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Achieving bacterial killing and osteogenic formation on an implant surface rarely occurs. In this study, a novel surface design-a palladium hydride (PdH x ) film that enables these two distinct features to coexist is introduced. The PdH x lattice captures protons in the extracellular microenvironment of bacteria, disrupting their normal metabolic activities, such as ATP synthesis, nutrient co-transport, and oxidative stress. This disruption leads to significant bacterial death, as evidenced by RNA sequence analysis. Additionally, the unique enzymatic activity and hydrogen-loading properties of PdH x activate the human antioxidant system, resulting in the rapid clearance of reactive oxygen species. This process reshapes the osteogenic immune microenvironment, promoting accelerated osteogenesis. These findings reveal that the downregulation of the NOD-like receptor signaling pathway is critical for activating immune cells toward M2 phenotype polarization. This novel surface design provides new strategies for modifying implant coatings to simultaneously prevent bacterial infection, reduce inflammation, and enhance tissue regeneration, making it a noteworthy contribution to the field of advanced materials., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Infection and poor tissue repair are the key causes of percutaneous implantation failure. However, there is a lack of effective strategies to cope with due to its high requirements of sterilization, soft tissue healing, and osseointegration. In this work, l-arginine (L-Arg) was loaded onto a sulfonated polyetheretherketone (PEEK) surface to solve this issue. Under the infection condition, nitric oxide (NO) and reactive oxygen species (ROS) are produced through catalyzing L-Arg by inducible nitric oxide synthase (iNOS) and thus play a role in bacteria sterilization. Under the tissue repair condition, L-Arg is catalyzed to ornithine by Arginase-1 (Arg-1), which promotes the proliferation and collagen secretion of L929 and rBMSCs. Notably, L-Arg loading samples could polarize macrophages to M1 and M2 in infection and tissue repair conditions, respectively. The results in vivo show that the L-Arg loading samples could enhance infected soft tissue sealing and bone regeneration. In summary, L-Arg loading sulfonated PEEK could polarize macrophage through metabolic reprogramming, providing multi-functions of antibacterial abilities, soft tissue repair, and bone regeneration, which gives a new idea to design percutaneous implantation materials., Competing Interests: Kelvin W. K. Yeung is an associate editor for Bioactive Materials and was not involved in the editorial review or the decision to publish this article. Xuanyong Liu is an editorial board member for Bioactive Materials and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests., (© 2024 The Authors.)

Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu., (© 2024. The Author(s).)

The development of magnesium-derived biomaterials is one of the most promising research in bone tissue engineering, and related strategies have been extensively used for tendon, skull, cartilage, and bone regeneration. Also, alendronate, a well-recognized drug for osteoporosis treatment, has recently attracted a great deal of attention for bone repair. However, rapid corrosion in vivo of Mg 2+ and low systemic bioavailability of alendronate are the main limitations hampering their full exploitation. In this work, by means of physical and chemical cross-linking conjugating magnesium-metal-organic frameworks (Mg-MOFs) and bone-targeting alendronate to biocompatible gelatin scaffolds, a facile method is developed for the preparation of organic/inorganic nanocomposite gel scaffolds. The results affirmed that the nanocomposite gel scaffolds possessed excellent biocompatibility, continuous slow release of Mg 2+ and alendronate, strong bone affinity, and bone regeneration. It is noteworthy that the continuous slow release of Mg 2+ and alendronate could induce the macrophage switch to the M2 phenotype and promote osteogenic differentiation in the early stage, resulting in improved bone regeneration during implanting the scaffolds into the distal femoral. In summary, Mg-MOFs-loaded alendronate-modified gelatin gel scaffolds have been developed, exhibiting great potential for bone regenerative.

Fungal infections affect over 13 million people worldwide and are responsible for 1.5 million deaths annually. Some deep cutaneous fungal infections may extend the dermal barriers to cause systemic infection, resulting in substantial morbidity and mortality. However, the management of deep cutaneous fungal infection is challenging and yet overlooked by traditional treatments, which only offer limited drug availability within deep tissue. In this study, we have developed an electrically stimulated microneedle patch to deliver miconazole into the subcutaneous layer. We tested its antifungal efficacy using in vitro and ex vivo models that mimic fungal infection. Moreover, we confirmed its anti-fungal and wound-healing effects in a murine subcutaneous fungal infection model. Furthermore, our findings also showed that the combination of miconazole and applied current synergistically stimulated the nociceptive sensory nerves, thereby activating protective cutaneous immunity mediated by dermal dendritic and γδ-T cells. Collectively, this study provides a new strategy for minimally invasive delivery of therapeutic agents and the modulation of the neuro-immune axis in deep tissue., (Copyright © 2024. Published by Elsevier Ltd.)

There is an evident advantage in personalized customization of orthopedic implants by 3D-printed titanium (Ti) and its alloys. However, 3D-printed Ti alloys have a rough surface structure caused by adhesion powders and a relatively bioinert surface. Therefore, surface modification techniques are needed to improve the biocompatibility of 3D-printed Ti alloy implants. In the present study, porous Ti6Al4V scaffolds were manufactured by a selective laser melting 3D printer, followed by sandblasting and acid-etching treatment and atomic layer deposition (ALD) of tantalum oxide films. SEM morphology and surface roughness tests confirmed that the unmelted powders adhered on the scaffolds were removed by sandblasting and acid-etching. Accordingly, the porosity of the scaffold increased by about 7%. Benefiting from the self-limitation and three-dimensional conformance of ALD, uniform tantalum oxide films were formed on the inner and outer surfaces of the scaffolds. Zeta potential decreased by 19.5 mV after depositing tantalum oxide films. The in vitro results showed that the adhesion, proliferation, and osteogenic differentiation of rat bone marrow mesenchymal stem cells on modified Ti6Al4V scaffolds were significantly enhanced, which may be ascribed to surface structure optimization and the compatibility of tantalum oxide. This study provides a strategy to improve the cytocompatibility and osteogenic differentiation of porous Ti6Al4V scaffolds for orthopedic implants.

With the discovery of the pivotal role of macrophages in tissue regeneration through shaping the tissue immune microenvironment, various immunomodulatory strategies have been proposed to modify traditional biomaterials. Decellularized extracellular matrix (dECM) has been extensively used in the clinical treatment of tissue injury due to its favorable biocompatibility and similarity to the native tissue environment. However, most reported decellularization protocols may cause damage to the native structure of dECM, which undermines its inherent advantages and potential clinical applications. Here, we introduce a mechanically tunable dECM prepared by optimizing the freeze-thaw cycles. We demonstrated that the alteration in micromechanical properties of dECM resulting from the cyclic freeze-thaw process contributes to distinct macrophage-mediated host immune responses to the materials, which are recently recognized to play a pivotal role in determining the outcome of tissue regeneration. Our sequencing data further revealed that the immunomodulatory effect of dECM was induced via the mechnotrasduction pathways in macrophages. Next, we tested the dECM in a rat skin injury model and found an enhanced micromechanical property of dECM achieved with three freeze-thaw cycles significantly promoted the M2 polarization of macrophages, leading to superior wound healing. These findings suggest that the immunomodulatory property of dECM can be efficiently manipulated by tailoring its inherent micromechanical properties during the decellularization process. Therefore, our mechanics-immunomodulation-based strategy provides new insights into the development of advanced biomaterials for wound healing., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

