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Immunomodulation Of Acellular Dermal Matrix Through Strategic Cytokine Incorporation Enhances Biointegration
Hannah Kang, B.S.1, Victoria A. Nash, M.S.2, Gregory Risser, B.S.2, Meng Zuang, B.S.1, Lisa S. Salopek, A.S.1, Cassandra L. Fraser, Ph.D.1, Chris A. Campbell, M.D.1, Kara L. Spiller, Ph.D2, Patrick S. Cottler, Ph.D.1.
1University of Virginia, Charlottesville, VA, USA, 2Drexel University, Philadelphia, PA, USA.

PURPOSE: The use of acellular dermal matrices (ADM) in implant-based breast reconstruction has grown significantly since the first reports in 2005. Success of ADM relies on its rapid integration into this host, which is reliant on cellular and vascular ingrowth. Macrophages are major regulators of tissue vascularization, and transition from pro-inflammatory M1, which initiate angiogenesis, to a phenotype referred to as M2, which is associated with stabilization of blood vessels and resolution of tissue healing. Both M1 and M2 macrophages in the proper order are required for tissue vascularization. In this study, we investigated incorporating immunomodulatory cytokines that promote the M1 and M2 macrophage phenotypes in order to improved ADM biointegration. We hypothesized that short-term release of pro-inflammatory, M1-promoting interferon-gamma (IFNg) or sustained release of the M2-promoting cytokine interleukin-4 (IL4) would control the dynamics of inflammation within the wound, leading to accelerated vascularization and collagen deposition in the ADM, thereby decreasing complications and improving outcomes. 
METHODS: Low (375ng) or high (750ng) doses of IFNg was adsorbed to ADM or to porous collagen scaffolds. Additionally, IL4 (5ug) was adsorbed onto ADM samples. Samples were then washed and the amount of unadsorbed protein was measured. Release studies were also performed to determine the elution profiles. Next, a mouse dorsal skinfold window chamber model was used to determine the effects of IL4 treated ADM on biointegration (n=8 IL4 treated ADM, n=8 untreated ADM). Real-time evaluations of the vascular integration and oxygen saturation within the ADM were made through repeated use of novel oxygen sensing nanoparticles over 21 days. At the terminal time point, macrophage function (M2:M1 ratio), and vascular ingrowth (CD31) were evaluated by immunohistochemistry. 
RESULTS: Surprisingly, ADM samples released high levels of cytokine for up to 11 days in vitro (Fig. 1a), unlike porous collagen scaffold controls, which released most of the cytokine within 2 hours (Fig. 1b). The adsorption of IL4 was highest when the 300uL volume was used (Fig. 1c). In vivo, IL4 treatment of ADM was associated with increased vasculogenesis at the implant/host interface at day 21 (Fig. 1d) compared to untreated ADM (Fig. 1e), resulting in an increase in oxygen saturation within the ADM as seen through repeated oxygen sensing imaging of the window chamber. IL4-treated ADM drove a 31% increase in vascular coverage and a 38% increase in oxygen levels within the ADM at day 21, compared to control samples. 
CONCLUSION: The use of ADM as an immunomodulatory drug delivery vehicle has great potential to improve clinical outcomes. Our in vivo model provides the ability to serially assess ADM integration. This novel approach to improve the clinical outcomes of ADM use in implant-based breast reconstruction through modulating the immune response to facilitate integration, provides the foundation for increasing the complexity and designing a clinically useful pharmacologic strategy to gain spatial and temporal control of key signaling cytokine.


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