Multifunctional scaffolds for bone repair following age-related biological decline: Promising prospects for smart biomaterial-driven technologies.

The repair of large bone defects due to trauma, disease, and infection can be exceptionally challenging in the elderly. Despite best clinical practice, bone regeneration within contemporary, surgically implanted synthetic scaffolds is often problematic, inconsistent, and insufficient where additional osteobiological support is required to restore bone. Emergent smart multifunctional biomaterials may drive important and dynamic cellular crosstalk that directly targets, signals, stimulates, and promotes an innate bone repair response following age-related biological decline and when in the presence of disease or infection. However, their role remains largely undetermined. By highlighting their mechanism/s and mode/s of action, this review spotlights smart technologies that favorably align in their conceivable ability to directly target and enhance bone repair and thus are highly promising for future discovery for use in the elderly. The four degrees of interactive scaffold smartness are presented, with a focus on bioactive, bioresponsive, and the yet-to-be-developed autonomous scaffold activity. Further, cell- and biomolecular-assisted approaches were excluded, allowing for contemporary examination of the capabilities, demands, vision, and future requisites of next-generation biomaterial-induced technologies only. Data strongly supports that smart scaffolds hold significant promise in the promotion of bone repair in patients with a reduced osteobiological response. Importantly, many techniques have yet to be tested in preclinical models of aging. Thus, greater clarity on their proficiency to counteract the many unresolved challenges within the scope of aging bone is highly warranted and is arguably the next frontier in the field. This review demonstrates that the use of multifunctional smart synthetic scaffolds with an engineered strategy to circumvent the biological insufficiencies associated with aging bone is a viable route for achieving next-generation therapeutic success in the elderly population.

Antibacterial sponge for rapid noncompressible hemostatic treatment: spatiotemporal studies using a noninvasive model.

Hemorrhage is one of the leading causes of preventable death. While minor injuries can be treated mainly by conventional methods, deep and irregular wounds with profuse bleeding present significant challenges, some of which can be life-threatening and fatal. This underscores the need to develop easily applicable FDA-approved hemostatic treatments that can effectively stanch blood loss at the point of care before professional medical care. A silicone-based bandage system (SilFoam), a non-compressible, self-expanding, antibacterial hemostatic treatment, is reported here. Its two-component system reacts in situ upon mixing to form a stretchable sponge that acts as a 'tamponade' by expanding within seconds with the evolution of oxygen gas from the interaction of the reactive components present in the formulation. This generates autogenous pressure on the wound that can effectively arrest heavy bleeding within minutes. Possessing optimal adhesive properties, the expanded sponge can be easily removed, rendering it optimal for hemostatic wound dressing. With recent advances in biotechnological research, there is a growing awareness of the potential issues associated with in vivo trials, spanning ethical, psychological, economic, and physiological concerns like burnout and fatigue. Bearing this in mind, a unique manikin system simulating a deep abdominal wound has been employed to investigate SilFoam's hemostatic efficacy with different blood-flow rates using a non-invasive model that aims to provide an easy, fast, and economical route to test hemostatic treatments before in vivo studies. This is the first time an Ag2O-based oxygen-induced foaming system has been reported as a hemostatic agent.

A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis.

By 2060, an estimated one in four Americans will be elderly. Consequently, the prevalence of osteoporosis and fragility fractures will also increase. Presently, no available intervention definitively prevents or manages osteoporosis. This study explores whether Pool 7 Compound 3 (P7C3) reduces progressive bone loss and fragility following the onset of ovariectomy (OVX)-induced osteoporosis. Results confirm OVX-induced weakened, osteoporotic bone together with a significant gain in adipogenic body weight. Treatment with P7C3 significantly reduced osteoclastic activity, bone marrow adiposity, whole-body weight gain, and preserved bone area, architecture, and mechanical strength. Analyses reveal significantly upregulated platelet derived growth factor-BB and leukemia inhibitory factor, with downregulation of interleukin-1 R6, and receptor activator of nuclear factor kappa-B (RANK). Together, proteomic data suggest the targeting of several key regulators of inflammation, bone, and adipose turnover, via transforming growth factor-beta/SMAD, and Wingless-related integration site/be-catenin signaling pathways. To the best of the knowledge, this is first evidence of an intervention that drives against bone loss via RANK. Metatranscriptomic analyses of the gut microbiota show P7C3 increased Porphyromonadaceae bacterium, Candidatus Melainabacteria, and Ruminococcaceae bacterium abundance, potentially contributing to the favorable inflammatory, and adipo-osteogenic metabolic regulation observed. The results reveal an undiscovered, and multifunctional therapeutic strategy to prevent the pathological progression of OVX-induced bone loss.

