Investigation of anti-fibrotic effects of capsaicin and prostaglandin E-2 on poly(lactic-co-glycolic) acid (PLGA) induced fibrosis.

Field: Chemical Engineering (Physical Sciences)

Event Abstract Back to Event Investigation of anti-fibrotic effects of capsaicin and prostaglandin E-2 on poly(lactic-co-glycolic) acid (PLGA) induced fibrosis. Tich Truong1, Kimia Sorouri2 and Kim S. Jones1, 3 1 McMaster University, Chemical Engineering, Canada 2 University of Toronto, Faculty of Medicine, Canada 3 McMaster University, School of Biomedical Engineering, Canada Introduction: Scar tissue formation (fibrosis) around biomaterials can decrease the efficacy of an implant and ultimately lead to its loss of function/failure, which is important for next generation material uses such as implanted sensors, drug delivery devices and tissue engineering scaffolds. Nearly all materials elicit fibrosis, yet the mechanism is not well understood. Here, we try to reduce fibrosis through two putative mechanisms: using drug delivery from a biomaterial to alter macrophage phenotype and to prevent myofibroblast differentiation. We also compared in vitro measurements to in vivo results. Observational studies of implanted biomaterials suggest that an early transition to macrophages polarized to the M2 phenotype minimizes fibrosis[1]. We hypothesized that capsaicin, an anti-inflammatory molecule that had the potential to alter macrophage phenotype[2], would also decrease fibrosis. The clinical literature suggests that myofibroblast differentiation plays a key role in fibrotic disease, so we also investigated the effect of prostaglandin E-2 (PGE-2), which has been shown to reverse differentiation of myofibroblasts[3]. Materials and Methods: Ideally, we wanted to develop in vitro testing methods that would be predictive of in vivo fibrotic results. First, we tested whether capsaicin altered macrophage response to PLGA. RAW 264.7 cells were cultured on PLGA coated dishes, with capsaicin or PGE-2 for 24 hours. High gene expression of iNOS indicated the M1 phenotype and high arginase gene expression indicated the M2 phenotype. Next, we tested if PGE-2 reversed myofibroblast differentiation (myofibroblast marker: low E-cadherin expression) caused by PLGA. HK-2 cells were stimulated with combinations of TGF-β1, PLGA and PGE-2 for 24 hours, then E-cadherin concentration was quantified using Western blots. We then implanted PLGA discs into the peritoneal cavity of C57BL/6 mice. The discs were pure PLGA, or released capsaicin or PGE-2. Discs were explanted, fixed and stained for collagen 2 days or 14 days after implant. Peritoneal lavage samples were also analysed for M1/M2 markers using qPCR. Results and Discussion: Our in vitro results showed that PLGA induced an M2 phenotype, while capsaicin downregulated it (Figure 1a). When implanted in vivo, PLGA induced a substantial fibrotic capsule, which was reduced by capsaicin release (Figure 2). PLGA still induced an M2 response in vivo, though capsaicin, if anything, increased the M2 response (Figure 3). In our hands, in vitro analysis of M1/M2 responses was not predictive of fibrotic outcome. We also did not see increased M2 responses (in vitro or in vivo) correlating to decreased fibrotic responses, as had been reported previously in the literature[1]. As hypothesized, our in vitro studies showed that PLGA induced myofibroblast differentiation, which PGE-2 reversed (Figure 1b). Release of PGE-2 in vivo also decreased the fibrotic response to PLGA (Figure 2). We also showed that PGE-2 initially induced a lower M2 response than PLGA alone (in vivo), and it increased with time to become higher than PLGA at the 14 day timepoint. Conclusion: We have demonstrated that capsaicin and prostaglandin E-2 show promise as antifibrotic compounds that could be released from biomaterials. We also showed that in vitro M1/M2 results were not predictive of in vivo fibrosis, though myofibroblast differentiation studies showed some promise. This work was funded by the Natural Sciences and Engineering Research (NSERC)References:[1] Brown, B. N.; Ratner, B. D.; Goodman, S. B.; Badylak, S. F. “Macrophage polarization: An opportunity for improved outcomes in biomaterials and regenerative medicine”. Biomaterials. 2012, 33(15), 3792-3802.[2] Garrison G.; Huang S. K.; Okunishi, K.; Scott, J. P.; Penke L. R. K.; Scruggs A. M.; et al. “Reversal of myofibroblast differentiation by prostaglandin E-2”. American Journal of Respiratory Cell and Molecular Biology. 2013, 48(5), 550-558.[3] Park, J-Y.; Kawada, T.; Han, I-S.; Kim, B-S.; Goto, T.; Takahashi, N.; et al. “Capsaicin inhibits the production of tumor necrosis factor alpha by LPS-stimulated murine macrophages, RAW 264.7: a PPAR gamma ligand-like action as a novel mechanism”. FEBS Lett. 2004, 572(1-3), 266-270. Keywords: Drug delivery, Biocompatibility, cell phenotype, Biodegradable material Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: General Session Oral Topic: Fibrosis and biomaterials Citation: Truong T, Sorouri K and Jones KS (2016). Investigation of anti-fibrotic effects of capsaicin and prostaglandin E-2 on poly(lactic-co-glycolic) acid (PLGA) induced fibrosis.. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02302 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Tich Truong Kimia Sorouri Kim S Jones Google Tich Truong Kimia Sorouri Kim S Jones Google Scholar Tich Truong Kimia Sorouri Kim S Jones PubMed Tich Truong Kimia Sorouri Kim S Jones Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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