Electrospun Polydioxanone Loaded With Chloroquine Modulates Template-Induced NET Release and Inflammatory Responses From Human Neutrophils.
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ABSTRACT:
SUBMITTER: Fetz AE
PROVIDER: S-EPMC8111017 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:During the acute inflammatory response, the release of neutrophil extracellular traps (NETs) is a pro-inflammatory, preconditioning event on a biomaterial surface. Therefore, regulation of NET release through biomaterial design is one strategy to enhance biomaterial-guided in situ tissue regeneration. In this study, IgG adsorption on electrospun polydioxanone biomaterials with differing fiber sizes was explored as a regulator of in vitro human neutrophil NET release. The propensity to release NETs was increased and decreased by modulating adsorbed IgG, suggesting a functional link between IgG and NET formation. Fiber-size dependent NET release was reduced by blocking FcγRIIIb, but not FcγRI, FcγRIIa, or Mac-1 (CD11b/CD18), indicating a specific receptor mediated neutrophil response. Inhibition of transforming growth factor-β-activated kinase 1 (TAK1), which is activated downstream of FcγRIIIb, significantly reduced the release of NETs in a fiber size-independent manner. These results indicate that in vitro electrospun biomaterial-induced NET release is largely regulated by IgG adsorption, engagement of FcγRIIIb, and signaling through TAK1. Modulation of this pathway may have beneficial therapeutic effects for regulating neutrophil-mediated inflammation by avoiding the adverse effects of NETs and increasing the potential for in situ tissue regeneration. STATEMENT OF SIGNIFICANCE: Electrospun biomaterials have great potential for in situ tissue engineering because of their versatility and biomimetic properties. However, understanding how to design the biomaterial to regulate acute inflammation, dominated by neutrophils, remains a great challenge for successful tissue integration and regeneration. In this work, we demonstrate for the first time how protein adsorption on the biomaterial surface and engagement of a specific neutrophil receptor induces intracellular signals that regulate the pro-inflammatory release of neutrophil extracellular traps (NETs). Given the deleterious effects of NETs during the acute inflammatory response to a biomaterial, our work highlights the importance of considering biomaterial-neutrophil interactions on degradable and non-degradable biomaterials to achieve the desired biological outcome.
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Project description:Zinc plays an important physiological role in the entire body, especially in the immune system. It is one of the most abundant microelements in our organism and an essential component of enzymes and antibacterial proteins. Zinc levels were reported to be correlated with the intensity of innate immunity responses, especially those triggered by neutrophils. However, as the results are fragmentary, the phenomenon is still not fully understood and requires further research. In this study, we aimed to perform a comprehensive assessment and study the impact of zinc on several basic neutrophils' functions in various experimental setups. Human and murine neutrophils were preincubated in vitro with zinc, and then phagocytosis, oxidative burst, degranulation and release of neutrophil extracellular traps (NETs) were analyzed. Moreover, a murine model of zinc deficiency and zinc supplementation was introduced in the study and the functions of isolated cells were thoroughly studied. We showed that zinc inhibits NETs release as well as degranulation in both human and murine neutrophils. Our study revealed that zinc decreases NETs release by inhibiting citrullination of histone H3. On the other hand, studies performed in zinc-deficient mice demonstrated that low zinc levels result in increased release of NETs and enhanced neutrophils degranulation. Overall, it was shown that zinc affects neutrophils' functions in vivo and in vitro. Proper zinc level is necessary to maintain efficient functioning of the innate immune response.
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Project description:Electrospun fibrous membranes loaded with chemotherapy drugs have been broadly studied, many of which have had promising data demonstrating therapeutic effects on cancer cell inhibition, tumor size reduction, the life extension of tumor-bearing animals, and more. Nevertheless, their drug release profiles are difficult to predict since their degradation pattern varies with crystalline polymers. In addition, there is room for improving their release performances, optimizing the release patterns, and achieving better therapeutic outcomes. In this review, the key factors affecting electrospun membrane drug release profiles have been systematically reviewed. Case studies of the release profiles of typical chemotherapy drugs are carried out to determine the preferred polymer choices and techniques to achieve the expected prolonged or enhanced release profiles. The therapeutic effects of these electrospun, chemo-drug-loaded membranes are also discussed. This review aims to assist in the design of future drug-loaded electrospun materials to achieve preferred release profiles with enhanced therapeutic efficacies.
