Tacrolimus action pathways in an ointment base for hypertrophic scar prevention in a rabbit ear model

Abstract Background: Tacrolimus is used to prevent unaesthetic scars due to its action on fibroblast activity and collagen production modulation. Objectives: To evaluate the action pathways, from the histopathological point of view and in cytokine control, of tacrolimus ointment in the prevention of hypertrophic scars. Methods: Twenty-two rabbits were submitted to the excision of two 1-cm fragments in each ear, including the perichondrium. The right ear received 0.1% and 0.03% tacrolimus in ointment base twice a day in the upper wound and in the lower wound respectively. The left ear, used as the control, was treated with petrolatum. After 30 days, collagen fibers were evaluated using special staining, and immunohistochemistry analyses for smooth muscle actin, TGF-β and VEGF were performed. Results: The wounds treated with 0.1% tacrolimus showed weak labeling and a lower percentage of labeling for smooth muscle actin, a higher proportion of mucin absence, weak staining, fine and organized fibers for Gomori's Trichrome, strong staining and organized fibers for Verhoeff when compared to controls. The wounds treated with 0.03% tacrolimus showed weak labeling for smooth muscle actin, a higher proportion of mucin absence, strong staining for Verhoeff when compared to the controls. There was absence of TGF-β and low VEGF expression. Study limitations: The analysis was performed by a single pathologist. Second-harmonic imaging microscopy was performed in 2 sample areas of the scar. Conclusions: Both drug concentrations were effective in suppressing TGF-β and smooth muscle actin, reducing mucin, improving the quality of collagen fibers, and the density of elastic fibers, but only the higher concentration influenced elastic fiber organization.

Emodin alleviates hypertrophic scar formation by suppressing macrophage polarization and inhibiting the Notch and TGF-β pathways in macrophages

Hypertrophic scar (HS) formation is a common complication that develops after skin injury; however, there are few effective and specific therapeutic approaches for HS. Emodin has previously been reported to inhibit mechanical stress-induced HS inflammation. Here, we investigated the molecular mechanisms underlying the inhibitory effects of emodin on HS formation. First, we conducted in vitro assays that revealed that emodin inhibited M1 and M2 polarization in rat macrophages. We subsequently established a combined rat model of tail HS and dorsal subcutaneous polyvinyl alcohol (PVA) sponge-induced wounds. Rats were treated with emodin or vehicle (DMEM). Tail scar specimens were harvested at 14, 28, and 42 days post-incision and subjected to H&E staining and Masson's trichrome staining. Histopathological analyses confirmed that emodin attenuated HS formation and fibrosis. Macrophages were separated from wound cells collected from the PVA sponge at 3 and 7 days after implantation. Flow cytometry analysis demonstrated that emodin suppressed in vivo macrophage recruitment and polarization at the wound site. Finally, we explored the molecular mechanisms of emodin in modulating macrophage polarization by evaluating the expression levels of selected effectors of the Notch and TGF-β pathways in macrophages isolated from PVA sponges. Western blot and qPCR assays showed that Notch1, Notch4, Hes1, TGF-β, and Smad3 were downregulated in response to emodin treatment. Taken together, our findings suggested that emodin attenuated HS formation and fibrosis by suppressing macrophage polarization, which is associated with the inhibition of the Notch and TGF-β pathways in macrophages.

Eficacia y seguridad de triamcinolona acetónido intralesional como tratamiento de cicatrices hipertroficas o queloides post quemadura / Efficacy and safety of triamcinolone acetonide intralesional as treatment of hypertrophic scars or post-burn keloids

