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Immunofluorescence images of (A) Ly6G (Neutrophils marker, red) and (B) CitH3 (NETs marker, green) in bone tissues (scale bar = 100 μm). (C) Histological evaluation of bone tissues adjacent to different implants on day 3 after implantation (scale bar = 100 μm). Asterisks represent the implants. Yellow arrows indicate neutrophils.
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The widespread use of orthopedic implants to support or replace bones is increasingly threatened by the risk of incurable bacterial infections, impenetrable microbial biofilms, and irreversible antibiotic resistance. In the past, the development of anti-infective biomaterials focused solely on direct antibacterial properties while ignoring the host...
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... in vivo immune response and antibacterial activity of Zn were evaluated using a rat model of implant-associated infection. Bone tissues surrounding the implants were decalcified and subjected to immunofluorescence and H&E. As shown in Fig. 5A, more immunofluorescencestained Ly6G (red fluorescence, a marker for myeloid neutrophils) was observed in the Zn group on day 3 after implantation, suggesting that Zn was more beneficial for the recruitment of neutrophils. Moreover, CitH3 immunofluorescence observed in the Zn group suggested that the recruited neutrophils could form ...
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... Ly6G (red fluorescence, a marker for myeloid neutrophils) was observed in the Zn group on day 3 after implantation, suggesting that Zn was more beneficial for the recruitment of neutrophils. Moreover, CitH3 immunofluorescence observed in the Zn group suggested that the recruited neutrophils could form more NETs surrounding the Zn implant (Fig. 5B). H&E staining showed more neutrophils (indicated by yellow arrows) surrounding Zn implants, indicating more serious acute inflammation and better bacterial elimination (Fig. 5C, high magnification shown in Fig. ...
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... of neutrophils. Moreover, CitH3 immunofluorescence observed in the Zn group suggested that the recruited neutrophils could form more NETs surrounding the Zn implant (Fig. 5B). H&E staining showed more neutrophils (indicated by yellow arrows) surrounding Zn implants, indicating more serious acute inflammation and better bacterial elimination (Fig. 5C, high magnification shown in Fig. ...
Citations
... In general, according to Ron et al. [61], this can be mainly attributed to the inherent anti-inflammatory capabilities of Zn-base alloys. This explanation is also supported by numerous studies that highlight the anti-inflammatory characteristics of Zn [37,40,62,63]. Furthermore, the beneficial cell viability tendency related to the tested alloys was enlarged as the Nd content was increased from 1 to 3%. ...
The present study aims to evaluate the effect of up to 3 wt.% Nd on pure Zn in terms of physical properties and in vitro analysis. The use of Nd as an alloying element is due to its relatively adequate biocompatibility and its potential capability to reinforce metals with a hexagonal close-packed (HCP) crystal structure, such as Mg and Zn. The microstructural assessment was executed using X-ray diffraction analysis, along with optical and scanning electron microscopy. The mechanical properties were evaluated by hardness and tensile strength testing. The corrosion performance in simulated physiological environments was examined by means of immersion tests, potentiodynamic polarization, and impedance spectroscopy using phosphate-buffered saline (PBS) solution. Cytotoxicity assessment was carried out by indirect cell viability analysis according to the ISO 10993-5/12 standard using Mus musculus 4T1 cells, which are known to be very sensitive to toxic environments. The obtained results clearly highlighted the reinforcing effect of Nd in Zn-base alloys, mainly due to the formation of a secondary phase: NdZn5. This strengthening effect was acquired without impairing the inherent ductility and corrosion performance of the tested alloys. The cytotoxicity assessment indicated that the addition of Nd has a strong favorable effect on cell viability, which stimulates the inherent anti-inflammatory characteristics of Zn.
... In this work, we proposed that absorbable filaments made with a base of Zn would be biocompatible and have advantages over Mg in nerve repair. The potential advantages of Zn include a slower in vivo degradation rate (better for support across longer nerve gaps, an issue that we encountered with Mg), less reactivity to water (Mg degradation produces hydrogen bubbles that can disrupt tissue attachment), and that there are greater anti-inflammatory and antisepsis effects of Zn versus Mg ions [18][19][20][21][22][23][24]. Our studies on Mg filaments for nerve regeneration showed that the Mg filaments developed gaps by six weeks in vivo, which we speculated would be too soon to provide sufficient physical support for longer injury gaps [12][13][14]. ...
Peripheral nerve damage that results in lost segments requires surgery, but currently available hollow scaffolds have limitations that could be overcome by adding internal guidance support. A novel solution is to use filaments of absorbable metals to supply physical support and guidance for nerve regeneration that then safely disappear from the body. Previously, we showed that thin filaments of magnesium metal (Mg) would support nerve regeneration. Here, we tested another absorbable metal, zinc (Zn), using a proprietary zinc alloy with 2% iron (Zn-2%Fe) that was designed to overcome the limitations of both Mg and pure Zn metal. Non-critical-sized gaps in adult rat sciatic nerves were repaired with silicone conduits plus single filaments of Zn-2%Fe, Mg, or no metal, with autografts as controls. After seventeen weeks, all groups showed equal recovery of function and axonal density at the distal end of the conduit. The Zn alloy group showed some improvements in early rat health and recovery of function. The alloy had a greater local accumulation of degradation products and inflammatory cells than Mg; however, both metals had an equally thin capsule (no difference in tissue irritation) and no toxicity or inflammation in neighboring nerve tissues. Therefore, Zn-2%Fe, like Mg, is biocompatible and has great potential for use in nervous tissue regeneration and repair.