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Project description:Many surgical tendon repairs fail despite advances in surgical materials and techniques. Tendon repair failure can be partially attributed to the tendon’s poor intrinsic healing capacity and the repurposing of sutures from use in other tissues. Electrospun materials show promise as a biological scaffold to support endogenous tendon repair, but their relatively low tensile strength has limited their clinical translation. It is hypothesized that combining electrospun fibres with a stronger material may improve the suture’s mechanical properties while retaining biophysical cues necessary to encourage cell-mediated repair. This paper describes the production of a hybrid electrospun-extruded suture with a sheath of submicron electrospun fibres and a core of melt-extruded fibres. The porosity and tensile strength of this hybrid suture is compared to an electrospun-only braided suture and clinically used sutures Vicryl and PDS. Bioactivity is assessed by measuring the adsorbed serum proteins on electrospun and melt-extruded filaments using mass spectrometry. Human hamstring tendon fibroblast attachment and proliferation was quantified and compared between the hybrid and control sutures. Combining an electrospun sheath with melt-extruded cores created a hybrid braid with increased tensile strength (70.1±0.3N) compared to an electrospun only suture (12.9±1N, p<0.0001). The hybrid suture had a similar force at break to clinical sutures, but lower stiffness and stress. The Young’s modulus was 772.6±32Mpa for the hybrid suture, 1693.0±69Mpa for PDS, and 3838.0±132MPa for Vicryl, p<0.0001. Hybrid sutures had lower overall porosity than electrospun-only sutures (40±4% and 60±7%, respectively, p=0.0018) but had a significantly larger overall porosity and average pore diameter compared to surgical sutures. There were similar clusters of adsorbed proteins on electrospun and melt-extruded filaments, which were distinct from PDS. Tendon fibroblast attachment on hybrid and electrospun sutures was significantly higher than on clinical sutures (hybrid 28±7%; electrospun 24±7%; Vicryl 10±5%; PDS 2±0.1%, p<0.0001). Cell proliferation was significantly higher on hybrid and electrospun sutures compared to on clinical sutures. Overall, this study demonstrated that a bioactive suture with increased tensile strength and lower stiffness could be produced by adding a core of 10um melt-extruded fibres to a sheath of electrospun fibres. In contrast to currently used sutures, the hybrid sutures promoted a bioactive response: serum proteins adsorbed, and fibroblasts attached, survived, grew along the sutures, and adopted appropriate morphologies.
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Project description:Streptococcus pneumoniae is a major human pathogen and a leading cause of pneumonia, septicemia, and meningitis worldwide. Despite clinical studies linking vitamin D deficiency and pneumonia, molecular mechanisms behind these observations remain unclear. In particular, the effects of vitamin D on neutrophil responses remain unknown. Using pneumococcal strains, primary neutrophils isolated from human blood, and sera from patients with frequent respiratory tract infections (RTIs), we investigated the effects of vitamin D on neutrophil bactericidal and inflammatory responses, including pattern recognition receptors, antimicrobial peptides, and cytokine regulation. We found that vitamin D upregulated pattern recognition receptors, TLR2, and NOD2, and induced the antimicrobial human neutrophil peptides (HNP1-3) and LL-37, resulting in increased killing of pneumococci in a vitamin D receptor-dependent manner. Antibodies targeting HNP1-3 inhibited bacterial killing. Vitamin D supplementation of serum from patients with bacterial RTIs enhanced neutrophil killing. Moreover, vitamin D lowered inflammatory cytokine production by infected neutrophils via IL-4 production and the induction of suppressor of cytokine signaling (SOCS) proteins SOCS-1 and SOCS-3, leading to the suppression of NF-?B signaling. Thus, vitamin D enhances neutrophil killing of S. pneumoniae while dampening excessive inflammatory responses and apoptosis, suggesting that vitamin D could be used alongside antibiotics when treating pneumococcal infections.
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