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Hypertrophic scar pain, pruritus, and paresthesia symptoms are major and particular concerns for burn patients. However, because no effective and satisfactory methods exist for their alleviation, the clinical treatment for these symptoms is generally considered unsatisfactory. Therefore, their risk factors should be identified and prevented during management. We reviewed the medical records of 129 postburn hypertrophy scar patients and divided them into two groups for each of three different symptoms based on the University of North Carolina "4P" Scar Scale: patients with scar pain requiring occasional or continuous pharmacological intervention (HSc pain, n = 75) vs. patients without such scar pain (No HSc pain, n = 54); patients with scar pruritus requiring occasional or continuous pharmacological intervention (HSc pruritus, n = 63) vs. patients without such scar pruritus (No HSc pruritus, n = 66); patients with scar paresthesia that influenced the patients' daily activities (HSc paresthesia, n = 31) vs. patients without such scar paresthesia (No HSc paresthesia, n = 98). Three multivariable logistic regression models were built, respectively, to identify the risk factors for hypertrophic burn scar pain, pruritus, and paresthesia development. Multivariable analysis showed that hypertrophic burn scar pain development requiring pharmacological intervention was associated with old age (odds ratio [OR] = 1.046; 95% confidence interval [CI], 1.011-1.082, p = 0.009), high body mass index (OR = 1.242; 95%CI, 1.068-1.445, p = 0.005), 2-5-mm-thick postburn hypertrophic scars (OR = 3.997; 95%CI, 1.523-10.487, p = 0.005), and 6-12-month postburn hypertrophic scars (OR = 4.686; 95%CI, 1.318-16.653, p = 0.017). Hypertrophic burn scar pruritus development requiring pharmacological intervention was associated with smoking (OR = 3.239; 95%CI, 1.380-7.603; p = 0.007), having undergone surgical operation (OR = 2.236; 95%CI, 1.001-4.998; p = 0.049), and firm scars (OR = 3.317; 95%CI, 1.237-8.894; p = 0.017). Finally, hypertrophic burn scar paresthesia development which affected the patients' daily activities was associated with age (OR = 1.038; 95%CI, 1.002-1.075; p = 0.040), fire burns (OR = 0.041; 95%CI, 0.005-0.366; p = 0.004, other burns vs. flame burns), and banding and contracture scars (OR = 4.705; 95%CI, 1.281-17.288, p = 0.020)., (© 2018 by the Wound Healing Society.)

Hypertrophic scar is a major clinical outcome of deep-partial thickness to full thickness thermal burn injury. Appropriate animal models are a limitation to burn research due to the lack of, or access to, animal models which address the endpoint of hypertrophic scar. Lower species, such as rodents, heal mainly by contracture, which limits the duration of study. Higher species, such as pigs, heal more similarly to humans, but are associated with high cost, long duration for scar development, challenges in quantifying scar hypertrophy, and poor manageability. Here, we present a quantifiable deep-partial thickness burn model in the rabbit ear. Burns were created using a dry-heated brass rod for 10 and 20 seconds at 90 °C. At the time of eschar excision on day 3, excisional wounds were made on the contralateral ear for comparison. Burn wound progression, in which the wound size expands over time is a major distinction between excisional and thermal injuries, was quantified at 1 hour and 3 days after the injuries using calibrated photographs and histology and the size of the wounds was found to be unchanged from the initial wound size at 1 hour, but 10% in the 20 seconds burn wounds at 3 days. A quantifiable hypertrophic scar, measured by histology as the scar elevation index, was present in both 20 seconds burn wounds and excisional wounds at day 35. ImageJ measurements revealed that the 20 seconds burn wound scars were 22% larger than the excisional wound scars and the 20 seconds burn scar area measurements from histology were 26% greater than in the excisional wound scar. The ability to measure both burn progression and scar hypertrophy over a 35-day time frame suits this model to screening early intervention burn wound therapeutics or scar treatments in a burn-specific scar model., (© 2017 by the Wound Healing Society.)

