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Background: Skin scarring is associated with psychosocial distress and has a negative effect on quality of life. The transforming growth factor (TGF)-β family of cytokines plays a key role in scarring. TGF-β3 improves scar appearance in a range of mammalian species. This study was performed to assess the efficacy of intradermal avotermin (TGF-β3) for the improvement of scar appearance following scar revision surgery., Methods: Sixty patients (35 men and 25 women; age, 19 to 78 years; 53 Caucasians; scar length, 5 to 21 cm) received intradermal avotermin (200 ng/100 μl/linear cm wound margin) and placebo to outer wound segments immediately after, and again 24 hours after, complete (group 1) or staged (group 2) scar revision surgery. A within-patient design was chosen to control for interindividual factors that affect scarring. The primary efficacy variable was a total scar score derived from a visual analogue scale, scored by a lay panel from standardized photographs from months 1 through 7 following treatment., Results: : Primary endpoint data from the combined surgical groups showed that avotermin significantly improved scar appearance compared with placebo (total scar score difference, 21.93 mm; p = 0.04). Profilometry showed a greater reduction in scar surface area from baseline with avotermin treatment compared with placebo, significant in group 2 at months 7 and 12 (difference, 41.99 mm and 25.85 mm, respectively; p = 0.03 for both comparisons). Histologic analysis from group 2 showed that, compared with placebo treatment, collagen organization in avotermin-treated scars more closely resembled normal skin in 14 of 19 cases. Avotermin was well tolerated., Conclusion: Avotermin administration following scar revision surgery is well tolerated and significantly improves scar appearance compared with placebo., Clinical Question/level of Evidence: Therapeutic, I.(Figure is included in full-text article.).

Background: This study is a clinical characterization of keloid scars in an African population comprising three rural tribes with familial keloids. Site distribution, morphologic features, and other characteristics of the scars were studied to assess whether each tribe had a specific scar phenotype., Methods: Keloid scar clinics were set up at Soba Hospital in Khartoum, Sudan, for patient recruitment and management. In addition, familial keloid cases were recruited from rural tribal populations during field trips. A database including clinical and demographic data and digital photographs of all keloid cases was established. Statistical analysis was conducted using SPSS and SAS software., Results: One hundred eleven individuals with keloid scarring (67 male subjects and 44 female subjects) were recruited. Patients were predominantly from three multigenerational pedigrees (total of 38 nuclear families) afflicted with keloid scars residing in different rural regions of Sudan. Two distinct morphologic phenotypes of keloid scarring were observed. The first phenotype has been designated "superficial spreading" (horizontal) keloid and the second has been designated "raised" (vertical) keloid. Clinically significant features and statistically measurable morphologic parameters were compared among these phenotypes (p = 0.001). Furthermore, linear claw-like extensions of keloid (transgression) were noted to be significantly higher in the superficial spreading keloid phenotype (p = 0.03)., Conclusions: There is strong evidence of different phenotypes of keloid scarring. Two distinct phenotypes have been observed, described, and statistically verified. Each tribe demonstrated one particular phenotype, with two being superficial spreading and one being raised. Other significant clinical characteristics have been described. This is of significance in understanding both the clinical basis and the genetic basis of keloid scarring.

Background: Cutaneous scarring is affected by genetic, physiologic, and biochemical factors. These produce a continuum of scar types (i.e., keloid, hypertrophic, atrophic, contracted, and fine line) that can be symptomatic, aesthetically unsatisfactory, psychologically distressing, and functionally restrictive to the affected individual. Accurate scar assessment allows for quantification of scar evolution and management, and is key to evaluating the effectiveness of applied modulating therapies and treatments. Numerous objective instruments exist for the evaluation of different scar characteristics, but no consensus has been reached as to the most appropriate device. This review aims to explore the current range of noninvasive objective assessment tools available for cutaneous skin scarring, with specific emphasis on their application to research trials and clinical practice., Methods: An extensive search of the literature was completed to assemble comprehensive data surrounding the objective assessment of skin scars by both validation studies and clinical trials., Results: A wide range of tools exist to monitor cutaneous scar physical characteristics. Primarily, there are four parameters explored by these instruments: (1) color, including pigmentation and vascularity (e.g., laser Doppler); (2) surface area (e.g., three-dimensional scanning); (3) height/depth (e.g., ultrasonography); and (4) pliability (e.g., tonometry). Many studies appraise single instruments in specific scar patient groups with subjective comparator tools., Conclusions: There is no overall valid and reliable noninvasive objective assessment tool for measurement of cutaneous skin scar characteristics. Further studies are warranted that compare multiple, parameter-specific instruments in a single-sample group and across a range of scar types.

