The misuse and overuse of antibiotics have caused the emergence of antibiotic-resistant bacteria, making bacterial infections more challenging. The increasing prevalence of multidrug-resistant pathogens has driven researchers to explore novel therapeutic strategies. Phototherapy strategies that utilize photo-responsive biomaterials for their antibacterial properties have gained widespread attention due to their capability of precisely controlling bacterial inactivation with minimal side effects. Despite their potential, photodynamic therapies suffer from phototoxicity and low efficiency of photosensitizers, while photothermal therapy risks overheating, which may harm healthy tissues, thus restricting its broader application. Metal organic frameworks (MOFs) have unique physicochemical properties, which provide a promising way to deal with these challenges. MOFs can function as reservoirs, loading and releasing antibacterial agents, such as antibiotics or metal ions, upon light illumination by virtue of their metastable coordination bonds. Their porous structures enable controlled drug release and encapsulation of photosensitizers. Furthermore, MOFs' tunable composition and pore structure allow for the light-triggered generation of heat and reactive oxygen species, enhancing their antibacterial effectiveness. By doping MOFs with functional materials, it is possible to achieve multi-mode antibacterial effects. In this review, we will outline recent advancements of photo-responsive antibacterial MOFs, categorize their underlying mechanisms of action and highlight their prospects in addressing bacterial resistance.

Orthopedic implant failure due to inadequate osseointegration and infection remains a critical challenge. To address this, we engineered a polydopamine (PDA)-mediated dual-functional platform for lithium (Li+) and copper (Cu2+) co-incorporation on titanium alloy (Ti6Al4V) implants, aiming to synergize osteogenic and antibacterial properties through a scalable surface modification strategy.

PDA coatings were polymerized onto polished Ti64 substrates, followed by sequential immersion in LiCl (800 μM) and CuCl2 (10 μM) solutions to construct Li+/Cu2+ co-doped surfaces (PDA@Li 800-Cu 10). In vitro assays assessed MC3T3-E1 pre-osteoblast proliferation (CCK-8), osteogenic differentiation (ALP activity, RT-PCR for ALP/Axin2), and antibacterial activity against S. aureus and E. coli (live/dead staining, CFU assays). In vivo efficacy was evaluated in a rat femoral defect model via micro-CT and histology.

Li+-functionalized surfaces (PDA@Li 800) enhanced osteoblast proliferation and osteogenesis via Wnt/β-catenin activation. Cu2+-loaded coatings (PDA@Cu 10) eradicated >99% bacteria but moderately suppressed osteogenic markers. The dual-doped PDA@Li 800-Cu 10 surface resolved this bioactivity conflict, maintaining antibacterial efficacy comparable to PDA@Cu 10 while elevating the osteogenic capacity of Cu2+-only modified surfaces. In vivo, dual-modified implants eliminated bacterial colonization within 72 h and significantly increased peri-implant bone volume (BV/TV) in comparison to Ti64 controls, outperforming PDA-only counterparts. By harmonizing Li-driven osteoinduction and Cu-mediated bactericidal action through a scalable PDA platform, this work advances a transformative strategy for next-generation orthopedic and dental implants, simultaneously addressing infection risks and bone regeneration demands.

The failure rate of orthodontic mini-screws depends strongly on primary stability and, thus, on insertion torque. Further improvement regarding the failure rate might be achieved by modifying the surface coating. Therefore, the aim of the study was to investigate the stability of a newly designed and surface-modified orthodontic mini-screw in beagle dogs.

Newly designed mini-screws coated either with DOTIZE® or DOTIZE®-copper (DOT GmbH, Rostock, Germany; each: n = 24) were inserted in the mandibles of eight beagle dogs for a duration of 8 months. Insertion and removal torque were measured. These data were compared to values generated by using the artificial bone material Sawbones® (Sawbones Europe AB, Malmö, Sweden). Experiments with and without torque limitation (each: n = 5) were run. The bone-to-implant contact rate and the amount of bone between the threads were examined. Statistical significance was set at P < 0.05.

The success rates of the in vivo study reached high levels with 95.3% for the DOTIZE-coated and 90.5% for the DOTIZE-copper-coated screws, whereas the insertion and removal torque did not differ between the coatings. During insertion, a torque limitation of 20 Ncm was necessary to ensure that the recommended limit was not exceeded. The insertion in Sawbones without torque limitation revealed a significantly higher torque compared to torque-limited insertion (18.2 ± 1.3 Ncm, 23.6 ± 1.3 Ncm). Bending occurred (n = 5) in the thread-free part of the mini-screw.

Surface coating might be able to improve the performance of orthodontic mini-screws. The study showed high success rates and stable mini-screws until the end of observation. Further investigations are necessary.

In recent years, hyaluronic acid (HA) and the natural tripeptide glycyl-l-histidyl-l-lysine (GHK), especially its copper(II) complex (GHK-Cu), individually have been shown to exert helpful properties for bone protection and regeneration. However, they are not strong enough to handle oxidative stress, hydrolytic attack, or environmental conditions. Being aware that conjugation chemistry has recently emerged as an appealing approach for generating new molecular entities capable of preserving the molecular integrity of their moieties or delaying their degradation, herein we present the synthesis of conjugates of HA with GHK (GHK-HA), at different loadings of the tripeptide. GHK-HA binds copper(II) ions and potentiates the chemical and biological properties of the two components in in vitro assays. The results highlight copper's role in promoting the expression and release of certain trophic, angiogenic, and osteogenic factors, including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), as well as bone morphogenetic protein-2 (BMP-2). The protective and regenerative activities of the metal ion are related to the translocation of its intracellular chaperones Copper Chaperone for Superoxide Dismutase (CCS) and Antioxidant-1 (Atox1) to the nucleus where they act as transcription factors.

