Search

Background: Amphotericin is admixed to Polymethylmethacrylic (PMMA) spacers for fungal periprosthetic joint infections (PJI) during two-stage exchanges. We aimed to analyse the mechanical properties of PMMA cement with admixed Amphotericin B., Materials and Methods: We tested Amphotericin in PMMA cement mechanically, its elution properties in vitro and present two cases of fungal PJI treated with Amphotericin B powder in Copal cement in vivo., Results: Sterile Amphotericin B is not available as a pure substance but only as powder for infusions. PMMA mixed with such pharmaceutical Amphotericin B formulations colored the cement orange. Compression strength was slightly decreased, bending and impact strength significantly decreased whereas bending modulus was increased. Drug elution was high within the first 24 h and decreased over time until day 5. Amphotericin B in combination with Copal was successfully used in two cases with Candida ssp., Infections: No negative side effects, especially no nephrotoxic effects, were observed. Sterile Amphotericin B powder for preparing an infusion solution contains only small amounts of pure drug. In vivo polymicrobial Candida-infections with bacterial co-infection were successfully treated using the combination of Copal cements with added Amphotericin B without systemic nephrotoxic impact., Conclusions: The addition of Amphotericin B to PMMA cement affects the cement's properties in vitro whereas in vivo the combination with Copal is clinically successful in treating complex cases of fungal PJI., Level of Evidence: Level IV., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Written informed consent has been obtained from the patients to publish this paper. Competing interests: F.F., M.M. and J.S. declare they have no competing interests. M.C. received a grant from Heraeus Medical unrelated to this research. B.K., R.S. and K.-D.K. are employed by Heraeus Medical., (© 2025. The Author(s).)

The objective of this study is to fabricate and develop hydroxypropyl methylcellulose (HPMC) hydrogel (HG)-based composite bone cements with incorporation of hydroxyapatite (HA), beta-tricalcium phosphate (β-TCP), and with/without polymethylmethacrylate (PMMA) for vertebroplasty. For animal study, twenty female Wister rats (250-300 g, 12 weeks of age) were divided into four groups including a two non-ovariectomy (NOVX) groups and two ovariectomy (OVX)-induced osteoporosis groups. Two prepared biocomposites including HG/β-TCP/HA and HG/β-TCP/HA/PMMA were injected into the tibial defects of both OVX and NOVX rats for evaluating in vivo osteogenesis after 12 weeks. Micro-computed tomography and histological analysis using hematoxylin and eosin (H&E) and Masson's trichrome stains of the two composite cements implanted into the tibial defects of OVX and NOVX rats revealed enhanced bone regeneration potential. However, no statistically significant differences were noted among the groups based on new bone formation, demonstrating that the injected composite cements showed similar osteogenesis effects in both OVX and NOVX rats. These findings suggest that the newly developed composite bone cement composed of HG, β-TCP, HA and/or PMMA may be a promising and professional tool for treating osteoporotic and non-osteoporotic vertebral fractures., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests. Ethics approval: This study was conformed to the ethical guidelines of the World Medical Association Declaration of Helsinki. The animal experiment study was reviewed and approved by the Animal Ethics Committee of Soonchunhyang University Bucheon Hospital, Bucheon, South Korea (Approval no. SCHBCA2021-01)., (© 2024. The Author(s).)

