Mesoporous Silicon with Strontium-Powered Poly(Lactic-Co-Glycolic acid)/Gelatin-Based Dressings Facilitate Skin Tissue Repair.

Purpose: Functional inorganic nanomaterials (NMs) are widely exploited as bioactive materials and drug depots. The lack of a stable form of application of NMs at the site of skin injury, may impede the removal of the debridement, elevate pH, induce tissue toxicity, and limit their use in skin repair. This necessitates the advent of innovative wound dressings that overcome the above limitations. The overarching objective of this study was to exploit strontium-doped mesoporous silicon particles (PSiSr) to impart multifunctionality to poly(lactic-co-glycolic acid)/gelatin (PG)-based fibrous dressings (PG@PSiSr) for excisional wound management. Methods: Mesoporous silicon particles (PSi) and PSiSr were synthesized using a chemo-synthetic approach. Both PSi and PSiSr were incorporated into PG fibers using electrospinning. A series of structure, morphology, pore size distribution, and cumulative pH studies on the PG@PSi and PG@PSiSr membranes were performed. Cytocompatibility, hemocompatibility, transwell migration, scratch wound healing, and delineated angiogenic properties of these composite dressings were tested in vitro. The biocompatibility of composite dressings in vivo was assessed by a subcutaneous implantation model of rats, while their potential for wound healing was discerned by implantation in a full-thickness excisional defect model of rats. Results: The PG@PSiSr membranes can afford the sustained release of silicon ions (Si4+) and strontium ions (Sr2+) for up to 192 h as well as remarkably promote human umbilical vein endothelial cells (HUVECs) and NIH-3T3 fibroblasts migration. The PG@PSiSr membranes also showed better cytocompatibility, hemocompatibility, and significant formation of tubule-like networks of HUVECs in vitro. Moreover, PG@PSiSr membranes also facilitated the infiltration of host cells and promoted the deposition of collagen while reducing the accumulation of inflammatory cells in a subcutaneous implantation model in rats as assessed for up to day 14. Further evaluation of membranes transplanted in a full-thickness excisional wound model in rats showed rapid wound closure (PG@SiSr vs control, 96.1% vs 71.7%), re-epithelialization, and less inflammatory response alongside skin appendages formation (eg, blood vessels, glands, hair follicles, etc.). Conclusion: To sum up, we successfully fabricated PSiSr particles and prepared PG@PSiSr dressings using electrospinning. The PSiSr-mediated release of therapeutic ions, such as Si4+ and Sr2+, may improve the functionality of PLGA/Gel dressings for an effective wound repair, which may also have implications for the other soft tissue repair disciplines.

In vitro antifungal and physicochemical properties of polymerized acrylic resin containing strontium-modified phosphate-based glass.

Acrylic resins are widely used as the main components in removable orthodontic appliances. However, poor oral hygiene and maintenance of orthodontic appliances provide a suitable environment for the growth of pathogenic microorganisms. In this study, strontium-modified phosphate-based glass (Sr-PBG) was added to orthodontic acrylic resin at 0% (control), 3.75%, 7.5%, and 15% by weight to evaluate the surface and physicochemical properties of the novel material and its in vitro antifungal effect against Candida albicans (C. albicans). Surface microhardness and contact angle did not vary between the control and 3.75% Sr-PBG groups (p > 0.05), and the flexural strength was lower in the experimental groups than in the control group (p < 0.05), but no difference was found with Sr-PBG content (p > 0.05). All experimental groups showed an antifungal effect at 24 and 48 h compared to that in the control group (p < 0.05). This study demonstrated that 3.75% Sr-PBG exhibits antifungal effects against C. albicans along with suitable physicochemical properties, which may help to minimize the risk of adverse effects associated with harmful microbial living on removable orthodontic appliances and promote the use of various materials.

SrTiO3 Nanotube-Based "Pneumatic Nanocannon" for On-Demand Delivery of Antibacterial and Sustained Osseointegration Enhancement.

