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Best in Class: Scottsdale Wound Management Guide
Comprehensive pocket handbook offers differential diagnosis and treatment options at your fingertips
Malvern, PA (June 8, 2009) – Proper wound care management has become one of the top concerns for many clinicians across various medical specialties. Treatment is specific to the wound type, the patient and the long-term care plan and requires ongoing assessment. Read More
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Regenerative Healing in Fetal Skin: A Review of the Literature
Exploration of fetal wound healing began in the 1950s with examination of animal models. Initial studies by Hess1,2 indicated that fetal wounds heal rapidly and show signs of regeneration, in some cases making it difficult to identify the wound site. In subsequent studies,3-7 a lack of inflammation and healing without a scar4 were described in fetal wounds. Similar differences in healing were noted in the human fetus8 and were confirmed when the first human fetal surgeries were performed.9
As experimental studies continued, it became evident that fetal wounds heal differently depending on the gestational age of the fetus (see Figure 1).10-17 In the first and second trimesters of development, fetal skin undergoes rapid healing with little or no inflammation and no scarring. Scarless healing in early fetal skin is a form of regeneration, with renewal of skin appendages such as hair follicles and sebaceous glands in addition to the restoration of a normal dermal matrix and no scar. Near the third trimester, a transition period occurs. At this point, the skin begins to lose its ability to regenerate and instead undergoes fibrotic healing similar to that seen in postnatal skin. After this transition to fibrotic fetal healing, cutaneous wounds heal more slowly, exhibiting inflammation and significant scarring. After the transition period, wWilgus_fig_1.jpgWilgus_Keypoints.jpgWilgus_Table_1.jpg**
Glycosaminoglycans. One of the first differences identified in the ECM of fetal wounds was the presence of high levels of glycosaminoglycans (GAGs).34,90 Glycosaminoglycans are polysaccharides comprised of repeating acidic and basic disaccharides found at high levels in connective tissues.91 Important GAGs in the skin include chondroitin sulfate, dermatan sulfate, heparin sulfate, heparin, and hyaluronic acid (HA). Whitby and Ferguson20 studied the expression of two GAGs, chondroitin sulfate and heparin sulfate, in fetal lip wounds. They found that significant amounts of chondroitin sulfate are produced in fetal but not adult wounds, suggesting chondroitin sulfate may help facilitate regenerative healing. However, no differences were observed in heparin sulfate expression between fetal and adult wounds.
Many initial fetal wound healing studies focused on one particular GAG, hyaluronic acid (HA), which appears to be present at the highest levels in fetal wounds.34,90 Hyaluronic acid can influence the structure, assembly, and hydration of the ECM and appears to support cell growth and migration, especially during development.92,93 Amniotic fluid has high levels of HA, especially earlier in gestation94,95; high levels of HA-stimulating activity (HASA), a factor that promotes HA deposition, also are present in amniotic fluid.96 Higher levels of HA have been described in wounds or PVA sponge implants in fetal rabbits.34,90 In sheep, wound fluid from early gestation fetal wounds contains higher levels of HA and HASA than late gestation fetal or adult wound fluid.95 Higher HA and HASA levels are maintained for a longer period of time in fetal versus adult wound fluid.95,97,98 Fetal wounds also have less of the HA-degrading enzyme hyaluronidase than adult wounds.99 Together, the high levels of HA and HASA, combined with low levels of hyaluronidase, are thought to be responsible for the persistent, high levels of HA in fetal wounds.
The relevance of high HA levels to scarless healing has been highlighted by several studies. When forced degradation of HA occurs in fetal skin through the addition of hyaluronidase in PVA sponge implants, a fibrotic response occurs; this is not the case when control sponges are implanted.83 Similarly, in adult mice, PVA sponge implants containing hyaluronidase caused a fibrotic response; whereas, sponges containing HA resulted in normal ECM deposition.100 An in vitro model101 of wounded mouse limbs where E14 limbs underwent scarless repair and E18 limbs healed with scar was used to study the effects of exogenous HA on the repair process. When E18 wounds, which normally heal with a scar, were cultured in the presence of HA, scarless healing resulted.101 Together, these data suggest that continual high levels of HA are important for regenerative healing.
Glycoproteins. Integral components of the ECM, glycoproteins bind integrins, collagen, and proteoglycans, holding tissues together and functioning in cell adherence.102 The glycoproteins laminin, fibronectin, and tenascin have been studied during fetal wound repair. In murine wounds, laminin is present in the endothelial basement membrane and also in the epithelial basement membrane but only after reepithelialization is complete.20 This is consistent for both fetal and adult wounds. Fibronectin, part of the provisional wound matrix, displays similar staining patterns and timing of expression in fetal and adult wounds in mice and sheep,20,60 but may be expressed a few hours earlier in fetal rabbit wounds.103 Tenascin-C appears to be the most differentially expressed glycoprotein in scarless repair. Although tenascin is expressed in all wounds, it is deposited much sooner in early fetal wounds compared to either late gestation fetal or adult wounds.20,60 In mice, tenascin is expressed as early as 1 hour post-wounding in fetal wounds compared to 24 hours post-wounding in adult wounds.20 Tenascin is deposited before reepithelialization — the fact that it is deposited more quickly in fetal wounds suggests it may mediate the quick reepithelialization seen in early fetal skin.