The development of new artificial biomaterials for bone defect repair is an ongoing area of clinical research. Metal ions such as zinc, copper, magnesium, calcium, strontium, silver, and cerium play various roles in bone tissue regeneration in the human body and possess a range of biochemical functions. Studies have demonstrated that appropriate concentrations of these metal ions can promote osteogenesis and angiogenesis, inhibit osteoclast activity, and deter bacterial infections. Researchers have incorporated metal ions into biomaterials using various methods to create artificial bone materials with enhanced osteogenic and antibacterial capabilities. In addition to the osteogenic properties of all the aforementioned metal ions, Zn, Sr, and Ce can indirectly promote osteogenesis by inhibiting osteoclast activity. Cu, Mg, and Sr significantly enhance angiogenesis, while the antibacterial properties of Zn, Cu, Ag, and Ce can reduce the likelihood of infection and inflammation caused by implanted materials. This paper reviews the mechanisms through which metal ions promote bone tissue growth and improve the antibacterial activity of biomaterials. It also summarizes common loading methods on the surface of biomaterials with different metals and highlights the potential clinical applications of these new artificial bone materials.

Bone defect repair remains a great challenge in the field of orthopedics. Human body essential trace element such as copper is essential for bone regeneration, but how to use it in bone defects and the underlying its mechanisms of promoting bone formation need to be further explored. In this study, by doping copper into mesoporous bioactive glass nanoparticles (Cu-MBGNs), we unveil a previously unidentified role of copper in facilitating osteoblast mitophagy and mitochondrial dynamics, which enhance amorphous calcium phosphate (ACP) release and subsequent biomineralization, ultimately accelerating the process of bone regeneration. Specifically, by constructing conditional knockout mice lacking the autophagy gene Atg5 in osteogenic lineage cells, we first confirmed the role of Cu-MBGNs-promoted bone formation via mediating osteoblast autophagy pathway. Then, the in vitro studies revealed that Cu-MBGNs strengthened mitophagy by inducing ROS production and recruiting PINK1/Parkin, thereby facilitating the efficient release of ACP from mitochondria into matrix vesicles for biomineralization during bone regeneration. Moreover, we found that Cu-MBGNs promoted mitochondrion fission via activating dynamin related protein 1 (Drp1) to reinforce mitophagy pathway. Together, this study highlights the potential of Cu-MBGNs-mediated mitophagy and biomineralization for augmenting bone regeneration, offering a promising avenue for the development of advanced bioactive materials in orthopedic applications.

Two-dimensional (2D) nanoarchitectonics involve the creation of functional material assemblies and structures at the nanoscopic level by combining and organizing nanoscale components through various strategies, such as chemical and physical reforming, atomic and molecular manipulation, and self-assembly. Significant advancements have been made in the field, with the goal of producing functional materials from these nanoscale components. 2D nanomaterials, in particular, have gained substantial attention due to their large surface areas which are ideal for numerous surface-active applications. In this review article, nanoarchitectonics of 2D nanomaterials based biomedical applications are discussed. We aim to provide a concise overview of how nanoarchitectonics using 2D nanomaterials can be applied to dental healthcare, with an emphasis on biosensing and drug delivery. By offering a deeper understanding of nanoarchitectonics with programmable structures and predictable properties, we hope to inspire new innovations in the dental bioapplications of 2D nanomaterials.

Post-surgical recurrence and extensive bone defects pose significant challenges during osteosarcoma treatment. These issues can be addressed using a novel strategy that promotes bone repair after removing residual tumors. Therefore, a 3D-printed porous polylactic acid (PLA) scaffold (PH-GBS@CCP) filled with hydrogel and surface-modified with nano-hydroxyapatite (nHA) is designed. The hydrogel, composed of gelatin modified with methacrylic anhydride (GelMA), sodium alginate (SA), and borax, contains Cu-Cys-PEG nanoparticles (CCP) modified with cRGDfk-PEG2K-DSPE. It is injected into the PLA scaffold and crosslinked under UV. This hydrogel acts as a buffer medium between scaffold and bone, reducing cell abrasion, and as a carrier for the responsive release of tumor-targeting CCP. The scaffold provides the support and microenvironment required for bone repair. In early treatment, the acidic tumor microenvironment promotes hydrogel disintegration and CCP release, depleting glutathione and converting Cu2+ to Cu+ for the Fenton-like reaction. This generates reactive oxygen species, strengthening the proptosis effect, and killing the tumor. In later treatment, after tumor elimination, normalized pH and slow CCP release, along with scaffold nHA, promote osteogenic differentiation, providing a sustained osteogenic effect. Overall, the multifunctional composite scaffold achieved the sequential management of post-surgical osteosarcoma through early tumor-killing and later osteogenic effects.

Implants aim to restore skeletal dysfunction associated with ageing and trauma, yet infection and ineffective immune responses can lead to failure. This project characterized the microbiological and host cell responses to titanium alloy with or without electroplated metallic copper. Bacterial viability counting and scanning electron microscopy quantified and visualized the direct and indirect bactericidal effects of the Cu-electroplated titanium (Cu-Ep-Ti) against two different Staphylococcus aureus strains. Human THP-1 macrophage adhesion and viability was analyzed, along with phagocytosis. Results showed potent antimicrobial activity alongside promising host-immunomodulatory properties. Direct and indirect exposure to Cu-Ep-Ti produced potent bactericidal effects resulting in 94-100% reductions in bacterial viability at 24 h, with complete eradication in some cases. As expected, cytotoxicity was observed in THP-1 macrophages without media exchange, though when media was exchanged at 8, 24 and 48 h cell viability was equivalent to Control-Ti. Interestingly macrophages adhered to the copper material or grown in the presence of copper ions showed 7-fold increase in phagocytosis of S. aureus bioparticles compared to Control-Ti, suggesting a dual bactericidal and host immunomodulatory mechanism. In conclusion, this Cu-electroplated Ti biomaterial can limit bacterial contamination on the implant surface, whilst simultaneously promoting a beneficial antimicrobial immune response.