Infection and aseptic loosening caused by bacteria and poor osseointegration remain serious challenges for orthopedic implants. The advanced surface modification of implants is an effective strategy for addressing these challenges. This study presents a "pneumatic nanocannon" coating for titanium orthopedic implants to achieve on-demand release of antibacterial and sustained release of osteogenic agents. SrTiO3 nanotubes (SrNT) were constructed on the surface of Ti implants as "cannon barrel," the "cannonball" (antibiotic) and "propellant" (NH4HCO3) were codeposited into SrNT with assistance of mussel-inspired copolymerization of dopamine and subsequently sealed by a layer of polydopamine. The encapsulated NH4HCO3 within the nanotubes could be thermally decomposed into gases under near-infrared irradiation, propelling the on-demand delivery of antibiotics. This coating demonstrated significant efficacy in eliminating typical pathogenic bacteria both in planktonic and biofilm forms. Additionally, this coating exhibited a continuous release of strontium ions, which significantly enhanced the osteogenic differentiation of preosteoblasts. In an implant-associated infection rat model, this coating demonstrated substantial antibacterial efficiency (>99%) and significant promotion of osseointegration, along with alleviated postoperative inflammation. This pneumatic nanocannon coating presents a promising approach to achieving on-demand infection inhibition and sustained osseointegration enhancement for titanium orthopedic implants.

Titanium-doped phosphate glasses containing zinc and strontium applied in bone regeneration.

Phosphate bioactive glass has been studied for its advanced biodegradability and active ion release capability. Our previous research found that phosphate glass containing (P2O5)-(Na2O)-(TiO2)-(CaO)-(SrO) or (ZnO) showed good biocompatibility with MG63 and hMSCs. This study further investigated the application of 5 mol% zinc oxide or 17.5 mol% strontium oxide in titanium-doped phosphate glass for bone tissue engineering. Ti-Ca-Na-Phosphate glasses, incorporating 5% zinc oxide or 17.5% strontium oxide, were made with melting quenching technology. The pre-osteoblast cell line MC3T3-E1 was cultured for indirect contact tests with graded diluted phosphate glass extractions and for direct contact tests by seeding cells on glass disks. The cell viability and cytotoxicity were analysed in vitro over 7 days. In vivo studies utilized the tibial defect model with or without glass implants. The micro-CT analysis was performed after surgery and then at 2, 6, and 12 weeks. Extractions from both zinc and strontium phosphate glasses showed no negative impact on MC3T3-E1 cell viability. Notably, non-diluted Zn-Ti-Ca-Na-phosphate glass extracts significantly increased cell viability by 116.8% (P < 0.01). Furthermore, MC3T3-E1 cells cultured with phosphate glass disks exhibited no increase in LDH release compared with the control group. Micro-CT images revealed that, over 12 weeks, both zinc-doped and strontium-doped phosphate glasses demonstrated good bone incorporation and longevity compared to the no-implant control. Titanium-doped phosphate glasses containing 5 mol% zinc oxide, or 17.5 mol% strontium oxide have promising application potential for bone regeneration research.

Alginate-containing 3D-printed hydrogel scaffolds incorporated with strontium promotes vascularization and bone regeneration.

Bone defects persist as a significant challenge in the field of clinical orthopedics. This study focuses on the fabrication and characterization of 3D-printed composite hydrogel scaffolds composed of sodium alginate, gelatin, and α-tricalcium phosphate (α-TCP) with varying ratios of Strontium ions (Sr2+). These scaffolds aim to address the clinical challenges associated with bone defect repair by providing mechanical support and promoting bone formation and vascularization. The degradation, swelling, mechanical properties, and release profiles of Sr2+ from the hydrogel scaffolds were comprehensively characterized. In vitro tests were conducted to assess cell viability and proliferation, as well as osteogenic and angiogenic gene expression, to investigate the osteogenic and pro-angiogenic potential of the composite hydrogel scaffolds. Furthermore, skull defect simulations were performed, and composite scaffolds with varying Sr2+ ratios were implanted to evaluate their effectiveness in bone repair. This research establishes a foundation for advancing bone tissue engineering through composite scaffolds containing biological macromolecules and strontium, with alginate serving as a key element in enhancing performance and expanding clinical applicability.