Acne is an inflammatory skin disease mainly caused by Propionibacterium acnes , which can cause local inflammatory reactions and develop into chronic inflammatory diseases in severe cases. To avoid the use of antibiotics and to effectively treat the site of acne, we report a sodium hyaluronate microneedle patch that mediates the transdermal delivery of ultrasound-responsive nanoparticles for the effective treatment of acne. The patch contains nanoparticles formed by zinc porphyrin-based metal-organic framework and zinc oxide (ZnTCPP@ZnO). We demonstrated activated oxygen-mediated killing of P. acnes with an antibacterial efficiency of 99.73% under 15 min of ultrasound irradiation, resulting in a decrease in levels of acne-related factors, including tumor necrosis factor-α, interleukins, and matrix metalloproteinases. The zinc ions up-regulated DNA replication-related genes, promoting the proliferation of fibroblasts and, consequently, skin repair. This research leads to a highly effective strategy for acne treatment through the interface engineering of ultrasound response.

Intelligent control of the immune response is essential for obtaining percutaneous implants with good sterilization and tissue repair abilities. In this study, polypyrrole (Ppy) nanoparticles enveloping a 3D frame of sulfonated polyether ether ketone (SP) surface are constructed, which enhance the surface modulus and hardness of the sulfonated layer by forming a cooperative structure of simulated reinforced concrete and exhibit a superior photothermal effect. Ppy-coated SP could quickly accumulate heat on the surface by responding to 808 nm near-infrared (NIR) light, thereby killing bacteria, and destroying biofilms. Under NIR stimulation, the phagocytosis and M1 activation of macrophages cultured on Ppy-coated SP are enhanced by activating complement 3 and its receptor, CD11b. Phagocytosis and M1 activation are impaired along with abolishment of NIR stimulation in the Ppy-coated SP group, which is favorable for tissue repair. Ppy-coated SP promotes Collagen-I, vascular endothelial growth factor, connective tissue growth factor, and α-actin (Acta2) expression by inducing M2 polarization owing to its higher surface modulus. Overall, Ppy-coated SP with enhanced mechanical properties could be a good candidate for clinical percutaneous implants through on-off phagocytosis and switchable macrophage activation stimulated with NIR., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Hierarchical vasculature reconstruction is fundamental for tissue regeneration. The regeneration of functional vascular network requires a proper directional guidance, especially in case of large-size defects. To provide the "running track" for vasculature, a leaf-vein mimetic membrane using soft and elastic poly(lactide-co-propylene glycol-co-lactide) dimethacrylate is developed. Engraved with an interconnected and perfusable leaf-vein micropattern, the membrane can guide human umbilical vein endothelial cells (HUVECs) to form vasculature in vitro. In particular, the "running track" upregulates the angiogenesis-related gene expression and promotes the HUVECs to differentiate into tip cells and stalk cells via tuning vascular endothelial growth factor receptor 2 signaling transduction. As a proof of concept, its revascularization capability using a rat calvarial defect model in vivo is evaluated. The in vivo results demonstrate that the leaf-vein engraved membrane accelerates the formation and maturation of vasculature, leading to a hierarchical blood vessel network. With the superior pro-vasculature property, it is believed that the leaf-vein engraved membrane is not only an ideal candidate for the reconstruction of calvarial vasculature but also a promising solution for more complicated vasculature reconstruction, such as muscle, skin, and heart., (© 2022 Wiley-VCH GmbH.)

It is important to eliminate lipopolysaccharide (LPS) along with killing bacteria in periprosthetic joint infection (PJI) therapy for promoting bone repair due to its effect to regulate macrophages response. Although natural antimicrobial peptides (AMPs) offer a good solution, the unknown toxicity, high cost and exogenetic immune response hamper their applications in clinic. In this work, we fabricated a nanowire-like composite material, named P@C, by combining chitosan and puerarin via solid-phase reaction, which can finely mimic the bio-functions of AMPs. Chitosan, serving as the bacteria membrane puncture agent, and puerarin, serving as the LPS target agent, synergistically destroy the bacterial membrane structure and inhibit its recovery, thus endowing P@C with good antibacterial property. In addition, P@C possesses good osteoimmunomodulation due to its ability of LPS elimination and macrophage differentiation modulation. The in vivo results show that P@C can inhibit the LPS induced bone destruction in the Escherichia coli infected rat. P@C exhibits superior bone regeneration in Escherichia coli infected rat due to the comprehensive functions of its superior antibacterial property, and its ability of LPS elimination and immunomodulation. P@C can well mimic the functions of AMPs, which provides a novel and effective method for treating the PJI in clinic., Competing Interests: 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., (© 2022 The Authors.)

Biogenic collagen membranes have been widely used as soft tissue barriers in guided bone regeneration (GBR) and guided tissue regeneration (GTR). Nevertheless, their clinical performance remains unsatisfactory because of their low mechanical strength and fast degradation rate in vivo. Although cross-linking with chemical agents is effective and reliable for prolonging the degradation time of collagen membranes, some adverse effects including potential cytotoxicity and undesirable tissue integration have been observed during this process. As a fundamental nutritional trace element, zinc plays an active role in promoting the growth of cells and regulating the degradation of the collagen matrix. Herein, a biogenic collagen membrane was cross-linked with glutaraldehyde-alendronate to prolong its degradation time. The physiochemical and biological properties were enhanced by the incorporation of zinc-doped nanohydroxyapatite (nZnHA), with the native structure of collagen preserved. Specifically, the cross-linking combined with the incorporation of 1% and 2% nZnHA seemed to endow the membrane with the most appropriate biocompatibility and tissue integration capability among the cross-linked membranes, as well as offering a degradation period of six weeks in a rat subcutaneous model. Thus, improving the clinical performance of biogenic collagen membranes by cross-linking together with the incorporation of nZnHA is a promising strategy for the improvement of biogenic collagen membranes. STATEMENT OF SIGNIFICANCE: The significance of this research includes., 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 © 2022. Published by Elsevier Ltd.)

Background: Exosomes derived from stem cells have been widely studied for promoting regeneration and reconstruction of multiple tissues as "cell-free" therapies. However, the applications of exosomes have been hindered by limited sources and insufficient therapeutic potency., Results: In this study, a stem cell-mediated gene therapy strategy is developed in which mediator mesenchymal stem cells are genetically engineered by bone morphogenetic protein-2 gene to produce exosomes (MSC-BMP2-Exo) with enhanced bone regeneration potency. This effect is attributed to the synergistic effect of the content derived from MSCs and the up-regulated BMP2 gene expression. The MSC-BMP2-Exo also present homing ability to the injured site. The toxic effect of genetical transfection vehicles is borne by mediator MSCs, while the produced exosomes exhibit excellent biocompatibility. In addition, by plasmid tracking, it is interesting to find a portion of plasmid DNA can be encapsulated by exosomes and delivered to recipient cells., Conclusions: In this strategy, engineered MSCs function as cellular factories, which effectively produce exosomes with designed and enhanced therapeutic effects. The accelerating effect in bone healing and the good biocompatibility suggest the potential clinical application of this strategy., (© 2022. The Author(s).)