Eradication of osteomyelitis caused by bacterial infections is still a major challenge. Microwave therapy has the inherent advantage of deep penetration in curing deep tissue infections. However, the antibacterial efficiency of sensitizers is limited by the weak energy of microwaves. Here, a hybrid heterojunction system (Fe3O4/CuS/Emo) is designed for curing bacterially infected osteomyelitis. As an enhanced microwave sensitizer, it shows supernormal microwave response ability. Specifically, Fe3O4 acts as a matrix to mediate magnetic loss. After CuS loading, the heterogeneous interface forms induce significant interfacial polarization, which increasing dielectric loss. On the basis of the heterojunction formed by the two semiconductors, emodin is innovatively introduced to modify it. This integration not only accelerates the movement of charge carriers but also enhances polarization loss due to the numerous functional groups present on the surface. This further optimizes the microwave thermal and catalytic response. In addition, the unique anti-inflammatory properties of emodin confer the ability of hybrid heterojunction to regulate the immune microenvironment. In vivo studies reveal that heterojunction modified by emodin programmed elimination of bacteria and regulation of the immune microenvironment. It offers a revolutionary approach to the treatment of bacterial osteomyelitis.

Early healing of bone defects is still a clinical challenge. Many bone-filling materials have been studied, among which photocrosslinked alginate has received significant attention due to its good biocompatibility and morphological plasticity. Although it has been confirmed that photocrosslinked alginate can be used as an extracellular matrix for 3D cell culture, it lacks osteogenesis-related biological functions. This study constructed a copper ions-photo dual-crosslinked alginate hydrogel scaffold by controlling the copper ion concentration. The scaffolds were shaped by photocrosslinking and then endowed with biological functions by copper ions crosslinking. According to in vitro research, the dual-crosslinked hydrogel increased the compressive strength and favored copper dose-dependent osteoblast differentiation and cell surface adherence of rat bone marrow mesenchymal stem cells and the expression of type I collagen (Col1), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), vascular endothelial growth factor (VEGF). In addition, hydrogel scaffolds were implanted into rat skull defects, and more angiogenesis and osteogenesis could be observed in in vivo studies. The above results show that the copper-photo-crosslinked hydrogel scaffold has excellent osseointegration properties and can potentially promote angiogenesis and early healing of bone defects, providing a reference solution for bone tissue engineering materials.

Critical-sized bone defects present a formidable challenge in tissue engineering, necessitating innovative approaches that integrate osteogenesis and angiogenesis for effective repair. Inspired by the hierarchical porous structure of natural bone, this study introduces a novel method for the scalable production of ultra-long, copper-doped hydroxyapatite (Cu-HAp) fibers, utilizing the rapid gelation properties of guar gum (GG) under controlled conditions. These fibers serve as foundational units to fabricate three-dimensional porous scaffolds with a biomimetic hierarchical architecture. The scaffolds exhibit a broad pore size distribution (1-500 μm) and abundant nanoporous features, mimicking the native bone extracellular matrix. Physicochemical characterization and in vitro assays demonstrated that the copper doping significantly enhanced osteogenic and angiogenic activities, with optimized concentrations (0.8 % and 1.2 % Cu) facilitating the upregulation of osteogenesis-related genes and proteins, as well as promoting endothelial cell proliferation. In vivo studies further confirmed the scaffolds' efficacy, with the 1.2Cu-HAp group showing a remarkable increase in bone regeneration (bone volume/total volume ratio: 35.7 ± 1.87 %) within the defect site. This research offers a promising strategy for the rapid fabrication of multifunctional scaffolds that not only support bone tissue repair but also actively accelerate the healing process through enhanced vascularization.

Additive manufacturing (AM) of Ti-based biomedical implants is a pivotal research topic because of its ability to produce implants with complicated geometries. Despite desirable mechanical properties and biocompatibility of Ti alloys, one major drawback is their lack of inherent antibacterial properties, increasing the risk of postoperative infections. Hence, this research focuses on the Ti536 (Ti5Al3V6Cu) alloy, developed through Electron Beam Powder Bed Fusion (EB-PBF), exploring bio-corrosion, antibacterial features, and cell biocompatibility. The microstructural characterization revealed grain refinement and the formation of Ti2Cu precipitates with different morphologies and sizes in the Ti matrix. Electrochemical tests showed that Cu content minimally influenced the corrosion current density, while it slightly affected the stability, defect density, and chemical composition of the passive film. According to the findings, the Ti536 alloy demonstrated enhanced antibacterial properties without compromising its cell biocompatibility and corrosion behavior, thanks to Ti2Cu precipitates. This can be attributed to both the release of Cu ions and the Ti2Cu precipitates. The current study suggests that the EB-PBF fabricated Ti536 sample is well-suited for use in load-bearing applications within the medical industry. This research also offers an alloy design roadmap for novel biomedical Ti-based alloys with superior biological performance using AM methods.

Metals play a crucial role in the human body, especially as ions in metalloproteins. Essential metals, such as calcium, iron, and zinc are crucial for various physiological functions, but their interactions within biological networks are complex and not fully understood. Mesenchymal stem/stromal cells (MSCs) are essential for tissue regeneration due to their ability to differentiate into various cell types. This review article addresses the effects of physiological and unphysiological, but not directly toxic, metal ion concentrations, particularly concerning MSCs. Overloading or unbalancing of metal ion concentrations can significantly impair the function and differentiation capacity of MSCs. In addition, excessive or unbalanced metal ion concentrations can lead to oxidative stress, which can affect viability or inflammation. Data on the effects of metal ions on MSC differentiation are limited and often contradictory. Future research should, therefore, aim to clarify the mechanisms by which metal ions affect MSC differentiation, focusing on aspects such as metal ion interactions, ion concentrations, exposure duration, and other environmental conditions. Understanding these interactions could ultimately improve the design of biomaterials and implants to promote MSC-mediated tissue regeneration. It could also lead to the development of innovative therapeutic strategies in regenerative medicine.