... 97 Studies have shown that Zn promotes the formation of NETs by neutrophils to clear pathogens and promote osseointegration at the site of infection in a ROS-dependent manner. 98,99 Furthermore, biomaterial surface modification is also an excellent strategy for neutrophil regulation. For example, magnetron-sputtered tantalum nanofilms showed no significant antibacterial effect in in vitro tests; however, in vivo, studies unexpectedly found that it enhanced the phagocytic activity of polymorphonuclear neutrophils and reduced neutrophil lysis. ...
Bacterial infectious diseases are one of the leading causes of death worldwide. Even with the use of multiple antibiotic treatment strategies, 4.95 million people died from drug-resistant bacterial infections in 2019. By 2050, the number of deaths will reach 10 million annually. The increasing mortality may be partly due to bacterial heterogeneity in the infection microenvironment, such as drug-resistant bacteria, biofilms, persister cells, intracellular bacteria, and small colony variants. In addition, the complexity of the immune microenvironment at different stages of infection makes biomaterials with direct antimicrobial activity unsatisfactory for the long-term treatment of chronic bacterial infections. The increasing mortality may be partly attributed to the biomaterials failing to modulate the active antimicrobial action of immune cells. Therefore, there is an urgent need for effective alternatives to treat bacterial infections. Accordingly, the development of immunomodulatory antimicrobial biomaterials has recently received considerable interest; however, a comprehensive review of their research progress is lacking. In this review, we focus mainly on the research progress and future perspectives of immunomodulatory antimicrobial biomaterials used at different stages of infection. First, we describe the characteristics of the immune microenvironment in the acute and chronic phases of bacterial infections. Then, we highlight the immunomodulatory strategies for antimicrobial biomaterials at different stages of infection and their corresponding advantages and disadvantages. Moreover, we discuss biomaterial-mediated bacterial vaccines’ potential applications and challenges for activating innate and adaptive immune memory. This review will serve as a reference for future studies to develop next-generation immunomodulatory biomaterials and accelerate their translation into clinical practice.
... From an opposite perspective, Peng et al. [36] proposed an innovative solution for developing orthopedic implants with antimicrobial properties. They have used zinc implants to induce the formation of NETs and therefore prevent possible implant-associated infections. ...
Tissue engineering and regenerative medicine are pursuing clinical valid solutions to repair and restore function of damaged tissues or organs. This can be achieved in different ways, either by promoting endogenous tissue repair or by using biomaterials or medical devices to replace damaged tissues. The understanding of the interactions of the immune system with biomaterials and how immune cells participate in the process of wound healing are critical for the development of successful solutions. Until recently, it was thought that neutrophils participate only in the initial steps of an acute inflammatory response with the role of eliminating pathogenic agents. However, the appreciation that upon activation the longevity of neutrophils is highly increased and the fact that neutrophils are highly plastic cells and can polarize into different phenotypes led to the discovery of new and important actions of neutrophils. In this review, we focus on the roles of neutrophils in the resolution of the inflammatory response, in biomaterial–tissue integration and in the subsequent tissue repair/regeneration. We also discuss the potential of neutrophils for biomaterial-based immunomodulation.
Bone fractures and critical-size bone defects are significant public health issues, and clinical treatment outcomes are closely related to the intrinsic properties of the utilized implant materials. Zinc (Zn)-based biodegradable metals (BMs) have emerged as promising bioactive materials because of their exceptional biocompatibility, appropriate mechanical properties, and controllable biodegradation. This review summarizes the state of the art in terms of Zn-based metals for bone repair and regeneration, focusing on bridging the gap between biological mechanism and required bioactivity. The molecular mechanism underlying the release of Zn ions from Zn-based BMs in the improvement of bone repair and regeneration is elucidated. By integrating clinical considerations and the specific bioactivity required for implant materials, this review summarizes the current research status of Zn-based internal fixation materials for promoting fracture healing, Zn-based scaffolds for regenerating critical-size bone defects, and Zn-based barrier membranes for reconstituting alveolar bone defects. Considering the significant progress made in the research on Zn-based BMs for potential clinical applications, the challenges and promising research directions are proposed and discussed.
Zinc(Zn)-based materials have contributed greatly to the rapid advancements in tissue engineering. The qualities they possess that make them so beneficial include their excellent biodegradability, biocompatibility, anti-bacterial activity, among and several others. Biomedical materials that act as a foreign body, will inevitably cause host immune response when introduced to the human body. As the osteoimmunology develops, the immunomodulatory characteristics of biomaterials have become an appealing concept to improve implant-tissue interaction and tissue restoration. Recently, Zn-based materials have also displayed immunomodulatory functions, especially macrophage polarization states. It can promote the transformation of M1 macrophages into M2 macrophages to enhance the tissue regeneration and reconstruction. This review covers mainly Zn-based materials and their characteristics, including metallic Zn alloys and Zn ceramics. We highlight the current advancements in the type of immune responses, as well as the mechanisms, that are induced by Zn-based biomaterials, most importantly the regulation of innate immunity and the mechanism of promoting tissue regeneration. To this end, we discuss their applications in biomedicine, and conclude with an outlook on future research challenges.
