Zinc-doped bioactive glass-functionalized polyetheretherketone to enhance the biological response in bone regeneration.

Polyether ether ketone (PEEK) is gaining recognition as a highly promising polymer for orthopedic implants, attributed to its exceptional biocompatibility, ease of processing, and radiation resistance. However, its long-term in vivo application faces challenges, primarily due to suboptimal osseointegration from postimplantation inflammation and immune reactions. Consequently, biofunctionalization of PEEK implant surfaces emerges as a strategic approach to enhance osseointegration and increase the overall success rates of these implants. In our research, we engineered a multifaceted PEEK implant through the in situ integration of chitosan-coated zinc-doped bioactive glass nanoparticles (Zn-BGNs). This novel fabrication imbues the implant with immunomodulatory capabilities while bolstering its osseointegration potential. The biofunctionalized PEEK composite elicited several advantageous responses; it facilitated M2 macrophage polarization, curtailed the production of inflammatory mediators, and augmented the osteogenic differentiation of bone marrow mesenchymal stem cells. The experimental findings underscore the vital and intricate role of biofunctionalized PEEK implants in preserving normal bone immunity and metabolism. This study posits that utilizing chitosan-BGNs represents a direct and effective method for creating multifunctional implants. These implants are designed to facilitate biomineralization and immunomodulation, making them especially apt for orthopedic applications.

Secure output containment of heterogeneous multi-agent systems against hybrid attacks.

In this paper, the secure containment control issue for heterogeneous multi-agent systems subject to hybrid attacks is studied. In the network channels among agents, adversaries launch replay attacks such that the followers can only retrieve the previous information of their neighbors. To characterize the effects of replay attacks, a distributed auxiliary system with heterogeneous time-varying delay is constructed to estimate the convex hull of the leaders' state. The control input of each follower may be contaminated by the malicious false data injection (FDI) attacks with unknown bounded time-varying signals, which are intended to compromise the containment performance of the whole system. A local adaptive compensator is designed for each follower to eliminate the adverse effects of the FDI attacks. Based on the distributed auxiliary system and the local adaptive compensator, a secure distributed control protocol is proposed to ensure that the output trajectories of each follower can converge to the dynamic convex hull spanned by the leader outputs. Finally, two illustrative examples are provided to show the feasibility of the proposed secure control scheme.

Multifunctional biomimetic hydrogel dressing provides anti-infection treatment and improves immunotherapy by reprogramming the infection-related wound microenvironment.

The advancement of biomaterials with antimicrobial and wound healing properties continues to present challenges. Macrophages are recognized for their significant role in the repair of infection-related wounds. However, the interaction between biomaterials and macrophages remains complex and requires further investigation. In this research, we propose a new sequential immunomodulation method to enhance and expedite wound healing by leveraging the immune properties of bacteria-related wounds, utilizing a novel mixed hydrogel dressing. The hydrogel matrix is derived from porcine acellular dermal matrix (PADM) and is loaded with a new type of bioactive glass nanoparticles (MBG) doped with magnesium (Mg-MBG) and loaded with Curcumin (Cur). This hybrid hydrogel demonstrates controlled release of Cur, effectively eradicating bacterial infection in the early stage of wound infection, and the subsequent release of Mg ions (Mg2+) synergistically inhibits the activation of inflammation-related pathways (such as MAPK pathway, NF-κB pathway, TNF-α pathway, etc.), suppressing the inflammatory response caused by infection. Therefore, this innovative hydrogel can safely and effectively expedite wound healing during infection. Our design strategy explores novel immunomodulatory biomaterials, offering a fresh approach to tackle current clinical challenges associated with wound infection treatment.

Copper-Zinc-Doped Bilayer Bioactive Glasses Loaded Hydrogel with Spatiotemporal Immunomodulation Supports MRSA-Infected Wound Healing.