Dermal papilla cells (DPCs) show phenotypic plasticity during wound healing. The multipotency of DPCs is well recognized, but the signaling pathways that regulate the differentiation of these cells into fibroblasts are poorly understood. A preliminary experiment showed that transforming growth factor beta1 (TGF-β1) can induce DPCs to differentiate into fibroblast-like cells, which suggests that DPCs may be a source of wound-healing fibroblasts. Bone morphogenetic protein-7 (BMP-7), a member of the TGF-β superfamily, can prevent and reverse fibrosis by counteracting the TGF-β1-mediated profibrotic effect. To determine whether BMP-7 attenuates the TGF-β1-induced differentiation of DPCs into fibroblasts, we established an in vitro system for DPC differentiation and recorded the gene expression patterns that distinguished DPCs from fibroblasts. The proportion of fibroblast-like cells was significantly enhanced in DPCs treated with TGF-β1, as evidenced by immunocytochemistry, flow cytometry, quantitative real-time reverse transcriptase polymerase chain reaction, and Western blot analysis. BMP-7 and TGF-β1 administration substantially decreased fibroblast-like differentiation, indicating inhibition of TGF-β1-induced differentiation. The antagonistic BMP-7- and TGF-β1-activated signaling pathways can be used to promote wound healing or suppress hypertrophic scarring., (© 2013 by the Wound Healing Society.)

Hypertrophic scars arise when there is an overproduction of collagen during wound healing. These are often associated with poor regulation of the rate of programmed cell death (apoptosis) of the cells synthesizing the collagen or by an exuberant inflammatory response that prolongs collagen production and increases wound contraction. Severe contractures that occur, e.g., after a deep burn, can cause loss of function especially if the wound is over a joint such as the elbow or knee. Recently, we have developed a morphoelastic mathematical model for dermal repair that incorporates the chemical, cellular, and mechanical aspects of dermal wound healing. Using this model, we examine pathological scarring in dermal repair by first assuming a smaller than usual apoptotic rate for myofibroblasts, and then considering a prolonged inflammatory response, in an attempt to determine a possible optimal intervention strategy to promote normal repair, or terminate the fibrotic scarring response. Our model predicts that in both cases it is best to apply the intervention strategy early in the wound healing response. Further, the earlier an intervention is made, the less aggressive the intervention required. Finally, if intervention is conducted at a late time during healing, a significant intervention is required; however, there is a threshold concentration of the drug or therapy applied, above which minimal further improvement to wound repair is obtained., (© 2012 by the Wound Healing Society.)

The mechanophysiological conditions of injured skin greatly influence the degree of scar formation, scar contracture, and abnormal scar progression/generation (e.g., keloids and hypertrophic scars). It is important that scar mechanobiology be understood from the perspective of the extracellular matrix and extracellular fluid, in order to analyze mechanotransduction pathways and develop new strategies for scar prevention and treatment. Mechanical forces such as stretching tension, shear force, scratch, compression, hydrostatic pressure, and osmotic pressure can be perceived by two types of skin receptors. These include cellular mechanoreceptors/mechanosensors, such as cytoskeleton (e.g., actin filaments), cell adhesion molecules (e.g., integrin), and mechanosensitive (MS) ion channels (e.g., Ca(2+) channel), and sensory nerve fibers (e.g., MS nociceptors) that produce the somatic sensation of mechanical force. Mechanical stimuli are received by MS nociceptors and signals are transmitted to the dorsal root ganglia that contain neuronal cell bodies in the afferent spinal nerves. Neuropeptides are thereby released from the peripheral terminals of the primary afferent sensory neurons in the skin, modulating scarring via skin and immune cell functions (e.g., cell proliferation, cytokine production, antigen presentation, sensory neurotransmission, mast cell degradation, vasodilation, and increased vascular permeability under physiological or pathophysiological conditions). Mechanoreceptor or MS nociceptor inhibition and mechanical force reduction should propel the development of novel methods for scar prevention and treatment., (© 2011 by the Wound Healing Society.)

Abnormal scarring occurring after wounds and burns remains a major source of functional and cosmetic disorders. The dermal part of the skin is recognized as playing a major role in the contraction process. The skin dermis may be involved in superficial wounds, but when the basal membrane and the sources of keratinocytes, like hair follicles and adnexa, are left intact, little visible scarring is observed. The skin elasticity may be preserved, even when the extracellular matrix is somehow altered. On the opposite extreme, in wounds of extended depth, the loss of dermal component results in the absence of elasticity and fibroblastic cell proliferation, leading to hypertrophy and contracture. These phenomena may be explained either by differences in cell populations, by extracellular matrix reactions to different stimuli, or by chemical control of interactions between cells and matrix., (© 2011 by the Wound Healing Society.)

