Characterizing the Macrophage Response to Immunomodulatory Biomaterials Through Gene Set Analyses

Blatt, Sarah E.; Lurier, Emily; Risser, Gregory E.; Spiller, Kara L.

doi:10.1089/ten.tec.2019.0309

Cited by 9 publications

(8 citation statements)

References 29 publications

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“…We also examined the extended effect of a single TLR2 neutralizing antibody pre-treatment, administered prior to seeding the macrophages within the various test conditions, to determine if the influence of Frontiers in Bioengineering and Biotechnology frontiersin.org transient TLR2-neutralization was maintained at later time points or overwhelmed by pro-inflammatory signaling via non-TLR2-dependent pathways. Teflon ™ AF surfaces preconditioned with 10% FBS was used as a reference for macrophage activation in traditional cell-material interaction models, which frequently use FBS or human serum to recapitulate the in vivo protein adsorption (Amer et al, 2019;Blatt et al, 2020;Buck et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The extended effect of adsorbed damage-associated molecular patterns and Toll-like receptor 2 signaling on macrophage-material interactions

Kaushal

Zhang

Ballantyne

et al. 2022

Front. Bioeng. Biotechnol.

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Implanted biomaterials elicit an immune-mediated foreign body reaction (FBR) that results in the fibrous encapsulation of the implant and can critically impact the performance of some implants. Consequently, understanding the molecular mechanisms that underpin cell-materials interactions that initiate biomaterial-induced inflammation and fibrosis is critical to improving the performance of biomaterial implants negatively impacted by the FBR. Damage-associated molecular patterns (DAMPs) are endogenous mediators of inflammation that are released upon tissue injury and induce sterile inflammation via Toll-like receptors (TLRs). However, the prevalence of DAMPs within the adsorbed protein layer on material surfaces and their role mediating cell-material interactions is unclear. Previously, our group demonstrated that molecules in fibroblast lysates adsorbed to various biomaterials and induced a potent TLR2-dependent inflammatory response in macrophages at 24 h. In this study, we examined the extended response of RAW-Blue reporter macrophages on lysate or serum-adsorbed Teflon™ AF surfaces to understand the potential role of adsorbed DAMPs in macrophage-material interactions at later time points. Lysate-conditioned surfaces maintained increased nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) transcription factor activity and increased expression Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES/CCL5) at 72 h and 120 h, compared to FBS-conditioned surfaces. In contrast, monocyte chemoattractant protein 1 (MCP-1/CCL2) was only elevated at 72 h in lysate conditions. Transforming growth factor beta 1 (TGF-β1) secretion was significantly increased on lysate-conditioned surfaces, while conditioned media from macrophages on lysate-conditioned surfaces induced alpha smooth muscle actin (αSMA) expression in 3T3 fibroblasts. TLR2 neutralizing antibody treatment significantly decreased NF-κB/AP-1 activity and attenuated TGF-β1 expression at both time points, and MCP-1 and RANTES at 72 h. Finally, multinucleated cells were observed on lysate-conditioned surfaces at 72 h, indicating adsorbed DAMPs induced a fusion permissive environment for adherent macrophages. This study demonstrates that adsorbed DAMPs continue to influence macrophage-material responses beyond the initial 24-h period and maintain a pro-inflammatory and fibrotic response that models aspects of the early FBR. Furthermore, the transient inhibition of TLR2 continued to exert an effect at these later time points, suggesting TLR2 may be a target for therapeutic interventions in FBR.

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Section: Discussionmentioning

confidence: 99%

The extended effect of adsorbed damage-associated molecular patterns and Toll-like receptor 2 signaling on macrophage-material interactions

Kaushal

Zhang

Ballantyne

et al. 2022

Front. Bioeng. Biotechnol.