Titania (TiO2) nanotube surfaces doped with zinc and strontium for improved cell compatibility.

Titanium-based orthopedic implants are gaining popularity in recent years due to their excellent biocompatibility, superior corrosion resistance and lightweight properties. However, these implants often fail to perform effectively due to poor osseointegration. Nanosurface modification approaches may help to resolve this problem. In this work, TiO2 nanotube (NT) arrays were fabricated on commercially available pure titanium (Ti) surfaces by anodization and annealing. Then, zinc (Zn) and strontium (Sr), important for cell signaling, were doped on the NT surface by hydrothermal treatment. This very simple method of Zn and Sr doping takes less time and energy compared to other complicated techniques. Different surface characterization tools such as scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDS), static water contact angle, X-ray diffraction (XRD) and nanoindentation techniques were used to evaluate the modified surfaces. Then, adipose derived stem cells (ADSCs) were cultured with the surfaces to evaluate cell adhesion, proliferation, and growth on the surfaces. After that, the cells were differentiated towards osteogenic lineage to evaluate alkaline phosphatase (ALP) activity, osteocalcin expression, and calcium phosphate mineralization. Results indicate that NT surfaces doped with Zn and Sr had significantly enhanced ADSC adhesion, proliferation, growth, and osteogenic differentiation compared to an unmodified surface, thus confirming the enhanced performance of these surfaces.

On the Ion Implantation Synthesis of Ag-Embedded Over Sr-Substituted Hydroxyapatite on a Nano-Topography Patterned Ti for Application in Acetabular Fracture Sites.

Introduction: There is an ongoing need for improved healing response and expedited osseointegration on the Ti implants in acetabular fracture sites. To achieve adequate bonding and mechanical stability between the implant surface and the acetabular fracture, a new coating technology must be developed to promote bone integration and prevent bacterial growth. Methods: A cylindrical Ti substrate mounted on a rotating specimen holder was used to implant Ca2+, P2+, and Sr2+ ions at energies of 100 KeV, 75 KeV and 180 KeV, respectively, using a low-energy accelerator to synthesize strontium-substituted hydroxyapatite at varying conditions. Ag2+ ions of energy 100 KeV were subsequently implanted on the as-formed surface at the near-surface region to provide anti-bacterial properties to the as-formed specimen. Results: The properties of the as-formed ion-implanted specimen were compared with the SrHA-Ag synthesized specimens by cathodic deposition and low-temperature high-speed collision technique. The adhesion strength of the ion-implanted specimen was 43 ± 2.3 MPa, which is well above the ASTM standard for Ca-P coating on Ti. Live/dead cell analysis showed higher osteoblast activity on the ion-implanted specimen than the other two. Ag in the SrHA implanted Ti by ion implantation process showed superior antibacterial activity. Discussion: In the ion implantation technique, nano-topography patterned surfaces are not concealed after implantation, and their efficacy in interacting with the osteoblasts is retained. Although all three studies examined the antibacterial effects of Ag2+ ions and the ability to promote bone tissue formation by MC3T3-E1 cells on SrHA-Ag/Ti surfaces, ion implantation techniques demonstrated superior ability. The synthesized specimen can be used as an effective implant in acetabular fracture sites based on their mechanical and biological properties.

Investigation of Osteomyelitis Inducing Methicillin-Resistant Staphylococcus aureus Inhibition Effect by Strontium-Substituted Borate Bioactive Glasses.

Borate glass transforms into hydroxycarbonate apatite more rapidly than silicate glass. This research aims to evaluate strontium's structural and biological effects on borate bioactive glass (BBG) and the influence of strontium concentrations (0%, 5%, 10%, and 15% Sr) prepared via the sol-gel method. The study reveals significant findings related to the physicochemical properties of the glass. Immersion of the glass powders in a simulated body fluid (SBF) led to the development of a hydroxyapatite (HAP) layer on the glass surfaces. This transformation was verified through X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared (FTIR) analyses. In particular, 5% strontium exhibited gradual degradation, resulting in particle sizes below 100 nm. The BBG-15%Sr demonstrates heightened pathogenic activity as it shows a significant inhibition zone of 14 mm at 250 µg/mL, surpassing other substituted BBGs. It effectively combats Gram-positive bacteria, completely inhibiting MRSA growth at 50 µg/mL. This underscores its robust biofilm disruption capabilities, eradicating biofilms, even at minimal concentrations after prolonged exposure. C. elegans when subjected to BBG-15%Sr shows less ROS production when compared with the others. Moreover, the results suggest that the modified glass could be a potential material for the treatment of osteomyelitis-affected bone repair.