INTRODUCCIÓN: Antecedentes: El Instituto de Evaluación de Tecnologías en Salud e Investigación ha recibido la solicitud de evaluar el uso de triamcinolona inyectable para su uso en pacientes con cicatrices post quemadura dentro del sistema de EsSalud, indicación actualmente no contemplada en el petitorio de medicamentos. Aspectos Generales: Los queloides y las cicatrices hipertróficas representan una respuesta exagerada del tejido hacia un daño dérmico y caracterizado por proliferación local de fibroblastos con sobreproducción de colágeno. En el caso de queloides el crecimiento del tejido fibroso se extiende más allá del área original de la lesión, comprometiendo también a la piel normal adyacente. En cambio, las cicatrices hipertróficas pueden tener una apariencia clínica similar, pero en contraste a los queloides, permancen confinados a los limites del área de la herida y tienden a regresionar espontáneamente. Ambos tipos de lesiones cicatricilaes pueden causar afectación de la funcionalidad y deformidad cosmética y están frecuentemente asociados con disminución de la calidad de vida de los pacientes afectados. Tecnología Sanitaria de Interés: Acetónido de triamcinolona es un glucocorticoide con marcada acción antiinflamatoria. La presentación en suspensión estéril para inyectable se usa para la administración intra-articular. Cada ml de la solución acuosa provee 10 mg de acetónido de triamcinolona. Contienen a benzil alcohol como preservante. La administración intralesional de la inyección de acetónido de triamcinolona está indicada para la alopecia areata, lupus eritematoso discoide, queloides y placas de psoriasis. METODOLOGÍA: Estratégia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de triamcinoloma intralesional para el tratamiento de las cicatrices hipertróficas y queloides en las bases de datos de MEDLINE, EMBASE, CENTRAL, DARE y TRIPDATASE. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica que sustente el uso de acetónido de triamcinolona intralesional en el tratamiento de las cicatrices hipertróficas o queloides según la pregunta PICO establecida. Para el presente documento se seleccionó el siguiente cuerpo de evidencia: Guías Clínicas: Se identificó una única guía consensuada de recomendaciones en el manejo de las cicatrices. No se identifcó evidencias sobre el uso de acetónido de triamcinolona intralesional en el tratamiento de las cicatrices hipertróficas o queloides para Evaluaciones de tecnologías sanitaria, Revisiones sistemáticas y Ensayos clínicos. Revisiones narraticas: Se indentificaron tres revisiones que incluyeron la descripción de estudios de series de casos y un estudo prospectivo del uso de triamcinolona. CONCLUSIONES: Los hallazgos de las mejoras del volumen de las cicatrices hipertróficas y queloides proviene de estudios de baja calidad. Se trataron principalmente de reportes de casos con dismiles dosis y regimenes de adminstración de triamcinolona y con mediciones poco claras, insuficientes e consistentes de desenlaces de respuesta al tratamiento. Actualmente, el tratamiento de las cicatrices presenta varios retos derivados de la complejidad de los mecanismos patofisiológicos, la dificuldad para cuantificar los cambios de la cicatriz y estudios de baja calidad metodológica. Como resultado, el manejo ha diso dirigido por la experiencia del clínico. El uso de corticoesteroides intralesionales como la triamcinolona, está recomendado generalmente como segunda línea de tratamiento después del uso de estrategias dirigidas a contener o prevenir el desarrollo de cicatrices.La población objetivo de esta evaluación sufren de cicatrices que tienen un impacto importante a nivel funcional y sociológico, por lo que requieren que se los ofrezca opciones con potencial benefício como los corticoesteroides intralesionales. El tratamiento con triamcinolona no supone una complejidade importante en su aplicación y de bajo costo. Además, los efectos adversos observados con su uso son generalmente locales y de baja gravedad. El Instituto de Evaluación de Tecnologías Sanitarias-IETSI, aprueba por el período de 2 años a partir de la fecha de publicación del presente dictamen preliminar, el uso de triamcinolona acetónido intralesional para el tratamiento de pacientes con cicatrices hipertróficas o queloides post quemadura.

Results of a combination of bleomycin and triamcinolone acetonide in the treatment of keloids and hypertrophic scars / Resultados de uma combinação de bleomicina e triamcinolone acetonide no tratamento de quelóides e cicatrizes hipertróficas