Myofibroblasts play a key role in the wound-healing process, promoting wound closure and matrix deposition. These cells normally disappear from granulation tissue by apoptosis after wound closure, but under some circumstances, they persist and may contribute to pathological scar formation. Myofibroblast differentiation and apoptosis are both modulated by cytokines, mechanical stress, and, more generally, cell-cell and cell-matrix interactions. Tissue repair allows tissues and organs to recover, at least partially, functional properties that have been lost through trauma or disease. Embryonic skin wounds are repaired without scarring or fibrosis, whereas skin wound repair in adults always leads to scar formation, which may have functional or esthetic consequences, as in the case of hypertrophic scars, for example. Skin wound repair involves a precise remodeling process, particularly in the dermal compartment, during which fibroblasts/myofibroblasts play a central role. This article reviews the origins of myofibroblasts and their role in normal and pathological skin wound healing. This article focuses on traumatic skin wound healing, but largely, the same mechanisms apply in other physiological and pathological settings. Tissue healing in other organs is examined by comparison, as well as the stromal reaction associated with cancer. New approaches to wound/scar therapy are discussed., (© 2011 by the Wound Healing Society.)

Early gestation fetal wounds heal without scar formation. Understanding the mechanism of this scarless healing may lead to new therapeutic strategies for improving adult wound healing. The aims of this study were to develop a human fetal wound model in which fetal healing can be studied and to compare this model with a human adult and scar tissue model. A burn wound (10 x 2 mm) was made in human ex vivo fetal, adult, and scar tissue under controlled and standardized conditions. Subsequently, the skin samples were cultured for 7, 14, and 21 days. Cells in the skin samples maintained their viability during the 21-day culture period. Already after 7 days, a significantly higher median percentage of wound closure was achieved in the fetal skin model vs. the adult and scar tissue model (74% vs. 28 and 29%, respectively, p<0.05). After 21 days of culture, only fetal wounds were completely reepithelialized. Fibroblasts migrated into the wounded dermis of all three wound models during culture, but more fibroblasts were present earlier in the wound area of the fetal skin model. The fast reepithelialization and prompt presence of many fibroblasts in the fetal model suggest that rapid healing might play a role in scarless healing.

To explore further the role of substance P (SP) in wound healing and scar formation, SP concentrations in wounds of scalded rats were assayed. Expressions of apoptosis-associated genes in fibroblasts cultured with SP were detected. SP concentrations in superficial wounds increased earlier than those in deep wounds. SP was associated with an increased proliferation and a decreased apoptosis of fibroblasts. It had a greater influence on keloid fibroblasts than on hypertrophic scar fibroblasts by elevating the expression of proliferating cell nuclear antigen and BCL-2 in fibroblasts. Spantide completely suppressed the effects of SP on hypertrophic scar fibroblasts, and partly inhibited its effects on keloid scar fibroblasts. SP may play an important role in wound healing by promoting wound fibroblast proliferation and inhibiting apoptosis. It may also participate in pathological scar formation by modulating the expression of apoptosis-associated genes. SP is postulated to play a dual role in wound repair.

The mechanism of hypertrophic scar reduction using silicone gel sheeting remains elusive. We hypothesize that the decrease in scar formation is due to occlusion and homeostasis of the barrier layer. Using an established model of hypertrophic scarring, rabbits were divided into four groups and scars were tape-stripped or occluded with Kelocote, Cavilon, or Indermil, with each rabbit serving as its own internal control. All wounds were harvested on day 28 and examined histologically to measure the scar elevation index (SEI), epithelial thickness, and cellularity. Immunohistochemistry fluorescence was used to quantify inflammation in the dermis. Transepidermal water loss (TEWL) was measured for each occlusive agent and tape stripping. Ultrastructural analysis was performed by electron microscopy. Kelocote, Cavilon, and Indermil all significantly decreased SEI when compared with controls. Each of the occlusive treatments was shown to decrease TEWL while tape stripping increased TEWL. Tape stripping significantly increased the SEI, epithelial thickness, and cellularity. Immunostaining for macrophages showed increased density of inflammatory cells in the tape-stripped scars. Under electron microscopy, the tape-stripped wounds displayed extensive inflammation and keratinocyte damage. Both unwounded skin and occlusion-treated scars did not display these characteristics. In conclusion, hypertrophic scarring was reduced regardless of occlusive method used. Furthermore, repeated disruption of the permeability barrier by tape stripping led to an increase in scarring. Ultrastructural analysis suggests that occluded wounds may be in an advanced state of wound repair. Occlusion may mediate its effects through establishing homeostasis of the epidermal barrier layer.