Bone formation induced by divalent metal cations has been widely reported; however, the underlying mechanism is unclear. Here we report that these cations stimulate skeleton interoception by promoting prostaglandin E2 secretion from macrophages. This immune response is accompanied by the sprouting and arborization of calcitonin gene-related polypeptide-α + nerve fibers, which sense the inflammatory cue with PGE 2 receptor 4 and convey the interoceptive signals to the central nervous system. Activating skeleton interoception downregulates sympathetic tone for new bone formation. Moreover, either macrophage depletion or knockout of cyclooxygenase-2 in the macrophage abolishes divalent cation-induced skeleton interoception. Furthermore, sensory denervation or knockout of EP4 in the sensory nerves eliminates the osteogenic effects of divalent cations. Thus, our study reveals that divalent cations promote bone formation through the skeleton interoceptive circuit, a finding which could prompt the development of novel biomaterials to elicit the therapeutic power of these divalent cations., (© 2022. The Author(s).)

Bone grafts are commonly used for the treatment of critical sized bone defects. Since the supply of autologous bone is insufficient, allogeneic bone grafts have been used most of the time. However, the poor osteogenic property of allogeneic bone grafts after pretreatment results in delayed union, non-union, or even occasional deformity. Calcium phosphate cement (CPC) is one of the most promising bone filling materials due to its good biocompatibility and similar chemical components as natural bone. However, clinical applications of CPC were hampered by limited osteogenic effects, undesired immune response which results in resorption, and poor mechanical stability in vivo . Magnesium (Mg) has been proven to trigger bone regeneration through modulating cell behaviors of mesenchymal stem cells and macrophages significantly. Unfortunately, the degradation raters of pure Mg and Mg oxide are extremely fast, resulting in early collapse of Mg contained CPC. In this study, we developed a novel magnesium contained calcium phosphate bone cement (Mg-CPC), possessing long-term mechanical stability and osteogenic effects through sustained release of Mg. Furthermore , in vitro studies showed that Mg-CPC had no cytotoxic effects on hBMMSCs and macrophage RAW 264.7, and could enhance the osteogenic differentiation as determined by alkaline phosphate (ALP) activity and calcium nodule staining, as well as suppress the inflammatory as determined by expression of anti-inflammatory cytokine IL-1RA. We also found that Mg-CPC promoted new bone formation and bone maturation in vivo . These results suggest that Mg-CPC should be a good substitute material for bone grafts in clinical use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Liu, Wang, Liu, Zhao, Fang, Leung, Yeung and Wong.)

The most critical factor determining the success of biodegradable bone implants is the host tissue response, which greatly depends on their degradation behaviors. Here, a new magnesium-based implant, namely magnesium-silicon-calcium (Mg-0.2Si-1.0Ca) alloy, that coordinates its biodegradation along with the bone regenerative process via a self-assembled, multilayered bone-implant interface is designed. At first, its rapid biocorrosion contributes to a burst release of Mg 2+ , leading to a pro-osteogenic immune microenvironment in bone. Meanwhile, with the simultaneous intervention of Ca and Si in the secondary phases of the new alloy, a hierarchical layered calcified matrix is rapidly formed at the degrading interface that favored the subsequent bone mineralization. In contrast, pure Mg or Mg-0.2Si alloy without the development of this interface at the beginning will unavoidably induce detrimental bone loss. Hence, it is believed this biomimicking interface justifies its bioadaptability in which it can modulate its degradation in vivo and accelerate bone mineralization., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Regardless of the advancement of synthetic bone substitutes, allograft-derived bone substitutes still dominate in the orthopaedic circle in the treatments of bone diseases. Nevertheless, the stringent devitalization process jeopardizes their osseointegration with host bone and therefore prone to long-term failure. Hence, improving osseointegration and transplantation efficiency remains important. The alteration of bone tissue microenvironment (TME) to facilitate osseointegration has been generally recognized. However, the concept of exerting metal ionic cue in bone TME without compromising the mechanical properties of bone allograft is challenging. To address this concern, an interfacial tissue microenvironment with magnesium cationc cue was tailored onto the gamma-irradiated allograft bone using a customized magnesium-plasma surface treatment. The formation of the Mg cationic cue enriched interfacial tissue microenvironment on allograft bone was verified by the scanning ion-selective electrode technique. The cellular activities of human TERT-immortalized mesenchymal stem cells on the Mg-enriched grafts were notably upregulated. In the animal test, superior osseointegration between Mg-enriched graft and host bone was found, whereas poor integration was observed in the gamma-irradiated controls at 28 days post-operation. Furthermore, the bony in-growth appeared on magnesium-enriched allograft bone was significant higher. The mechanism possibly correlates to the up-regulation of integrin receptors in mesenchymal stem cells under modified bone TME that directly orchestrate the initial cell attachment and osteogenic differentiation of mesenchymal stem cells. Lastly, our findings demonstrate the significance of magnesium cation modified bone allograft that can potentially translate to various orthopaedic procedures requiring bone augmentation., Competing Interests: The authors declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in the manuscript entitled “Magnesium Cationic Cue Enriched Interfacial Tissue Microenvironment Nurtures the Osseointegration of Gamma-irradiated Allograft Bone”., (© 2021 The Authors.)

Although efforts have been devoted to develop new antibacterial agents and techniques, the challenge of bacterial infection remains unresolved and is even increasing. Sonodynamic therapy (SDT) driven by ultrasound (US) has demonstrated effectiveness in terms of penetration and it can help to clinically address the problem of deep tissue bacterial infection. In recent years, a variety of sonosensitizers, which were originally designed for photodynamic therapy, have been adopted for SDT. Yet, their unstable chemical stability and ineffective electron-hole separation are not favorable for clinical applications. Hence, we designed a new type of antibacterial sonosensitizer-namely, Au@Cu 2 O hybrid nanocubes-in which an interfacial Schottky junction was built between a p-type semiconductor Cu 2 O and a noble metal Au. When US stimulation was applied, the electrons from Cu 2 O could be excited at the junction and transferred to Au. Since the formed Schottky barrier could block the backflow of US-excited electrons, a prolonged electron-hole separation can be successfully established. Additionally, because of the boosted sonocatalytic activity, the Au@Cu 2 O hybrid nanocubes could produce a large amount of reactive oxygen species (ROS), which are subject to US stimulation. Furthermore, we found that the sonocatalytic activity of the Au@Cu 2 O hybrid nanocubes could be reinforced by increasing the amount of Au, enabling 99.67% of Staphylococcus aureus ( S. aureus ) to be killed by US stimulation for 15 minutes. The cytocompatibility of Au@Cu 2 O hybrid nanocubes was improved by a red blood cell membrane (RBC) coating over the surface, and the membrane did not sacrifice its superior antibacterial properties.