Developing biomaterials with antimicrobial and wound-healing activities for the treatment of wound infections remains challenging. Macrophages play non-negligible roles in healing infection-related wounds. In this study, a new sequential immunomodulatory approach is proposed to promote effective and rapid wound healing using a novel hybrid hydrogel dressing based on the immune characteristics of bacteria-associated wounds. The hydrogel dressing substrate is derived from a porcine dermal extracellular matrix (PADM) and loaded with a new class of bioactive glass nanoparticles (BGns) doped with copper (Cu) and zinc (Zn) ions (Cu-Zn BGns). This hybrid hydrogel demonstrates a controlled release of Cu2+ and Zn2+ and sequentially regulates the phenotypic transition of macrophages from M1 to M2 by alternately activating nucleotide-binding oligomerization domain (NOD) and inhibiting mitogen-activated protein kinases (MAPK) signaling pathways. Additionally, its dual-temporal bidirectional immunomodulatory function facilitates enhanced antibacterial activity and wound healing. Hence, this novel hydrogel is capable of safely and efficiently accelerating wound healing during infections. As such, the design strategy provides a new direction for exploring novel immunomodulatory biomaterials to address current clinical challenges related to the treatment of wound infections.

Cu-Sr Bilayer Bioactive Glass Nanoparticles/Polydopamine Functionalized Polyetheretherketone Enhances Osteogenic Activity and Prevents Implant-Associated Infections through Spatiotemporal Immunomodulation.

Key factors contributing to implantation failures include implant-associated infections (IAIs) and insufficient osseointegration of the implants. Polyetheretherketone (PEEK) is widely used in orthopedics, yet its clinical applications are restricted due to its poor osteogenic and antibacterial properties as well as inadequate immune responses. To overcome these drawbacks, a novel spatiotemporal immunomodulation approach is proposed, chelating Cu-Sr bilayer bioactive glass nanoparticles (CS-BGNs) onto the PEEK surface via polydopamine (PDA). The CS-BGNs possess a bilayer core-shell structure where copper is distributed in the outer layer and strontium is clustered in the inner layer. The results show that CS-BGNs/PDA functionalized PEEK demonstrates a controlled and sequential release of Cu2+ and Sr2+ . In the early stage, Cu2+ from the outer layer releases rapidly, while Sr2+ from the inner layer releases in the late stage. This well-ordered release pattern modulates the phenotypic transition of macrophages, which induces M1 polarization in the early stage and M2 polarization in the late stage. Combined with the direct effects of Cu2+ and Sr2+ , the spatiotemporal immunomodulation not only benefits the early antibacterial and tissue-healing process, but also promotes the long-term process of osseointegration, providing new perspectives on the design of novel immunomodulatory biomaterials.

Magnesium bioactive glass hybrid functionalized polyetheretherketone with immunomodulatory function to guide cell fate and bone regeneration.

Polyetheretherketone (PEEK) is being increasingly recognized as a highly promising polymer implant in orthopaedics due to its advantageous biocompatibility, favorable processability, and radiation resistance. Nonetheless, the long-term application of PEEK implants in vivo faces challenges due to unfavorable post-implantation inflammatory and immune reactions, which result in suboptimal osseointegration rates. Hence, biofunctionalizing the surface of PEEK implants emerges as a viable strategy to enhance osseointegration and increase the success rate. In this study, we developed a multifunctional PEEK implant through the in-situ incorporation of chitosan-coated bioactive glass nanoparticles (BGNs). This approach can impart immunomodulatory properties and enhance the potential for osseointegration. The resulting biofunctionalized PEEK material exhibited multiple beneficial effects. For instance, it facilitated M2 phenotypic polarization of macrophages, diminished the expression of inflammatory factors, and enhanced the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro. Moreover, it exhibited an improved capacity for osseointegration when tested in vivo. The findings of the experiment highlighted the pivotal and complex role of the biofunctionalized PEEK implant in maintaining typical bone immunity and metabolism. The study proposes that the application of chitosan-BGNs presents a straightforward approach to developing multifunctional implants with the ability to promote biomineralization and immunomodulation, specifically tailored for orthopaedic applications.

GSK 650394 Inhibits Osteoclasts Differentiation and Prevents Bone Loss via Promoting the Activities of Antioxidant Enzymes In Vitro and In Vivo.