Mg-Sr-Ca containing bioactive glass nanoparticles hydrogel modified mineralized collagen scaffold for bone repair.

The aim of this study is to explore the therapeutic effects of Mg-Sr-Ca containing bioactive glass nanoparticles sodium alginate hydrogel modified mineralized collagen scaffold (Mg-Sr-Ca-BGNs-SA-MC) on the repair of osteoporotic bone defect. During the study, Mg-Sr-Ca containing bioactive glass nanoparticles (Mg-Sr-Ca-BGNs) were synthesized using the sol-gel method, and the Mg-Sr-Ca-BGNs-SA-MC scaffold was synthesized by a simple method. The Mg-Sr-Ca-BGNs and the Mg-Sr-Ca-BGNs-SA-MC scaffold were observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The elements of Mg, Sr, Ca and Si were effectively integrated into Mg-Sr-Ca-BGNs. SEM analysis revealed the presence of Mg-Sr-Ca-BGNs on the scaffold's surface. Furthermore, the cytotoxicity of the scaffolds were assessed using a live/dead assay. The result of the live/dead assay demonstrated that the scaffold materials were non-toxic to cell growth. More importantly, the in vivo study indicated that implanted scaffold promoted tissue regeneration and integration with newly formed bone. Overall, the Mg-Sr-Ca-BGNs-SA-MC scaffold is suitable for guided bone regeneration and beneficial to repair of osteoporotic bone defects.

Sr-Incorporated Bioactive Glass Remodels the Immunological Microenvironment by Enhancing the Mitochondrial Function of Macrophage via the PI3K/AKT/mTOR Signaling Pathway.

The repair of critical-sized bone defects continues to pose a challenge in clinics. Strontium (Sr), recognized for its function in bone metabolism regulation, has shown potential in bone repair. However, the underlying mechanism through which Sr2+ guided favorable osteogenesis by modulating macrophages remains unclear, limiting their application in the design of bone biomaterials. Herein, Sr-incorporated bioactive glass (SrBG) was synthesized for further investigation. The release of Sr ions enhanced the immunomodulatory properties and osteogenic potential by modulating the polarization of macrophages toward the M2 phenotype. In vivo, a 3D-printed SrBG scaffold was fabricated and showed consistently improved bone regeneration by creating a prohealing immunological microenvironment. RNA sequencing was performed to explore the underlying mechanisms. It was found that Sr ions might enhance the mitochondrial function of macrophage by activating PI3K/AKT/mTOR signaling, thereby favoring osteogenesis. Our findings demonstrate the relationship between the immunomodulatory role of Sr ions and the mitochondrial function of macrophages. By focusing on the mitochondrial function of macrophages, Sr2+-mediated immunomodulation sheds light on the future design of biomaterials for tissue regenerative engineering.

Synergistic Improvement of Antibacterial and Osteogenic Differentiation of Thermomechanically Processed Mg-Zr-Sr-Ce Alloy: Insights into the Role of Precipitate Evolution Supported by AIMD Simulation Study.