Macrophage has been gradually recognized as a central regulator in tissue regeneration, and the study of how macrophage mediates biomaterials-induced bone regeneration through immunomodulatory pathway becomes popular. However, the current understanding on the roles of different macrophage phenotypes in regulating bone tissue regeneration remains controversial. In this study, we demonstrate that sequential infiltration of heterogeneous phenotypes of macrophages triggered by bio-metal ions effectively facilitates bone healing in bone defect. Indeed, M1 macrophages promote the recruitment and early commitment of osteogenic and angiogenic progenitors, while M2 macrophages and osteoclasts support the deposition and mineralization of the bone matrix, as well as the maturation of blood vessels. Moreover, we have identified a group of bone biomaterial-related multinucleated cells that behave similarly to M2 macrophages with wound-healing features rather than participate in the bone resorption cascade similarly to osteoclasts. Our study shows how sequential activation of macrophage-osteoclast lineage contribute to a highly orchestrated immune response in the bone tissue microenvironment around biomaterials to regulate the complex biological process of bone healing. Therefore, we believe that the temporal activation pattern of heterogeneous macrophage phenotypes should be considered when the next generation of biomaterials for bone regeneration is engineered., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The potential translation of bio-inert polymer scaffolds as bone substitutes is limited by the lack of neovascularization upon implantation and subsequently diminished ingrowth of host bone, most likely resulted from the inability to replicate appropriate endogenous crosstalk between cells. Human umbilical vein endothelial cell-derived decellularized extracellular matrix (HdECM), which contains a collection of angiocrine biomolecules, has recently been demonstrated to mediate endothelial cells(ECs) - osteoprogenitors(OPs) crosstalk. We employed the HdECM to create a PCL (polycaprolactone)/fibrin/HdECM (PFE) hybrid scaffold. We hypothesized PFE scaffold could reconstitute a bio-instructive microenvironment that reintroduces the crosstalk, resulting in vascularized bone regeneration. Following implantation in a rat femoral bone defect, the PFE scaffold demonstrated early vascular infiltration and enhanced bone regeneration by microangiography (μ-AG) and micro-computational tomography (μ-CT). Based on the immunofluorescence studies, PFE mediated the endogenous angiogenesis and osteogenesis with a substantial number of type H vessels and osteoprogenitors. In addition, superior osseointegration was observed by a direct host bone-PCL interface, which was likely attributed to the formation of type H vessels. The bio-instructive microenvironment created by our innovative PFE scaffold made possible superior osseointegration and type H vessel-related bone regeneration. It could become an alternative solution of improving the osseointegration of bone substitutes with the help of induced type H vessels, which could compensate for the inherent biological inertness of synthetic polymers., Competing Interests: The authors declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in the manuscript entitled “Fabrication of a bio-instructive scaffold conferred with a microenvironment allowing for superior implant osseointegration and accelerated in situ vascularized bone regeneration via type H vessel formation”., (© 2021 The Authors.)

Despite the widespread observations on the osteogenic effects of magnesium ion (Mg 2+ ), the diverse roles of Mg 2+ during bone healing have not been systematically dissected. Here, we reveal a previously unknown, biphasic mode of action of Mg 2+ in bone repair. During the early inflammation phase, Mg 2+ contributes to an upregulated expression of transient receptor potential cation channel member 7 (TRPM7), and a TRPM7-dependent influx of Mg 2+ in the monocyte-macrophage lineage, resulting in the cleavage and nuclear accumulation of TRPM7-cleaved kinase fragments (M7CKs). This then triggers the phosphorylation of Histone H3 at serine 10, in a TRPM7-dependent manner at the promoters of inflammatory cytokines, leading to the formation of a pro-osteogenic immune microenvironment. In the later remodeling phase, however, the continued exposure of Mg 2+ not only lead to the over-activation of NF-κB signaling in macrophages and increased number of osteoclastic-like cells but also decelerates bone maturation through the suppression of hydroxyapatite precipitation. Thus, the negative effects of Mg 2+ on osteogenesis can override the initial pro-osteogenic benefits of Mg 2+ . Taken together, this study establishes a paradigm shift in the understanding of the diverse and multifaceted roles of Mg 2+ in bone healing.

Some infectious or malignant diseases such as cancers are seriously threatening the health of human beings all over the world. The commonly used antibiotic therapy cannot effectively treat these diseases within a short time, and also bring about adverse effects such as drug resistance and immune system damage during long-term systemic treatment. Phototherapy is an emerging antibiotic-free strategy to treat these diseases. Upon light irradiation, phototherapeutic agents can generate cytotoxic reactive oxygen species (ROS) or induce a temperature increase, which leads to the death of targeted cells. These two kinds of killing strategies are referred to as photodynamic therapy (PDT) and photothermal therapy (PTT), respectively. So far, many photo-responsive agents have been developed. Among them, the metal-organic framework (MOF) is becoming one of the most promising photo-responsive materials because its structure and chemical compositions can be easily modulated to achieve specific functions. MOFs can have intrinsic photodynamic or photothermal ability under the rational design of MOF construction, or serve as the carrier of therapeutic agents, owing to its tunable porosity. MOFs also provide feasibility for various combined therapies and targeting methods, which improves the efficiency of phototherapy. In this review, we firstly investigated the principles of phototherapy, and comprehensively summarized recent advances of MOF in PDT, PTT and synergistic therapy, from construction to modification. We expect that our demonstration will shed light on the future development of this field, and bring it one step closer to clinical trials.

Proper immune responses are critical for successful biomaterial implantation. Here, four scales of honeycomb-like TiO 2 structures were custom made on titanium (Ti) substrates to investigate cellular behaviors of RAW 264.7 macrophages and their immunomodulation on osteogenesis. We found that the reduced scale of honeycomb-like TiO 2 structures could significantly activate the anti-inflammatory macrophage phenotype (M2), in which the 90-nanometer sample induced the highest expression level of CD206, interleukin-4 , and interleukin-10 and released the highest amount of bone morphogenetic protein-2 among other scales. Afterward, the resulting immune microenvironment favorably triggered osteogenic differentiation of murine mesenchymal stem cells in vitro and subsequent implant-to-bone osteointegration in vivo. Furthermore, transcriptomic analysis revealed that the minimal scale of TiO 2 honeycomb-like structure (90 nanometers) facilitated macrophage filopodia formation and up-regulated the Rho family of guanosine triphosphatases ( RhoA, Rac1, and CDC42 ), which reinforced the polarization of macrophages through the activation of the RhoA/Rho-associated protein kinase signaling pathway., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The effects of dual Zr and O plasma immersion ion implantation (Zr & O PIII) on antibacterial properties of ZK60 Mg alloys are systematically investigated. The results show that a hydrophobic, smooth, and ZrO 2 -containing graded film is formed. Electrochemical assessment shows that the corrosion rate of the plasma-treated Mg alloy decreases and the decreased degradation rate is attributed to the protection rendered by the surface oxide. In vitro and in vivo antibacterial tests reveal Zr & O PIII ZK60 presents higher antibacterial rate compared to Zr PIII ZK60 and untreated control. The hydrophobic and smooth surface suppresses bacterial adhesion. High concentration of oxygen vacancies in the surface films are determined by X-ray photoelectron spectroscopy (XPS), UV-vis diffuse reflectance spectra (UV-vis DRS) and electron paramagnetic resonance (EPR) and involved in the production of reactive oxygen species (ROS). The higher level of ROS expression inhibits biofilm formation by down-regulating the expression of icaADBC genes but up-regulating the expression of icaR gene. In addition, Zr & O PIII improves cell viability and initial cell adhesion confirming good cytocompatibility. Dual Zr & O PIII is a simple and practical means to expedite clinical acceptance of biodegradable magnesium alloys., Competing Interests: The authors declare that there is no known conflict of interest that could influence the findings reported in this paper, neither at personal nor at organizational level., (© 2021 The Authors.)