Bone cement is commonly utilized to secure prosthetic joints in the body because of its robust fixation, stability, biocompatibility, and immediate load-bearing capability. However, issues such as loosening, leakage, and insufficient bioactivity can lead to its failure. Therefore, improving its mechanical, physical, and biological properties is crucial for enhancing its efficiency. This study examines the impact of incorporating four different nanomaterials-Titanium Dioxide (TiO 2 ), Magnesium Oxide (MgO), Calcium Phosphate (Ca 3 (PO 4 ) 2 ), and Alumina Oxide (Al 2 O 3 )-into bone cement on its mechanical, physical, and biological properties. TiO 2 and Al 2 O 3 nanoparticles are selected to enhance the compression strength of bone cement, thereby preventing loosening. Magnesium Oxide (MgO) and Ca 3 (PO 4 ) 2 nanoparticles are chosen to improve cell adhesion and reducing the risk of cement leakage. Five specimens were prepared: the first with 100% pure bone cement powder, the second with 98% pure bone cement powder and modified with 2% MgO and TiO2, and the remaining three with 95% pure bone cement powder and modified with 5% varying ratios of MgO, TiO 2 , Ca 3 (PO 4 ) 2 , and Al 2 O 3 . Compression, tensile, hardness, and bending strengths were assessed to determine improvements in mechanical properties. Setting temperature, porosity, and degradation were measured to evaluate physical properties. Cell adhesion and toxicity tests were conducted to examine the surface structure and biological properties. The results demonstrated that the modified specimens increased compression strength by 8.14%, tensile strength by 3.4%, and bending strength by 4.96%. Porosity, degradation, and setting temperature in modified specimens increased by 3.24%, 0.64%, and 5.17% respectively pure bone cement values. Cell adhesion in modified bone cement specimens showed normal attachment when scanned with FE-SEM. All of the tested modified specimens showed no toxicity, except for specimens with 2% Al 2 O 3 that showed 25% toxicity which could be averted by employing antibiotics., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

This study aimed to evaluate the effects of nanoparticulate CaCO 3 (NPCC) on the biological properties of calcium silicate-based cements (CSCs), including their cytotoxicity, in vitro osteogenic activity, and interactions with rat femur tissue. The average size of NPCC was 90.3±26.0 nm. Cytotoxicity and osteogenic activity assays were performed using mouse bone marrow mesenchymal stem cells (BMSCs). BMSCs exposed to the eluents from CSC alone and CSC containing 2.5% NPCC (CSC-NPCC (2.5%)) for 24 h showed decreased cell viability at an eluent concentration of 75%. In contrast, CSC-NPCCs (5%, 10%, and 20%) did not affect cell viability. Regarding osteogenic activity, CSC-NPCCs (5%, 10%, 20%) enhanced the expression of osteogenic genes, including runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), type I collagen (COL-1), and osteocalcin (OCN). Additionally, mineralization in cell cultures was enhanced by CSC-NPCC, indicating that NPCC promoted the osteogenic activity of CSCs. In rat femurs, NPCC accelerates CSC resorption and stimulates bone regeneration at the implantation site. CSC alone occupied 22.2%±3.25% of the total femoral area at the implantation site, whereas CSC-NPCC (20%) occupied only 4%. These histological findings suggest that CSC-NPCC has potential as a biodegradable bone cement for use in bone defect areas that require regeneration., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: This study was approved by the Institutional Animal Care and Use Committee (IACUC) of Seoul National University (SNU-240220-3). All the ethical standards for animal research were followed and implemented in accordance with international and institutional guidelines, particularly the ARRIVE guidelines., (© 2024. The Author(s).)