Background: Skin scars have a unique impact on patients' lives. Quantification with disease-specific patient-reported outcome measures is essential for assessing disease severity. This study aimed to develop and validate the first scar-specific patient-reported outcome measure., Methods: Instrument content was derived from qualitative interviews with scar patients. Quotes were identified from transcripts for use as instrument items. This draft measure was field tested in cognitive debriefing interviews. The final instrument was determined using Rasch analysis in a large-scale validation survey., Results: Five hundred sixty-seven potential items were extracted from interviews (n = 34 patients; 24 women; mean age, 35.7 years). Patients primarily reported physical symptoms and impacts on quality of life. Consequently, a symptom scale (16 items) and quality-of-life scale (36 items) were created. Cognitive debriefing (n = 16 patients; 10 women; mean age, 32.8 years) indicated the draft measure was relevant, clear, and practical. Two quality-of-life items, considered too extreme by patients, were deleted. Ten quality-of-life and three symptom items were removed as a result of the validation survey (n = 103 patients; 69 women; mean age, 35.5 years). Final Rasch analysis confirmed two unidimensional scales (p > 0.05) with good internal consistency (0.85 for the symptom scale and 0.93 for the quality-of-life scale). Reproducibility was adequate for the symptom scale (0.83) and good for the quality-of-life scale (0.89)., Conclusions: The Patient-Reported Impact of Scars Measure is the first scientifically rigorous, scar-specific, patient-reported outcome measure. It has two unidimensional scales with good psychometric and scaling properties. It is well accepted by patients and easy to use, and should prove valuable for assessing scar disease severity in clinical trials and in general and specialty clinics.

Background: There is a lack of rigorously validated patient-based outcomes measures of scarring. The aim of this study was to construct such a scale and demonstrate reliability and validity by applying the scale in a wide range of scarring samples., Methods: The Patient Scar Assessment Questionnaire with five subscales (i.e., Appearance, Symptoms, Consciousness, Satisfaction with Appearance, and Satisfaction with Symptoms) was constructed using multiple categorical response items. The Patient Scar Assessment Questionnaire was applied to various surgical samples (total scar assessments n = 667) at months 3, 6, and 12 after surgery (and preoperatively in the scar revision group) and tested for internal consistency, test-retest reliability, convergent validity, known group differences, and sensitivity, against widely accepted criteria from psychometric measurement science., Results: Subscales showed high internal consistency (Cronbach alpha, 0.73 to 0.93), except the Symptoms subscale. Test-retest reliability was high across all subscales (intraclass correlation coefficient, 0.74 to 0.87) across all groups except the scar revision group. Change in Patient Scar Assessment Questionnaire scores was significant between months 3 and 6 postoperatively (p < 0.001) and subscales demonstrated known group differences (p < 0.001). Convergent validity was demonstrated by significant moderate correlations with various measures of similar constructs (r = 0.26 to 0.61, p < 0.001)., Conclusions: The Patient Scar Assessment Questionnaire is a reliable and valid measure of the patient's perception of scarring, although the Symptoms subscale requires further refinement. Subscales can be used independently of each other to allow assessment of scar change in specific domains.