Osteoporosis (OP) is one of the most common bone disorders among the elderly, characterized by abnormally elevated bone resorption caused by formation and activation of osteoblast (OC). Excessive reactive oxygen species (ROS) accumulation might contribute to the formation process of OC as an essential role. Although accumulated advanced treatment target on OP have been proposed in recent years, clinical outcomes remain unexcellence attributed to severe side effects. The purpose of present study was to explore the underlying mechanisms of GSK 650394 (GSK) on inhibiting formation and activation of OC and bone resorption in vitro and in vivo. GSK could inhibit receptor activator of nuclear-κB ligand (RANKL-)-mediated Oc formation via suppressing the activation of NF-κB and MAPK signaling pathways, regulating intracellular redox status, and downregulate the expression of nuclear factor of activated T cells c1 (NFATc1). In addition, quantitative RT-PCR results show that GSK could suppress the expression of OC marker gene and antioxidant enzyme genes. Consistent with in vitro cellular results, GSK treatment improved bone density in the mouse with ovariectomized-induced bone loss according to the results of CT parameters, HE staining, and Trap staining. Furthermore, GSK treatment could enhance the capacity of antioxidant enzymes in vivo. In conclusion, this study suggested that GSK could suppress the activation of osteoclasts and therefore maybe a potential therapeutic reagent for osteoclast activation-related osteoporosis.

Bone infection site targeting nanoparticle-antibiotics delivery vehicle to enhance treatment efficacy of orthopedic implant related infection.

Orthopedic implants account for 99% of orthopedic surgeries, however, orthopedic implant-related infection is one of the most serious complications owing to the potential for limb-threatening sequelae and mortality. Current antibiotic treatments still lack the capacity to target bone infection sites, thereby resulting in unsatisfactory therapeutic effects. Here, the bone infection site targeting efficacy of D6 and UBI29-41 peptides was investigated, and bone-and-bacteria dual-targeted nanoparticles (NPs) with D6 and UBI29-41 peptides were first fabricated to target bone infection site and control the release of vancomycin in bone infection site. The results of this study demonstrated that the bone-and-bacteria dual-targeted mesoporous silica NPs exhibit excellent bone and bacteria targeting efficacy, excellent biocompatibility and effective antibacterial properties in vitro. Furthermore, in a rat model of orthopedic implant-related infection with methicillin-resistant Staphylococcus aureus, the growth of bacteria was evidently inhibited without cytotoxicity, thus realizing the early treatment of implant-related infection. Hence, the bone-and-bacteria dual-targeted molecule-modified NPs may target bacteria-infected bone sites and act as ideal candidates for the therapy of orthopedic implant-related infections.

CaP-based anti-inflammatory HIF-1α siRNA-encapsulating nanoparticle for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a common inflammatory disease and its treatment is largely limited by drug ineffectiveness or severe side effects. In RA progression, multiple signalling pathways, such as hypoxia-inducible factor (HIF)-1α, nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways, act synergistically to maintain the inflammatory response. To downregulate HIF-1α, NF-κB, and MAPK expression, we proposed HIF-1α siRNA-loaded calcium phosphate nanoparticles encapsulated in apolipoprotein E3-reconstituted high-density lipoprotein (HIF-CaP-rHDL) for RA therapy. Here, we evaluated the potential of CaP-rHDL nanoparticles in RA therapy using a murine macrophage line (RAW 264.7) and a collagen-induced arthritis (CIA) mouse model. The CaP-rHDL nanoparticles showed significant anti-inflammatory effects along with HIF-1α knockdown and NF-κB and MAPK signalling pathway inhibition in lipopolysaccharide-activated macrophages. Moreover, they inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast formation. In CIA mice, their intravenous administration resulted in high accumulation at the arthritic joint sites, and HIF-CaP-rHDL effectively suppressed inflammatory cytokine secretion and relieved bone erosion, cartilage damage, and osteoclastogenesis. Thus, HIF-CaP-rHDL demonstrated great potential in RA precision therapy by inhibiting multiple inflammatory signalling pathways.

Smart Nanomaterials for Treatment of Biofilm in Orthopedic Implants.