In the present study, we have discussed the influence of forging temperature (623 K (FT623), 723 K (FT723) and 823 K (FT823)) on microstructure and texture evolution and its implication on mechanical behavior, in vitro-in vivo biocorrosion, antibacterial response, and cytocompatibility of microalloyed Mg-Zr-Sr-Ce alloy. Phase analysis, SEM, and TEM characterization confirm the presence of Mg12Ce precipitate, and its stability was further validated by performing ab initio molecular dynamic simulation study. FT723 exhibits strengthened basal texture, higher fraction of second phases, and particle-stimulated nucleation-assisted DRX grains compared to other two specimens, resulting in superior strength with comparable ductility. FT723 also exhibits superior corrosion resistance mainly due to the strengthened basal texture and lower dislocation density. All the specimens exhibit excellent antibacterial behavior with Gram-negative E. coli, Gram-positive Staphylococcus aureus, and Pseudomonas aeruginosa bacteria. 100% reduction of bacterial growth is observed within 24 h of culture of the specimens. Cytocompatibility was determined by challenging specimen extracts with the MC3T3-E1 cell lines. FT723 specimen exhibits the highest cell proliferation and alkaline phosphatase activity (ALP) because of its superior corrosion resistance. The ability of the specimens to be used in orthopedic implant application was evaluated by in vivo study in rabbit femur. Neither tissue-related infection nor the detrimental effect surrounding the implant was confirmed from histological analysis. Significant higher bone regeneration surrounding the FT723 specimen was observed in SEM analysis and fluorochrome labeling. After 60 days, the FT723 specimen exhibits the highest bone formation, suggesting it is a suitable candidate for orthopedic implant application.

Osteosarcoma cell death induced by innovative scaffolds doped with chemotherapeutics.

Osteosarcoma (OS) cancer treatments include systemic chemotherapy and surgical resection. In the last years, novel treatment approaches have been proposed, which employ a drug-delivery system to prevent offside effects and improves treatment efficacy. Locally delivering anticancer compounds improves on high local concentrations with more efficient tumour-killing effect, reduced drugs resistance and confined systemic effects. Here, the synthesis of injectable strontium-doped calcium phosphate (SrCPC) scaffold was proposed as drug delivery system to combine bone tissue regeneration and anticancer treatment by controlled release of methotrexate (MTX) and doxorubicin (DOX), coded as SrCPC-MTX and SrCPC-DOX, respectively. The drug-loaded cements were tested in an in vitro model of human OS cell line SAOS-2, engineered OS cell line (SAOS-2-eGFP) and U2-OS. The ability of doped scaffolds to induce OS cell death and apoptosis was assessed analysing cell proliferation and Caspase-3/7 activities, respectively. To determine if OS cells grown on doped-scaffolds change their migratory ability and invasiveness, a wound-healing assay was performed. In addition, the osteogenic potential of SrCPC material was evaluated using human adipose derived-mesenchymal stem cells. Osteogenic markers such as (i) the mineral matrix deposition was analysed by alizarin red staining; (ii) the osteocalcin (OCN) protein expression was investigated by enzyme-linked immunosorbent assay test, and (iii) the osteogenic process was studied by real-time polymerase chain reaction array. The delivery system induced cell-killing cytotoxic effects and apoptosis in OS cell lines up to Day 7. SrCPC demonstrates a good cytocompatibility and it induced upregulation of osteogenic genes involved in the skeletal development pathway, together with OCN protein expression and mineral matrix deposition. The proposed approach, based on the local, sustained release of anticancer drugs from nanostructured biomimetic drug-loaded cements is promising for future therapies aiming to combine bone regeneration and anticancer local therapy.

Effect of strontium on transcription factors identified by transcriptome analyses of bovine ruminal epithelial cells.

BACKGROUND: Strontium (Sr) has similar physicochemical properties as calcium (Ca) and is often used to evaluate the absorption of this mineral. Because the major route of Ca absorption in the bovine occurs in the rumen, it is essential to understand whether Sr impacts the ruminal epithelial cells and to what extent. RESULTS: In the present study, RNA sequencing and assembled transcriptome assembly were used to identify transcription factors (TFs), screening and bioinformatics analysis in bovine ruminal epithelial cells treated with Sr. A total of 1405 TFs were identified and classified into 64 families based on an alignment of conserved domains. A total of 174 differently expressed TFs (DE-TFs) were increased and 52 DE-TFs were decreased; the biological process-epithelial cell differentiation was inhibited according to the GSEA-GO analysis of TFs; The GO analysis of DE-TFs was enriched in the DNA binding. Protein-protein interaction network (PPI) found 12 hubs, including SMAD4, SMAD2, SMAD3, SP1, GATA2, NR3C1, PPARG, FOXO1, MEF2A, NCOA2, LEF1, and ETS1, which verified genes expression levels by real-time PCR. CONCLUSIONS: In this study, SMAD2, PPARG, LEF1, ETS1, GATA2, MEF2A, and NCOA2 are potential candidates that could be targeted by Sr to mediate cell proliferation and differentiation, as well as lipid metabolism. Hence, these results enhance the comprehension of Sr in the regulation of transcription factors and provide new insight into the study of Sr biological function in ruminant animals.