The design of orthopedic biomaterials has gradually shifted from "immune-friendly" to "immunomodulatory," in which the biomaterials are able to modulate the inflammatory response via macrophage polarization in a local immune microenvironment that favors osteogenesis and implant-to-bone osseointegration. Despite the well-known effects of bioactive metallic ions on osteogenesis, how extracellular metallic ions manipulate immune cells in bone tissue microenvironments toward osteogenesis and subsequent bone formation has rarely been studied. Herein, we investigate the osteoimmunomodulatory effect of an extracellular bioactive cation (Mg 2+ ) in the bone tissue microenvironment using custom-made poly lactic-co-glycolic acid (PLGA)/MgO-alendronate microspheres that endow controllable release of magnesium ions. The results suggest that the Mg 2+ -controlled tissue microenvironment can effectively induce macrophage polarization from the M0 to M2 phenotype via the enhancement of anti-inflammatory (IL-10) and pro-osteogenic (BMP-2 and TGF-β1) cytokines production. It also generates a favorable osteoimmune microenvironment that facilitates the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells. The in vivo results further verify that a large amount of bony tissue, with comparable bone mineral density and mechanical properties, has been generated at an early post-surgical stage in rat intramedullary bone defect models. This study demonstrates that the concept of in situ immunomodulated osteogenesis can be realized in a controlled magnesium tissue microenvironment., Competing Interests: 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., (© 2021 The Authors. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

High-pressure torsion (HPT) can refine the microstructure and consequently modify the properties, such as mechanical and corrosion properties, of Mg and its alloys. Biodegradable magnesium materials alloyed with the essential elements of life, such as Ca and Sr, are a current research frontier. In this study, biodegradable ultrafine-grained pure Mg, Mg-Ca alloy, and Mg-Sr alloy were prepared using HPT processing. The microstructure, mechanical properties, biodegradable behaviors, and biocompatibility in vitro and in vivo of these materials were systematically investigated. Our results revealed that HPT pure Mg with a bimodal and ultrafine-grained microstructure showed higher mechanical strength, ductility, and degradation rate compared with the as-received materials. The good biocompatibility of HPT pure Mg was confirmed both in vitro and in vivo. The HPT Mg-Ca alloy and Mg-Sr alloy with homogeneous ultrafine-grained microstructures showed higher mechanical strength and lower degradation rate than their as-cast counterparts. The good biocompatibility of the HPT Mg-Ca alloy and Mg-Sr alloy was also revealed. All these findings indicate that HPT is an alternative avenue to fabricate biodegradable Mg-based materials.

Implant-associated infections is one of the most challenging post-operative complications in bone-related implantations. To tackle this clinical issue, we developed a low-cost and durable surface coating for medical grade titanium implants that uses positively charged silane molecules. The in vitro antimicrobial tests revealed that the titanium surface coated with (3-aminopropyl) triethoxysilane, which has the appropriate length of hydrophobic alkyl chain and positive charged amino group, suppressed more than 90% of the initial bacterial adhesion of S. aureus, P. aeruginosa, and E. coli after 30 min of incubation. In terms of growth inhibitory rate, the treated surface was able to reduce 75.7% ± 11.9% of bacterial growth after a 24-hour culturing, thereby exhibiting superior anti-biofilm formation in the late stage. When implanted into the rat model infected by S. aureus, the treated surface eliminated the implant-associated infection through the mechanism of inhibition of bacterial adhesion on the implant surface. Additionally, the treated surface was highly compatible with mammalian cells. In general, our design demonstrated its potential for human clinical trials as a low-cost and effective antibacterial strategy to minimize post-operative implant-related bacterial infection., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The fate of cells and subsequent bone regeneration is highly correlated with temporospatial coordination of chemical, biological, or physical cues within a local tissue microenvironment. Deeper understanding of how mammalian cells react to local tissue microenvironment is paramount important when designing next generation of biomaterials for tissue engineering. This study aims to investigate that the regulation of magnesium cationic (Mg 2+ ) tissue microenvironment is able to convince early-stage bone regeneration and its mechanism undergoes intramembranous ossification. It was discovered that moderate Mg 2+ content niche (~4.11 mM) led to superior bone regeneration, while Mg 2+ -free and strong Mg 2+ content (~16.44 mM) discouraged cell adhesion, proliferation and osteogenic differentiation, thereby bone formation was rarely found. When magnesium ions diffused into free Mg zone from concentrated zone in late time point, new bone formation on free Mg zone became significant through intramembranous ossification. This study successfully demonstrates that magnesium cationic microenvironment serves as an effective biochemical cue and is able to modulate the process of bony tissue regeneration. The knowledge of how a Mg 2+ cationic microenvironment intertwines with cells and subsequent bone formation gained from this study may provide a new insight to develop the next generation of tissue-repairing biomaterials., Competing Interests: 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., (© 2020 [The Author/The Authors].)