A neoteric antibacterial ceria-silver nanozyme for abiotic surfaces.

Community-associated and hospital-acquired infections caused by bacteria continue to yield major global challenges to human health. Bacterial contamination on abiotic surfaces is largely spread via high-touch surfaces and contemporary standard disinfection practices show limited efficacy, resulting in unsatisfactory therapeutic outcomes. New strategies that offer non-specific and broad protection are urgently needed. Herein, we report our novel ceria-silver nanozyme engineered at a molar ratio of 5:1 and with a higher trivalent (Ce3+) surface fraction. Our results reveal potent levels of surface catalytic activity on both wet and dry surfaces, with rapid, and complete eradication of Pseudomonas aeruginosa, Staphylococcus aureus, and methicillin resistant S. aureus, in both planktonic and biofilm form. Preferential electrostatic adherence of anionic bacteria to the cationic nanozyme surface leads to a catastrophic loss in both aerobic and anaerobic respiration, DNA damage, osmodysregulation, and finally, programmed bacterial lysis. Our data reveal several unique mechanistic avenues of synergistic ceria-Ag efficacy. Ag potentially increases the presence of Ce3+ sites at the ceria-Ag interface, thereby facilitating the formation of harmful H2O2, followed by likely permeation across the cell wall. Further, a weakened Ag-induced Ce-O bond may drive electron transfer from the Ec band to O2, thereby further facilitating the selective reduction of O2 toward H2O2 formation. Ag destabilizes the surface adsorption of molecular H2O2, potentially leading to higher concentrations of free H2O2 adjacent to bacteria. To this end, our results show that H2O2 and/or NO/NO2-/NO3- are the key liberators of antibacterial activity, with a limited immediate role being offered by nanozyme-induced ROS including O2•- and OH•, and likely other light-activated radicals. A mini-pilot proof-of-concept study performed in a pediatric dental clinic setting confirms residual, and continual nanozyme antibacterial efficacy over a 28-day period. These findings open a new approach to alleviate infections caused by bacteria for use on high-touch hard surfaces.

Extracellular Proteins Isolated from L. acidophilus as an Osteomicrobiological Therapeutic Agent to Reduce Pathogenic Biofilm Formation, Regulate Chronic Inflammation, and Augment Bone Formation In Vitro.

Periprosthetic joint infection (PJI) is a challenging complication that can occur following joint replacement surgery. Efficacious strategies to prevent and treat PJI and its recurrence remain elusive. Commensal bacteria within the gut convey beneficial effects through a defense strategy named "colonization resistance" thereby preventing pathogenic infection along the intestinal surface. This blueprint may be applicable to PJI. The aim is to investigate Lactobacillus acidophilus spp. and their isolated extracellular-derived proteins (LaEPs) on PJI-relevant Staphylococcus aureus, methicillin-resistant S. aureus, and Escherichia coli planktonic growth and biofilm formation in vitro. The effect of LaEPs on cultured macrophages and osteogenic, and adipogenic human bone marrow-derived mesenchymal stem cell differentiation is analyzed. Data show electrostatically-induced probiotic-pathogen species co-aggregation and pathogenic growth inhibition together with LaEP-induced biofilm prevention. LaEPs prime macrophages for enhanced microbial phagocytosis via cathepsin K, reduce lipopolysaccharide-induced DNA damage and receptor activator nuclear factor-kappa B ligand expression, and promote a reparative M2 macrophage morphology under chronic inflammatory conditions. LaEPs also significantly augment bone deposition while abating adipogenesis thus holding promise as a potential multimodal therapeutic strategy. Proteomic analyses highlight high abundance of lysyl endopeptidase, and urocanate reductase. Further, in vivo analyses are warranted to elucidate their role in the prevention and treatment of PJIs.

A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss.

Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone. Presently, no effective countermeasure exists, and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity. The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy. Our studies revealed that P7C3 repressed ionizing radiation (IR)-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition in vitro. We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened, osteoporotic bone. However, the administration of P7C3 significantly inhibited osteoclastic activity, lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area, architecture, and mechanical strength. Our findings revealed significant enhancement of cellular macromolecule metabolic processes, myeloid cell differentiation, and the proteins LRP-4, TAGLN, ILK, and Tollip, with downregulation of GDF-3, SH2B1, and CD200. These proteins are key in favoring osteoblast over adipogenic progenitor differentiation, cell matrix interactions, and shape and motility, facilitating inflammatory resolution, and suppressing osteoclastogenesis, potentially via Wnt/ß-catenin signaling. A concern was whether P7C3 afforded similar protection to cancer cells. Preliminarily, and remarkably, at the same protective P7C3 dose, a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro. Together, these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy, leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications. Our data uncover a new approach for the prevention of radiation-induced bone damage, and further work is needed to investigate its ability to selectively drive cancer cell death.

Promising applications of D-amino acids in periprosthetic joint infection.

Due to the rise in our aging population, a disproportionate demand for total joint arthroplasty (TJA) in the elderly is forecast. Periprosthetic joint infection (PJI) represents one of the most challenging complications that can occur following TJA, and as the number of primary and revision TJAs continues to rise, an increasing PJI burden is projected. Despite advances in operating room sterility, antiseptic protocols, and surgical techniques, approaches to prevent and treat PJI remain difficult, primarily due to the formation of microbial biofilms. This difficulty motivates researchers to continue searching for an effective antimicrobial strategy. The dextrorotatory-isoforms of amino acids (D-AAs) are essential components of peptidoglycan within the bacterial cell wall, providing strength and structural integrity in a diverse range of species. Among many tasks, D-AAs regulate cell morphology, spore germination, and bacterial survival, evasion, subversion, and adhesion in the host immune system. When administered exogenously, accumulating data have demonstrated that D-AAs play a pivotal role against bacterial adhesion to abiotic surfaces and subsequent biofilm formation; furthermore, D-AAs have substantial efficacy in promoting biofilm disassembly. This presents D-AAs as promising and novel targets for future therapeutic approaches. Despite their emerging antibacterial efficacy, their role in disrupting PJI biofilm formation, the disassembly of established TJA biofilm, and the host bone tissue response remains largely unexplored. This review aims to examine the role of D-AAs in the context of TJAs. Data to date suggest that D-AA bioengineering may serve as a promising future strategy in the prevention and treatment of PJI.

Vacancy-Induced Visible Light-Driven Fluorescence in Toxic Ion-Free Resorbable Magnetic Calcium Phosphates for Cell Imaging Applications.

Multifunctional nanosized particles are very beneficial in the field of biomedicine. Bioactive and highly biocompatible calcium phosphate (CaP) nanoparticles (∼50 nm) exhibiting both superparamagnetic and fluorescence properties were synthesized by incorporating dual ions (Fe3+ and Sr2+) in HAp (hydroxyapatite) [Ca10(PO4)6(OH)2]. Insertion of Fe3+ creates oxygen vacancies at the PO43- site, thereby destabilizing the structure. Thus, in order to maintain the structural stability, Sr2+ has been incorporated. This incorporation of Sr2+ leads to an intense emission at 550 nm. HAp nanoparticles when subjected to thermal treatment (800 °C) transform to ß-TCP, exhibiting emission at 710 nm due to the emergence of an intermediate band. Moreover, these nanoparticles exhibit fluorescence in visible light when compared to the other UV and IR fluorescence excitation sources which could damage the tissues. The synthesis involving the combination of ultrasound and microwave techniques resulted in the distribution of Fe3+ in the interstitial sites of CaP, which is responsible for the excellent fluorescent properties. Moreover, thermally treated CaP becomes superparamagnetic, without affecting the desired optical properties. The bioactive, biocompatible, magnetic, and fluorescent properties of this resorbable CaP which is free from toxic heavy metals (Eu, Gd, etc.) could help in overcoming the long-term cytotoxicity. This could also be useful in tracking the location of the nanoparticles during drug delivery and magnetic hyperthermia. The bioactive fluorescent CaP nanoparticle helps in monitoring the bone growth and in addition, it could be employed in cell imaging applications. The in vitro MCF-7 imaging using the nanoparticles after 24 h of uptake at 465 nm evidences the bioimaging capability of the prepared nanoparticles. The reproducibility of the defect level is essential for the defect-induced emission properties. The synthesis of nontoxic fluorescent CaP is highly reproducible with the present synthesis method. Hence, it could be safely employed in various biomedical applications.