Biofilms refer to complex bacterial communities that are attached to the surface of animate or inanimate objects, which highly resist the antibiotics or the host immune defense mechanisms. Pathogenic biofilms in medicine are general, chronic, and even costly, especially on medical devices and orthopedic implants. Bacteria within biofilms are the cause of many persistent infections, which are almost impossible to eradicate. Though some progress has been made in comprehending the mechanisms of biofilm formation and persistence, novel alternative compounds or strategies and effective anti-biofilm antibiotics are still lacking. Smart materials of nano size which are able to respond to an external stimulus or internal environment have a great range of applications in clinic. Recently, smart nanomaterials with or without carriage of antibiotics, targeting specific bacteria and biofilm under some stimuli, have shown great potential for pathogenic biofilm and resident bacteria eradication. First, this review briefly summarizes and describes the significance of biofilms and the process of biofilm formation. Then, we focus on some of the latest research studies involving biofilm elimination, which probably could be applied in orthopedic implants. Finally, some outstanding challenges and limitations that need to be settled urgently in order to make smart nanomaterials effectively target and treat implant biofilms are also discussed. It is hoped that there will be more novel anti-biofilm strategies for biofilm infection in the prospective future.

p300/CBP inhibitor A-485 inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss.

Osteoporosis is one of the most common metabolic bone diseases among pre- and post-menopausal women. Despite numerous advances in the treatment of osteoporosis in recent years, the outcomes remain poor due to severe side effects. In this study, we investigated whether A-485, a highly selective catalytic p300/CBP inhibitor, could attenuate RANKL-induced osteoclast differentiation and explored the underlying molecular mechanisms. The protective role of A-485 in osteoporosis was verified using a mouse model of ovariectomy (OVX)-induced bone loss and micro-CT scanning. A-485 inhibited RANKL-induced osteoclast differentiation in vitro by reducing the number of tartrate-resistant acid phosphatase-positive osteoclasts without inducing significant cytotoxicity. In particular, A-485 dose-dependently disrupted F-actin ring formation and downregulated the expression of genes associated with osteoclast differentiation, such as CTSK, c-Fos, TRAF6, VATPs-d2, DC-STAMP, and NFATc1, in a time- and dose-dependent manner. Moreover, A-485 inhibited the RANKL-induced phosphorylation of MAPK pathways and attenuated OVX-induced bone loss in the mouse model while rescuing the loss of bone mineral density. Our in vitro and in vivo findings suggest for the first time that A-485 has the potential to prevent postmenopausal osteoporosis and could therefore be considered as a therapeutic molecule against osteoporosis.

Hydrofluoric acid and nitric acid cotreatment for biofunctionalization of polyetheretherketone in M2 macrophage polarization and osteogenesis.

Due to its excellent mechanical and low-friction properties, polyetheretherketone (PEEK) has been widely investigated for use in orthopedic applications over the past decade. However, the bioinertness and poor osteogenic properties of PEEK have hampered its clinical application. In this study, the surface of PEEK was modified by co-treatment with hydrofluoric acid and nitric acid (AFN). The microstructures of the modified PEEK surfaces were investigated using scanning electron microscopy. The water contact angles of the surfaces were also measured. To evaluate their cytocompatibility, PEEK samples were used as substrates to culture rat bone mesenchymal stem cells, and cell adhesion, viability, and expression of specific marker genes were measured. Treatment of PEEK with AFN (PEEK-AFN) was found to enable better osteoblast adhesion, spreading, and proliferation; the activity of alkaline phosphatase (an early osteogenic differentiation marker) was also found to be enhanced post-treatment. Furthermore, PEEK-AFN was able to modulate macrophage polarization and down regulated the expression of proinflammatory factors via inhibiting the NF-κB pathway. Thus, treatment of PEEK with AFN could promote M2 polarization of the macrophages and stimulate the differentiation of osteoblasts. These results provide valuable information that could facilitate the use of PEEK-based composites as bone implant materials.

Overcoming Planktonic and Intracellular Staphylococcus aureus-Associated Infection with a Cell-Penetrating Peptide-Conjugated Antimicrobial Peptide.