Very high heat is generated during the polymerization of poly (methyl methacrylate) (PMMA) bone cement, which is used for implant fixation in orthopedic surgery. As such, it has been suggested that irrigating the bone cement layer in the surgical site with a saline solution is a way of cooling the layer. In this study, we aimed to determine the influence of irrigation with a saline solution on the flexural strength and the microstructure of the test specimens of two PMMA bone cement brands: Simplex P and FIX 1. Specimens were assigned to three groups: (1) irrigation with normal saline solution at 25 °C (RS group), (2) irrigation with cold saline at 4 °C (CS group), and (3) no irrigation (control group). For each of the groups, the specimens were tested after various times of aging in phosphate-buffered saline solution (PBS) at 37 °C for 1 h, 24 h, and 7 days. Flexural strength was measured following ISO 5833 protocol, and the surface microstructure was determined using scanning electron microscopy (SEM). The flexural strength results showed that for each of the cement brands, the difference between the groups was not significant, except for Simplex P specimens aged for 24 h, for which flexural strength of the RS and CS group specimens was lower than in the control group. The microstructural features of the surface of the specimens were similar across groups. These findings suggest that in a cemented arthroplasty, irrigation of the bone cement for the purpose of cooling it must only be used after very careful consideration., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Decellularized extracellular matrix (dECM) hydrogels are engineered constructs that are widely-used in the field of regenerative medicine. However, the development of ECM-based hydrogels for bone tissue engineering requires enhancement in its osteogenic properties. For this purpose, we initially employed bone-derived dECM hydrogel (dECM-Hy) in combination with calcium phosphate cement (CPC) paste to improve the biological and structural properties of the dECM hydrogel. A decellularization protocol for bovine bone was developed to prepare dECM-Hy, and the mechanically-tuned dECM/CPC-Hy was built based on both rheological and mechanical characteristics. The dECM/CPC-Hy displayed a double swelling ratio and compressive strength. An interconnected structure with distinct hydroxyapatite crystals was evident in dECM/CPC-Hy. The expression levels of Alp, Runx2 and Ocn genes were upregulated in dECM/CPC-Hy compared to the dECM-Hy. A 14-day follow-up of the rats receiving subcutaneous implanted dECM-Hy, dECM/CPC-Hy and mesenchymal stem cells (MSCs)-embedded (dECM/CPC/MSCs-Hy) showed no toxicity, inflammatory factor expression or pathological changes. Radiography and computed tomography (CT) of the calvarial defects revealed new bone formation and elevated number of osteoblasts-osteocytes and osteons in dECM/CPC-Hy and dECM/CPC/MSCs-Hy compared to the control groups. These findings indicate that the dECM/CPC-Hy has substantial potential for bone tissue engineering., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Although bone morphogenetic protein-2 (BMP-2) possesses potent osteoinductivity, there have been some concerns on the safety of BMP-2 and BMP-2-incorporated bone substitutes used for bone formation. On the other hand, BMP-2-loaded calcium phosphate cement (BMP-2@CPC) has been developed and used for bone regeneration in oral implantology. Therefore, this study aims to investigate this product's biocompatibility and clinical safety after being used in maxillofacial surgery., Materials and Methods: A rat model was employed to assess the osteoinduction and biocompatibility of BMP-2@CPC. Further, a retrospective investigation was carried out: 110 patients who received BMP-2@CPC treatment after their maxillofacial surgery were recruited to describe relative adverse events., Results: In vivo, BMP-2@CPC showed a significantly higher mean bone volume density and osteoblasts volume density (15 ± 2% and 3 ± 1%)than those of the CPC group (p < 0.05) after being implanted in the dorsal area of rats. Regarding biocompatibility, the mean fibrous tissue volume density was significantly lower in the BMP-2@CPC group (20 ± 5% compared to 31 ± 6%, p = 0.026). The retrospective clinical study showed that only five mild/moderate adverse events were identified in four patients based on the medical records of 110 patients, including swelling, bony mass, and wound dehiscence. This adverse event occurrence was not affected by gender, age, the dose of filled materials, and operations in the study (p > 0.05)., Conclusions: BMP-2-loaded CPC has osteoinductivity and more promising biocompatibility than pure CPC. However, its degradation is slower than CPC. The safety of BMP-2-loaded CPC with 0.5 or 1 mg BMP-2 is promising in oral maxillofacial surgery., Clinical Implications: This study confirmed the promising safety of this BMP-2 incorporated CPC used in dental clinical practice, which can promote its reassuring application for dental implant placement in bone insufficient areas., (© 2024. The Author(s).)

Background: Prosthetic joint infection is a serious complication that can arise after total joint replacement surgery. When bacteria colonise an orthopaedic implant, they form biofilms that protect them from their environment, making them difficult to remove. Treatment is further complicated by a global rise of antimicrobial resistance. These protective mechanisms make treatment of prosthetic joint infection increasingly complex. Non-contact induction heating is an upcoming technology that uses heat to eradicate bacteria that are present on the surface of metallic implants. This study aims to provide insight into the feasibility of using non-contact induction heating on metallic implants that are in direct contact with other biomaterials, such as coatings composed of hydroxyapatite and bone cement composed of poly (methyl methacrylate) (PMMA)., Methods: Characterisation of hydroxyapatite coatings and adhesion strength tests were conducted according to standards set by the International Organisation for Standardisation (ISO 13779-2). The fixation strength of acrylic bone cement was tested according to an adapted method from ISO., Results: It was found that non-contact induction heating did not significantly affect the adhesion strength of hydroxyapatite coatings. In contrast to hydroxyapatite coatings, acrylic bone cement softened temporarily as the temperature exceeded the glass transition temperature (83.38 ± 10.88°C). However, the induction heating temperature had no significant effect on the fixation strength after the cement was allowed to cool down., Conclusion: This study shows the feasibility of using non-contact induction heating up to 80°C when bone cement or ceramic coatings are present in contact with infected metallic implants., Competing Interests: Competing interests: This article was written in collaboration with CAM Bioceramics B.V., situated in Leiden, The Netherlands. CAM Bioceramics B.V. is a contract development and manufacturing organisation of Orthobiologic Calcium Phosphates., (Copyright: © 2024 Kamphof R et al.)