A Multifunctional Metal-Phenolic Nanocoating on Bone Implants for Enhanced Osseointegration via Early Immunomodulation.

Surface modification is an important approach to improve osseointegration of the endosseous implants, however it is still desirable to develop a facile yet efficient coating strategy. Herein, a metal-phenolic network (MPN) is proposed as a multifunctional nanocoating on titanium (Ti) implants for enhanced osseointegration through early immunomodulation. With tannic acid (TA) and Sr2+ self-assembled on Ti substrates, the MPN coatings provided a bioactive interface, which can facilitate the initial adhesion and recruitment of bone marrow mesenchymal stem cells (BMSCs) and polarize macrophage toward M2 phenotype. Furthermore, the TA-Sr coatings accelerated the osteogenic differentiation of BMSCs. In vivo evaluations further confirmed the enhanced osseointegration of TA-Sr modified implants via generating a favorable osteoimmune microenvironment. In general, these results suggest that TA-Sr MPN nanocoating is a promising strategy for achieving better and faster osseointegration of bone implants, which can be easily utilized in future clinical applications.

Effect of strontium fluoride on mechanical and remineralization properties of enamel: An in-vitro study on a modified orthodontic adhesive.

OBJECTIVES: Evaluate the ability of strontium fluoride on bond strength and enamel integrity after incorporation within orthodontic adhesive system as a delivery vehicle. METHODS: Experimental orthodontic adhesive system Transbond™ XT were modified with 1% Sr2+, 0.5% SrF2, 1% strontium, 0.5% Sr2+, 1% F-, 0.5% F-, and no additions were control. Mixing of formulation was monitored using Fourier transform infrared spectroscopy. Small-molecule drug-discovery suite was used to gain insights into Sr2+, F-, and SrF2 binding. Shear bond testing was performed after 6-months of ageing. Enamel blocks were cut, and STEM pictures were recorded. Specimens were indented to evaluate elastic modulus. Raman microscope was used to collect Raman spectra and inspected using a scanning electron microscope. Crystal structural analysis was performed using X-ray diffraction. Effect of material on cellular proliferation was determined. Confocal was performed to evaluate the effect of formulation on biofilms. RESULTS: FTIR of modified adhesives depicted peak changes within range due to various functional groups existing within samples. TEM represented structurally optimized hexagonal unit-cell of hydroxyapatite. Mean shear bond strength is recorded highest for Transbond XT with 1% SrF2. Dead bacterial percentage appeared higher in 0.5% SrF2 and 1% F- specimens. Crystal lengths showed an increase in 0.5% and 1% SrF2 specimens. Phase contrast within TEM images showed a union of 0.5% SrF2 crystal with enamel crystal with higher elastic modulus and highly mineralized crystalline hydroxyapatite. Intensity of ν1 PO43- and ν1 CO32- along with carbonate - / ν1PO43- ratio displayed good association with strontium fluoride. The formulation showed acceptable cell biocompatibility (p < 0.353). All specimens displayed characteristic diffraction maxima of different apatite angles within XRD. SIGNIFICANCE: Experimental results suggested good biocompatibility, adequate mechanical strength, and far-ranging crystallization ability. This would provide a new strategy to overcome the two major challenges of fixed orthodontics, biofilm growth, and demineralization of enamel.

Remodeling Microenvironment for Implant-Associated Osteomyelitis by Dual Metal Peroxide.

