Search

Obesity is a metabolic disease resulting from excess body fat accumulation associated with chronic systemic inflammation. Obesity has been shown to impact the function and activity of neutrophils, macrophages, and T cells, contributing to higher circulating levels of pro-inflammatory cytokines. Biomaterial surface properties such as roughness and hydrophilicity can influence the behavior of immune cells in the peri-implant microenvironment. This study aimed to determine how obesity induced by a high-fat diet (HFD) affects the inflammatory response to modified titanium (Ti) implants and subsequent bone formation. Obese mice had significantly more neutrophils, pro-inflammatory macrophages, and T cells and fewer anti-inflammatory macrophages and mesenchymal stem cells (MSCs) in the peri-implant tissue than lean mice. Obesity also increased circulating adipokines and pro-inflammatory cytokines when compared to lean animals. Bone formation around Ti implants was reduced in obese mice compared to controls. Adoptive transfer of bone marrow cells isolated from obese mice into wild-type mice demonstrated the localized impact of obesity on immune cell function and phenotype, promoting a pro-inflammatory peri-implant microenvironment and attenuating bone formation post-implantation. These results show that obesity significantly affects the inflammatory response to modified Ti implants, prolonging the pro-inflammatory response to the implanted biomaterial and compromising bone formation. STATEMENT OF SIGNIFICANCE: Obesity has been shown to significantly alter physiological processes, including the behavior of immune cells, inducing a state of systemic chronic inflammation. Our study demonstrates that obesity-induced via a high-fat diet alters immune cell response to implanted biomaterials, with increased pro-inflammatory response and attenuated immunomodulation that results in decreased biomaterial integration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Macrophages play a central role in orchestrating the inflammatory response to implanted biomaterials and are sensitive to changes in the chemical and physical characteristics of the implant. Macrophages respond to biological, chemical, and physical cues by polarizing into pro-inflammatory (M1) or anti-inflammatory (M2) states. We previously showed that rough-hydrophilic titanium (Ti) implants skew macrophage polarization towards an anti-inflammatory phenotype and increase mesenchymal stem cell (MSC) recruitment and bone formation around the implant. In the present study, we aimed to investigate whether the adoptive transfer of macrophages in different polarization states would alter the inflammatory microenvironment and improve biomaterial integration in macrophage-competent and macrophage-ablated mice. We found that ablating macrophages increased the presence of neutrophils, reduced T cells and MSCs, and compromised the healing and biomaterial integration process. These effects could not be rescued with adoptive transfer of naïve or polarized macrophages. Adoptive transfer of M1 macrophages into macrophage-competent mice increased inflammatory cells and inflammatory microenvironment, resulting in decreased bone-to-implant contact. Adoptive transfer of M2 macrophages into macrophage-competent mice reduced the pro-inflammatory environment in the peri‑implant tissue and increased bone-to-implant contact. Taken together, our results show the importance of macrophages in controlling and modulating the inflammatory process in response to implanted biomaterials and suggest they can be used to improve outcomes following biomaterial implantation. STATEMENT OF SIGNIFICANCE: Macrophages are central in orchestrating the inflammatory response to implanted biomaterials and are sensitive to biomaterial chemical and physical characteristics. Our study shows that a deficiency of macrophages results in prolonged inflammation and abolishes bone-biomaterial integration. Adoptive transfer of immunomodulatory macrophages into macrophage-competent mice reduced the inflammatory environment and increased bone-implant contact., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Physiochemical cues like topography and wettability can impact the inflammatory response and tissue integration after biomaterial implantation. T cells are essential for immunomodulation of innate immune cells and play an important role in the host response to biomaterial implantation. This study aimed to understand how CD4 + and CD8 + T cell subsets, members of the αβ T cell family, polarize in response to smooth, rough, or rough-hydrophilic titanium (Ti) implants and whether their presence modulates immune cell crosstalk and mesenchymal stem cell (MSC) recruitment following biomaterial implantation. Post-implantation in mice, we found that CD4 + and CD8 + T cell subsets polarized differentially in response to modified Ti surfaces. Additionally, mice lacking αβ T cells had significantly more pro-inflammatory macrophages, fewer anti-inflammatory macrophages, and