Hypertrophic scarring remains a major problem for patients who have suffered from surgeries or burns. Vascularization plays an important role in the early phase of hypertrophic scarring. Therefore, the inhibition of angiogenesis might be used as a preventive strategy. In this study, we assessed the effect of anti-angiogenesis resulting from adenovirus-mediated METH1 (metalloprotease and thrombospondin1) gene expression on the hypertrophic scar formation in a rabbit ear model of hypertrophic scarring. We first investigated the number of microvessel and microcirculatory perfusion in untreated scars on days 10, 30, 60, and 90 after epithelialization. Then, we examined the effect of anti-angiogenesis by adenovirus-mediated METH1 expression on hypertrophic scar formation by calculating the scar elevation index, counting the microvessel and argyrophilic nucleolar organizer region particle, and detecting the amount of collagen on days 30 and 60 after treatment. We found that untreated scar tissues at the proliferative phase (days 10-60 after epithelialization) had a significantly higher density of microvessel and microcirculatory perfusion than those at the mature phase (day 90 after epithelization) (both p<0.05). On days 30 and 60 after treatment, the hypertrophic scar formation was significantly inhibited in the treatment group. There was significantly reduced scar elevation index, microvessel count, number of argyrophilic nucleolar organizer region, and total collagen content for treated scars. Our results demonstrate that METH1 has a markedly inhibitive effect on the formation of hypertrophic scar, and may thus have a promising application in the prevention of human hyperthropic scars.

Hypertrophic scar and keloids are fibroproliferative disorders of the skin which occur often unpredictably, following trauma and inflammation that compromise cosmesis and function and commonly recur following surgical attempts for improvement. Despite decades of research in these fibrotic conditions, current non-surgical methods of treatment are slow, inconvenient and often only partially effective. Fibroblasts from these conditions are activated to produce extracellular matrix proteins such as collagen I and III, proteoglycans such as versican and biglycan and growth factors, including transforming growth factor-beta and insulin like growth factor I. However, more consistently these cells produce less remodeling enzymes including collagenase and other matrix metalloproteinases, as well as the small proteoglycan decorin which is important for normal collagen fibrillogenesis. Recently, the systemic response to injury appears to influence the local healing process whereby increases in Th2 and possibly Th3 cytokines such as IL-2, IL-4 and IL-10 and TGF-beta are present in the circulating lymphocytes in these fibrotic conditions. Finally, unique bone marrow derived cells including mesenchymal and endothelial stem cells as well as fibrocytes appear to traffic into healing wounds and influence the healing tissue. On this background, clinicians are faced with patients who require treatment and the pathophysiologic basis as currently understood is reviewed for a number of emerging modalities.

In order to identify a means to reduce scar formation of the skin after incision, this study examined the effect of local administration of basic fibroblast growth factor (bFGF) in humans. bFGF was administered to a sutured wound immediately after an operation. The drug was injected once into the dermis of the margins of wounds using a 27G needle or rinsing after performing dermostitches. The lengths of the treated wounds varied from 1 to 32 cm, and the subjects were 2-86 years old. Sutured wounds after excision of skin tumors from the face, trunk, and limbs and sutured wounds such as those at the donor sites of full-thickness skin grafts were treated with low-dose bFGF injections (0.1 microg/cm wound; Group 2), high-dose bFGF injections (1 microg/cm wound; Group 3), and rinsed with high-dose bFGF (1 microg/cm wound; Group 4). No patient treated with bFGF had hypertrophic scars, while some patients had hypertrophic or very wide scars in the control group (Group 1), and the ratios of minimum scarring of Group 2 (p<0.001), Group 3 (p<0.0001), and Group 4 (p<0.0001) were statistically significantly higher than those of Group 1. Postoperative administration of bFGF inhibited hypertrophic scarring and widening of remaining scars without any serious side effects.

Hypertrophic scarring after burns is an unsolved problem and remains as devastating today as it was in the 40s and it may be that the main reason for this is the lack of an accepted, useful animal model. The female, red Duroc pig was described as a model of hypertrophic scarring nearly 30 years ago but then vanished from the literature. This seemed strange since the authors reported that 12 of 12 pigs developed thick scar. In the mid 90s we explored the model and found that, indeed, the red Duroc pig does make thick scar. Other authors have established that the Yorkshire pig does not heal in this fashion so there is the possibility of a same species control. We have continued to explore the Duroc/Yorkshire model and herein describe our experiences. Is it a perfect model of hypertrophic scarring? No. Is it a useful model of hypertrophic scarring? Time will tell. We have now obtained gene expression data from the Duroc/Yorkshire model and analysis is underway.