Bioactive glasses are inorganic biocompatible materials that can find applications in many biomedical fields. The main application is bone and dental tissue engineering. However, some applications in contact with soft tissues are emerging. It is well known that both bulk (such as composition) and surface properties (such as morphology and wettability) of an implanted material influence the response of cells in contact with the implant. This review aims to elucidate and compare the main strategies that are employed to modulate cell behavior in contact with bioactive glasses. The first part of this review is focused on the doping of bioactive glasses with ions and drugs, which can be incorporated into the bioceramic to impart several therapeutic properties, such as osteogenic, proangiogenic, or/and antibacterial ones. The second part of this review is devoted to the chemical functionalization of bioactive glasses using drugs, extra-cellular matrix proteins, vitamins, and polyphenols. In the third and final part, the physical modifications of the surfaces of bioactive glasses are reviewed. Both top-down (removing materials from the surface, for example using laser treatment and etching strategies) and bottom-up (depositing materials on the surface, for example through the deposition of coatings) strategies are discussed.

In bone defects, infections lead to excessive inflammation, increased bacterial, and bone lysis, resulting in irregular wounds that hinder new bone regeneration. Injectable bioactive materials with adequate antimicrobial activity and strong osteogenic potential are urgently required to remedy irregular defects, eradicate bacteria, and facilitate the generation of new bone tissue. In this research, injectable dual-network composite hydrogels consisting of sulfated chitosan, oxidized hyaluronic acid, β-sodium glycerophosphate, and CuSr doped mesoporous bioactive glass loaded with bone morphogenetic protein (CuSrMBGBMP-2) were utilized for the first time to treat infectious bone defects. Initially, the hydrogel was injected into the wound at 37 °C with minimal invasion to establish a stable state and prevent hydrogel loss. Subsequently, sulfated chitosan eliminated bacteria at the wound site and facilitated cell proliferation with oxidized hyaluronic acid. Additionally, CuSrMBGBMP-2 strengthened antibacterial properties, regulated inflammatory reactions, promoted angiogenesis and osteogenic differentiation, addressing the deficiency in late-stage osteogenesis. Specifically, the injectable dual-network hydrogel based on chitosan and hyaluronic acid is minimally invasive, offering antibacterial, anti-inflammatory, pro-angiogenic, and bone regeneration properties. Therefore, this hydrogel with injectable dual network properties holds great promise for the treatment of bone infections in the future.

One of the primary risk factors for implant failure is thought to be implant-related infections during the early healing phase. Developing coatings with cell stimulatory behaviour and bacterial adhesion control is still difficult for bone implants. This study proposes an approach for one-step deposition of biocompatible and antimicrobial Cu-doped TiO2 coatings via glow-discharge sputtering of a mosaic target. During the deposition, the bias of the Ti6Al4V substrates was changed. Structure examination, phase analysis, and surface morphology were carried out using X-ray diffraction (XRD) analysis, scanning electron microscopy (SEM), atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). The hardness values and hydrophilic and corrosion performance were also evaluated together with cytocompatible and antibacterial examinations against E. coli and S. aureus. The results show great chemical and phase control of the bias identifying rutile, anatase, CuO, or ternary oxide phases. It was found that by increasing the substrate bias from 0 to -50 V the Cu content increased from 15.3 up to 20.7 at% while at a high bias of -100 V, the copper content reduced to 3 at%. Simultaneously, apart from the Cu2+ state, Cu1+ is also found in the biased samples. Compared with the bare alloy, the hardness, the water contact angle and corrosion resistance of the biased coatings increased. According to an assessment of in vitro cytocompatibility, all coatings were found to be nontoxic to MG-63 osteoblast cells over the time studied. Copper release and cell-surface interactions generated an antibacterial effect against E. coli and S. aureus strains. The -50 V biased coating combined the most successful results in inhibiting bacterial growth and eliciting the proper responses from osteoblastic cells because of its phase composition, electrochemical stability, hydrophilicity, improved substrate adhesion, and surface roughness. Using this novel surface modification approach, we achieved multifunctionality through controlled copper content and oxide phase composition in the sputtered films.

Designing adaptive and smart hydrogel wound dressings to meet specific needs across different stages of wound healing is crucial. Here, we present a composite hydrogel, GSC/PBE@Lut, that offers self-regulating release of cupric ions and luteolin and modulates mechanical properties to promote chronic wound healing. The double network hydrogel, GSC, is fabricated through photo-cross-linking of gelatin methacrylate, followed by Cu2+-alginate coordination cross-linking. On one hand, GSC allows for rapid Cu2+ release to eliminate bacteria in the acidic pH environment during inflammation and reduces the hydrogel's mechanical strength to minimize tissue trauma during early dressing changes. On the other hand, GSC enables slow Cu2+ release during the proliferation stage, promoting angiogenesis and biocompatibility. Furthermore, the inclusion of pH- and reactive oxygen species (ROS)-responsive luteolin nanoparticles (PBE@Lut) in the hydrogel matrix allows for controlled release of luteolin, offering antioxidant and anti-inflammatory effects and promoting anti-inflammatory macrophage polarization. In a murine model of Staphylococcus aureus infected wounds, GSC/PBE@Lut demonstrates exceptional therapeutic benefits in antibacterial, anti-inflammatory, angiogenic, and tissue regeneration. Overall, our results suggest that smart hydrogels with controlled bioactive agent release and mechanical modulation present a promising solution for treating chronic wounds.

Copper is an essential trace element for the human body. Abnormalities in copper metabolism can lead to bone defects, mainly by directly affecting the viability of osteoblasts and osteoclasts and their bone remodeling function, or indirectly regulating bone metabolism by influencing enzyme activities as cofactors. Copper ions released from biological materials can affect osteoblasts and osteoclasts, either directly or indirectly by modulating the inflammatory response, oxidative stress, and rapamycin signaling. This review presents an overview of recent progress in the impact of copper on bone metabolism. Translational potential of this article: The impact of copper on bone metabolism can provide insights into clinical application of copper-containing supplements and biomaterials.

