cell surface pro- Wound healing is delayed in old age, but there is less scarring. Diminished inflammatory responses due to impaired macrophage and T-cell functions, loss of fibro- blast responsiveness and motility, as well as reduced quantity and distribution pattern of various growth fac- tors, including TGF-b, and their receptors may contribute to this effect. Estrogen upregulates TGF-b1 through bind- ing to its receptors on fibroblasts. The decline of estrogen after menopause may explain decreased scarring in the postmenopausal period. Systemic hormone replacementtherapy for 3 months accelerates re-epithelialization and HA, hyaluronan; HASA, HA-stimulating activity; FGF, collagen deposition of acute wounds in postmenopausal fibroblast growth factor; MMP, matrix metalloproteinases; PDGF, platelet-derived growth factor; TGF, transforming In normal aging skin, the levels of proteases such as growth factor; TIMP, tissue inhibitors of metalloproteinases; MMPs increase, while the levels of proteolytic inhibitors VEGF, vascular endothelial-derived growth factor.
(e.g. TIMPs) decrease, leading to less scar formation.35,36 TGF-b3 increases at Day 7 postwounding in old mice, while TGF-b1 and TGF-b2 increase at all time points in and growth factor profile. In addition, the larger exci- the wounds of younger mice. This may also explain the sional wounds may stimulate the formation of myofibro- better cosmesis of wound healing in aging.12 blasts in the wound, resulting in scar formation.32 The differences between fetal and adult wound healing • Occlusive therapy can reduce scar formation. Occlu- discussed above are summarized in Table 1.
sive therapy includes silicone gels and sheets, non-siliconeocclusive sheets, cordran tape and Scarguard MDÒ Accepted, potentially useful and questionable strategies (Redrock Laboratories, Great Neck, NY, USA; see below). Occlusion can reduce pro-inflammatory/pro-fibrotic • The use of proper surgical techniques, which ensure cytokine levels. Increased temperature, even 1 °C, due to minimal tension and inflammation, and avoiding incisions occlusion can upregulate collagenase expression.34 over the midchest and joints, which are scar-prone sites, Topical silicone gel has been employed for scar reduc- tion since the 1980s. It is probably of value by enhancing As mucosal wounds heal with reduced scar formation wound hydration as occlusive therapy with both silicone- when compared with skin,26 when possible there should and nonsilicone-based therapies appears to be of equal be consideration of endoscopic surgical technique.37 Larger wounds may be more likely to heal with scar Scarguard MDÒ is a new topical over-the-counter med- formation. It is not unreasonable to assume that larger ication containing silicone, vitamin E and hydrocortisone.
wounds may extend the time of the healing response, thus In a pilot study on 12 patients, Scarguard MDÒ was exposing wound tissues to a different extracellular matrix applied twice daily after removal of a mole, and nothing ª 2011 The International Society of Dermatology International Journal of Dermatology 2011, 50, 85–93 was applied after removal of a second mole. After less angiogenesis, and less collagen and fibronectin. Inter- 2 months, nine out of the 12 patients described a reduc- estingly, the tensile strength of the scars of these wounds tion in erythema and better cosmesis of the scar at the was comparable with controls.47 Whether these antibod- site treated with Scarguard MDÒ compared with the site ies are capable of reducing scar formation should be that was not treated with Scarguard MDÒ. These results answered by the above-mentioned trials. Activation of must be interpreted with caution, however, as the latent TGF-b requires binding of the latent TGF-b to the improved cosmesis may be the result of occlusion of mannose 6-phosphate/insulin-like growth factor-2 recep- a wound rather than the Scarguard MD product. An tor in the presence of plasmin/urokinase. Activation could in vitro study showed that Scarguard MDÒ may stimulate be blocked by mannose 6-phosphate or by antibodies to the release of inactive collagenase precursors that may inhibit scar formation and reduce existing scars.34 Another potential target of therapy is connexin 43 • Seprafilm (Genzyme Corporation, Cambridge, MA, (Cx43), which mediates TGF-b signaling. Studies on USA) is a type of absorbable barrier film composed of Cx43 antisense-based gene therapy to prevent scar forma- un-crosslinked, carboxymethylcellulose/sodium hyaluro- tion are under way. As lithium increases Cx43 expression, nate.40 After application, by absorbing moisture from the patients who are taking it may exhibit increased suscepti- application site, the dry film acquires a gel consistency bility to scar formation. MicroRNAs, which are single- over 24 hours.40 This product decreases the incidence of stranded RNA molecules partially complementary to one adhesion formation, and enhances the repair of damaged or more messenger RNA molecules, may be employed to tissues by acting as an occlusive barrier between damaged tissue sites.40 Several studies have reported the effective- Smad3 plays an important role in the TGF-b-induced ness of Seprafilm in reducing postoperative intra-abdomi- fibrosis. Downregulation of Smad3 expression in fibro- nal adhesion formation.40–42 This product has also been blasts by small interfering RNA (siRNA) can signifi- • Topical application of HA or saponins, which upre- attenuate the process of fibrosis. RNA interference is a gulate HA, could exert an anti-scarring effect.44 The process in which brief RNA sequences, called siRNA, effects of topical exogenous HA on the healing of dermal block signals from a particular gene. This process, called wounds have been investigated by many independent gene silencing, inhibits the gene from carrying out its investigators in recent years. Most researchers have found function. However, this approach is facing some chal- that HA provides a beneficial effect with regard to the lenges, such as the need to develop improved siRNA quality of tissue repair scar formation. The results indi- delivery strategies that combine high specificity and effi- cate that the greatest benefit is achieved using highly puri- ciency with a low immunostimulatory and tumorigenic fied, high-molecular-weight HA at a concentration more than 1 mg/ml, and under conditions in which the HA is • Tamoxifen is shown to downregulate the production maintained at the wound site on a continuous basis for a of TGF-b1, basic FGF and VEGF.49,50 Some in vivo prolonged period of time. In studies in which HA failed reports indicate that it delays wound healing but amelio- to promote or enhance the wound repair process, testing conditions were suboptimal. Low-molecular-weight and/ • Starting at the day of suture removal, 585-nm pulsed or very dilute HA preparations rapidly diffuse from the dye laser treatment has improved the quality and cos- injured site. The purity of exogenous HA is critical in metic appearance of surgical scars in a controlled study order to limit contaminating substances, such as proteins, on 11 patients.51 Both 585-nm pulsed dye laser and the endotoxin, etc., which may be inflammatory in nature and may produce undesirable biological effects.13 garnet laser treatment of acne scars in the same patient The synthesis of HA appears to be limited by glucosa- showed both lasers to be effective modalities for the treat- mine availability.45 Thus, administration of adequate amounts of glucosamine by mouth during the first few • Botulinum toxin has shown improvement in several days after surgery or trauma has been hypothesized to patients when injected into the muscle underlying a enhance HA production in the wound, thereby promoting wound immediately after surgery.53 A recent evaluation swifter healing and also diminishing complications related of 19 patients found botulinum toxin type A injections of value in the treatment of hypertrophic scars.54 • For reduction of scar formation, clinical trials for the • An investigator-blinded, controlled study showed that use of TGF-b3 and neutralizing antibodies to TGF-b1 the onion extract gel significantly improved scar softness, redness, texture and global appearance at the excision antibody-treated wounds contained fewer macrophages, International Journal of Dermatology 2011, 50, 85–93 ª 2011 The International Society of Dermatology • A double-blind, randomized, placebo-controlled study did not demonstrate efficacy of imiquimod, an anti-fibro-sis cytokine inducer, on scar cosmesis.56 1 Rumsey N, Clarke A, White P. 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