Role of connective tissue growth factor in breast implant elastomer capsular formation.

Transforming growth factor-beta (TGF-beta) has been demonstrated to be a mediator in scar formation and in multiple fibrotic disorders such as in Dupuytren contractures and in pulmonary fibrosis. Recently, it has been demonstrated that connective tissue growth factor (CTGF) is a downstream mediator of TGF-beta and acts to stimulate wound contraction and fibrosis. The purpose of this study is to assess the role of CTGF in the development of breast implant elastomer capsule formation over time and to evaluate the effects of TGF-beta and CTGF antisense (AS) oligonucleotides on capsule formation. Fifteen Sprague-Dawley rats were randomly assigned to treatment (n = 12) and control (n = 3) groups. Four 2- x 2-cm pockets were created on the dorsum deep to the panniculus carnosus in each rat. A 1- x 1-cm smooth breast implant elastomer was placed. Each rat in the treatment group received 1 ml vehicle, AS-TGF-beta, AS-CTGF, or scramble antisense oligonucleotide (AS-scramble). Control rats received either 1 ml vehicle or 1 ml saline in each pocket. At weeks 1, 3, and 5, four treatment rats and one control rat were randomly selected and killed. Tissue blocks were harvested for determination of CTGF levels using the enzyme-linked immunosorbent assay technique and for hematoxylin and eosin slides to evaluate capsule formation. Levels of CTGF in capsular tissue treated with vehicle or AS-scrambled were similar and progressively increased in tissues on weeks 1, 3, and 5, compared with normal skin. At weeks 1 and 3 after surgery, levels of CTGF were suppressed in capsules treated with AS-CTGF or AS-TGF-beta compared with normal skin and with tissues treated with vehicle or AS-scramble (p = 0.002). At week 5, levels of CTGF were similar to levels in normal skin. Histological analysis revealed reduced capsular formation in samples treated with AS-CTGF or AS-TGF-beta compared with the two other treated sites. In conclusion, a single and local treatment with AS-CTGF or AS-TGF-beta at the time of surgery reduced CTGF levels in tissue and correlated with reduced capsular formation in a rat model. These data suggest a new therapeutic strategy to reduce early capsular formation based on local application of antisense oligonucleotides targeting CTFG and TGF-beta.