Angiogenesis plays a crucial role in bone regeneration. Hypoxia is a driving force of angiogenesis at the initial stage of tissue repair. The hypoxic microenvironment could activate the hypoxia-inducible factor (HIF)-1α signaling pathway in cells, thereby enhancing the proliferation, migration and pro-angiogenic functions of stem cells. However, long-term chronic hypoxia could inhibit osteogenic differentiation and even lead to apoptosis. Therefore, shutdown of the HIF-1α signaling pathway and providing oxygen at later stage probably facilitate osteogenic differentiation and bone regeneration. Herein, an oxygen tension regulating hydrogel that sequentially activate and deactivate the HIF-1α signaling pathway were prepared in this study. Its effect and mechanism on stem cell differentiation were investigated both in vitro and in vivo. We proposed a gelatin-based hydrogel capable of sequentially delivering a hypoxic inducer (copper ions) and oxygen generator (calcium peroxide). The copper ions released from the hydrogels significantly enhanced cell viability and VEGF secretion of BMSCs via upregulating HIF-1α expression and facilitating its translocation into the nucleus. Additionally, calcium peroxide promoted alkaline phosphatase activity, osteopontin secretion, and calcium deposition through the activation of ERK1/2. Both Cu2+ and calcium peroxide demonstrated osteogenic promotion individually, while their synergistic effect within the hydrogels led to a superior osteogenic effect by potentially activating the HIF-1α and ERK1/2 signaling pathways.

Guided tissue regeneration (GTR) and guided bone regeneration (GBR) are the two surgical techniques generally used for periodontitis disease treatment. These techniques are based on a barrier membrane to direct the growth of new bone and gingival tissue at sites with insufficient volumes or dimensions of bone or gingiva for proper function, esthetics, or prosthetic restoration. Numerous studies have highlighted biocompatibility, space-creation, cell-blocking, bioactivity, and proper handling as essential characteristics of a membrane's performance. Given that bacterial infection is the primary cause of periodontitis, we strongly believe that addressing the antimicrobial properties of these membranes is of utmost importance. Indeed, the absence of effective inhibition of periodontal pathogens has been recognized as a primary factor contributing to the failure of GTR/GBR membranes. Therefore, we suggest considering antimicrobial properties as one of the key factors in the design of GTR/GBR membranes. Antibiotics are potent medications frequently administered systemically to combat microbes and mitigate bacterial infections. Nevertheless, the excessive use of antibiotics has resulted in a surge in bacterial resistance. To overcome this challenge, alternative antibacterial substances have been developed. In this review, we explore the utilization of alternative substances with antimicrobial properties for topical application in membranes. The use of antibacterial nanoparticles, phytochemical compounds, and antimicrobial peptides in this context was investigated. By carefully selecting and integrating antimicrobial agents into GTR/GBR membranes, we can significantly enhance their effectiveness in combating periodontitis. These antibacterial substances not only act as barriers against pathogenic bacteria but also promote the process of periodontal healing.

The incorporation of biologically active metallic elements into nano/micron-scale coatings through micro-arc oxidation (MAO) shows significant potential in enhancing the biological characteristics and functionality of titanium-based materials. By introducing diverse metal ions onto titanium implant surfaces, not only can their antibacterial, anti-inflammatory and corrosion resistance properties be heightened, but it also promotes vascular growth and facilitates the formation of new bone tissue. This review provides a thorough examination of recent advancements in this field, covering the characteristics of commonly used metal ions and their associated preparation parameters. It also highlights the diverse applications of specific metal ions in enhancing osteogenesis, angiogenesis, antibacterial efficacy, anti-inflammatory and corrosion resistance properties of titanium implants. Furthermore, the review discusses challenges faced and future prospects in this promising area of research. In conclusion, the synergistic approach of micro-arc oxidation and metal ion doping demonstrates substantial promise in advancing the effectiveness of biomedical titanium and its alloys, promising improved outcomes in medical implant applications.

The use of biomaterials in regenerative medicine has expanded to treat various disorders caused by trauma or disease in orthopedics and dentistry. However, the treatment of large and complex bone defects presents a challenge, leading to a pressing need for optimized biomaterials for bone repair. Recent advances in chemical sciences have enabled the incorporation of therapeutic ions into bone grafts to enhance their performance. These ions, such as strontium (for bone regeneration/osteoporosis), copper (for angiogenesis), boron (for bone growth), iron (for chemotaxis), cobalt (for B12 synthesis), lithium (for osteogenesis/cementogenesis), silver (for antibacterial resistance), and magnesium (for bone and cartilage regeneration), among others (e.g., zinc, sodium, and silica), have been studied extensively. This review aims to provide a comprehensive overview of current knowledge and recent developments in ion incorporation into biomaterials for bone and periodontal tissue repair. It also discusses recently developed biomaterials from a basic design and clinical application perspective. Additionally, the review highlights the importance of precise ion introduction into biomaterials to address existing limitations and challenges in combination therapies. Future prospects and opportunities for the development and optimization of biomaterials for bone tissue engineering are emphasized.

Periodontitis is a chronic inflammatory disease caused by the local microbiome and the host immune response, resulting in periodontal structure damage and even tooth loss. Scaling and root planning combined with antibiotics are the conventional means of nonsurgical treatment of periodontitis, but they are insufficient to fully heal periodontitis due to intractable bacterial attachment and drug resistance. Novel and effective therapeutic options in clinical drug therapy remain scarce. Nanotherapeutics achieve stable cell targeting, oral retention and smart release by great flexibility in changing the chemical composition or physical characteristics of nanoparticles. Meanwhile, the protectiveness and high surface area to volume ratio of nanoparticles enable high drug loading, ensuring a remarkable therapeutic efficacy. Currently, the combination of advanced nanoparticles and novel therapeutic strategies is the most active research area in periodontitis treatment. In this review, we first introduce the pathogenesis of periodontitis, and then summarize the state-of-the-art nanotherapeutic strategies based on the triple concerto of antibacterial activity, immunomodulation and periodontium regeneration, particularly focusing on the therapeutic mechanism and ingenious design of nanomedicines. Finally, the challenges and prospects of nano therapy for periodontitis are discussed from the perspective of current treatment problems and future development trends.

