Duncan A. McGrouther

Molecular dissection of abnormal wound healing processes resulting in keloid disease

Keloids are locally aggressive scars that typically invade into healthy surrounding skin and cause both physical and psychosocial distress to the patient. These pathological scars occur following minimal skin trauma after a variety of causes including burns and trauma. Although the pathogenesis of keloid disease is not well understood, it is considered to be the end product of an abnormal healing process. The aim of this review was to investigate the molecular and cellular pathobiology of keloid disease in relation to the normal wound healing process. The molecular aberrances in keloids that correlate with the molecular mechanisms in normal wound healing can be categorized into three groups: (1) extracellular matrix proteins and their degradation, (2) cytokines and growth factors, and (3) apoptotic pathways. With respect to cellular involvements, fibroblasts are the most well‐studied cell population. However, it is unclear whether the fibroblast is the causative cell; they are modulated by other cell populations in wound repair, such as keratinocytes and macrophages. This review presents a detailed account of individual phases of the healing process and how they may potentially be implicated in aberrant raised scar formation, which may help in clarifying the mechanisms involved in keloid disease pathogenesis.

Epidemiological evaluation of Dupuytren's disease incidence and prevalence rates in relation to etiology.

Dupuytren’s Disease (DD) is a common, fibroproliferative disorder affecting the palmar surface of the hands which is often irreversible and progressive. Understanding the epidemiology of DD is important in order to provide clues to its etiopathogenesis. This review aims to evaluate the epidemiological studies carried out in DD since 1951. Studies evaluating the epidemiology of DD were searched using Medline, Pubmed, and Scopus which dated back from 1951 to current date. Inclusion criteria were any studies investigating the prevalence or incidence of DD in any population group. A total of 620 articles were cited. Forty-nine studies were subsequently identified as relevant to evaluating the epidemiology of DD. The prevalence of DD in all studies increased with age with a male to female ratio of approximately 5.9:1. Prevalence rates ranged from 0.2% to 56% in varying age, population groups, and methods of data collection. The highest prevalence rate was reported in a study group of epileptic patients. Although, only one study calculated the incidence (as opposed to prevalence) of DD to be equal to 34.3 per 100,000 men (0.03%). In conclusion, the prevalence of DD in different geographical locations is extremely variable, and it is not clear whether this is genetic, environmental, or a combination of both. The majority of the prevalence studies have been conducted in Scandinavia or the UK, and the vast changes in population structure, the changes in prevalence of associated diseases, and the change in diagnostic criteria of DD makes understanding the epidemiology of this condition difficult.

Fibroblasts from the growing margin of keloid scars produce higher levels of collagen I and III compared with intralesional and extralesional sites: clinical implications for lesional site-directed therapy.

Background  Overproduction of collagen and its abnormal assembly are hallmarks of keloid scars. Type I/III collagen ratios are altered in keloids compared with normal skin. Fibroblasts from different sites in keloid tissue, perilesional compared with intralesional and extralesional sites, show differential apoptosis and contraction. Additionally, early vs. later cell culture passages display differential collagen expression. We therefore hypothesize that keloid fibroblasts from the growing margin of the keloid express higher levels of collagen type I and III, and that collagen production is altered by extended cell culture passage.

Current scales for assessing human scarring: A review

Patients can have wide-ranging problems related to scars, in terms of cosmesis, function, symptoms, psychological problems and overall quality of life issues. A range of treatments have been recommended for problematic scarring, however it has been acknowledged that the evidence base for most of the recommendations for scar therapy is limited, with few studies using validated measures of scar assessment in generating data. This review critically evaluates the subjective scar assessment scales developed to date and provides an insight into developments required in this area for the future. The principles of psychometric theory are discussed as a means of developing reliable and valid outcome measures and these are also applicable for measuring outcomes in other fields of plastic surgery research.