While treatment of keloids and hypertrophic scars normally shows modest results, we found that treatment with bleomycin was more promising. The present study was divided into two parts. In the first part the aim was to show the results using a combination of bleomycin and triamcinolone acetonide per cm2 (BTA). In the second part the objective was to determine the response to both drugs in large keloids that were divided into 1 cm2 squares, treating each square with the dose previously used. In the first part of the study, the clinical response of 37 keloids ranging from 0.3 to 1.8 cm2 treated with BTA were followed up over a period of 1- 2 years. 0.375 IU bleomycin and 4 mg triamcinolone acetonide were injected every 3 months. In the second part of the study we reviewed the clinical response in six patients with large keloids. The monthly dose administered never exceeded 3 IU of bleomycin. The first study showed 36 keloids (97.29%) softening after the first dose. In the second study, 5 showed different responses (the response was complete in the four smaller keloids). The largest keloid needed 9 doses to achieve an improvement of 70%. In conclusion, combined treatment with 0.375 IU of bleomycin and 4mg of triamcinolone acetonide to 1 cm2 was considered to be an acceptable procedure for the treatment of keloids. The best results were obtained in keloids over 1 cm2 or when divided into 1 cm2 square areas. Larger series need to be performed in order to confirm these results..

Enquanto normalmente o tratamento de queloides e cicatrizes hipertróficas mostra resultados moderados, o tratamento com bleomicina revelou resultados mais promissores. Este estudo foi dividido em duas partes. Na primeira parte, o objetivo foi mostrar os resultados da utilização de uma combinação de bleomicina e acetonido de triancinolona por cm2 (BAT). Na segunda parte, o objetivo foi determinar a resposta aos dois medicamentos em queloides grandes, que foram divididos em quadrados de 1 cm2, tratando cada quadrado com a dose utilizada anteriormente. Na primeira parte do estudo, a resposta clínica de 37 queloides de 0,3 to 1,8 cm2 tratados com BAT foi monitorada por um período de 1 a 2 anos. Injeções de 0,375 UI de bleomicina e 4 mg de acetonido de triancinolona foram aplicadas a cada 3 meses. Na segunda parte do estudo, revisamos a resposta clínica em 6 pacientes com queloides grandes. A dose mensal administrada nunca excedeu 3 UI de bleomicina. O primeiro estudo mostrou que 36 queloides (97,29%) amoleceram após a primeira dose. No segundo estudo, 5 mostraram diferentes respostas (a resposta foi completa nos quatro queloides menores). O queloide maior necessitou de 9 doses para apresentar melhora de 70%. Concluindo, o tratamento combinado com 0,375 UI de bleomicina e 4 mg de acetonido de triancinolona por cm2foi considerado um procedimento aceitável para o tratamento de queloides. Os melhores resultados foram obtidos em queloides com mais de 1 cm2 ou divididos em áreas de 1cm2. Estudos mais amplos deveriam ser realizados, para confirmar esses resultados.

Mechanical evaluation of the resistance and elastance of post-burn scars after topical treatment with tretinoin

OBJECTIVE: After burn injuries, scarred skin lacks elasticity, especially in hypertrophic scars. Topical treatment with tretinoin can improve the appearance and quality of the skin (i.e., texture, distensibility, color, and hydration). The objective of this prospective study was to examine the effects of treatment with 0.05 percent tretinoin for one year on the biomechanical behavior and histological changes undergone by facial skin with post-burn scarring. Setting: Tertiary, Institutional. METHOD: Fifteen female patients who had suffered partial thickness burns with more than two years of evolution were selected. Skin biopsies were obtained initially and after one year of treatment. The resistance and elastance of these skin biopsies were measured using a mechanical oscillation analysis system. The density of collagen fibers, elastic fibers, and versican were determined using immunohistochemical analysis. RESULTS: Tretinoin treatment significantly lowered skin resistance and elastance, which is a result that indicates higher distensibility of the skin. However, tretinoin treatment did not significantly affect the density of collagen fibers, elastic fibers, or versican. CONCLUSION: Topical tretinoin treatment alters the mechanical behavior of post-burn scarred skin by improving its distensibility and thus leads to improved quality of life for patients.

Comparison of intralesional verapamil with intralesional triamcinolone in the treatment of hypertrophic scars and keloids.