Proteoglycans. Proteoglycans are made up of a core protein linked to one or more GAGs.102 The expression of several members of the small leucine-rich proteoglycan (SLRP) family has been studied in fetal wound repair. This family of proteoglycans, including decorin and fibromodulin, regulate collagen fibrillogenesis, growth factor activity, and cellular proliferation.104 By RT-PCR, reduced decorin expression was found in early scarless fetal wounds but did not change in scar-forming fetal wounds.105 In adult wounds, decorin expression increases during healing.106 These data suggest that reduced mRNA levels of decorin may correlate with scarless healing. In other models, reports conflict about the role of decorin in scar formation and fibrosis.107-116 One potential explanation for the conflicting data is that mRNA and protein levels of decorin do not always correlate.117 Additional studies to clarify the role of decorin in scar formation and fibrosis are needed.
Protein levels of fibromodulin, another SLRP family member, are significantly increased in scarless fetal wounds compared to scar-forming fetal wounds.106 This correlates with data demonstrating the ability of small proteoglycans to reduce collagen fibrillogenesis and of fibromodulin to bind TGF-b with high affinity.118,119 Further studies to more clearly define the role of proteoglycans in scarless repair and to determine whether their influence on collagen fibrillogenesis or TGF-b activity play a role in this process should be performed.
Collagen. Collagen production obviously differs between scarless and scar-forming fetal wounds. In the first and second trimesters of development, fetal skin is capable of healing wounds with newly formed collagen in a fine reticular or basket-weave pattern identical to normal skin.12,13,15,17,20,30 This type of collagen network allows for regeneration rather than scar formation and is distinctly different from the thick, disorganized, parallel bundles of collagen that make up scar tissue. Many aspects of collagen synthesis have been studied in scarless fetal healing, including the amount, types, and speed of collagen production, tensile strength, and level of cross-linking.
In normal fetal skin, the amount of total collagen increases during development.120-122 However, reports conflict about the timing and amount of collagen production in scarless fetal wounds compared to scar-forming wounds. Some studies have reported less collagen production in fetal wounds compared to adult wounds46,123 and in early fetal wounds compared to late fetal wounds in a PVA sponge model.121 One study showed that relative collagen synthesis (normalized to non-collagen protein synthesis) is similar in fetal wounds compared to unwounded skin but increases significantly in adult wounds and several studies have reported more rapid synthesis of collagen in early fetal wounds.20,47,120,124
Similar discrepancies have been noted in the types of collagen produced. Some investigators have reported lower collagen I:III ratios in fetal wounds.123 Others have reported an increased ratio of collagen I:III in early gestation fetal sponge implants120 or no difference in the ratio121,125 when compared to scar-forming fetal or adult wounds. It appears that in both scarless and scar-forming wounds, type III collagen is primarily deposited early in the repair process and later switches to production of collagen I.121,125 Although reports conflict as to whether the ratio of collagen I:III differs in scarless and fibrotic wounds, uninjured fetal skin clearly contains higher levels of type III collagen compared to type I. 120-123,125,126
Aside from characterizing the collagen content of scarless fetal wounds, studies also have determined the amount of collagen cross-linking and the tensile strength of these wounds. Collagen cross-linking has been reported to be lower in earlier stages of fetal development in sponge implants, indicating that less mature collagen is manufactured.120 It has been suggested that mature, more cross-linked collagen may correlate to increased rigidity and enhanced scar formation. Although less collagen cross-linking has been described in early fetal skin, this does not appear to correlate with a reduction in strength — the tensile strength of fetal wounds is similar to adult wounds when normalized to age-matched, unwounded skin.46
Inconsistencies in the reported amounts and types of collagen produced during fetal wound healing likely stem from differences in the animal models used, whether collagen assessments were made in wounds or in sponge implants, and what methods were used to examine the collagen. Regardless of the absolute amount, timing, or types of collagen produced during the healing of scarless fetal wounds, a limited amount of organized collagen is made, unlike the overproduction of disorganized collagen in scar tissue. It is evident that the collagen is deposited and arranged in a fundamentally different way during scarless repair, allowing for the regeneration of normal skin with the re-growth of subepidermal appendages and a reticular network of collagen.
