The Collagenase of the Bacterium Clostridium histolyticum in the Treatment of Irradiation-Induced Capsular Contracture.

BACKGROUND: Irradiation therapy is an important pillar in the treatment of breast cancer. However, it can trigger capsular fibrosis, the most significant complication of implant-based breast reconstruction. As collagen is the main component of fibrotic capsules, the collagenase of the bacterium Clostridium histolyticum poses a potential treatment option for this pathological condition. METHODS: Thirty-six rats received miniature silicone implants on their backs. On day 1, the implant sites of two groups were irradiated with 10 Gy. On day 120, one irradiated group received collagenase injections into the implant pockets (n = 12). Non-irradiated (n = 12) and irradiated capsules (n = 12) were injected with plain solvent solution serving as controls. Data were analyzed by means of in vivo imaging, histology, immunohistochemistry and gene expression analysis. RESULTS: Compared with both controls, the injection of collagenase led to significantly thinner capsules. This was verified by in vivo imaging and histology. Although irradiation provoked alterations in capsule collagen structure and vessel wall thickness, the application of collagenase resulted in a significant reduction of collagen density. This was accompanied by an up-regulation of VEGF-A gene expression. Of note, hematoma formation inside the implant pocket occurred in two cases after collagenase injection. CONCLUSIONS: The collagenase of the bacterium Clostridium histolyticum is effective in degrading irradiation-induced capsular fibrosis around silicone implants. Hematoma formation occurred most likely because of irradiation-induced alterations in vessel wall architecture and capsule vascularization. Further studies need to be performed to address the clinical safety of this novel treatment option.

Efficacy and Safety of the Collagenase of the Bacterium Clostridium Histolyticum for the Treatment of Capsular Contracture after Silicone Implants: Ex-Vivo Study on Human Tissue.

BACKGROUND: The fibrotic capsule that surrounds silicone implants consists mainly of collagen. The FDA-approved collagenase of the bacterium clostridium histolyticum provides a reasonable treatment option. Safety and efficacy at the female breast site must be evaluated before clinical utilization. MATERIALS AND METHODS: We incubated 20 samples of fibrotic capsule as well as 12 full thickness skin grafts harvested from the female breast site for 24 hours with different doses of collagenase. Outcome measures involved histological assessment of thickness and density of the capsule tissue as well as the skin grafts. Furthermore, we performed a collagen assay and immunohistochemistry staining for collagen subtypes. RESULTS: Collagenase treatment was able to degrade human capsule contracture tissue ex-vivo. The remaining collagen subtype after degradation was type 4 only. 0.3 mg/ml of collagenase was most effective in reducing capsule thickness when compared with higher concentrations. Of note, effectiveness was inversely related to capsule density, such that there was less reduction in thickness with higher capsule densities and vice versa. Furthermore, the application of 0.3mg/ml collagenase did not lead to thinning or perforation of full thickness skin grafts. CONCLUSION: Adjustment of collagenase dose will depend on thickness and density of the contracted capsule. A concentration of 0.3mg/ml seems to be safe and effective in an ex-vivo setting. The remaining collagen subtype 4 is suitable to serve as a neo-capsule/acellular tissue matrix. Collagenase treatment for capsular contracture may soon become a clinical reality.

Effects of Different Concentrations of Injectable Collagenase Enzyme on Capsular Tissue Around Silicone Implants: A Preliminary Experimental Study for the Development of a New Treatment Strategy.

OBJECTIVES: In recent studies, collagen organization was blamed for the formation of capsular contracture which is still a challenging problem after silicone implant-based breast operations. In this study, effects of different concentrations of collagenase enzyme derived from Clostridium histolyticum on the capsular tissue formation around the silicone implants were investigated. The injectable form of collagenase has a routine clinical use in the treatment of both Dupuytren's and Peyronie's diseases. MATERIALS AND METHODS: Thirty-two Wistar albino rats were randomized into four groups. A 2 × 1 × 0.3-cm-sized silicone block was inserted inside a dorsal subcutaneous pocket in all groups. After 2 months of insertion, capsule thicknesses around the implants were detected under ultrasonography. This was followed by injection of isotonic saline, 150, 300, and 600 IU in Gr-1, 2, 3, and 4, respectively. All the animals were sacrificed at the end of the first week for histologic sampling to determine fibroblast proliferation, vessel density of the tissue, necrosis, edema, inflammation, and capsule thickness. All the data were statistically analyzed using Kruskal-Wallis and Mann-Whitney U tests and compared for significance of the results. RESULTS: There was no significant difference in terms of capsule thinning between the 300 and 600 IU groups but in both groups thinning was significantly higher than the sham group. In the 150 IU group there was no significant thinning as compared to the sham group (p > 0.05). However, complications such as skin necrosis, infection, and seroma formation were seen only in the 600 IU injection group. The optimal safe and effective dose of the enzyme was accepted as 300 IU. The 300 IU injection provided up to 89 % thinning in the capsule tissue. There was thinning of the collagen bundles parallel to capsule thickness. In the 600 IU group, micro-pores were encountered at the thinnest points. CONCLUSION: However, the late results and recurrence rates of capsular contracture were not included in this study; collagenase seemed effective for the reduction of capsular tissue around the implants. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Opções a capsulotomia e capsulectomia no tratamento da contratura capsular: existem alternativas medicamentosas ao tratamento cirúrgico? Revisão de literatura / Options for capsulotomy and capsulectomy in the treatment of capsular contracture: are there clinical treatment alternatives to surgery? A literature review

