Capsaicin reduces PLGA‐induced fibrosis by promoting M2 macrophages and suppressing overall inflammatory Response

Abstract

Capsaicin reduced poly(lactic-co-glycolic) acid (PLGA)-induced fibrosis by promoting IL-10 secretion and suppressing alpha-smooth muscle actin (α-SMA) expression. The lifetime and efficacy of tissue engineering scaffolds are determined by the foreign body response. In this study, we investigated the in vitro and in vivo effects of capsaicin to reduce biomaterial-induced fibrosis. RAW 264.7 cells cultured on PLGA films with capsaicin responded with significant (p < 0.05) upregulation in M2 markers arginase-1 and IL-10 and downregulation of M1 markers iNOS and IL-12, demonstrating the potential of capsaicin to reduce PLGA-induced inflammation. Subsequent animal studies were conducted where PLGA and capsaicin-embedded PLGA discs were implanted in C57BL/6 mice for 2 and 14 days. Explanted capsaicin-embedded PLGA implants had 40% less collagen than PLGA-only implants. Capsaicin caused a 35% increase in IL-10 which played a key role in suppressing fibrosis. Macrophage phenotype markers in peritoneal cells and adherent cells were unaffected by capsaicin; however, capsaicin suppressed the myofibroblast marker α-SMA in adherent cells by day 14. Overall, our results revealed that capsaicin reduced biomaterial-induced fibrosis and demonstrates that capsaicin has the potential to extend the lifetime of a tissue engineering scaffold when used in long-term drug release applications from hydrophobic biomaterials. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2424-2432, 2018.

Impact of Select Sophorolipid Derivatives on Macrophage Polarization and Viability

“…Comparing our results more broadly to alternate approaches to promote M1 → M2 is difficult for a variety of reasons, many of which are listed above. Generally, several reports have characterized this transition by demonstrating a decrease in selected M1 markers and an increase in selected M2 markers, − consistent with the effects of certain SL formulations noted herein. Importantly, these reports also demonstrated a reduced fibrotic response in their respective applications, suggesting the antifibrotic potential of SLs.…”

“…Ideally, M1 macrophages transition toward an M2 phenotype after phagocytosis, signifying the resolution of inflammation and the promotion of wound healing. Therefore, the transition from a M1 to a M2 macrophage phenotype is likely both necessary and beneficial for reducing inflammation and promoting proper wound healing processes after biomaterial implantation. − Such an approach is supported by other groups which have demonstrated reduced, albeit not completely absent, fibrotic outcomes in select model systems when molecules that promote the M1 → M2 transition were incorporated into the biomaterial. − …”

Macrophage and Fibroblast Interactions in Biomaterial‐Mediated Fibrosis

“…Others have also investigated macrophage and fibroblast behavior in response to other M2‐promoting biomaterials. Truong and Jones hypothesized that biomaterial release of capsaicin, an anti‐inflammatory capsinoid derived from chili peppers, would promote M2‐like behavior to reduce the foreign body response . To test this hypothesis, capsaicin‐laden PLGA films were developed for in vitro studies and capsaicin‐laden PLGA disks for subcutaneous implantation in C57BL/6 mice.…”

Protein Adsorption on Surfaces Functionalized with COOH Groups Promotes Anti-inflammatory Macrophage Responses

“…Under normal healing conditions, macrophages secrete pro-inflammatory signals, such as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β), to initiate angiogenesis and clear debris during the early stage of wound healing . Then, during later stages, they can undergo polarization, a phenotypic change allowing them to secrete anti-inflammatory signals, such as interleukin 10 (IL-10), transforming growth factor β (TGF-β), and CC chemokine ligand 18 (CCL-18), to end inflammation and promote tissue regeneration. , During the FBR, however, macrophages prolong the secretion of pro-inflammatory signals, fuse to form foreign body giant cells (FBGCs), and secrete fibrotic signals that ultimately prevent integration. , Therefore, enhancing the anti-inflammatory response of macrophages to implants may help mitigate the FBR and improve their integration in the body …”

“…1,2 Therefore, enhancing the anti-inflammatory response of macrophages to implants may help mitigate the FBR and improve their integration in the body. 6 One strategy for improving biomaterial integration involves the modification of biomaterial surfaces to reduce proinflammatory and/or increase anti-inflammatory macrophage reactions. While modifications to surface properties like topography, 7,8 chemistry, 9,10 and wettability 9,11−13 have been shown to affect macrophage responses, there are several conflicting studies about the effects of surface properties, especially wettability.…”