BACKGROUND: The calcium channel blocker, verapamil stimulates procollagenase synthesis in keloids and hypertrophic scars. AIM: To study the effect of verapamil in the treatment of hypertrophic scars and keloids and to evaluate the effect of verapamil on the rate of reduction of hypertrophic scars and keloids in comparison with triamcinolone. METHODS: The study was a randomized, single blind, parallel group study in which 54 patients were allocated to to receive either verapamil or triamcinolone. Drugs were administered intralesionally in both groups. Improvement of the scar was measured using modified Vancouver scale and by using a centimeter scale serially till the scar flattened. RESULTS: There was a reduction in vascularity, pliability, height and width of the scar with both the drugs after 3 weeks of treatment. These changes were present at one year of follow-up after stopping treatment. Scar pigmentation was not changed desirably by either drug. Length of the scars was also not altered significantly by either drug. The rate of reduction in vascularity, pliability, height and width of the scar with triamcinolone was faster than with verapamil. Adverse drug reactions were more with triamcinolone than with verapamil. CONCLUSION: Intralesional verapamil may be a suitable alternative to triamcinolone in the treatment of hypertrophic scars and keloids.

effect of different concentrations of topical vitamin E on cosmetic appearance of hypertrophic and keloid scars

There are a few clinical trials on human that show the effect of topical vitamin E on keloid and hypertrophic scars. In this investigation we try to study this effect and also show the effect of the concentrations which have not been considered yet in improving hypertrophic scar and keloid healing. In a double-blind randomized clinical trial, 32 patients who had hypertrophic scar from 12 weeks ago were given three ointments including placebo and ointments contaning injectional vitamin E [d-a tocopheryl] with different concentrations [300Iu/mg and 600Iu/mg]. The scars size, erythema and hardness were evaluated by patients and physicians after 1, 4 and 12 weeks. Data was analyzed using ANOVA and Kruskal Walis tests. After 12 weeks there were no signs or symptoms of dermatitis and rash. Comparison of the scar size after 1 week showed difference between the high concentrated ointment with the others and in the 12[th] week all of the ointments were different [p<0.001]. Evaluation of the scar erythema, in the 1[th], 4[th] and 12[th] week showed significant difference between vitamin ointments and placebo [p<0.001], also scar hardness in the 12[th] week was significantly different between groups [p<0.001], but in the first and 4[th] week no difference was detected in hardness. This study shows that topical vitamin E has good effects on keloid and hypertropic scars. Their effect in decreasing size and erythema is more considerable than scar hardness

Terapia de cicatriz hipertrófica e quelóide em mucosa bucal: relato de caso clínico / Hypertophic cicatrix and keloid therapy in oral mucosa: caso report

O presente trabalho aborda as características clínicas e histopatológicas das cicatrizes hipertróficas e quelóides, além do tratamento proposto atualmente na literatura. É relatado ainda, um caso clínico de cicatriz hipertrófica em mucosa interna de lábio superior, onde se utilizou, intralesionalmente, o acetato de triamcinolona como terapia

Self-adhesive silicone gel sheet: a treatment for hypertrophic scars and keloids.

An open clinical trial was conducted to assess the effect of self-adhesive silicone gel sheet (SASGS) for the treatment of hypertrophic scars and keloids in Thai people. Patients were instructed to apply the SASGS to the scars as long as possible, but not less than 12 hours per day for at least 8 weeks. The subjective results of the treatment were evaluated by the patients. The scars were evaluated for color, height, weight before and after treatment at 4 and 8 weeks. Eighteen patients with 18 hypertrophic scars or keloids were recruited into the study. Their ages ranged from 6 to 33 years (mean 21 years). The average duration of the scars was 5.7 years. Twelve patients (66.67%) stated good results. All of the 18 patients wanted to continue the treatment with SASGS. Heights of the scars were reduced in 12 lesions (66.67%) after treatment for 8 weeks (P = 0.058). Weights of the lesions were decreased in 10 lesions (55.55%) but were not statistically different (P = 0.090). Seven lesions (36.84%) were improved in color. Two patients (11.11%) developed erythematous rash around the lesions which subsided after withdrawal of the treatment. The long term follow-up for the recurrence and the mechanism of action of this treatment should be studied further.

use of common insulin syringe for intralesional steroid injection in hypertrophic scars and keloids

A technique of delivering intralesional steroid injection in hypertrophic scars and keloids is described using the ubiquitous insulin syringe with fixed needle