Dataset Information

CD200 modulates macrophage cytokine secretion and phagocytosis in response to poly(lactic co-glycolic acid) microparticles and films.

ABSTRACT: Biocompatibility is a major concern for developing biomaterials used in medical devices, tissue engineering and drug delivery. Poly(lactic-co-glycolic acid) (PLGA) is one of the most widely used biodegradable materials, yet still triggers a significant foreign body response that impairs healing. Immune cells including macrophages respond to the implanted biomaterial and mediate the host response, which can eventually lead to device failure. Previously in our laboratory, we found that CD200, an immunomodulatory protein, suppressed macrophage inflammatory activation in vitro and reduced local immune cell infiltration around a biomaterial implant. While in our initial study we used polystyrene as a model material, here we investigate the effect of CD200 on PLGA, a commonly used biomaterial with many potential clinical applications. We fabricated PLGA with varied geometries, modified their surfaces with CD200, and examined macrophage cytokine secretion and phagocytosis. We found that CD200 suppressed secretion of the pro-inflammatory cytokine TNF-? and enhanced secretion of the anti-inflammatory cytokine IL-10, suggesting a role for CD200 in promoting wound healing and tissue remodeling. In addition, we found that CD200 increased phagocytosis in both murine macrophages and human monocytes. Together, these data suggest that modification with CD200 leads to a response that simultaneously prevents inflammation and enhances phagocytosis. This immunomodulatory feature may be used as a strategy to mitigate inflammation or deliver drugs or anti-inflammatory agents targeting macrophages.

SUBMITTER: Chen EY

PROVIDER: S-EPMC5515357 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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CD200 modulates macrophage cytokine secretion and phagocytosis in response to poly(lactic co-glycolic acid) microparticles and films.

Chen E Y EY Chu S S Gov L L Kim Y K YK Lodoen M B MB Tenner A J AJ Liu W F WF

Journal of materials chemistry. B 20170110 8

Biocompatibility is a major concern for developing biomaterials used in medical devices, tissue engineering and drug delivery. Poly(lactic-co-glycolic acid) (PLGA) is one of the most widely used biodegradable materials, yet still triggers a significant foreign body response that impairs healing. Immune cells including macrophages respond to the implanted biomaterial and mediate the host response, which can eventually lead to device failure. Previously in our laboratory, we found that CD200, an i ...[more]

PMID: 28736613

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Project description:This study investigated the effects of incorporating glucose microparticles (GMPs) and poly(lactic-co-glycolic acid) microparticles (PLGA MPs) within a calcium phosphate cement on the cement's handling, physicochemical properties, and the respective pore formation. Composites were fabricated with two different weight fractions of GMPs (10 and 20 wt%) and two different weight fractions of PLGA MPs (10 and 20 wt%). Samples were assayed for porosity, pore morphology, and compressive mechanical properties. An in vitro degradation study was also conducted. Samples were exposed to a physiological solution for 3 days, 4 wks, and 8 wks in order to understand how the inclusion of GMPs and PLGA MPs affects the composite's porosity and mass loss over time. GMPs and PLGA MPs were both successfully incorporated within the composites and all formulations showed an initial setting time that is appropriate for clinical applications. Through a main effects analysis, we observed that the incorporation of GMPs had a significant effect on the overall porosity, mean pore size, mode pore size, and in vitro degradation rate of PLGA MPs as early as after 3 days (p < 0.05). After 4 wks and 8 wks, these same properties were affected by the inclusion of both types of MPs (p < 0.05). Advanced polymer chromatography confirmed that the degradation of PLGA MPs coincided with an increase in composite porosity, mean pore size, and mode pore size. Finally, it was observed that the inclusion of GMPs slowed the degradation of PLGA MPs in vitro and reduced the solution acidity due to PLGA degradation products. Our results suggest that the dual inclusion of GMPs and PLGA MPs is a valuable approach for the generation of early macropores, while also mitigating the effect of acidic degradation products from PLGA MPs on their degradation kinetics.Statement of significanceA multitude of strategies and techniques have been investigated for the introduction of macropores with calcium phosphate cements (CPC). However, many of these strategies take several weeks to months to generate a maximal porosity or the degradation products of the porogen can trigger a localized inflammatory response in vivo. As such, it was hypothesized that the fast dissolution of glucose microparticles (GMPs) in a CPC composite also incorporating poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) will create an initial macroporosity and increase the surface area within the CPC, thus enhancing the diffusion of PLGA degradation products and preventing a significant decrease in pH. Furthermore, as PLGA degradation occurs over several weeks to months, additional macroporosity will be generated at later time points within CPCs. The results offer a new method for generating macroporosity in a multimodal fashion that also mitigates the effects of acidic degradation products.

Project description:Background Pulmonary hypertension (PH) is a deadly disease characterized by vascular stiffness and altered cellular metabolism. Current treatments focus on vasodilation and not other root causes of pathogenesis. Previously, it was demonstrated that glutamine metabolism, as catalyzed by GLS1 (glutaminase 1) activity, is mechanoactivated by matrix stiffening and the transcriptional coactivators YAP1 (yes-associated protein 1) and transcriptional coactivator with PDZ-binding motif (TAZ), resulting in pulmonary vascular proliferation and PH. Pharmacologic inhibition of YAP1 (by verteporfin) or glutaminase (by CB-839) improved PH in vivo. However, systemic delivery of these agents, particularly YAP1 inhibitors, may have adverse chronic effects. Furthermore, simultaneous use of pharmacologic blockers may offer additive or synergistic benefits. Therefore, a strategy that delivers these drugs in combination to local lung tissue, thus avoiding systemic toxicity and driving more robust improvement, was investigated. Methods and Results We used poly(lactic-co-glycolic) acid polymer-based microparticles for delivery of verteporfin and CB-839 simultaneously to the lungs of rats suffering from monocrotaline-induced PH. Microparticles released these drugs in a sustained fashion and delivered their payload in the lungs for 7 days. When given orotracheally to the rats weekly for 3 weeks, microparticles carrying this drug combination improved hemodynamic (right ventricular systolic pressure and right ventricle/left ventricle+septum mass ratio), histologic (vascular remodeling), and molecular markers (vascular proliferation and stiffening) of PH. Importantly, only the combination of drug delivery, but neither verteporfin nor CB-839 alone, displayed significant improvement across all indexes of PH. Conclusions Simultaneous, lung-specific, and controlled release of drugs targeting YAP1 and GLS1 improved PH in rats, addressing unmet needs for the treatment of this deadly disease.

Dataset Information

CD200 modulates macrophage cytokine secretion and phagocytosis in response to poly(lactic co-glycolic acid) microparticles and films.

Publications

CD200 modulates macrophage cytokine secretion and phagocytosis in response to poly(lactic co-glycolic acid) microparticles and films.

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