Cutaneous wounds, especially chronic wounds, remain clinical challenges, and this is partially due to the complex healing process composed of four overlapping but distinct stages including hemostasis, inflammation, proliferation and remodeling. Therefore, wound dressings with spatially designed structures which can temporally regulate certain bioactive components to function at specific healing stages might be able to accelerate the healing process. In this study, nanobioglass incorporated chitosan-PVA (polyvinyl alcohol) trilayer nanofibrous membrane (nBG-TFM) was fabricated via sequential electrospinning. This membrane exhibited excellent biocompatibility, antibacterial activity and regeneration promotion effect. Furthermore, spatially designed structure optimized functions of each component and provided more suitable microenvironment as compared with uniform membrane. Rat full-thickness skin defects model and mice diabetic chronic wound model showed that nBG-TFM could achieve significantly accelerated and enhanced healing, in terms of complete re-epithelialization, improved collagen alignment and formation of skin appendages. It was revealed that nBG-TFM functioned through upregulating growth factors including VEGF and TGF-β. Meanwhile inflammatory cytokines such as TNF-α and IL-1β were downregulated. The technology presented in this study shed new light on designing functional wound dressings which can promote healing of chronic wounds., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Magnesium biometals exhibit great potentials for orthopeadic applications owing to their biodegradability, bioactive effects and satisfactory mechanical properties. However, rapid corrosion of Mg implants in vivo combined with large amount of hydrogen gas evolution is harmful to bone healing process which seriously confines their clinical applications. Enlightened by the superior biocompatibility and corrosion resistance of passive titanium oxide layer automatically formed on titanium alloy, we employ the Ti and O dual plasma ion immersion implantation (PIII) technique to construct a multifunctional TiO 2 based nano-layer on ZK60 magnesium substrates for enhanced corrosion resistance, osteoconductivity and antimicrobial activity. The constructed nano-layer (TiO 2 /MgO) can effectively suppress degradation rate of ZK60 substrates in vitro and still maintain 94% implant volume after post-surgery eight weeks. In animal study, a large amount of bony tissue with increased bone mineral density and trabecular thickness is formed around the PIII treated group in post-operation eight weeks. Moreover, the newly formed bone in the PIII treated group is well mineralized and its mechanical property almost restores to the level of that of surrounding mature bone. Surprisingly, a remarkable killing ratio of 99.31% against S. aureus can be found on the PIII treated sample under ultra-violet (UV) irradiation which mainly attributes to the oxidative stress induced by the reactive oxygen species (ROS). We believe that this multifunctional TiO 2 based nano-layer not only controls the degradation of magnesium implant, but also regulates its implant-to-bone integration effectively. STATEMENT OF SIGNIFICANCE: Rapid corrosion of magnesium implants is the major issue for orthopaedic applications. Inspired by the biocompatibility and corrosion resistance of passive titanium oxide layer automatically formed on titanium alloy, we construct a multifunctional TiO 2 /MgO nanolayer on magnesium substrates to simultaneously achieve superior corrosion resistance, satisfactory osteoconductivity in rat intramedullary bone defect model and excellent antimicrobial activity against S. aureus under UV irradiation. The current findings suggest that the specific TiO 2 /MgO nano-layer on magnesium surface can achieve the three objectives aforementioned and we believe this study can demonstrate the potential of biodegradable metals for future clinical applications., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Surface topography has been reported to play a key role in modulating cell behaviors, yet the mechanism through which it modulates these behaviors is not fully understood, especially in the case of three-dimensional (3D) topographies. In this study, a series of novel hemispherical 3D imprints ranging from the nanoscale to the microscale were prepared on titanium (Ti) surfaces using a customized interfacial lithography method. Mouse embryo osteoblast precursor cells (MC3T3-E1) were selected to investigate the solitary effect of specific hemispherical 3D imprints on cellular behaviors. The results indicated that varied hemispherical 3D imprints can affect the formation of filopodia and the arrangement of the cytoskeleton in different ways. Specifically, they can alter the spreading morphologies of cells and lead to deformation of the nucleus, which eventually affects cell proliferation and osteogenic differentiation. Cells cultured on different hemispherical 3D imprints exhibited promoted proliferation and osteogenic differentiation to different degrees; for example, cells cultured on 90 and 500 nm hemispherical imprints formed abundant filopodia and exhibited the highest alkaline phosphatase activity and osteogenic gene expression, respectively. Four-week tibia implantation also confirmed that 90 nm hemispherical imprints improved the osteogenic ability in vivo compared with an unpatterned Ti substrate. In addition to promoted proliferation, colonization of more cells on the surface of implants and induction of rapid osteogenic differentiation can occur. Our work provides a rational way to balance cell proliferation and differentiation, which can accelerate bone integration of an implant and host tissue.

Rapid corrosion of biodegradable magnesium alloys under in vivo condition is a major concern for clinical applications. Inspired by the stability and biocompatibility of titanium oxide (TiO 2 ) passive layer, a functionalized TiO 2 /Mg 2 TiO 4 nano-layer has been constructed on the surface of WE43 magnesium implant by using plasma ion immersion implantation (PIII) technique. The customized nano-layer not only enhances corrosion resistance of Mg substrates significantly, but also elevates the osteoblastic differentiation capability in vitro due to the controlled release of magnesium ions. In the animal study, the increase of new bone formation adjacent to the PIII-treated magnesium substrate is 175% higher at post-operation 12 weeks, whereas the growth of new bone on titanium control and untreated magnesium substrate are only 97% and 29%, respectively. In addition, its Young's modulus can be restored to about 82% as compared with the surrounding matured bone. Furthermore, this specific TiO 2 /Mg 2 TiO 4 layer even exhibits photoactive bacteria disinfection capability when irradiated by ultraviolet light which is attributed to the intracellular reactive oxygen species (ROS) production. With all these constructive observations, it is believed that the TiO 2 /Mg 2 TiO 4 nano-layer on magnesium implants can significantly promote new bone formation and suppress bacterial infection, while the degradation behavior can be controlled simultaneously., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Prevention of implant-associated infections and insufficient bone tissue integration is critical to exploit the immunomodulatory properties and antibacterial effects of implant materials, which have attracted considerable attention. Modulation of the functions of immune cells in different environments is crucial for managing infection and inferior bone integration via immunomodulation. In this work, sodium butyrate, a fermentation product of gut microbiota, was loaded onto 3D porous sulfonated polyetheretherketone (SP) to modulate the immune responses of cells in different environments. Evaluation of in vitro antibacterial effects showed that sodium butyrate-loaded SP exhibited superior antibacterial activity, especially in the samples containing high concentrations of sodium butyrate. Under bacterial stimulation, the phagocytic activity of macrophages increased with an increase in the sodium butyrate concentration via the production of reactive oxygen species (ROS), which favoured bactericidal activity in the implant-associated infection stage. For bacterial elimination, sodium butyrate-containing SP could polarize macrophages to the M2 phenotype and subsequently stimulate anti-inflammatory cytokine secretion, which is considered beneficial for bone regeneration in the tissue repair stage. In vitro osteogenesis was evaluated and the results demonstrated that treatment with sodium butyrate-containing SP increased the expression of osteogenic genes and proteins. An in vivo rat osteomyelitis model was used to evaluate the protective effect of the SP-loaded with sodium butyrate on bone destruction and osteolysis under infection conditions. To study osteogenesis in vivo, a rat femoral model without infection was used. The results indicated that the SP-B2 group exhibited superior anti-infection capacity and induced new bone formation around the implant in vivo. Treatment with sodium butyrate-containing porous SP modulated the macrophage response under different stimuli, thereby serving as a new approach for the design of smart implant materials with superior antibacterial and bone repair properties.