Implant-associated osteomyelitis (IAOM) is characterized by bone infection and destruction; current therapy of antibiotic treatment and surgical debridement often results in drug resistance and bone defect. It is challenging to develop an antibiotic-free bactericidal and osteogenic-enhanced strategy for IAOM. Herein, an IAOM-tailored antibacterial and osteoinductive composite of copper (Cu)-strontium (Sr) peroxide nanoparticles (CSp NPs), encapsulated in polyethylene glycol diacrylate (PEGDA) (CSp@PEGDA), is designed. The dual functional CSp NPs display hydrogen peroxide (H2O2) self-supplying and Fenton catalytic Cu2+ ions' release, generating plenty of hydroxyl radical (•OH) in a pH-responsive manner for bacterial killing, while the released Sr2+ promotes the in vitro osteogenicity regarding cell proliferation, alkaline phosphatase activity, extracellular matrix calcification, and osteo-associated genes expression. The integration of Cu2+ and Sr2+ in CSp NPs together with the coated PEGDA hydrogel ensures the stable and sustainable ion release during short- and long-term periods. Benefitted from the injectablity and photo-crosslink ability, CSp@PEGDA is able to thoroughly fill the infectious site and gelate in situ for bacterial elimination and bone regeneration, which is verified through in vivo evaluation using a clinical-simulating IAOM mouse model. These favorable abilities of CSp@PEGDA precisely meet the multiple therapeutic needs and pave a promising way for implant-associated osteomyelitis treatment.

A nontoxic strontium nanoparticle that holds the potential to act upon osteocompetent cells: An in vitro and in vivo characterization.

Estrogen deficiency, long-term immobilization, and/or aging are commonly related to bone mass loss, thus increasing the risk of fractures. One option for bone replacement in injuries caused by either traumas or pathologies is the use of orthopedic cement based on polymethylmethacrylate (PMMA). Nevertheless, its reduced bioactivity may induce long-term detachment from the host tissue, resulting in the failure of the implant. In view of this problem, we developed an alternative PMMA-based porous cement (pPMMA) that favors cell invasion and improves osteointegration with better biocompatibility. The cement composition was changed by adding bioactive strontium-nanoparticles that mimic the structure of bone apatite. The nanoparticles were characterized regarding their physical-chemical properties, and their effects on osteoblasts and osteoclast cultures were assessed. Initial in vivo tests were also performed using 16 New Zealand rabbits as animal models, in which the pPMMA-cement containing the strontium nanoparticles were implanted. We showed that the apatite nanoparticles in which 90% of Ca2+ ions were substituted by Sr2+ (NanoSr 90%) upregulated TNAP activity and increased matrix mineralization. Moreover, at the molecular level, NanoSr 90% upregulated the mRNA expression levels of, Sp7, and OCN. Runx2 was increased at both mRNA and protein levels. In parallel, in vivo tests revealed that pPMMA-cement containing NanoSr 90%, upregulated two markers of bone maturation, OCN and BMP2, as well as the formation of apatite minerals after implantation in the femur of rabbits. The overall data support that strontium nanoparticles hold the potential to up-regulate mineralization in osteoblasts when associated with synthetic biomaterials.

Ion-incorporated titanium implants for staged regulation of antibacterial activity and immunoregulation-mediated osteogenesis.

Antibacterial properties and osteogenic activity are considered as two crucial factors for the initial healing and long-term survivability of orthopedic implants. For decades, various drug-loaded implants to enhance biological activities have been investigated extensively. More importantly, to control the drug release timing is equally significant due to the sequential biological processes after implantation. Hence, developing a staged regulation system on the titanium surface is practically significant. Here, we prepared TiO2 nanotubes (TiO2 NTs) on the titanium surface by anodization, followed by the incorporation of zinc (Zn) and strontium (Sr) sequentially through a hydrothermal process. Surface characterization confirmed the successful fabrication of Zn and Sr-incorporated TiO2 NTs (Zn-Sr/TiO2) on the titanium surface. The ion release results exhibited the differential release characteristic of Zn and Sr, which meant the early-stage release of Zn and the long-term release of Sr. It was exactly in accord with  the biological process after implantation, laying the basis of staged regulation after implantation. Zn-Sr/TiO2 showed favorable anti-early infection properties both in vitro and in vivo. Its inhibition effect on bacterial biofilm formation was attributed to the resistance against bacteria's initial adhesion and the killing effect on planktonic bacteria. Additionally, the release of Sr could alleviate infection-induced damage via immunoregulation. The biocompatibility and osteogenic activity mediated by M2 macrophage activation were confirmed with in vitro and in vivo studies. Therefore, it exhibited great potential in staged regulation for antibacterial activity in the early stage and the M2 activation-mediated osteogenic activity in the late stage. The staged regulation process was based on the differential release of Zn and Sr to achieve the early antibacterial effect and the long-term immune-induced osteogenic activity, to prevent implant-related infection and achieve better osseointegration. These two kinds of ions played their roles synergistically and complement mutually. This work is expected to provide an innovative idea for realizing sequential regulation after implantation.