Background: Many surgical procedures are complicated by adhesions. These restrictive fibrotic bands form between normally separate gliding tissue layers, potentially impairing function. The authors tested the adhesion-modifying effect of a novel fibronectin-derived biomimetic biomaterial in a tendon-synovial complex injury model., Methods: The deep flexor tendons of digits 2 and 4 in the right forepaw of 15 New Zealand White rabbits were subjected to 5-mm-long partial tenotomies. Animals were randomized to receive biomaterial tubes enveloping the tendon injuries or left untreated. Digits, amputated at 2 weeks, were randomized to mechanical pullout assessments of adhesion strength or to quantitative histologic cellularity and immunohistochemical proliferation (Ki67) assessments., Results: The mean peak pullout force required to break the adhesions was reduced from 7.70 N (n = 6) in untreated digits to 0.31 N (n = 7) in biomaterial-treated digits (p = 0.001). The mean structural stiffness of the adhesions was also significantly reduced (p = 0.001). Histologically, treated and untreated digits demonstrated an equal incidence of adhesions. The treated adhesions were 55 percent less cellular at their surface than the untreated injured controls (p = 0.003). Treated tendons were 8 percent more cellular (with equal numbers of proliferating cells) at their surface and significantly more cellular within their bulk than positive controls (p

Background: The association between scarring and the depth of dermal injury or burn is clinically recognized but not quantified. The authors tested the hypothesis that there is a critical depth beyond which a fibrous scar develops., Methods: A novel jig produced a wound that was deep dermal at one end and superficial dermal at the other. Pilot studies in cadaveric and ex vivo breast skin confirmed the depth of injury. Healthy volunteers had a standardized dermal wound made on the lateral aspect of the hip. Digital photography recorded the surface appearance of wound healing and scar development. High-frequency ultrasound demonstrated the depth of the healing wound and subsequent scar in vivo., Results: One hundred thirteen human subjects participated in the clinical study. Mean length of follow up was 28.6 +/- 13.2 weeks. The deep dermal end of the wound healed with a visible scar and the superficial end had no visible residual mark after week 18. The initial length of injury was 51.3 +/- 0.6 mm, which reduced to a scar of 34.9 +/- 1.0 mm at 36 weeks (corresponding areas were 196.6 +/- 7.5 mm and 92.7 +/- 9.4 mm). High-frequency ultrasound analysis showed a gradual reduction in scar thickness at the deep end and no detectable scar at the shallow end. The transition point between scar and no scar marked the threshold depth for scarring. This was calculated as 0.56 +/- 0.03 mm, or 33.1 percent of normal hip skin thickness., Conclusions: The dermal scratch provides a well-tolerated, standardized, and reproducible wound model for investigating the healing response to dermal injury of different depths. There is a threshold depth of dermal injury at which scarring develops.

Background: Two theories exist regarding the revascularization of skin autografts: direct anastomosis between graft vessels and bed vessels, and ingrowth of bed vessels (angiogenesis) into the graft. This study characterizes revascularization, spatially and chronologically, in a murine skin autograft model using a double-labeling technique., Methods: Full-thickness (1 cm2) skin grafts were performed on adult male C57/Bl6 mice. After 48 hours, 60 hours, 3 days, 5 days, and 14 days (n = 3 mice per time point) terminal intracardiac perfusion with a fluorescein/dextran dye demonstrated vascular filling of graft blood vessels. Fluorescence immunohistochemistry of CD31+ endothelial cells allowed counting of total vessels and fluorescein perfusion quantification of patent vessels in the lateral graft area, central graft area, graft bed, and wound margins., Results: Initial filling of graft vessels was seen after 48 hours. This included vessels in the papillary dermis of the graft, and there was no significant difference in the percentage of filled vessels in the deep dermis of the graft compared with the papillary dermis of the graft. A rapid increase in vessel filling was seen between 48 and 60 hours in all areas of the graft. Vessel filling occurred mainly in the central area of the graft rather than in the lateral areas., Conclusions: The short time course of vessel filling indicates that the initial onset of revascularization is attributable to early anastomoses between graft and bed vessels, mainly in the central area of the graft. These findings have implications for both autograft revascularization in a clinical setting and in the development of tissue-engineered skin substitutes.

