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The Nucleic Acid Scavenger Polyamidoamine Third-Generation Dendrimer Inhibits Fibroblast Activation and Granulation Tissue Contraction

Holl, Eda K. Ph.D.; Bond, Jennifer E. Ph.D.; Selim, Maria A. M.D.; Ehanire, Tosan B.S.; Sullenger, Bruce Ph.D.; Levinson, Howard M.D.

Plastic and Reconstructive Surgery: September 2014 - Volume 134 - Issue 3 - p 420e–433e
doi: 10.1097/PRS.0000000000000471
Experimental: Original Articles
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Background: Pathologic cutaneous scarring affects over 40 million people worldwide and costs billions of dollars annually. Understanding mechanisms of fibroblast activation and granulation tissue contraction is the first step toward preventing pathologic scarring. The authors hypothesize that nucleic acids increase fibroblast activation and cause granulation tissue contraction and that sequestration of nucleic acids by application of a nucleic acid scavenger dendrimer, polyamidoamine third-generation dendrimer, will decrease pathologic scarring.

Methods: In vitro experiments were performed to assess the effect of nucleic acids on pathologic scar–associated fibroblast activity. The effect of nucleic acids on cytokine production and migration on mouse fibroblasts was evaluated. Immunofluorescence microscopy was used to determine the effect of nucleic acids on the differentiation of human primary fibroblasts into myofibroblasts. Using a murine model, the effect of polyamidoamine third-generation dendrimer on granulation tissue contraction was evaluated by gross and histologic parameters.

Results: Mouse fibroblasts stimulated with nucleic acids had increased cytokine production (i.e., transforming growth factor-β, monocyte chemotactic protein 1, interleukin-10, tumor necrosis factor-α, and interferon-γ), migration, and differentiation into myofibroblasts. Polyamidoamine third-generation dendrimer blocked cytokine production, migration, and differentiation into myofibroblasts. Using a murine model of granulation tissue contraction, polyamidoamine third-generation dendrimer decreased wound contraction and angiogenesis. Collagen deposition in polyamidoamine third-generation dendrimer–treated tissues was aligned more randomly and whorl-like compared with control tissue.

Conclusions: The data demonstrate that nucleic acid–stimulated fibroblast activation and granulation tissue contraction are blocked by polyamidoamine third-generation dendrimer. Sequestration of pathogen-associated molecular patterns may be an approach for preventing pathologic scarring.

Durham, N.C.

From the Departments of Surgery and Pathology, Duke University Medical Center.

Received for publication October 22, 2013; accepted February 10, 2014.

The first two authors should be considered co–first authors.

Disclosure: The authors have no financial interest to declare in relation to the content of this article.

Howard Levinson, M.D., Departments of Surgery and Pathology, Duke University Medical Center 3181, Durham, N.C. 27710, howard.levinson@duke.edu

©2014American Society of Plastic Surgeons