Staphylococcus aureus is a primary pathogen responsible for causing postoperative infections as it survives and persists in host cells, including osteoblasts and macrophages. These cells then serve as reservoirs resulting in chronic infections. Most traditional antibiotics have poor effects on intracellular S. aureus because they cannot enter the cell. Herein, a cell-penetrating peptide TAT-KR-12 was derived from the trans-activating transcription (TAT) peptide and KR-12 (residues 18-29 of human cathelicidin LL-37). The TAT acts as a "trojan horse" to deliver KR-12 peptide into the cells to kill S. aureus. Moreover, effective antibacterial properties and biocompatibility were observed in vitro, demonstrating that TAT-KR-12 is effective not only in eliminating planktonic S. aureus, but also in eliminating intracellular S. aureus cells in vitro. TAT-KR-12, as with LL-37, also elicits strong anti-inflammatory activities in LPS-stimulated macrophages, as demonstrated by significant inhibition of NO, TNF-α, and IL-1ß expression and secretion from LPS-stimulated RAW264.7 cells. In the subcutaneous infection mouse model of planktonic and intracellular infections, the growth of S. aureusin vivo is evidently inhibited without cytotoxicity. These results suggest that the novel antimicrobial TAT-KR-12 may prove to be an effective treatment option to overcome antibiotic resistance caused by intracellular bacterial infections.

Approaches to promoting bone marrow mesenchymal stem cell osteogenesis on orthopedic implant surface.

Bone marrow-derived mesenchymal stem cells (BMSCs) play a critical role in the osseointegration of bone and orthopedic implant. However, osseointegration between the Ti-based implants and the surrounding bone tissue must be improved due to titanium's inherent defects. Surface modification stands out as a versatile technique to create instructive biomaterials that can actively direct stem cell fate. Here, we summarize the current approaches to promoting BMSC osteogenesis on the surface of titanium and its alloys. We will highlight the utilization of the unique properties of titanium and its alloys in promoting tissue regeneration, and discuss recent advances in understanding their role in regenerative medicine. We aim to provide a systematic and comprehensive review of approaches to promoting BMSC osteogenesis on the orthopedic implant surface.

Effects of staphylococcal infection and aseptic inflammation on bone mass and biomechanical properties in a rabbit model.

BACKGROUND/OBJECTIVE: Orthopaedic implants are important devices aimed at relieving pain and improving mobility. Staphylococcal infection and aseptic loosening are two common events associated with inflammatory osteolysis that lead to implant failures. Bone mass and biomechanical properties are important indicators that could influence patient outcomes after revision surgery. However, the dynamics of bacterial infections and their influence on bone mass and biomechanical properties remain unclear. Hence, in this study, we developed rabbit aseptic inflammation and staphylococcal infection models to determine the effects of coagulase-positive and coagulase-negative bacterial infection, as well as aseptic inflammation, on the mass and biomechanical properties of the bone. METHODS: Sixty New Zealand white rabbits were randomly assigned to 6 groups, and each group had 10 rabbits. The medullary cavities in rabbits of each group were injected with phosphate-buffered saline (100 â€‹µL), titanium (Ti)-wear particles (300 µg/100 â€‹µL), a low concentration of Staphylococcus epidermidis (105/100 â€‹µL), a high concentration of S. epidermidis (108/100 â€‹µL), a low concentration of Staphylococcus aureus (105/100 â€‹µL), and a high concentration of S. aureus (108/100 â€‹µL), respectively. At four and eight weeks after surgery, the rabbits were sacrificed, and the tibias on the surgical side were analysed via histopathology, microcomputed tomography, and nanoindentation testing. RESULTS: Histopathological analysis demonstrated that inflammatory responses and bacterial loads caused by high concentrations of staphylococcal infections, particularly coagulase-positive staphylococci, are more detrimental than low concentrations of bacterial infection and Ti-wear particles. Meanwhile, microcomputed tomography and nanoindentation testing showed that high concentrations of S. aureus caused the highest loss in bone mass and most biomechanical function impairment in rabbits experiencing aseptic inflammation and staphylococcal infections. CONCLUSIONS: Inflammatory osteolysis caused by a high concentration of coagulase-positive staphylococci is significantly associated with low bone mass and impaired biomechanical properties. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: It is necessary to obtain an overall assessment of the bone mass and biomechanical properties before revision surgery, especially when S. aureus infection is involved. In addition, a better understanding of these two parameters might help develop a reasonable treatment regimen and reduce the risk of adverse events after revision surgery.

