Role of Connective Tissue Growth Factor in Breast Implant Elastomer Capsular Formation

Abstract

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.

Spider Silk Coatings as a Bioshield to Reduce Periprosthetic Fibrous Capsule Formation

“…[ 19,20 ] We observed a strongly reduced expression of TGFβ1 and a reduced abundance of TGFβ1-positive cells in the presence of spider silk-coated implants when compared to uncoated equivalents. Accordingly, the level of CTGF which is implicated in various fi brotic disorders and induced in fi broblasts after activation with TGFβ mediating capsule formation [ 21 ] and fi brosis persistence [ 22 ] was signifi cantly lower in the presence of silk coated silicone implants.…”

“…[ 9 ] Silk structures in general are typically slowly biodegraded in vertebrate tissues. [ 21 ] B) Exemplary SEM image of a silk coating peeled of a silicone surface, revealing diameters from ≈1 to 6 µm depending on the dip coating procedure. C) SEM image of a non-coated silicone implant surface.…”

Wire Tethering or ‘Bowstringing’ as a Long-Term Hardware-Related Complication of Deep Brain Stimulation

“…Scar remodelingcalled 'capsular contracture' -occurs when the capsule tightens and squeezes an implant following an immune response to foreign materials [7,8] . Scar formation has been reported in relation to many inert implants such as silicon, for example [9] . Two extension wires may exacerbate the scar formation in at least two ways.…”

Connective tissue growth factor hammerhead ribozyme attenuates human hepatic stellate cell function

“…The use of CCN2 antisense oligonucleotides has helped to establish the importance of CCN2 for TGF-b-induced collagen production in a variety of cell types including kidney mesangial cells, NRK cells, corneal fibroblasts, and conjunctival fibroblasts [28][29][30][31][32][33] . In in vivo animal models, CCN2 antisense oligonucleotides have proven effective in reducing matrix expansion or fibrosis in the skin or kidney [34][35][36] , and scarring around breast implants [37] . However, while CCN2 antisense therapy in CCl 4 -induced liver fibrosis is associated with reduced expression of mRNA for CCN2 or collagen, fibrous deposits are not reduced, an effect that has been attributed to high expression of TIMP-1 [38] .…”