INTRODUÇÃO: A contratura capsular é uma das principais complicações em cirurgias envolvendo implantes mamários. A classificação mais usada para avaliar o grau de contratura é a de Baker, que a divide em graus I, II, III e IV, sendo as de grau III e IV consideradas significativas. Apesar de existirem diversas teorias, a etiologia da contratura capsular permanece incerta. O tratamento convencional para os casos de contratura é a abordagem cirúrgica com realização de capsulotomia ou capsulectomia. Estes procedimentos, no entanto, não estão isentos de morbidades, com complicações como deiscências, hematomas, seromas, pneumotórax, assimetrias e recidiva da contratura. Este estudo faz uma revisão sobre as alternativas ao tratamento cirúrgico convencional, descritas na literatura. MÉTODOS: Foi realizada pesquisa nas bibliotecas da Pubmed e da Cochrane, utilizando-se os termos: 'capsular contracture', 'capsular contracture treatment' e 'capsular contracture breast treatment'. Foram identificados 991 artigos e selecionados os que discutiam opções medicamentosas para o tratamento de contratura, diferentes de capsulectomia e capsulotomia. RESULTADOS: Foram encontrados vårios estudos utilizando drogas com o fim de reduzir a contratura capsular, das quais o Zafirlucaste é apresentado em maior número de trabalhos. CONCLUSÃO: Dentre as várias drogas utilizadas, o Zafirlucaste apresentou boa eficácia, com baixos índices de complicação; a Triancinolona parece ser também uma boa opção, no entanto precisa de profissional habilitado para realizar as infiltrações. As demais drogas necessitam de maiores estudos.

INTRODUCTION: Capsular contracture is among the main complications of surgeries involving breast implants. The most commonly used classification to assess the degree of contracture is the Baker grading system, which divides contractures into grades I, II, III, and IV. Of these, grade III and IV contractures are considered significant. Although several causes have been postulated, the etiology of capsular contracture remains uncertain. Conventional treatment for contracture is based on a surgical approach, specifically capsulotomy or capsulectomy. These procedures, however, are not exempt from morbidity, and patients may develop complications such as dehiscence, hematoma, seroma, pneumothorax, asymmetry, and contracture recurrence. This study provides a review of alternatives to conventional surgery described in the literature. METHODS: We researched the PubMed and Cochrane Library databases using the following keywords: "capsular contracture", "capsular contracture treatment", and "capsular contracture breast treatment". We identified 991 articles from which we selected those discussing medication options for contracture treatment other than capsulectomy and capsulotomy. RESULTS: We identified several studies in which drugs, most commonly zafirlukast, were used to reduce capsular contracture. CONCLUSION: Among the various reported drugs, zafirlukast exhibited good efficacy and a low rate of complication. Triamcinolone also appears to be a good option, although professional assistance would be needed for drug administration via infiltration. The other drugs described would require further investigation.

Controlled clinical trial with pirfenidone in the treatment of breast capsular contracture: association of TGF-ß polymorphisms.

BACKGROUND: Breast capsular contracture (BCC) is a commonly adverse event postmammoplastly characterized by an immune response mediated by cytokines and transforming growth factor (TGF)-ß1 resulting in excessive synthesis and deposit of extracellular matrix around the breast implant. Presence of TGF-ß1 polymorphisms has been associated as a risk factor to develop fibroproliferative diseases. METHODS: This open, controlled, prospective, and pilot clinical trial with 6 months duration was carried out to evaluate the efficacy of 1800 mg a day, of oral Pirfenidone (PFD) in the treatment of BCC (Baker Score III/IV) postmammoplasty. Twenty BCC cases received PFD and 14 BCC control cases underwent capsulectomy after 6 months of enrollment. Both groups were followed up for 6 more months up to 12 months to determine the relapse in the absence of PFD. Determination of TGF-ß1 polymorphisms was performed to establish a correlation with capsular contracture. RESULTS: PFD group experienced BCC-reduction in all breasts 6 months after enrollment. Only 1 of 20 cases relapsed after follow-up. In capsulectomy group, 2 of 14 cases presented progression to grade IV during presurgical period. All capsulectomy cases relapsed at end of follow-up. Nearly hundred percent of all patients studied in this protocol had a profibrogenic homozygous TGF-ß1 polymorphism (codon 25; genotype Arg25Arg). CONCLUSIONS: PFD is useful to improve BCC (Baker Score III/IV) postmammoplasty with no relapse after drug administration. There is also an association between capsular contracture and the presence of homozygous G/G TGF-ß1 genotype.