Management of Dupuytren's Disease – Clear Advice for an Elusive Condition

Dupuytrens disease is a progressive fibroproliferative disorder of an unknown origin affecting the hands causing permanent flexion contracture of the digits. Significant risk factors for development of Dupuytrens disease include old age, male sex, white northern European extraction, presence of positive family history of Dupuytrens disease, and diabetes mellitus. The disease also seems to deteriorate rapidly in those cases showing young age of onset and additional fibromatosis affecting the back of the hands, soles of the feet and the penis. Although there is no cure, patients with Dupuytrens disease of the hand may gain a significant functional benefit following surgical improvement or correction of the deformity. With realistic expectations, timely and appropriate surgical technique in a specialist centre, and attention to postoperative recovery and rehabilitation (occupational therapy and physiotherapy support), a beneficial outcome can be achieved in most cases.

The Patient Scar Assessment Questionnaire: A Reliable and Valid Patient-Reported Outcomes Measure for Linear Scars

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 &agr;, 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.

Current tools for noninvasive objective assessment of skin scars.

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.

Avotermin for scar improvement following scar revision surgery: a randomized, double-blind, within-patient, placebo-controlled, phase II clinical trial.

Background: Skin scarring is associated with psychosocial distress and has a negative effect on quality of life. The transforming growth factor (TGF)-&bgr; family of cytokines plays a key role in scarring. TGF-&bgr;3 improves scar appearance in a range of mammalian species. This study was performed to assess the efficacy of intradermal avotermin (TGF-&bgr;3) 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 &mgr;l/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. No caption available.

The microvacuolar system: how connective tissue sliding works:

The term ‘fascia’ has been applied to a large number of very different tissues within the hand. These range from aligned ligamentous formations such as the longitudinal bands of the palmar fascia or Grayson’s and Cleland’s ligaments, to the loose packing tissues that surround all of the moving structures within the hand. In other parts of the body the terms ‘superficial’ and ‘deep fascia’ are often used but these have little application in the hand and fingers. Fascia can be divided into tissues that restrain motion, act as anchors for the skin, or provide lubrication and gliding. Whereas the deep fascia is preserved and easily characterized in anatomical dissection, the remaining fascial tissue is poorly described. Understanding its structure and dynamic anatomy may help improve outcomes after hand injury and disease. This review describes the sliding tissue of the hand or the ‘microvacuolar system’ and demonstrates how movement of tissues can occur with minimal distortion of the overlying skin while maintaining tissue continuity.

Tendon is covered by a basement membrane epithelium that is required for cell retention and the prevention of adhesion formation.

The ability of tendons to glide smoothly during muscle contraction is impaired after injury by fibrous adhesions that form between the damaged tendon surface and surrounding tissues. To understand how adhesions form we incubated excised tendons in fibrin gels (to mimic the homeostatic environment at the injury site) and assessed cell migration. We noticed cells exiting the tendon from only the cut ends. Furthermore, treatment of the tendon with trypsin resulted in cell extravagation from the shaft of the tendons. Electron microscopy and immunolocalisation studies showed that the tendons are covered by a novel cell layer in which a collagen type IV/laminin basement membrane (BM) overlies a keratinised epithelium. PCR and western blot analyses confirmed the expression of laminin β1 in surface cells, only. To evaluate the cell retentive properties of the BM in vivo we examined the tendons of the Col4a1+/Svc mouse that is heterozygous for a G-to-A transition in the Col4a1 gene that produces a G1064D substitution in the α1(IV) chain of collagen IV. The flexor tendons had a discontinuous BM, developed fibrous adhesions with overlying tissues, and were acellular at sites of adhesion formation. In further experiments, tenotomy of wild-type mice resulted in expression of laminin throughout the adhesion. In conclusion, we show the existence of a novel tendon BM-epithelium that is required to prevent adhesion formation. The Col4a1+/Svc mouse is an effective animal model for studying adhesion formation because of the presence of a structurally-defective collagen type IV-containing BM.