Background: Fibroproliferative disorders, such as Dupuytren's contracture of the hand, are characterized by excessive production of collagen. 5-Fluorouracil has been used to treat fibroproliferative disorders of the eye and skin and is thought to inhibit thymidylate synthetase blocking DNA replication. 5-Fluorouracil has been shown to down-regulate fibroblast proliferation and differentiation in vitro., Methods: This study investigated the dose-dependent effect of 5-fluorouracil on fibroblast extracellular matrix production. Fibroblasts were derived from tendon and primary Dupuytren's disease of the hand, a fibroproliferative disorder of the palmar aponeurosis (n = 4 patients). Total collagen synthesis was determined by means of the incorporation of radiolabeled proline. Fibroblast secretion of the profibrotic factor transforming growth factor-beta1 (TGF-beta1) was measured by a sandwich enzyme-linked immunosorbent assay. Gene expression of collagen types I and III and TGF-beta1 were quantified by means of reverse-transcriptase polymerase chain reaction assays., Results: The authors found that 5-fluorouracil caused a dose-dependent, selective, and specific decrease in collagen production by Dupuytren's fibroblasts compared with noncollagenous protein synthesis. By contrast, procollagen types I and III mRNA were unaffected by 5-fluorouracil treatment. These changes did not appear to be mediated by alterations in the endogenous secretion of TGF-beta1 or its autocrine effect on collagen metabolism., Conclusions: The clinical implication is that 5-fluorouracil could possibly reduce extracellular matrix production and therefore reduce recurrence of Dupuytren's disease of the hand.

Dupuytren's disease causes disability because of the development of finger flexion deformities, with distinct nodule and cord formation. This results in physical shortening of the diseased fascial tissue through a combination of cell-mediated contraction and matrix remodeling. It is this fixed tissue fabric shortening that prevents finger extension. In this experimental study, the relative contractile properties of Dupuytren nodule- and cord-derived fibroblasts were quantified in a culture force monitor model, in comparison with normal carpal ligament fibroblasts. Nine nodule, 10 cord, and four carpal ligament fibroblast cell lines were studied; each cell line was derived from a separate patient. The contractile forces generated by nodule and cord fibroblasts were significantly greater than the force generated by carpal ligament fibroblasts. There were also significant differences between nodule- and cord-derived fibroblasts, with the nodule cells demonstrating the greatest contractile force generation. The contraction profiles of both cord and nodule Dupuytren fibroblasts demonstrated delays in the attainment of tensional homeostasis, with an absence of a plateau phase by 20 hours. After the contraction phase, cell-seeded constructs were subjected to a series of four uniaxial mechanical overloads and cellular responses were monitored during each subsequent 30-minute period. Dupuytren nodule and cord fibroblast responses were significantly altered, compared with carpal ligament fibroblasts, exhibiting an increased and opposite response. Dupuytren fibroblasts, particularly nodule fibroblasts, exhibited increased force generation and a delay in reaching tensional homeostasis. The data suggest that these cells have an inherently higher basal tension and contractile ability. This results in increased shortening of the matrix, and the delay in reaching tensional homeostasis might exacerbate this response. These results represent a theoretical framework regarding the fundamental processes involved in the pathogenesis and progression of clinical flexion deformities in Dupuytren disease.

The anatomy and function of Cleland's ligaments--thought by the authors to require clarification because of the conflicting anatomic descriptions in the literature--are reviewed. A statistical representation of the structure of these ligamentous bundles was derived from the study of 16 fixed human cadaveric digits and five fresh cadaveric digits, all from different patients. The results demonstrate a large variation in anatomy. However, this anatomic heterogeneity is not indicative of an equally varied function. In general, it was found that the majority of Cleland's ligaments traversed a great distance adherent to the skin before actually inserting in the dermis. Over one-third of the dorsal fibers demonstrated a multiplanar organization, fanning out before inserting into the skin. In contrast, the ventral fibers did not fan out before inserting into the skin. Excision of these ventral fibers revealed a separate "ledgelike" plane of fibers arising from the fibrous flexor sheath and running in a straight line perpendicular to the long axis of the digit. A branch of the digital nerve was found to pierce this ligamentous layer in the majority of digits studied. Unlike those of previous reports, the results of the present study suggest that the ligaments have a constant function of anchoring the skin of the digit on both the dorsal and ventral aspects, thereby preventing the displacement of skin during flexion of the digits. All previous studies failed to make this conclusion. The anatomic relationship to the digital neurovascular bundle also suggests that Cleland's ligaments may stabilize the digital vessels during flexion. In conclusion, Cleland's ligaments are highly functional structures and are essential for normal cutaneous stability during digital movements.