The clinical need for bone adhesives as an alternative to osteosynthesis is evident. However, this is a challenging problem due to the moist environment in surgical sites with bone surfaces covered with blood and biomolecules like lipids or proteins. A nanoparticle-loaded hydrogel that is based on a freeze-dried powder of silica-coated calcium phosphate/carboxymethyl cellulose nanoparticles (CaP/CMC/SiO 2 ) and an aqueous solution of sodium alginate (2 wt%) was developed and optimized with respect to the gluing ability in air and in water. The final paste was crosslinked within about one minute by calcium ions released from the calcium phosphate nanoparticles and contained about 20 wt% nanoparticles and 80 wt% water. The mechanical properties of the hydrogel were determined by extensive rheological tests. The thixotropic pasty hydrogel can be applied with a syringe. The adhesion strength was about 84 kPa between moist bone fragments in air. The hydrogel kept fragments of cortical bone well connected for >3 months during complete submersion in water. Besides water, the material consists only of biocompatible and biodegradable components (calcium phosphate, CMC, alginate). It carries only a very low dose of these materials into the bone site (mainly calcium phosphate nanoparticles). In-vitro cell culture with hMSCs that differentiated to osteoblasts confirmed a good biocompatibility of the bone adhesive formulation., (© 2024. The Author(s).)

The development of synthetic bone substitutes that equal or exceed the efficacy of autologous graft remains challenging. In this study, a rat calvarial defect model was used as a reference to investigate the influence of composition and architecture of 3D-printed cement, with or without bioactives, on tissue regeneration. Printable cement pastes were formulated by combining hyaluronic acid and cement precursors. Cementitious scaffolds were printed with 3 different patterns. After 7 weeks of implantation with or without bone marrow, multiparametric qualitative and quantitative assessments were performed using µCT, SEM, and histology. None of the set-up strategies was as efficient as autologous cancellous bone graft to repair calvarial defects. Nonetheless, the presence of scaffold improved the skull vault closure, particularly when the scaffold was soaked in total bone marrow before implantation. No significant effect of scaffold macro-architecture was observed on tissue mineralization. Magnesium phosphate-based scaffolds (MgP) seemed to induce higher bone formation than their calcium-phosphate-based counterparts. They also displayed a quicker biodegradation and sparse remaining material was found after 7 weeks of implantation. Although further improvements are required to reach clinical settings, this study demonstrated the potential of organo-mineral cements for bone regeneration and highlighted the peculiar properties of MgP-based cements., (© 2024. The Author(s).)

Bone cement based on magnesium phosphate has extremely favorable properties for its application as a bioactive bone substitute. However, further improvement is still expected due to difficult injectability and high brittleness. This paper reported the preparation of novel biocomposite cement, classified as dual-setting, obtained through ceramic hydration reaction and polymer cross-linking. Cement was composed of magnesium potassium phosphate and sodium alginate cross-linked with calcium carbonate and gluconolactone. The properties of the obtained composite material and the influence of sodium alginate modification on cement reaction were investigated. Our results indicated that proposed cements have several advantages compared to ceramic cement, like shortened curing time, diverse microstructure, increased wettability and biodegradability and improved paste cohesion and injectability. The magnesium phosphate cement with 1.50% sodium alginate obtained using a powder-to-liquid ratio of 2.5 g/mL and cross-linking ratio 90/120 of GDL/CC showed the most favorable properties, with no adverse effect on mechanical strength and osteoblasts cytocompatibility. Overall, our research suggested that this novel cement might have promising medical application prospects, especially in minimally invasive procedures., (© 2024. The Author(s).)