Metal ions or nanoparticles are believed to be promising additives in developing antibacterial biomaterials, owing to possessing favorable bactericidal effects against antibiotic-resistant bacteria. However, the immunomodulatory antibacterial activity of metal ions has seldom been reported. Herein, a porous microstructure designed to trap methicillin-resistant Staphylococcus aureus (MRSA) is fabricated on polyetheretherketone biomaterial surface through sulfonation (SPEEK), following which copper (Cu) nanoparticles, which can kill the trapped MRSA, are immobilized on SPEEK surface using a customized magnetron sputtering technique. In vitro antibacterial and immunological experiments indicate that the Cu-incorporated SPEEK can exert a desirable bactericidal effect against MRSA through the combination of "trap killing" and "contact killing" actions; meanwhile, macrophages cultured on the Cu-incorporated SPEEK can be activated and polarized to a pro-inflammatory phenotype along with improved phagocytic ability on the MRSA. Further in vivo implant-associated infection models evidence the superior antibacterial activity of the Cu-incorporated SPEEK. These results demonstrate multimodal antibacterial actions of the Cu-incorporated SPEEK, which is capable of imposing direct antibacterial and indirect immunomodulatory antibacterial effects simultaneously, in order to prevent and cure MRSA infection. It is believed that this study may shed light on developing novel biomaterial implants that combine antibacterial and immunomodulatory functions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Polyetheretherketone (PEEK) is widely used in orthopedic and dental applications because of its similar mechanical properties to those of natural bones. However, the inferior osseointegration and bioinertness hamper the clinic application. The surface texture of biomaterials plays an essential role in controlling cell differentiation through affecting the cell-generated physical forces, thus improving the osseointegration of the substrate. In this work, argon PIII and subsequently hydrogen peroxide treatment are applied to construct the nanostructure on the PEEK surface. The in vitro results show that the cell adhesion, collagen secretion, and extracellular matrix (ECM) deposition can be enhanced on both nanostructured surfaces. The in vivo tests exhibit that the surface fabricated by physical-chemical treatment is more favorable for fibrous tissue filtration inhibition and osseointegration than that fabricated by argon PIII only. This work provides a candidate approach for improving the osseointegration ability of PEEK implant by constructing the nanostructure on its surface, which paves the way of applying PEEK in orthopedic and dental applications.

Ocean acidification (OA) is well-known for impairing marine calcification; however, the end response of several essential species to this perturbation remains unknown. Decreased pH and saturation levels (Ω) of minerals under OA is projected to alter shell crystallography and thus to reduce shell mechanical properties. This study examined this hypothesis using a commercially important estuarine oyster Magallana hongkongensis. Although shell damage occurred on the outmost prismatic layer and the undying myostracum at decreased pH 7.6 and 7.3, the major foliated layer was relatively unharmed. Oysters maintained their shell hardness and stiffness through altered crystal unit orientation under pH 7.6 conditions. However, under the undersaturated conditions (Ω Cal  ~ 0.8) at pH 7.3, the realigned crystal units in foliated layer ultimately resulted in less stiff shells which indicated although estuarine oysters are mechanically resistant to unfavorable calcification conditions, extremely low pH condition is still a threat to this essential species., (Copyright © 2018. Published by Elsevier Ltd.)

A biomaterials surface enabling the induction of tumor cell death is particularly desirable for implantable biomedical devices that directly contact tumor tissues. However, this specific antitumor feature is rarely found. Consequently, an antitumor-cell nanocoating comprised of vanadium dioxide (VO 2 ) prepared by customized reactive magnetron sputtering has been proposed, and its antitumor-growth capability has been demonstrated using human cholangiocarcinoma cells. The results reveal that the VO 2 nanocoating is able to interrupt the mitochondrial electron transport chain and then elevate the intracellular reactive oxygen species levels, leading to the collapse of the mitochondrial membrane potential and the destruction of cell redox homeostasis. Indeed, this chain reaction can effectively trigger oxidative damage in the cholangiocarcinoma cells. Additionally, this study has provided new insights into designing a tumor-cell-inhibited biomaterial surface, which is modulated by the mechanism of mitochondria-targeting tumor cell death., Competing Interests: The authors declare no conflict of interest., (© 2018 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

Xenograft, namely bone-derived biological apatite (BAp), is widely recognized as a favorable biomaterial in bone tissue engineering owing to its biodegradability, biocompatibility, and osteoconductive properties. Substitutions of endogenous trace ions are thought to improve the osteogenic capacity of xenograft compared with synthetic hydroxyapatite (HAp). In order to modify the physicochemical and biological properties of apatite, different approaches to induce trace ion incorporation have been widely considered. In this study, we demonstrated that the incorporation of fluoride ions into porcine bone-derived biological apatite (pBAp) contributes to altered crystal morphology of the apatite, the sustained release of fluoride, and the in situ release of endogenous trace ions (e.g., magnesium and calcium) into the peripheral tissue microenvironment. This ionic balanced perimaterial microenvironment not only led to superior proliferation and osteogenic differentiation of rat bone mesenchymal stem cells (rBMSCs), but also accelerated new bone formation of the calvarial defect on a rat model via the activation of Wnt/β-catenin signaling. These promising observations may be attributed to the controlled release of endogenous trace ions from the xenograft to the peripheral tissue microenvironment driven by fluoride ion incorporation. Lastly, this study may provide a new insight to strengthen the osteogenicity of xenografts for clinical applications in the future.

Near infrared (NIR) light induced photodynamic antibacterial therapy (PDAT) is a promising antibacterial technique in rapid in situ disinfection of bacterially infected artificial implants due to its penetration ability into tissues. However, the lower oxygen content in vivo may restrict the yields of reactive oxygen species (ROS), thus reducing the antibacterial efficacy of PADT significantly. Herein, liposome encapsulated photosensitizers (PS), IR780 and perfluorohexane (PFH), have been constructed on the surface of Ti implants via a covalent linkage to overcome this issue. Thanks to the high oxygen capacity of PFH, more ROS can be generated during NIR irradiation regardless of the low content of oxygen in vivo. As a result, in vitro tests demonstrated that 15 minutes of 808 nm near-infrared irradiation could achieve a high antibacterial efficacy of 99.62% and 99.63% on the implant surface against Escherichia coli and Staphylococcus aureus, respectively. By contrast, the PDAT system without PFH modification shows a lower antibacterial efficacy (only 66.54% and 48.04%, respectively). In addition, this enhanced PDAT system also possesses great biocompatibility based on the in vitro and in vivo subcutaneous assays. This surface system makes it possible for rapid bacteria-killing in artificial implants that have been implanted in vivo under local conditions with lower oxygen content.

The cytokines released by immune cells are considered important factors to induce bone tissue regeneration. However, the pathway of those bone-targeting macrophage cytokines induced by biomaterial surface under tissue microenvironment is rarely reported. In this study, the immunomodulatory capability of zinc ions on macrophage polarization and its effects on osteogenic differentiation are investigated. Hence, a layer of zinc ions are incorporated on sulfonated polyetheretherketone (SPEEK) biomaterials by using a customized magnetron sputtering technique. The results reveal that the microenvironment on Zn-coated SPEEK can modulate nonactivated macrophage polarization to an anti-inflammatory phenotype and induce the secretion of anti-inflammatory and osteogenic cytokines. The osteogenic differentiation capability of bone marrow stromal cells (BMSCs) is therefore enhanced, leading to improved osteointegration between the zinc-coated SPEEK and bone tissue. This study verifies that zinc ion is a promising additive in the osteoimmunomodulation process and provides knowledge that may pave the way to develop the next generation of immunomodulatory biomaterials.