Matrix metalloproteinases (MMPs). During normal adult wound repair, extensive ECM remodeling leads to collagen reorganizing and formation of a mature scar. The remodeling process consists of both the production and the degradation of collagen and other ECM components; a relative imbalance in this process by either an abnormally high production of collagen or inadequate degradation could result in excessive scarring. According to a review of the subject,127 MMPs and TIMPs (tissue inhibitors of the proteolytic activity of MMPs) are key to maintaining the appropriate balance between matrix production and degradation. Although little is known about the role of MMPs and TIMPs in scarless fetal healing, a few studies have suggested that alterations in the control of matrix degradation could be a factor in scarless repair. Bullard et al82 used immunohistochemistry to examine MMP levels in a model of subcutaneous transplantation of human fetal skin in immunodeficient mice and reported higher levels of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), and MMP-3 (stromelysin-1) in mid-gestation human fetal skin compared to adult skin. In addition, the authors showed that adding TGF-b reduced MMP levels in fetal skin. Although MMP levels were examined only in unwounded fetal and adult skin, the authors suggested that high levels of MMPs in fetal skin could contribute to scarless repair. Their results also suggest that one way TGF-b may augment scar formation is by reducing matrix degradation through the MMPs.
More recently, mRNA levels of a panel of MMPs and TIMPs were determined during scarless and fibrotic fetal wound healing in rat skin. Dang et al128 showed that scarless fetal wounds express MMP-1, MMP-9 (gelatinase B), and MMP-14 (membrane type-1 MMP) more quickly or at higher levels than fibrotic fetal wounds. In addition, while MMP-2, TIMP-1, and TIMP-3 expression is not altered during scarless healing, MMP-2 levels significantly decrease and TIMP-1 and TIMP-3 levels increase in fibrotic wounds. Together, these data indicate that high levels of MMPs exist in fetal skin and that a higher MMP:TIMP ratio is present in scarless versus scar-forming fetal wounds. The high levels of matrix-degrading enzymes, supporting matrix degradation rather than matrix production, may play an important role in the ability of fetal skin to repair wounds without the production of scar tissue.
Fibrogenic Growth Factors
Several growth factors with pro-fibrotic properties have been studied in fetal wound healing. Many of the published fetal wound healing experiments have focused on TGF-b family members because this family of proteins has been shown to have a defined role in fibrosis.129 Differences in TGF-b expression, with lower levels and rapid clearance of TGF-b1 and -b2 during scarless fetal repair compared to fibrotic healing, have been demonstrated repeatedly.19,41,43,79-81,130 In particular, reduced expression of TGF-b1 in early fetal wounds has been confirmed in incisional and excisional wounds in murine, rat, and human skin. The consistency of these findings in several diverse models suggests that minimal TGF-b1 expression in response to injury is a conserved response in early fetal skin.
Numerous studies demonstrate that adding TGF-b causes a fibrotic healing response in early fetal skin that would normally heal scarlessly or without fibrosis, further solidifying a role for TGF-b in scar formation.18,33,40-43,82 The TGF-b3 isoform, which has anti-fibrotic effects in adult wounds,131 is reportedly higher in non-scarring fetal wounds.81 In addition, TGF-b receptors TGF-bRI and TGF-bRII are present at lower levels in scarless fetal wounds than in fibrotic wounds.79,81
Aside from TGF-b, platelet-derived growth factor (PDGF) is also considered a fibrogenic cytokine. Whitby and Ferguson19 performed immunohistochemistry on scarless and fibrotic wounds and found that while PDGF is present in both types of wounds, it is produced for a shorter length of time in scarless fetal wounds. Additionally, in fetal rabbits, adding PDGF induces fibrosis,39 suggesting that it may play a role in scar formation.
Fibroblasts and Myofibroblasts
The fibroblast is the primary cell type responsible for determining whether scarless or fibrotic healing will occur; therefore, regenerative fetal healing must ultimately depend on the ability of fetal fibroblasts to produce and arrange new collagen and other ECM components in similar quantities, ratios, and arrangements to unwounded skin. These characteristics appear to be unique to early gestation fetal fibroblasts because skin fibroblasts past the transition period lose the ability to make normal ECM in response to wounding. The critical role of the fetal fibroblast in scarless healing was highlighted by Lorenz et al.16 Human fetal skin retains the ability to heal scarlessly when transplanted subcutaneously in nude mice but heals with a scar when transplanted as a cutaneous graft. Utilizing antibodies specific for either mouse or human collagen types I and III, the authors demonstrated that the healed dermis in scarless, subcutaneous grafts was made up of human collagen. The collagen contained within the newly formed dermis of the subcutaneous graft wounds was assessed histologically and found to be arranged in a reticular pattern similar to unwounded skin. The collagen is these scarless wounds was identified as human collagen and as such must have been produced by the human fetal fibroblasts. Conversely, the new matrix in the cutaneous grafts that healed with a scar consisted of mouse collagen, suggesting that the murine adult fibroblasts, not the human fetal fibroblasts, were involved in the production of scar tissue.16 These studies underscore the unique ability of fetal fibroblasts to facilitate scarless healing in the fetus.
