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W2.05 - Bioactive Materials for Transitioning Cell Phenotypes within Chronic Scar 
April 22, 2014   3:15pm - 3:45pm

Introduction: Success in tissue engineering of the vocal fold lamina propria extracellular matrix (ECM) for treatment of chronic vocal fold scarring demands an understanding of how cells integrate the signals presented from the scar microenvironment, in combination with the signals from the biomaterial scaffold, to alter their response. To date, approaches to biomaterial development for scarred lamina propria treatment have examined the response of “normal” (non-scar) vocal fold fibroblasts (VFFs) to the biomaterial. As a result, they have failed to capture cellular responses, from activated macrophages and from resident scar-tissue VFFs (also known as myofibroblasts), from the in vivo implant environment which critically impact the quality and rate of VFF ECM production. In the present work, we conjugate cytokines, previously identified as anti-fibrotic and/or immunomodulatory, to biocompatible poly(ethylene glycol) [PEGDA] hydrogel formulations shown to have mechanical properties which preserve mucosal wave activity with low average phonation threshold pressures. We demonstrate these biomaterials influence macrophage polarization — shifting activated macrophages from a pro-inflammatory phenotype to a phenotype that is anti-inflammatory and pro-healing — and shift myofibroblasts to a “normal” or anti-fibrotic VFF phenotype. Results and Discussion: Pro-inflammatory macrophages and/or myofibroblasts were encapsulated in PEG-bFGF gels. Following 3 days of culture in activation(pro-inflammatory, pro-fibrotic) media, expression of the fibrotic marker αSMA by myofibroblasts in PEG-bFGF gels was reduced over 7-fold relative to non-bFGF containing gels. Similarly, the expression of genes associated with matrix turnover (e.g. MMP1) were increased in response to bFGF. Activated macrophages exposed to bFGF gels displayed over a 50% reduction in inflammatory makers Nos2 and IL-12β relative to non-bFGF hydrogel controls. This reduction in fibrotic markers in myofibroblasts and inflammatory markers in macrophages in bFGF-containing gels occurred despite the continued presence of activating media and is consistent with anti-fibrotic and anti-inflammatory properties reported for bFGF. These results suggest that PEG-bFGF gels could be used to transition the activated cells present in chronic vocal fold scar to more phenotypes more conducive to healing.Conclusions: The design of material environments to transition activated cells that are present in wound environments to more “normal” cell phenotypes would be desirable in the treatment of chronic scar and other chronic wounds. The present results represent an important step toward using tissue engineering principles to modulate cell phenotypes within an active wound environment.

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