The effect of loading on the early cellular response to tendon injury was studied in a partial tenotomy (window) model in the extensor digitorum longus of the rat. Normal use of the limb was allowed, such that tendons were either loaded (group 1) or unloaded (group 2) when a distal tenotomy was performed. Thirty-four male Fischer rats were used. The tendons were harvested at intervals of 6 hours and 1, 3, 5, and 7 days. Quantitative cell counts were performed on light microscopic cross-sections of the window and tendon substance together with recording of cell orientation. Matrix changes in the tendon, window, and tendon-window junction were observed on transmission electron microscopy. There was a rapid and extensive change in the tendon structure with rapid loss of definition of the window edge, and an increase in cellularity of the tendon substance. The loaded tendons demonstrated less cellularity at 5 days (window cell density 3.48 +/- 0.49 cells per 0.01 mm2) with better longitudinal orientation of cells and matrix than the unloaded tendons(8.38 +/- 1.1 cells per 0.01 mm2). The numbers of inflammatory cells in both groups were roughly comparable (5 days: loaded 0.411 +/- 0.071 cells per 0.01 mm2; unloaded 0.554 +/- 0.11 cells per 0.01 mm2), but the unloaded windows had more fibroblasts at 5-day and 7-day stages (5 days: loaded 3.08 +/- 0.44 cells per 0.01 mm2; unloaded 7.82 +/- 1.0 cells per 0.01 mm2; p < 0.016). Cell counts in the tendon substance were also higher in the unloaded (3.99 +/- 0.44 cells per 0.01 mm2) than the loaded (1.95 +/- 0.45 cells per 0.01 mm2) tendons at 5 days. This study demonstrated that the cellular response after injury in this extensor tendon model is affected by tensile loading, there being increased cell numbers in both the window and tendon substance in the unloaded tendon.

The external nose is generally considered to have a relatively static shape. Movement of the nose and the potential for change of external shape and the internal airway have been assessed by (1) cadaver dissection and (2) dynamic studies during a standardized series of facial expressions in 13 subjects; video recording of the movement of skin markers, electromyography, and moving magnetic resonance images. A standard description of muscle anatomy is presented. The dynamic investigations indicated the following. Video analysis showed the components of muscle action: dilatation, constriction of the nostril, depression of the tip, vertical contraction in the bridge, and elevation of the alar, in different expressions. Electromyography confirmed muscle actions during expression and phonation. Magnetic resonance imaging demonstrated large changes in the external shape of the nose and nasal aperture due to muscle actions. Muscle function should be given greater consideration in aesthetic and cleft rhinoplasty.

Linear and area measurements on the surface contour of the face have been recorded in a variety of chosen facial postures using surface laser scanning techniques on healthy volunteers. Subjects were scanned before and after active and voluntary (against resistance) movements. Quantitative measurements of changes in these lengths and areas were made by computer integration to provide an impression of the changes that accompany facial expression. Lip movements were found to be associated with dimensional changes at all facial locations tested, imposed by the action of the underlying muscles. The system has a potential value for dynamic monitoring of facial movement.

After injury, adhesions may develop between the digital flexor tendons and their sheaths. Fibroblasts are key cells in this fibrotic adhesive process, and two possible sources for these cells are the synovial sheath and the endotenon tissue (tendon core). Fibroblasts seeded into a collagen lattice will contract the collagen. This fibroblast-populated collagen lattice contraction was used to investigate the ability of the fibroblasts from the synovial sheath and endotenon to reorganize collagen (an important function in the formation of adhesions). Endotenon and synovial fibroblasts isolated from 30 animals were used in the study. Synovial fibroblasts produced significantly greater collagen lattice contraction compared with endotenon fibroblasts (p < 0.05). The possibility of preventing collagen lattice contraction with a single, nontoxic 5-minute treatment of the fibroblast-populated collagen lattices with the antimetabolite 5-fluorouracil was investigated. Compared with controls the degree of fibroblast-populated collagen lattice contraction was significantly inhibited (p < 0.05) with the use of 5-fluorouracil for endotenon and synovial cells. These results demonstrate the potential for locally targeted therapy in tendon healing. Because of the different contractile properties of the two cell lines, a change in the balance between intrinsic and extrinsic healing might be achieved with this method of therapy; in turn, this might lead to better functional results following surgery.