Aside from normal fibroblasts, myofibroblasts, specialized contractile fibroblasts, also can contribute to wound repair. These cells express a-smooth muscle actin (a-SMA) and are characterized using transmission electron microscopy by a well-developed rough endoplasmic reticulum, nuclei with irregular borders, secretory vesicles denoting active collagen synthesis, and organized microfilament bundles.132,133 In fetal wounds, myofibroblast numbers appear to correlate with fibrotic healing. Studies in sheep133 have indicated that myofibroblasts are absent in early scarless fetal wounds but are present during healing at later stages when prominent scarring occurs. In addition, incisional or small excisional wounds (2 mm) heal without a scar and do not contain myofibroblasts.134 In contrast, larger excisional wounds that heal with a scar contain strong a-SMA staining, with the number of myofibroblasts correlating with the size of the wound and amount of scarring.134 A lack of myofibroblasts also has been reported in wounded mouse embryos.65 In addition, adding TGF-b1 to early fetal rabbit wounds induces fibrosis40 and increases the number of a-smooth muscle actin-positive myofibroblasts in the wounds,135 further supporting the association of myofibroblasts with scar formation in fetal wounds.
Discussion
In the past 20 or 30 years, scientists have discovered the remarkable ability of the fetus to heal cutaneous wounds by regeneration through a process that involves no inflammation, rapid reepithelialization, and no scarring. Studying this process has the potential to provide clues about how to make postnatal wounds heal more quickly and with less scarring. Several observations made in fetal wounds have been applied to adult wound healing with some success, at least in animal models.
Many studies have emphasized the importance of low levels of TGF-b1 to scarless fetal repair so it is not surprising that TGF-b1 inhibition is now a major anti-scarring strategy. Ferguson’s group initially showed the benefits of treatment with neutralizing TGF-b1 and TGF-b2 antibodies on minimizing scarring136,137 and since then several others have shown that blocking TGF-b1 activity or reducing TGF-b1 levels can reduce scarring in adult animals.138-140 Currently, clinical trials of drugs designed by the biotech company Renovo are underway in the UK to determine whether inhibiting TGF-b1 activation can improve scarring.
Another prominent feature of fetal skin is its ability to heal wounds without the induction of an acute inflammatory response. In the past few years, several groups have shown that limiting inflammation in adult wounds can enhance repair, either by increasing the rate of reepithelialization or by reducing scarring.48-50,141 Modulating angiogenesis, which is often linked to inflammation and may be dampened in scarless wounds, could turn out to be another way to reduce scar formation in adult wounds. Although blocking angiogenesis is frequently associated with delayed healing, in vivo evidence exists indicating that reducing angiogenesis has no effect on overall healing rates or can even enhance healing.89,142-147 In addition, several studies have shown that reducing angiogenesis or interrupting the VEGF signaling pathway can minimize scarring.85-89 More studies to determine whether reducing scar formation through anti-angiogenic therapy is a valid option and to more clearly define the effects this may have on reepithelialization and healing rates are needed. Whether limiting angiogenesis is an option will likely depend on the type of wound and whether the rate of healing or the amount of scarring is the primary concern.
The newest experimental wound healing therapies involve utilizing the regenerative capacity of fetal cells directly. A recent study by Hohlfeld et al148 emphasized the potential impact of fetal skin cells in healing postnatal wounds. These Swiss researchers generated skin constructs using skin cells from a 14-week aborted fetus and used the constructs as grafts for pediatric burn patients. The authors reported success using the fetal skin constructs, with relatively quick healing and minimal scarring. Although these studies are not without controversy and the mechanisms underlying the ability of these fetal grafts to facilitate healing are not known, they show that using fetal cells as a direct form of therapy may be a viable wound care option in the future.
Conclusion
Although quite a bit is known about the process of scarless fetal repair, many aspects of this unique type of healing still are not understood. Of particular concern is the fact that to date, no information is available about whether epithelial or mesenchymal stem cells are involved in regenerative fetal healing. However, with the development of new tools to study and identify stem cells and the increasing use of high-throughput analytical techniques such as gene array and proteomics, it is likely that in the coming years much more information will be uncovered about the mechanisms that allow fetal skin to heal perfectly. While the exact mechanisms behind scarless fetal healing are unknown, studies are beginning to show the feasibility of exploiting current knowledge about this process to benefit postnatal wound repair. Based on these studies, it is clear that learning more about regenerative healing in the fetus could have a tremendous impact on the future of wound care.
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