reduced MSC recruitment in response to modified Ti post-implantation than αβ T cell -competent mice. Our results demonstrate that T cell activation plays a significant role during the inflammatory response to implanted biomaterials, contributing to macrophage polarization and MSC recruitment and proliferation, and the absence of αβ T cells compromises new bone formation at the implantation site. STATEMENT OF SIGNIFICANCE: T cells are essential for immunomodulation and play an important role in the host response to biomaterial implantation. Our results demonstrate that T cells actively participate during the inflammatory response to implanted biomaterials, controlling macrophage phenotype and recruitment of MSCs to the implantation site., Competing Interests: Declaration of Competing Interest The authors declare that they do not have competing financial interests., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Materials for craniofacial and orthopedic implants are commonly selected based on mechanical properties and corrosion resistance. The biocompatibility of these materials is typically assessed in vitro using cell lines, but little is known about the response of immune cells to these materials. This study aimed to evaluate the inflammatory and immune cell response to four common orthopedic materials [pure titanium (Ti), titanium alloy (TiAlV), 316L stainless steel (SS), polyetheretherketone (PEEK)]. Following implantation into mice, we found high recruitment of neutrophils, pro-inflammatory macrophages, and CD4+ T cells in response to PEEK and SS implants. Neutrophils produced higher levels of neutrophil elastase, myeloperoxidase, and neutrophil extracellular traps in vitro in response to PEEK and SS than neutrophils on Ti or TiAlV. Macrophages co-cultured on PEEK, SS, or TiAlV increased polarization of T cells towards Th1/Th17 subsets and decreased Th2/Treg polarization compared to Ti substrates. Although SS and PEEK are considered biocompatible materials, both induce a more robust inflammatory response than Ti or Ti alloy characterized by high infiltration of neutrophils and T cells, which may cause fibrous encapsulation of these materials. STATEMENT OF SIGNIFICANCE: Materials for craniofacial and orthopedic implants are commonly selected based on their mechanical properties and corrosion resistance. This study aimed to evaluate the immune cell response to four common orthopedic and craniofacial biomaterials: pure titanium, titanium-aluminum-vanadium alloy, 316L stainless steel, and PEEK. Our results demonstrate that while the biomaterials tested have been shown to be biocompatible and clinically successful, the inflammatory response is largely driven by chemical composition of the biomaterials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Neutrophils are the most abundant immune cells in the blood and the first cells to be recruited to the biomaterial implantation site. Neutrophils are fundamental in recruiting mononuclear leukocytes to mount an immune response at the injury site. Neutrophils exert significant pro-inflammatory effects through the release of cytokines and chemokines, degranulation and release of myeloperoxidase (MPO) and neutrophil elastase (NE), and the production of large DNA-based networks called neutrophil extracellular traps (NETs). Neutrophils are initially recruited and activated by cytokines and pathogen- and damage-associated molecular patterns, but little is known about how the physicochemical composition of the biomaterial affects their activation. This study aimed to understand how ablating neutrophil mediators (MPO, NE, NETs) affected macrophage phenotype in vitro and osseointegration in vivo. We discovered that NET formation is a crucial mediator of pro-inflammatory macrophage activation, and inhibition of NET formation significantly suppresses macrophage pro-inflammatory phenotype. Furthermore, reducing NET formation accelerated the inflammatory phase of healing and produced greater bone formation around the implanted biomaterial, suggesting that NETs are essential regulators of biomaterial integration. Our findings emphasize the importance of the neutrophil response to implanted biomaterials and highlight innate immune cells' regulation and amplification signaling during the initiation and resolution of the inflammatory phase of biomaterial integration. Neutrophils are the most abundant immune cells in blood and are the first to be recruited to the injury/implantation site where they exert significant pro-inflammatory effects. This study aimed to understand how ablating neutrophil mediators affected macrophage phenotype in vitro and bone apposition in vivo. We found that NET formation is a crucial mediator of pro-inflammatory macrophage activation. Reducing NET formation accelerated the inflammatory phase of healing and produced greater appositional bone formation around the implanted biomaterial, suggesting that NETs are essential regulators of biomaterial integration. [Display omitted] [ABSTRACT FROM AUTHOR]