It's imperative to create a more ideal biological scaffold for bone defect repair. Calcium phosphate bone cements (CPC) could be used as a scaffold. Some ingredients and osteogenic factors could be added to improve its poor mechanical properties and biological activity. As a macromolecule extracted from traditional Chinese medicine, Hedysarum polysaccharides (HPS) would significantly promote the osteogenic activity of bone biomaterials. Zirconium oxide and starch were added to the solid phase and citric acid was added to the liquid phase to optimize CPC. HPS was loaded onto the scaffold as an osteogenic factor, and the prepared CPS + HPS was characterized. Further, the cytocompatibility of CPS + HPS was assessed according to activity, differentiation, and calcification in neonatal rat calvarial osteoblasts, and the biosafety of CPS + HPS was evaluated according to acute toxicity, pyrogen, sensitization, and hemolysis. The success of CPS + HPS in repairing bone defects was evaluated by using a rabbit femur implantation experiment. After optimization, CPS-20-CA-5 containing 10% starch and 5% citric acid displayed the highest mechanical strength of 28.96 ± 0.03 MPa. HPS-50 was demonstrated to exert the best osteogenic effect. The combination of CPS + HPS achieved HPS-loaded CPC. Material characterization, cytocompatibility, biosafety, and femoral implantation experiments indicated that CPS + HPS possessed better pressure resistance and improved osteogenic ability in bone defect repair.CPS + HPS demonstrated effective pressure resistance and superior osteogenic ability, which may be of great significance for bone defects and bone tissue engineering to promote bone regeneration and repair., (© 2024. The Author(s).)

Background: Polymethylmethacrylate (PMMA) bone cement is used in orthopedics and dentistry to get primary fixation to bone but doesn't provide a mechanically and biologically stable bone interface. Therefore, there was a great demand to improve the properties of the PMMA bone cement to reduce its clinical usage limitations and enhance its success rate. Recent studies demonstrated that the addition of halloysite nanotubes (HNTs) to a polymeric-based material can improve its mechanical and thermal characteristics., Objectives: The purpose of the study is to assess the compressive strength, flexural strength, maximum temperature, and setting time of traditional PMMA bone cements that have been manually blended with 7 wt% HNT fillers., Methods: PMMA powder and monomer liquid were combined to create the control group, the reinforced group was made by mixing the PMMA powder with 7 wt% HNT fillers before liquid mixing. Chemical characterization of the HNT fillers was employed by X-ray fluorescence (XRF). The morphological examination of the cements was done using a scanning electron microscope (SEM). Analytical measurements were made for the compressive strength, flexural strength, maximum temperature, and setting time. Utilizing independent sample t-tests, the data was statistically assessed to compare mean values (p < 0.05)., Results: The findings demonstrated that the novel reinforced PMMA-based bone cement with 7 wt% HNT fillers showed higher mean compressive strength values (93 MPa) and higher flexural strength (72 MPa). and lower maximum temperature values (34.8 °C) than the conventional PMMA bone cement control group, which was (76 MPa), (51 MPa), and (40 °C), respectively (P < 0.05). While there was no significant difference in the setting time between the control and the modified groups., Conclusion: The novel PMMA-based bone cement with the addition of 7 wt% HNTs can effectively be used in orthopedic and dental applications, as they have the potential to enhance the compressive and flexural strength and reduce the maximum temperatures., (© 2024. The Author(s).)