In the current study, the creation of a chitosan/alginate scaffold hydrogel with and without FeO-NPs or CuO-NPs was studied. From fetal ovine bone marrow mesenchymal stem cells (BM-MSCs) were isolated and cultivated. Their differentiation into osteocyte and adipose cells was investigated. Also, on the scaffolds, cytotoxicity and apoptosis were studied. To investigate the differentiation, treatment groups include: (1) BM-MSCs were plated in DMEM culture medium with high glucose containing 10% FBS and antibiotics (negative control); (2) BM-MSCs were plated in osteogenic differentiation medium (positive control); (3) positive control group + FeO-NPs, (4) positive control group + CuO-NPs; (5) BM-MSCs were plated in osteogenic differentiation medium on chitosan/alginate scaffold; (6) BM-MSCs were plated in osteogenic differentiation medium on chitosan/alginate/FeO-NPs scaffold; and (7) BM-MSCs were plated in osteogenic differentiation medium on chitosan/alginate/CuO-NPs scaffold. Alkaline phosphatase enzyme concentrations, mineralization rate using a calcium kit, and mineralization measurement by alizarin staining quantification were evaluated after 21 days of culture. In addition, qRT-PCR was used to assess the expression of the ALP, ColA, and Runx2 genes. When compared to other treatment groups, the addition of CuO-NPs in the chitosan/alginate hydrogel significantly increased the expression of the ColA and Runx2 genes (p < 0.05). However, there was no significant difference between the chitosan/alginate hydrogel groups containing FeO-NPs and CuO-NPs in the expression of the ALP gene. It appears that the addition of nanoparticles, in particular CuO-NPs, has made the chitosan/alginate scaffold more effective in supporting osteocyte differentiation.

Dysregulated metal homeostasis is associated with many pathological conditions, including arthritic diseases. Osteoarthritis and rheumatoid arthritis are the two most prevalent disorders that damage the joints and lead to cartilage and bone destruction. Recent studies show that the levels of zinc (Zn) and copper (Cu) are generally altered in the serum of arthritis patients. Therefore, metal dyshomeostasis may reflect the contribution of these trace elements to the disease's pathogenesis and manifestations, suggesting their potential for prognosis and treatment. Carnosine (Car) also emerged as a biomarker in arthritis and exerts protective and osteogenic effects in arthritic joints. Notably, its zinc(II) complex, polaprezinc, has been recently proposed as a drug-repurposing candidate for bone fracture healing. On these bases, this review article aims to provide an overview of the beneficial roles of Cu and Zn in bone and cartilage health and their potential application in tissue engineering. The effects of Car and polaprezinc in promoting cartilage and bone regeneration are also discussed. We hypothesize that polaprezinc could exchange Zn for Cu, present in the culture media, due to its higher sequestering ability towards Cu. However, future studies should unveil the potential contribution of Cu in the beneficial effects of polaprezinc.

There are still limitations in artificial bone materials used in clinical practice, such as difficulty in repairing large bone defects, the mismatch between the degradation rate and tissue growth, difficulty in vascularization, an inability to address bone defects of various shapes, and risk of infection. To solve these problems, our group designed stereolithography (SLA) 3D-printed calcium silicate artificial bone improved by a calcium sulfate-Cu2+ delivery system. SLA technology endows the scaffold with a three-dimensional tunnel structure to induce cell migration to the center of the bone defect. The calcium sulfate-Cu2+ delivery system was introduced to enhance the osteogenic activity of calcium silicate. Rapid degradation of calcium sulfate (CS) induces early osteogenesis in the three-dimensional tunnel structure. Calcium silicate (CSi) which degrades slowly provides mechanical support and promotes bone formation in bone defect sites for a long time. The gradient degradation of these two components is perfectly matched to the rate of repair in large bone defects. On the other hand, the calcium sulfate delivery system can regularly release Cu2+ in the temporal and spatial dimensions, exerting a long-lasting antimicrobial effect and promoting vascular growth. This powerful 3D-printed calcium silicate artificial bone which has rich osteogenic activity is a promising material for treating large bone defects and has excellent potential for clinical application.

Severe bone defects accompanied by vascular and peripheral nerve injuries represent a huge orthopedic challenge and are often accompanied by the risk of infection. Thus, biomaterials with antibacterial and neurovascular regeneration properties are highly desirable. Here, a newly designed biohybrid biodegradable hydrogel (GelMA) containing copper ion-modified germanium-phosphorus (GeP) nanosheets, which act as neuro-vascular regeneration and antibacterial agents, is designed. The copper ion modification process serves to improve the stability of the GeP nanosheets and offers a platform for the sustained release of bioactive ions. Study findings show that GelMA/GeP@Cu has effective antibacterial properties. The integrated hydrogel can significantly boost the osteogenic differentiation of bone marrow mesenchymal stem cells, facilitate angiogenesis in human umbilical vein endothelial cells, and up-regulate neural differentiation-related proteins in neural stem cells in vitro. In vivo, in the rat calvarial bone defect mode, the GelMA/GeP@Cu hydrogel is found to enhance angiogenesis and neurogenesis, eventually contributing to bone regeneration. These findings indicate that in the field of bone tissue engineering, GelMA/GeP@Cu can serve as a valuable biomaterial for neuro-vascularized bone regeneration and infection prevention.

The increasing number of peri-implant diseases and the unsatisfactory results of conventional treatment are causing great concern to patients and medical staff. The effective removal of plaque which is one of the key causes of peri-implant disease from the surface of implants has become one of the main problems to be solved urgently in the field of peri-implant disease prevention and treatment. In recent years, with the advancement of materials science and pharmacology, a lot of research has been conducted to enhance the implant antimicrobial properties, including the addition of antimicrobial coatings on the implant surface, the adjustment of implant surface topography, and the development of new implant materials, and significant progress has been made in various aspects. Antimicrobial materials have shown promising applications in the prevention of peri-implant diseases, but meanwhile, there are some shortcomings, which leads to the lack of clinical widespread use of antimicrobial materials. This paper summarizes the research on antimicrobial materials applied to implants in recent years and presents an outlook on the future development.