Strontium-Doped Hydroxyapatite Coating Improves Osteo/Angiogenesis for Ameliorative Graft-Bone Integration via the Macrophage-Derived Cytokines-Mediated Integrin Signal Pathway.

Polyethylene terephthalate (PET) artificial ligaments, renowned for their superior mechanical properties, have been extensively adopted in anterior cruciate ligament (ACL) reconstruction surgeries. However, the inherent bio-inertness of PET introduces formidable barriers to graft-bone integration, a critical aspect of rehabilitation. Previous interventions, ranging from surface roughening to chemical modifications, have aimed to address this challenge; however, consistently effective techniques for inducing graft-bone integration remain scarce. Our study employed advanced surface-coating methodologies to introduce strontium-doped hydroxyapatite (SrHA) onto PET ligaments. Detailed scanning electron microscopy (SEM) examinations revealed a uniform and integrative coating of SrHA on PET fibers. Furthermore, spectroscopic analysis confirmed the steady release of strontium ions from the coated surface under physiological conditions. In-depth cellular studies proved that extracellular strontium emanating from SrHA-coated PET (PET@SrHA) ligaments actively steers the M2 macrophage polarization. Additionally, macrophages (Mφs) manifested a heightened secretion of prohealing cytokines when exposed to PET@SrHA. Subsequent investigations showed that these cytokines acted as mediators, activating integrin signaling pathways among macrophages, vascular endothelial cells, and osteoblasts. As a direct consequence, an increased rate of angiogenesis and osteogenic differentiation was observed, vital for graft-bone integration following ACL reconstruction with PET@SrHA ligaments. From a biochemical standpoint, our results pinpoint strontium ions as influential immunomodulators, sculpting the graft-bone interface's immune environment. This insight presents the SrHA-coating technique as a viable therapeutic strategy, holding sound promise for improving angiogenesis and osseointegration outcomes during ACL reconstruction using PET-based grafts.

Janus Membrane with Intrafibrillarly Strontium-Apatite-Mineralized Collagen for Guided Bone Regeneration.

Commercial collagen membranes face difficulty in guided bone regeneration (GBR) due to the absence of hierarchical structural design, effective interface management, and diverse bioactivity. Herein, a Janus membrane called SrJM is developed that consists of a porous collagen face to enhance osteogenic function and a dense face to maintain barrier function. Specifically, biomimetic intrafibrillar mineralization of collagen with strontium apatite is realized by liquid precursors of amorphous strontium phosphate. Polycaprolactone methacryloyl is further integrated on one side of the collagen as a dense face, which endows SrJM with mechanical support and a prolonged lifespan. In vitro experiments demonstrate that the dense face of SrJM acts as a strong barrier against fibroblasts, while the porous face significantly promotes cell adhesion and osteogenic differentiation through activation of calcium-sensitive receptor/integrin/Wnt signaling pathways. Meanwhile, SrJM effectively enhances osteogenesis and angiogenesis by recruiting stem cells and modulating osteoimmune response, thus creating an ideal microenvironment for bone regeneration. In vivo studies verify that the bone defect region guided by SrJM is completely repaired by newly formed vascularized bone. Overall, the outstanding performance of SrJM supports its ongoing development as a multifunctional GBR membrane, and this study provides a versatile strategy of fabricating collagen-based biomaterials for hard tissue regeneration.