Bone cement is widely used in clinical with optimistic filling and mechanical properties. However, the setting time of bone cement is difficult to accurately control, and the existing bone cements exhibit limited therapeutic functionalities. In response to these challenges, we designed and synthesized Nd-doped whitlockite (Nd-WH), endowing bone cement with photothermal-responsive and fluorescence imaging capabilities. The doping amount and photothermal properties of Nd-doped whitlockite were studied, and the composite bone cement was prepared. The results showed that the setting time of bone cement could be regulated by near infrared irradiation, and the multiple functions of promoting osteogenic differentiation, antibacterial and anti-tumor could be realized by adjusting the power and irradiation time of near infrared. By incorporating Nd-doped whitlockite and bone cement, we developed an all-in-one strategy to achieve setting time control, enhanced osteogenic ability, tumor cell clearance, bacterial clearance, and bone tissue regeneration. The optimized physical and mechanical properties of composite bone cement ensure adaptability and plasticity. In vitro and in vivo experiments validated the effectiveness of this bone cement platform for bone repair, tumor cell clearance and bacterial clearance. The universal methods to regulate the setting time and function of bone cement by photothermal effect has potential in orthopedic surgery and is expected to be a breakthrough in the field of bone defect repair. Further research and clinical validation are needed to ensure its safety, efficacy and sustainability. STATEMENT OF SIGNIFICANCE: Bone cement is a valuable clinical material. However, the setting time of bone cement is difficult to control, and the therapeutic function of existing bone cement is limited. Various studies have shown that the bone repair capacity of bone cements can be enhanced by synergistic stimulatory effects in vivo and ex vivo. Unfortunately, most of the existing photothermal conversion materials are non-degradable and poorly biocompatible. This study provides a bone-like photothermal conversion material with photothermal response and fluorescence imaging properties, and constructed a platform for integrated regulation of the setting time of bone cement and diversification of its functions. Therefore, it helps to design multi-functional bone repair materials that are more convenient and effective in clinical operation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Active artificial bone substitutes are crucial in bone repair and reconstruction. Calcium phosphate bone cement (CPC) is known for its biocompatibility, degradability, and ability to fill various shaped bone defects. However, its low osteoinductive capacity limits bone regeneration applications. Effectively integrating osteoinductive magnesium ions with CPC remains a challenge. Herein, we developed magnesium malate-modified CPC (MCPC). Incorporating 5% magnesium malate significantly enhances the compressive strength of CPC to (6.18 ± 0.49) MPa, reduces setting time and improves disintegration resistance. In vitro, MCPC steadily releases magnesium ions, promoting the proliferation of MC3T3-E1 cells without causing significant apoptosis, proving its biocompatibility. Molecularly, magnesium malate prompts macrophages to release prostaglandin E2 (PGE2) and synergistically stimulates dorsal root ganglion (DRG) neurons to synthesize and release calcitonin gene-related peptide (CGRP). The CGRP released by DRG neurons enhances the expression of the key osteogenic transcription factor Runt-related transcription factor-2 (RUNX2) in MC3T3-E1 cells, promoting osteogenesis. In vivo experiments using minipig vertebral bone defect model showed MCPC significantly increases the bone volume fraction, bone density, new bone formation, and proportion of mature bone in the defect area compared to CPC. Additionally, MCPC group exhibited significantly higher levels of osteogenesis and angiogenesis markers compared to CPC group, with no inflammation or necrosis observed in the hearts, livers, or kidneys, indicating its good biocompatibility. In conclusion, MCPC participates in the repair of bone defects in the complex post-fracture microenvironment through interactions among macrophages, DRG neurons, and osteoblasts. This demonstrates its significant potential for clinical application in bone defect repair., (© 2024. The Author(s).)

Calcium phosphate cements, primarily brushite cements, require the addition of setting retarders to ensure adequate processing time and processability. So far, citric acid has been the primary setting retarder used in this context. Due to the poor biocompatibility, it is crucial to explore alternative options for better processing. In recent years, the setting retarder phytic acid (IP6) has been increasingly investigated. This study investigates the biological behaviour of calcium phosphate cements with varying concentrations of IP6, in addition to their physical properties. Therefore cytocompatibility in vitro testing was performed using osteoblastic (MG-63) and osteoclastic (RAW 264.7 differentiated with RANKL) cells. We could demonstrate that the physical properties like the compressive strength of specimens formed with IP6 (brushite&#95;IP6&#95;5 = 11.2 MPa) were improved compared to the reference (brushite = 9.8 MPa). In osteoblast and osteoclast assays, IP6 exhibited significantly better cytocompatibility in terms of cell activity and cell number for brushite cements up to 11 times compared to the brushite reference. In contrast, the calcium-deficient hydroxyapatite (CDHA) cements produced similar results for IP6 (CDHA&#95;IP6&#95;0.25 = 27.0 MPa) when compared to their reference (CDHA = 21.2 MPa). Interestingly, lower doses of IP6 were found to be more effective than higher doses with up to 3 times higher. Additionally, IP6 significantly increased degradation in both passive and active resorption. For these reasons, IP6 is emerging as a strong new competitor to established setting retarders such as citric acid. These cements have potential applications in bone augmentation, the stabilisation of non-load bearing fractures (craniofacial), or the cementation of metal implants., (© 2024. The Author(s).)

