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Percutaneous Injection of SMAD7 siRNA Heals Cranial Defects
John Layliev, MD, Denis Knobel, MD, Fabio Sagebin, BS, Andrew Weinstein, BS, Alexander Marchac, MD, Manisha Patel, BS, BA, Oriana Cohen, BA, Caroline Szpalski, MD, Daniel Ceradini, MD, Pierre B. Saadeh, MD, FACS, Stephen M. Warren, MD, FACS.
NYU Langone Medical Center, New York, NY, USA.

BACKGROUND:
Reconstruction of cranial defects is challenging and can require multiple operations. Previous research has implicated the BMP and TGF-Beta signaling cascades to be significant in calvarial osteogenesis. We hypothesized that locally silencing SMAD7, a negative regulator of both pathways, with small interfering RNA (siRNA) would enhance osteogenesis. Moreover, we aimed to develop a simple therapy that could be delivered percutaneously.
METHODS:
Critical-sized 3mm calvarial defects were trephined into the right parietal bones of C57 wild-type mice (n=24). Animals were divided into 3 groups (n=8/group): Group1 received no further treatment; Group 2 received an agarose matrix containing nonsense siRNA placed into the cranial defects; Group 3 received an agarose matrix with SMAD7 siRNA placed in the cranial defects. Percutaneous injection of either nonsense siRNA or SMAD7 siRNA into the cranial defects continued on a weekly basis after trephination. At 12 weeks, microcomputed tomography was used to assess for bony ingrowth. PCR of drilled and non-drilled bony specimens was done to quantify differences in RNA expression of SMAD7, SMAD4, SMAD5, RunX2, Tak1, TGFB-R2, and Collagen Type 1. Gomori Trichome staining was used to assess for bony architecture. Significance was determined by One-Way ANOVA.
RESULTS:
Micro-CT revealed that bony ingrowth was significantly greater in the SMAD7 siRNA treatment group (91.2 ± 5.9%) compared to the control (33.8 ± 1.3%) and nonsense siRNA (32.1 ± 1.0%) groups, p<0.001 and p<0.001, respectively. Bony ingrowth in the nonsense group was not significantly different from that of the control (p=X). Compared to uninjuried parietal bone, SMAD7 was increased 2.6 fold in untreated trephined bone. In contrast, the SMAD7 siRNA treated group had 68% SMAD7 suppression as well as a 3.8 fold increase in SMAD4 , 5.7 fold increase in SMAD5, 5.9 fold increase in TAK1, 7.1 fold increase in RunX2, 2.6 fold increase in TGFB-R2, and a 4.6 fold increase in Collagen Type 1. Histology demonstrated substantial bone formation in SMAD7 treated trephination defects.
CONCLUSIONS:
We present a novel percutaneous drug delivery method to enhance calvarial osteogenesis. Local inhibition of SMAD7 via small interfering RNA allows for increased BMP and TGF-Beta signaling which, in turn, yields remarkable calvarial osteogenesis. This relatively noninvasive and efficacious means to bony ingrowth may have applicability to human cranioplasty.


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