A range of magnesium ions (Mg 2+ ) used has demonstrated osteogenic tendency in vitro. Hence, we propose to actualize this concept by designing a new system to precisely control the Mg 2+ delivery at a particular concentration in vivo in order to effectively stimulate in-situ bone regeneration. To achieve this objective, a monodisperse core-shell microsphere delivery system comprising of poly (lactic-co-glycolic acid) (PLGA) biopolymer, alginate hydrogel, and magnesium oxide nano-particles has been designed by using customized microfluidic capillary device. The PLGA-MgO sponge-like spherical core works as a reservoir of Mg 2+ while the alginate shell serves as physical barrier to control the outflow of Mg 2+ at ∼50 ppm accurately for 2 weeks via its adjustable surface micro-porous network. With the aid of controlled release of Mg 2+ , the new core-shell microsphere system can effectively enhance osteoblastic activity in vitro and stimulate in-situ bone regeneration in vivo in terms of total bone volume, bone mineral density (BMD), and trabecular thickness after operation. Interestingly, the Young's moduli of formed bone on the core-shell microsphere group have been restored to ∼96% of that of the surrounding matured bone. These findings indicate that the concept of precisely controlled release of Mg 2+ may potentially apply for in-situ bone regeneration clinically., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Bone-implant-associated infections are common after orthopedic surgery due to impaired host immune response around the implants. In particular, when a biofilm develops, the immune system and antibiotic treatment find it difficult to eradicate, which sometimes requires a second operation to replace the infected implants. Most strategies have been designed to prevent biofilms from forming on the surface of bone implants, but these strategies cannot eliminate the biofilm when it has been established in vivo. To address this issue, a nonsurgical, noninvasive treatment for biofilm infection must be developed. Herein, a red-phosphorus-IR780-arginine-glycine-aspartic-acid-cysteine coating on titanium bone implants is prepared. The red phosphorus has great biocompatibility and exhibits efficient photothermal ability. The temperature sensitivity of Staphylococcus aureus biofilm is enhanced in the presence of singlet oxygen ( 1 O 2 ) produced by IR780. Without damaging the normal tissue, the biofilm can be eradicated through a safe near-infrared (808 nm) photothermal therapy at 50 °C in vitro and in vivo. This approach reaches an antibacterial efficiency of 96.2% in vivo with 10 min of irradiation at 50 °C. Meanwhile, arginine-glycine-aspartic-acid-cysteine decorated on the surface of the implant can improve the cell adhesion, proliferation, and osteogenic differentiation., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Bacterial infections and related complications are predominantly responsible for the failure of artificial biomaterials assisted tissue regeneration in clinic. In this work, a hybrid surface system is applied to prolong the drug release duration from dug-loaded titania nanotubes and thus to prevent Ti implants-associated bacterial infections. This feature is endowed by conjugating folic acid (FA) onto the surface of ZnO quantum dots (QDs)-NH 2 via an amidation reaction. Titania nanotubes (TNTs) loaded with vancomycin (Van) are capped by these FA functionalized ZnO (ZnO-FA) QDs that keep stable in normal physiological environments but dissolves to Zn 2+ in the mildly acidic environment after bacterial infections as validated by the drug release profile. The antibacterial ratio of TNTs-Van@ZnO-FA QDs against Staphylococcus aureus is enhanced from 60.8% to 98.8%while this value is only increased from 85.2% to 95.1% for TNTs-Van once the pH value of the environment is decreased from 7.4 to 5.5. This is due to the synergistic effects of Van and Zn 2+ because the gradual dissolution of ZnO-FA caps on TNTs with the decrease of pH value can induce the acceleration of both Van and Zn 2+ release. In addition, this TNTs-Van@ZnO-FA system also exhibits excellent biocompatibility because of the folic acid and sustained release of Zn ions. Hence, this surface system can be potentially used as a promising bioplatform on Ti-based metallic implants to prevent bacterial infection with a long-lasting effect., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Understanding cell-biomaterial interactions is critical for the control of cell fate for tissue engineering and regenerative medicine. Here, cerium oxide nanoparticles (CeONPs) are applied at different Ce 4+ /Ce 3+ ratios (i.e., 0.46, 1.23, and 3.23) to titanium substrate surfaces by magnetron sputtering and vacuum annealing. Evaluation of the cytotoxicity of the modified surface to cultured rat bone marrow mesenchymal stem cells (BMSCs) reveals that the cytocompatibility and cell proliferation are proportional to the increases in Ce 4+ /Ce 3+ ratio on titanium surface. The bone formation capability induced by these surface modified titanium alloys is evaluated by implanting various CeONP samples into the intramedullary cavity of rat femur for 8 weeks. New bone formation adjacent to the implant shows a close relationship to the surface Ce 4+ /Ce 3+ ratio; higher Ce 4+ /Ce 3+ ratio achieves better osseointegration. The mechanism of this in vivo outcome is explored by culturing rat BMSCs and RAW264.7 murine macrophages on CeONP samples for different durations. The improvement in osteogenic differentiation capability of BMSCs is directly proportional to the increased Ce 4+ /Ce 3+ ratio on the titanium surface. Increases in the Ce 4+ /Ce 3+ ratio also elevate the polarization of the M2 phenotype of RAW264.7 murine macrophages, particularly with respect to the healing-associated M2 percentage and anti-inflammatory cytokine secretion. The manipulation of valence states of CeONPs appears to provide an effective modulation of the osteogenic capability of stem cells and the M2 polarization of macrophages, resulting in favorable outcomes of new bone formation and osseointegration.

Tearing of the rotator cuff commonly occurs as among one of the most frequently experienced tendon disorders. While treatment typically involves surgical repair, failure rates to achieve or sustain healing range from 20 to 90%. The insufficient capacity to recover damaged tendon to heal to the bone, especially at the enthesis, is primarily responsible for the failure rates reported. Various types of biomaterials with special structures have been developed to improve tendon-bone healing and tendon regeneration, and have received considerable attention for replacement, reconstruction, or reinforcement of tendon defects. In this review, we first give a brief introduction of the anatomy of the rotator cuff and then discuss various design strategies to augment rotator cuff repair. Furthermore, we highlight current biomaterials used for repair and their clinical applications as well as the limitations in the literature. We conclude this article with challenges and future directions in designing more advanced biomaterials for augmentation of rotator cuff repair., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Biomaterial-related bacterial infections cause patient suffering, mortality, and extended periods of hospitalization and impose a substantial burden on medical systems. In this context, understanding the interactions between nanomaterials and bacteria is clinically significant. Herein, TiO 2 -based heterojunctions, including Co-TiO 2 , CoO-TiO 2 , and Co 3 O 4 -TiO 2 , were first designed by optimizing magnetron sputtering to establish a platform to explore the interactions between nanomaterials and bacteria. We found that the energy band bending and band gap narrowing were effectively promoted at the contact interface of the heterojunctions, which have the ability to induce abiotic reactive oxygen species formation. Using methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, in vitro studies showed that the heterojunctions of Co-TiO 2 , CoO-TiO 2 , and especially Co 3 O 4 -TiO 2 can effectively downregulate the expression levels of bacterial respiratory genes and cause oxidative damage to bacterial membrane respiration and viability. As a result, the surfaces of the heterojunctions possess a favorable antiadherent bacterial activity. Moreover, using an osteomyelitis model, the preclinical study on rats further confirmed the favorable anti-infection effect of the elaborately designed heterojunctions (especially Co 3 O 4 -TiO 2 ). We hope this study can provide new insights into the surface antibacterial design of biomaterials using energy band engineering for both basic research and clinical needs. Meanwhile, this attempt may also contribute to expanding the biomedical applications of cobalt-based nanoparticles for the treatment of antibiotic-resistant infections.