The clinical challenge of bone defects in the craniomaxillofacial region, which can lead to significant physiological dysfunction and psychological distress, persists due to the complex and unique anatomy of craniomaxillofacial bones. These critical-sized defects require the use of bone grafts or substitutes for effective reconstruction. However, current biomaterials and methods have specific limitations in meeting the clinical demands for structural reinforcement, mechanical support, exceptional biological performance, and aesthetically pleasing reconstruction of the facial structure. These drawbacks have led to a growing need for novel materials and technologies. The growing development of 3D printing can offer significant advantages to address these issues, as demonstrated by the fabrication of patient-specific bioactive constructs with controlled structural design for complex bone defects in medical applications using this technology. Poly (ether ether ketone) (PEEK), among a number of materials used, is gaining recognition as a feasible substitute for a customized structure that closely resembles natural bone. It has proven to be an excellent, conformable, and 3D-printable material with the potential to replace traditional autografts and titanium implants. However, its biological inertness poses certain limitations. Therefore, this review summarizes the distinctive features of craniomaxillofacial bones and current methods for bone reconstruction, and then focuses on the increasingly applied 3D printed PEEK constructs in this field and an update on the advanced modifications for improved mechanical properties, biological performance, and antibacterial capacity. Exploring the potential of 3D printed PEEK is expected to lead to more cost-effective, biocompatible, and personalized treatment of craniomaxillofacial bone defects in clinical applications.

Diseases or defects of the skeleton are hazardous because of their specificity and intricacy. Bone tissue engineering has become an important area of research that offers promising new tools for making biomimetic hydrogels that can be used to treat bone diseases. New hydrogels with a distinctive 3D network structure, high water content, and functional capabilities are ranked among the most promising candidates for bone tissue engineering. This makes them helpful in treating cartilage injury, skull deformity, and arthritis. This review will briefly introduce the variety of biocompatible functional hydrogels used in cell culture and bone tissue regeneration. Many gel design concepts, such as crosslinking procedures, controlled release properties, and alternative bionic methodology, were stressed regarding injectable hydrogels to form bone tissue. Hydrogels manufactured from biocompatible materials are a promising option for minimally invasive surgery because of their adaptable physicochemical qualities, ability to fill irregularly shaped defect sites, and ability to grow hormones or release drugs in response to external stimuli. Also included in this overview is a quick rundown of the more practical designs employed in treating bone disorders. Essential details on injectable hydrogel scaffolds for bone tissue regeneration are described in this article.

Mandibular defect becomes a prevalent maxillofacial disease resulting in mandibular dysfunctions and huge psychological burdens to the patients. Considering the routine presence of oral contaminations and aesthetic restoration of facial structures, the current clinical treatments are however limited, incapable to reconstruct the structural integrity and regeneration, spurring the need for cost-effective mandibular tissue engineering. Hydrogel systems possess great merit for mandibular reconstruction with precise involvement of cells and bioactive factors. In this review, current clinical treatments and distinct mode(s) of mandible formation and pathological resorption are summarized, followed by a review of hydrogel-related mandibular tissue engineering, and an update on the advanced fabrication of hydrogels with improved mechanical property, antibacterial ability, injectable form, and 3D bioprinted hydrogel constructs. The exploration of advanced hydrogel systems will lay down a solid foundation for a bright future with more biocompatible, effective, and personalized treatment in mandibular reconstruction.

Tissue engineering combines suitable cells, engineering methods, and proper biochemical factors to develop functional and biological tissues and repair damaged tissues. In this study, we focused on synthesizing and characterizing a nanocomposite scaffold based on glycerol and azelaic acid (Gl-Az) combined with copper chromite (CuCr₂O₄) nanoparticles in order to increase the osteogenic differentiation efficiency of human adipose-derived stem cells (hADSCs) on fabricated scaffolds. The degradability and hydrophobicity properties as well as mechanical and thermal behaviors of nanocomposite scaffolds were investigated. Next, the cell toxicity of glycerol, azelaic acid and CuCr₂O₄ nanoparticles was studied by MTT assay test and acridine orange staining. Finally, the osteogenic differentiation of hADSCs on Gl-Az-CuCr₂O₄ scaffolds was examined using alkaline phosphatase activity (ALP) and calcium content. The obtained results demonstrated that Gl-Az-1%CuCr₂O₄ not only showed appropriate mechanical strength, biocompatibility and degradability but also influenced the capability of hADSCs to differentiate into osteogenic lineages. The hADSCs culture in Gl-Az-1%CuCr₂O₄ showed a significant increase in ALP activity levels and calcium biomineralization after 14 days of osteogenic differentiation. In conclusion, the Gl-Az-1%CuCr₂O₄ nanocomposite could be used as a biocompatible and degradable scaffold to induce the bone differentiation of hADSCs and it could be a promising scaffold in bone regenerative medicine.

Advanced antibacterial biomaterials can help reduce the severe consequences of infections. Using copper compounds is an excellent option to achieve this goal; they offer a combination of regenerative and antimicrobial functions. In this study, new CuCl₂-doped sol-gel coatings were developed and physicochemically characterised. Their osteogenic and inflammatory responses were tested in vitro using human osteoblasts and THP-1 macrophages. Their antibacterial effect was evaluated using Escherichia coli and Staphylococcus aureus. The Cu influence on the adsorption of human serum proteins was analysed employing proteomics. The materials released Cu²⁺ and were not cytotoxic. The osteoblasts in contact with these materials showed an increased ALP, BMP2 and OCN gene expression. THP-1 showed an increase in pro-inflammatory markers related to M1 polarization. Moreover, Cu-doped coatings displayed a potent antibacterial behaviour against E. coli and S. aureus. The copper ions affected the adsorption of proteins related to immunity, coagulation, angiogenesis, fibrinolysis, and osteogenesis. Interestingly, the coatings had increased affinity to proteins with antibacterial functions and proteins linked to the complement system activation that can lead to direct bacterial killing via large pore-forming complexes. These results contribute to our understanding of the antibacterial mechanisms of Cu-biomaterials and their interaction with biological systems.

