Elimination of Radiation Induced Capsular Contracture By Blocking TGF-Beta Signaling
Evan B. Katzel, Peter F. Koltz, MD, Ryan tierney, BS, Jacqueline P. WIlliams, PhD, hani A. Awad, phD, Regis J. O'Keefe, MD, PhD, Howard N. Langstein, MD.
University of Rochester, Rochester, NY, USA.
Capsular contracture remains a major problem following prosthetic implantation of the breast, especially in post-mastectomy breast reconstruction patients receiving radiation therapy. Recent studies suggest that radiation injury is a cascading process of cytokine activation with TGF-beta acting as the “master switch” of this cascade. Since TGF-beta signals through phosphorylation of Smad3, a plausible approach to abate TGF-beta induced capsular contracture would be to interrupt Smad3 signaling. To test this hypothesis, capsular contracture formation in wildtype (WT) and Smad3 knockout (KO) mice was compared using microCT and histological examination.
On day 0, 32 mice were implanted with bilateral 300mg silicone gel implants (Mentor, Inc.). Mice were divided into four equal groups (non-irradiated WT, irradiated WT, non-irradiated KO and irradiated KO). Postoperatively, animals were imaged using livescan microCT to evaluate the initial shape and orientation of the implants. Animals in the radiation arm then received a 10 gray directed radiation dose. The targeted radiation was designed to induce capsular contracture while avoiding systemic effects of radiation. At post-operative animals underwent repeat imagining. Histological evaluation was performed at necropsy.
Non-irradiated implants changed very little from day 21 through day 42. MicroCT from non-irradiated WT and KO mice demonstrated minimal contour variation from day 0 through day 42. The corresponding histological specimens showed thin, uniform, and well organized collagen capsules surrounding these implants. On day 21, mean capsule thickness for WT capsules was 226um+/-36um (mean+/-SD) compared to 243um+/-73um for KO specimen (p=0.64). Non-irradiated capsules maintained a fairly modest thickness through day 42; mean capsules thickness were 168um+/-21um for WT and 118um+/-50um for KO (p=0.078).
Irradiated implants in the WT mice demonstrated shape and contour deformation on microCT beginning on post-operative day 21 and progressing through day 42. Conversely, microCT of irradiated implants in KO mice demonstrated minimal contour changes from day 0 through 42 (figure 1). Corresponding histological specimens in WT mice demonstrated irregular capsules composed of disorganized collagen fibers that became progressively thicker from day 21 through day 42. Irradiated KO specimen maintained consistently thin collagen capsules from day 21 through day 42. On day 21, the mean capsule thickness was 324um+/-39um for WT and 92um+/-12um for KO (p<0.001)(figure 2). By day 42, the average capsule thickness was 887um+/-130um for WT compared to 135um+/-12um for KO.
This is the first study of its kind to use radiation to induce and a knockout model to study the pathogenesis of capsular contracture. In this work, inhibiting TGF-beta by interrupting Smad3 signaling led to a reduction in radiation induced capsular contracture as measured by microCT and capsule thickness on histological evaluation. The findings presented here may lead to therapeutic advances to reduce capsular contracture in implant-based reconstruction.
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