Introduction: Lumbar interbody fusion is widely employed for both acute and chronic spinal diseases interventions. However, large incision created during interbody cage implantation may adversely impair spinal tissue and influence postoperative recovery. The aim of this study was to design a shape memory interbody fusion device suitable for small incision implantation., Methods: In this study, we designed and fabricated an intervertebral fusion cage that utilizes near-infrared (NIR) light-responsive shape memory characteristics. This cage was composed of bisphenol A diglycidyl ether, polyether amine D-230, decylamine and iron oxide nanoparticles. A self-hardening calcium phosphate-starch cement (CSC) was injected internally through the injection channel of the cage for healing outcome improvement., Results: The size of the interbody cage is reduced from 22 mm to 8.8 mm to minimize the incision size. Subsequent NIR light irradiation prompted a swift recovery of the cage shape within 5 min at the lesion site. The biocompatibility of the shape memory composite was validated through in vitro MC3T3-E1 cell (osteoblast-like cells) adhesion and proliferation assays and subcutaneous implantation experiments in rats. CSC was injected into the cage, and the relevant results revealed that CSC is uniformly dispersed within the internal space, along with the cage compressive strength increasing from 12 to 20 MPa., Conclusion: The results from this study thus demonstrated that this integrated approach of using a minimally invasive NIR shape memory spinal fusion cage with CSC has potential for lumbar interbody fusion., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Liu et al.)

Antibiotic-loaded calcium phosphate cement (CPC) has emerged as a promising biomaterial for drug delivery in orthopedics. However, there are problems such as the burst release of antibiotics, low cumulative release ratio, inappropriate release cycle, inferior mechanical strength, and poor anti-collapse properties. In this research, montmorillonite-gentamicin (MMT-GS) was fabricated by solution intercalation method and served as the drug release pathways in CPC to avoid burst release of GS, achieving promoted cumulative release ratios and a release cycle matched the time of inflammatory response. The results indicated that the highest cumulative release ratio and release concentration of GS in CPC/MMT-GS was 94.1 ± 2.8 % and 1183.05 μg/mL, and the release cycle was up to 504 h. In addition, the hierarchical GS delivery system was divided into three stages, and the kinetics followed the Korsmeyer-Peppas model, the zero-order model, and the diffusion-dissolution model, respectively. Meanwhile, the compressive strength of CPC/MMT-GS was up to 51.33 ± 3.62 MPa. Antibacterial results demonstrated that CPC/MMT-GS exhibited excellent in vitro long-lasting antibacterial properties to E. coli and S. aureus. Furthermore, CPC/MMT-GS promoted osteoblast proliferation and exhibited excellent in vivo histocompatibility. Therefore, CPC/MMT-GS has favorable application prospects in the treatment of bone defects with bacterial infections and inflammatory reactions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Vertebral compression fractures are often treated with vertebroplasty, and filling the injured vertebrae with bone cement is a key part of vertebroplasty. This meta-analysis was performed to compare the clinical efficacy and safety of mineralized collagen-polymethylmethacrylate (MC-PMMA) and polymethylmethacrylate (PMMA) bone cement in the treatment of vertebral compression fractures by vertebroplasty., Methods: A computerized search of the published literature on mineralized collagen-polymethylmethacrylate and polymethylmethacrylate bone cement in the treatment of vertebral compression fractures was conducted in the China National Knowledge Infrastructure (CNKI), Wanfang database, PubMed, Embase, and Cochrane Library. The search was carried out from the time the database was created to March 2023 and 2 researchers independently conducted literature searches to retrieve a total of 884 studies, of which 12 were included in this meta-analysis. Cochrane systematic review methods were used to assess the quality of the literature and a meta-analysis was performed using ReviewManager 5.4 software., Results: The results of the present meta-analysis showed that in postoperative adjacent vertebral fractures [OR = 0.25; 95% CI (0.15, 0.41)], postoperative cement leakage [OR = 0.45; 95% CI (0.30, 0.68)], Oswestry Disability Index (ODI) scores in the first 3 days after surgery [OR = -0.22; 95% CI (-0.42, -0.03)], ODI score at 6-12 months postoperatively [OR = -0.65; 95% CI (-0.97, -0.32)], visual analog scale (VAS) score at 6-12 months postoperatively [OR = -0.21; 95% CI (-0.46, 0.04)], and 1-year postoperative CT values [OR = 5.56; 95% CI (3.06, 8.06)], the MC-PMMA bone cement group was superior to the PMMA bone cement group. However, the differences between the two groups were not statistically different in terms of cement filling time, cement filling volume, operation time, intraoperative bleeding, hospitalization time, postoperative (<1 week, 3-6 months) vertebral body posterior convexity Cobb's angle, postoperative (<1 week, 6-12 months) vertebral body anterior margin relative height, postoperative (≤3 days, 1-3 months) pain VAS score and postoperative (1-3 months) ODI score., Conclusions: Compared with PMMA bone cement, the application of MC-PMMA bone cement is advantageous in reducing postoperative complications (adjacent vertebral fracture rate, cement leakage rate), pain relief, and functional recovery in the long-term postoperative period (>6 months), but there is still a need for more high-quality randomized controlled studies to provide more adequate evidence., Competing Interests: The authors declare that they have no conflict of interest., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: The aim of this study was to investigate the effects of adding hexagonal boron nitride at four different concentrations to polymethylmethacrylate (PMMA) bone cement, which is commonly used in orthopedic surgeries, on the mechanical properties and microarchitecture of the bone cement., Materials and Methods: The study included an unaltered control group and groups containing four different concentrations (40 g of bone cement with 0.5 g, 1 g, 1.5 g, 2 g) of hexagonal boron nitride. The samples used for mechanical tests were prepared at 20±2ºC in operating room conditions, using molds in accordance with the test standards. As a result of the tests, the pressure values at which the samples deformed were determined from the load-deformation graphs, and the megapascal (MPa) values at which the samples exhibited strength were calculated., Results: The samples with 0.5 g boron added to the bone cement had significantly increased mechanical strength, particularly in the compression test. In the group where 2 g boron was added, it was noted that, compared to the other groups, the strength pressure decreased and the porosity increased. The porosity did not change particularly in the group where 0.5 g boron was added., Conclusion: Our study results demonstrate that adding hexagonal boron nitride (HBN) to bone cement at a low concentration (0.5 g / 40 g PPMA) significantly increases the mechanical strength in terms of MPa (compression forces) without adversely affecting porosity. However, the incorporation of HBN at higher concentrations increases porosity, thereby compromising the biomechanical properties of the bone cement, as evidenced by the negative impact on compression and four-point bending tests. Boron-based products have gained increased utilization in the medical field, and HBN is emerging as a promising chemical compound, steadily growing in significance.