Titanium dioxide (TiO₂) nanotubes arrays have shown tremendous application foreground due to their unique characters of structure and performance. However, the single bio-function is still the limit on cardiovascular biomaterials.

The loadability function provides the possibility for the TiO₂ nanotubes arrays to realize composite multifunction. The copper can catalyze the release of nitric oxide to promote the proliferation of endothelium cells and improve the anticoagulant. Also, zinc can adjust the inflammatory responses to improve anti-inflammation.

In this patent work, we co-doped the copper and zinc onto TiO₂ nanotubes arrays to estimate the hemocompatibility, cytocompatibility and responses of inflammation. The results showed that copper and zinc could introduce better multi-biofunctions to the TiO₂ nanotubes arrays for the application in cardiovascular biomaterials.

In summary, the NTs@Cu/Zn sample as a new composite material in this study had significant biocompatibility in vascular implantation and can be used as a potential material for polymer- free drug-eluting stents.

Titanium (Ti) has been widely used for manufacturing of bone implants because of its mechanical properties, biological compatibility, and favorable corrosion resistance in biological environments. However, Ti implants are prone to infection (peri-implantitis) by bacteria which in extreme cases necessitate painful and costly revision surgeries. An emerging, viable solution for this problem is to use copper (Cu) as an antibacterial agent in the alloying system of Ti. The addition of copper provides excellent antibacterial activities, but the underpinning mechanisms are still obscure. This review sheds light on such mechanisms and reviews how incorporation of Cu can render Ti-Cu implants with antibacterial activity. The review first discusses the fundamentals of interactions between bacteria and implanted surfaces followed by an overview of the most common engineering strategies utilized to endow an implant with antibacterial activity. The underlying mechanisms for antibacterial activity of Ti-Cu implants are then discussed in detail. Special attention is paid to contact killing mechanisms because the misinterpretation of this mechanism is the root of discrepancies in the literature.

Robust antimicrobial coatings featuring high transparency, strong bactericidal activity, and an easy application procedure on generic surfaces can be widely accepted by the public to prevent pandemics. In this work, we demonstrated the hand-sprayer-based approach to deposit complex oxide coatings composed of Co-Mn-Cu-Zn-Ag on screen protectors of smartphones through acidic redox-assisted deposition (ARD). The as-obtained coatings possess high transparency (99.74% transmittance at 550 nm) and long-lasting durability against swiping (for 135 days of average use) or wet cleaning (for a routine of 3 times/day for 33 days). The spray coating enabling 3.14% Escherichia coli viability can further be reduced to 0.21% through a consistent elemental composition achieved via the immersion method. The high intake of Cu²⁺ in the coating is majorly responsible for the bactericidal activity, and the presence of Ag⁺ and Zn²⁺ is necessary to achieve almost complete eradication. The success of extending the bactericidal coatings on other typical hand-touched surfaces (e.g., stainless steel railings, rubber handrails, and plastic switches) in public areas has been demonstrated.

Copper is an indispensable trace metal element in human body, and copper deficiency is rare in clinic. However, diseases associated with serum copper deficiency, such as leukopenia, neutropenia, arthritis, osteoporosis, and bone defects, are well known. Copper ions can also achieve the effect of fighting pathogenic bacteria through the "contact killing" characteristic. Copper ion is also an important cofactor of bone matrix synthase, plays an important role in the pathophysiology of orthopedic diseases. The present review highlights the biological functions of copper in immunity, bone diseases and stem cells, as well as potential drug development targeting copper status for diagnostics and therapeutics of copper-associated bone diseases.

Titanium and titanium alloy with low density, high specific strength, good biological, excellent mechanical compatibility and easy to process have been widely used in the medical materials, but their application in orthopedics and dentistry often face bacterial infection, corrosion failure and stress shielding. In this paper, Ti-15Mo-7Cu (TM-7Cu) alloy was prepared by high vacuum non-consumable electric arc melting furnace and then treated by solution and aging treatment. The microstructure, mechanical properties, antibacterial properties and cytocompatibility were studied by X-ray diffraction, microhardness tester, electrochemical working station, antibacterial test and Live/Dead staining technology. The results have shown that the heat treatment significantly influenced the phase transformation, the precipitation of Ti₂Cu phase, the elastic modulus and the antibacterial ability. With the extension of the aging time, the elastic modulus slightly increased and the antibacterial rate obviously increased. TM-7Cu alloy with a low elastic modulus of 83GPa and a high antibacterial rate of > 93% was obtained. TM-7Cu alloy showed no cytotoxicity to MC3T3. It was suggested that TM-7Cu might be a highly competitive medical material.

As a typical metal-organic framework (MOF), Mg-MOF74 can release biocompatible Mg²⁺when the framework is degraded, and it has the potential to be used as filler in the field of bone tissue engineering. However, Mg-MOF74 has poor stability in aqueous environment and limited antibacterial ability, which limit its further development and applications. In this work, MgCu-MOF74 particles with different Cu content were synthesized through a facile one-step hydrothermal method. The physicochemical properties and water stability of the synthesized powders were characterized. The osteogenic potential of the MgCu-MOF74 particles on human osteogenic sarcoma cells (SaOS-2) was evaluated. The hybrid MgCu-MOF74 exhibited favorable water stability. These results indicated that MgCu-MOF74 enhanced cellular viability, alkaline phosphatase levels, collagen (COL) synthesis and osteogenesis-related gene expression. Moreover, the samples doped with Cu²⁺were more sensitive to the acidic microenvironment produced by bacteria, and exhibited stronger antibacterial ability than Mg-MOF74. In conclusion, MgCu-MOF-74 with good water stability, osteogenic ability and antibacterial ability, which could be attributed to the doping of Cu²⁺. Hence, MgCu-MOF74 shows great potential as a novel medical bio-functional fillers for the treatment of bone defects.