Healed partial thickness wounds including burns and donor sites cause hypertrophic scar formation and patient discomfort. For many patients with hypertrophic scars, pruritus is the most distressing symptom, which leads to wound excoriation and chronic wound formation. In spite of the clinical significance of abnormal innervation in scars, the nervous system has been largely ignored in the pathophysiology of hypertrophic scars. Evidence that neuropeptides contribute to inflammatory responses to injury include inflammatory cell chemotaxis, cytokine and growth factor production. The neuropeptide substance P, which is released from nerve endings after injury, induces inflammation and mediates angiogenesis, keratinocyte proliferation, and fibrogenesis. Substance P activity is tightly regulated by neutral endopeptidase (NEP), a membrane bound metallopeptidase that degrades substance P at the cell membrane. Altered substance P levels may contribute to impaired cutaneous healing responses associated with diabetes mellitus or hypertrophic scar formation. Topical application of exogenous substance P or an NEP inhibitor enhances wound closure kinetics in diabetic murine wounds suggesting that diabetic wounds have insufficient substance P levels to promote a neuroinflammatory response necessary for normal wound repair. Conversely, increased nerve numbers and neuropeptide levels with reduced NEP levels in human and porcine hypertrophic scar samples suggest that excessive neuropeptide activity induces exuberant inflammation in hypertrophic scars. Given these observations about the role of neuropeptides in cutaneous repair, neuronal modulation of repair processes at two extremes of abnormal wound healing, chronic non-healing ulcers in type II diabetes mellitus and hypertrophic scars in deep partial thickness wounds, may provide therapeutic targets.

The rat incisional wound is an important model for wound scarring research, but it is also difficult to mimic thick human incisional scarring. We hypothesized that such a thick linear scarring can be generated by inserting a gelatin sponge into a rat excisional wound. The results demonstrated that the new wound model could generate 11 times wider wound width (at day 7) and 4-5 times wider scar width (at days 14, 21, and 60), respectively, than the widths of incisional wounds (p<0.05) in adult Sprague-Dawley rats. The thick linear scar created was grossly apparent in contrast to the grossly unobvious scar of the incisional wound, and a regular linear shape could be achieved with a similar scar width along the wound. The mechanism study revealed several factors that might contribute to the enhanced scarring, including delayed wound healing, enhanced inflammation, increased expression of fibrotic factors, and abnormal wound remodeling due to the insertion of the gelatin sponge. These results indicate that the new wound model of thick linear scar might be valuable for clinically relevant study of scar manipulation. Moreover, this model may serve as a tool for studying gene-mediated tissue regeneration during wound repair using inserted gelatin sponge as a gene carrier.

Hypertrophic scarring, which results from excessive collagen deposition at sites of dermal wound repair, can be functionally and cosmetically debilitating to the surgical patient. Pharmacological regulation of collagen synthesis and deposition is a direct approach to the control of scar tissue formation. One of the key steps in collagen stabilization is the cleavage of the C-terminal propeptide from the precursor molecule to form collagen fibrils, a reaction catalyzed by procollagen C-proteinase (PCP). We tested the ability of a PCP inhibitor to reduce hypertrophic scar formation in a rabbit ear model. After the placement of four, 7-mm dermal wounds on each ear, New Zealand white rabbits received PCP inhibitor subcutaneously in the left ear at four time points postwounding: days 7, 9, 11, 13 (early treatment; n=20 wounds) or days 11, 13, 15, 17 (late treatment; n=20 wounds). The right ear of each animal served as a control (vehicle alone). Wounds were harvested on postoperative day 28 and scar hypertrophy quantified by measurement of the scar elevation index. Early treatment of wounds with PCP inhibitor did not reduce scar formation compared with controls (p>0.05). However, late treatment resulted in a statistically significant reduction in the scar elevation index (p<0.01). Our results point not only to the potential use of PCP inhibitors to mitigate hypertrophic scarring but also to the temporal importance of drug delivery for antiscarring therapy.