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“…These studies indicate that increased numbers of phenotype markers are needed to capture the increase in complexity of macrophage phenotypes in biomaterial studies. In this regard, gene expression is being pioneered to characterize macrophage phenotypes more thoroughly . In particular, alternatively activated M2 macrophages are important mediators of successful wound healing, and a thorough evaluation of their subtypes in lignin composite wounds would elucidate the mechanisms of their action on promoting wound healing.…”

Section: Resultsmentioning

confidence: 99%

“…The lignin composites used in our wound-healing studies are in the range of 1–2 kPa of storage modulus (Figure c), thus likely priming macrophage toward anti-inflammatory (M2) phenotypes. Although the markers to identify the inflammatory cell types, particularly those associated with macrophages, work very well for identifying macrophages using in vitro polarization with defined stimuli, there is evidence from the literature that macrophages do not respond to biomaterials in the same way as they do to the biochemical stimuli with distinct polarizations . For example, Graney et al investigated the behavior of macrophages cultured on ceramic-based scaffolds and found hybrid activation states that were not distinctly M1, M2a, or M2c and further noted that some markers were upregulated whereas others were downregulated in their various scaffold studies, which are not possible to distinguish by cell counting from histologic sections.…”

Section: Resultsmentioning

confidence: 99%

Injectable Antioxidant and Oxygen-Releasing Lignin Composites to Promote Wound Healing

Balaji

Short

Belgodere

et al. 2023

ACS Appl. Mater. Interfaces

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The application of engineered biomaterials for wound healing has been pursued since the beginning of tissue engineering. Here, we attempt to apply functionalized lignin to confer antioxidation to the extracellular microenvironments of wounds and to deliver oxygen from the dissociation of calcium peroxide for enhanced vascularization and healing responses without eliciting inflammatory responses. Elemental analysis showed 17 times higher quantity of calcium in the oxygen-releasing nanoparticles. Lignin composites including the oxygen-generating nanoparticles released around 700 ppm oxygen per day at least for 7 days. By modulating the concentration of the methacrylated gelatin, we were able to maintain the injectability of lignin composite precursors and the stiffness of lignin composites suitable for wound healing after photo-cross-linking. In situ formation of lignin composites with the oxygen-releasing nanoparticles enhanced the rate of tissue granulation, the formation of blood vessels, and the infiltration of α-smooth muscle actin+ fibroblasts into the wounds over 7 days. At 28 days after surgery, the lignin composite with oxygen-generating nanoparticles remodeled the collagen architecture, resembling the basket-weave pattern of unwounded collagen with minimal scar formation. Thus, our study shows the potential of functionalized lignin for wound-healing applications requiring balanced antioxidation and controlled release of oxygen for enhanced tissue granulation, vascularization, and maturation of collagen.

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“…Moderate conversion from the M1 to the M2 phenotype can be critical for implant materials fracture healing and osteointegration [ 25 ]. A moderate transition from the pro-inflammatory M1 phenotype to the immunoregulatory, or anti-inflammatory, M2 phenotype can be an important aspect of the bone healing process promotion, leading to a functional recovery rather than scar tissue formation [ 26 – 28 ]. In the present study, on the 3rd day, the early stage of inflammation presented mainly M1 macrophages (high proportion), while on the 14th day, the M2 type was dominant (moderate proportion) (Fig.…”

Section: Discussionmentioning

confidence: 99%

Bone response in vivo of Ti-45Zr alloy as dental implant material

Zhang

et al. 2022

J Mater Sci: Mater Med

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Ti-Zr alloys have gained increasing attention as a new metallic biomaterial, being used as implants for both orthopedics and dentistry. More recently, our group found promising results for the Ti-45Zr alloy, which presented a low elastic modulus, a pronounced and excellent mechanic character, and excellent cell compatibility in vitro. However, its biocompatibility and potential to promote osteogenesis in vivo remained unclear. In the present study, the biocompatibility, osteointegration ability, and immune response effects of the Ti-45Zr alloy were evaluated in animal experiments. The results showed that the alloy had good blood compatibility and no body side effects. After implantation in vivo, the inflammation turned out well and was beneficial to the polarization of macrophages. Additionally, the Ti-45Zr alloy presented a good osteointegration ability. Overall, these results confirmed that the Ti-45Zr alloy can be used as a dental implant material.

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Characterizing the Macrophage Response to Immunomodulatory Biomaterials Through Gene Set Analyses

Cited by 9 publications

References 29 publications

The extended effect of adsorbed damage-associated molecular patterns and Toll-like receptor 2 signaling on macrophage-material interactions

The extended effect of adsorbed damage-associated molecular patterns and Toll-like receptor 2 signaling on macrophage-material interactions

Injectable Antioxidant and Oxygen-Releasing Lignin Composites to Promote Wound Healing

Bone response in vivo of Ti-45Zr alloy as dental implant material

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