H∞ consensus of Markovian jump multi-agent systems under multi-channel transmission via output feedback control strategy.

This paper studies the H∞ consensus problem of discrete-time multi-agent systems with Markovian jump parameters and exogenous disturbances via static output feedback control strategy. Each agent's measurement information is transmitted to its neighbors through the multiple quantized channels in which each channel obtains transmission permission based on a Markovian jump dispatcher. A static output feedback consensus controller is employed. In terms of an appropriate Lyapunov function, some sufficient conditions are derived to assure stochastic consensus for multi-agent systems subject to a specified H∞ performance. At length, a simulation example is provided to illustrate the correctness of the result.

Distributed Dissipative State Estimation for Markov Jump Genetic Regulatory Networks Subject to Round-Robin Scheduling.

The distributed dissipative state estimation issue of Markov jump genetic regulatory networks subject to round-robin scheduling is investigated in this paper. The system parameters randomly change in the light of a Markov chain. Each node in sensor networks communicates with its neighboring nodes in view of the prescribed network topology graph. The round-robin scheduling is employed to arrange the transmission order to lessen the likelihood of the occurrence of data collisions. The main goal of the work is to design a compatible distributed estimator to assure that the distributed error system is strictly (Λ 1,Λ 2,Λ 3) - γ -stochastically dissipative. By applying the Lyapunov stability theory and a modified matrix decoupling way, sufficient conditions are derived by solving some convex optimization problems. An illustrative example is given to verify the validity of the provided method.

Flufenamic acid inhibits osteoclast formation and bone resorption and act against estrogen-dependent bone loss in mice.

Postmenopausal osteoporosis is one of the most common types of osteoporosis resulting from estrogen deficiency in elderly women. Nonsteroidal anti-inflammatory drugs (NSAIDs) are important drugs for pain relief in patients with osteoporosis. In this study, we report for the first time that flufenamic acid, a clinically approved and widely used NSAID, not only has analgesic properties but also shows a significant effect in terms of preventing postmenopausal osteoporosis. Quantitative RT-PCR analysis showed that treatment with flufenamic acid significantly downregulated the genes associated with osteoclast differentiation. Meanwhile, RNA-sequencing and western blot analyses suggested that flufenamic acid could inhibit the bone resorption by suppressing the phosphorylation of MAPK pathways. Moreover, an ovariectomy (OVX)-induced bone-loss mouse model indicated that flufenamic acid might be a potent drug for preventing osteoporotic fractures, as verified by micro-CT scanning and histological analysis. Therefore, this study proposes an attractive and potent drug with analgesic properties for the prevention of postmenopausal osteoporosis.

Felodipine blocks osteoclast differentiation and ameliorates estrogen-dependent bone loss in mice by modulating p38 signaling pathway.

Postmenopausal osteoporosis is one of the most common types of osteoporosis resulting from estrogen deficiency in elderly women. In addition, hypertension is another common disease in the elderly, and it has become an independent risk factor for osteoporosis and osteoporotic fractures. Here, we report for the first time that felodipine, a first-line antihypertensive agent, significantly prevents postmenopausal osteoporosis in addition to its vasodilation properties. Quantitative RT-PCR analysis revealed that treatment with felodipine significantly downregulated the genes associated with osteoclast differentiation. RNA-sequencing and western blotting suggested that felodipine could inhibit bone resorption by suppressing MAPK pathway phosphorylation. Moreover, micro-CT scanning and histological analysis in an ovariectomy (OVX)-induced bone-loss mouse model indicated that felodipine might be a potent drug for preventing osteoporotic fractures. Therefore, this study proposes an attractive and promising agent with vasodilation properties to treat postmenopausal osteoporosis.