Fibrocytes are a unique leukocyte subpopulation implicated in wound healing. They are derived from peripheral blood mononuclear cells, display fibroblast-like properties, and synthesize extracellular matrix macromolecules. This study investigated whether fibrocytes are present in healing burn wounds and whether the number of fibrocytes in tissue correlates with the degree of burn injury and the development of hypertrophic scar. Proteins extracted from cultured fibrocytes and nonadherent lymphocytes were found to be similar using two-dimensional gel electrophoresis and quite distinct from those obtained from fibroblasts. However, one protein, identified as leukocyte-specific protein 1 using mass spectrometric peptide mapping, was found in significantly larger amounts in fibrocytes than in lymphocytes but was undetectable in fibroblasts. Double immunostaining with antibodies to leukocyte-specific protein-1 and to the N-terminal propeptide of type I collagen was performed on cryosections of hypertrophic scar, mature scar, and normal skin. Fibrocytes were seen in scar tissue as dual-labeled spindle-shaped cells but were absent from normal skin. Moreover, the number of fibrocytes was higher in hypertrophic than in mature scar tissue. We conclude that fibrocytes, which have been reported to be antigen-presenting cells, are recruited to wounds following extensive burn injury and could potentially upregulate the inflammatory response and synthesize collagen and other matrix macromolecules, thus contributing to the development of hypertrophic scarring.

Hypertrophic scars result from excessive collagen deposition at sights of healing dermal wounds and can be functionally and cosmetically problematic. Pharmacological regulation of collagen synthesis and deposition is a direct approach to the control of scar tissue formation. We tested the ability of the phenanthrolinone derivative FG-1648 (in 0.5% Carbopol 971 PNF gel, pH 6.5), a prolyl 4-hydroxylase inhibitor, to reduce hypertrophic scar formation in a rabbit ear hypertrophic scar model. New Zealand White rabbits were divided into two treatment groups (n = 12 wounds per group with an equal number of controls): low-dose group: 0.5% FG-1648; high-dose group: 1% FG-1648. Left ears were used for treatment and right ear for control. Four 7-mm dermal ulcer wounds were made on each ear. The inhibitor was topically applied to the wound at the time of wounding and once daily up to postoperative day 7. Wounds were harvested at postoperative day 28 and scar hypertrophy quantified by measurement of the scar elevation index. All wounds showed complete healing. Treatment of wounds with 1% prolyl 4-hydroxylase inhibitor decreased the scar elevation index by 26% compared to control wounds (p < 0.01). Wounds treated with 0.5% FG-1648 inhibitor showed no difference in scar elevation compared to control wounds. These results suggest that inhibition of prolyl 4-hydroxylase may be a suitable agent for topical treatment for the prevention of hypertrophic scar tissue.

Recent studies have suggested that the regulation of apoptosis during wound healing is important in scar establishment and the development of pathological scarring. In this study, we demonstrate that keloid fibroblasts can be identified as apoptotic cells because of their highly condensed chromatin and discrete nuclear fragments. To further reveal the phenomenon of apoptosis, we quantified the number of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in surgically resected tissues of keloids (N = 10), hypertrophic scars (N = 10), normal healed flat scars (N = 10), and dermatofibroma (N = 10). The number of TUNEL-positive cells was relatively low, but was significantly higher for the keloid group compared with the normally healed flat scar group (p = 0.004), suggesting reduced cell survival and increased apoptotic cell death in a subpopulation of keloid fibroblasts. Furthermore, the number of TUNEL-positive cells was significantly higher for the keloid group compared with the dermatofibroma group (p = 0.044), suggesting that a subpopulation of keloid fibroblasts may suppress tumorgenicity at a greater rate than dermatofibroma by undergoing cell death. Hypertrophic scars had significantly higher levels of apoptosis than normally healed flat scars (p = 0.033). Therefore, these results suggest that selected fibroblasts in keloids and hypertrophic scars undergo apoptosis, which may play a role in the process of pathological scarring.

Hypertrophic scarring is devastating for the patient, however the pathophysiology and treatment remain unknown after decades of research. The process follows deep dermal injury, occurs only on certain body parts, does not occur in the early fetus or in animals, and is a localized event. This suggests that an anatomic structure in human, deep dermis may be involved. The dermis is a matrix perforated by cones containing many structures including skin appendages and fat domes. We hypothesized that studying the cones might reveal a structure related to scarring. We examined tangential wounds from various body parts on human cadavers along with skin histology from various human body parts, the early fetus, partial thickness burns, hypertrophic scars, and two other species-rats and rabbits. We found that the cones may in fact be the structure. They exist where hypertrophic scar occurs-cheek, neck, chest, abdomen, back, buttock, arm, forearm, dorsal hand, thigh, leg, dorsal foot, helix and ear lobe. They do not exist where hypertrophic scar does not occur-scalp, forehead, concha, eyelid, palm, early fetus, and in rat, or rabbit. It also became apparent that the cones have been omitted from most considerations of skin histology. We suggest that the cones need to be studied in relation to hypertrophic scarring and restored to skin diagrams.