Background: Injectable bone cement is commonly used in clinical orthopaedics to fill bone defects, treat vertebral compression fractures, and fix joint prostheses during joint replacement surgery. Poly(propylene fumarate) (PPF) has been proposed as a biodegradable and injectable alternative to polymethylmethacrylate (PMMA) bone cement. Recently, there has been considerable interest in two-dimensional (2D) black phosphorus nanomaterials (BPNSs) in the biomedical field due to their excellent photothermal and osteogenic properties. In this study, we investigated the biological and physicochemical qualities of BPNSs mixed with PPF bone cement created through thermal cross-linking., Methods: PPF was prepared through a two-step process, and BPNSs were prepared via a liquid phase stripping method. BP/PPF was subsequently prepared through thermal cross-linking, and its characteristics were thoroughly analysed. The mechanical properties, cytocompatibility, osteogenic performance, degradation performance, photothermal performance, and in vivo toxicity of BP/PPF were evaluated., Results: BP/PPF exhibited low cytotoxicity levels and mechanical properties similar to that of bone, whereas the inclusion of BPNSs promoted preosteoblast adherence, proliferation, and differentiation on the surface of the bone cement. Furthermore, 200 BP/PPF demonstrated superior cytocompatibility and osteogenic effects, leading to the degradation of PPF bone cement and enabling it to possess photothermal properties. When exposed to an 808-nm laser, the temperature of the bone cement increased to 45-55 °C. Furthermore, haematoxylin and eosin-stained sections from the in vivo toxicity test did not display any anomalous tissue changes., Conclusion: BP/PPF exhibited mechanical properties similar to that of bone: outstanding photothermal properties, cytocompatibility, and osteoinductivity. BP/PPF serves as an effective degradable bone cement and holds great potential in the field of bone regeneration., (© 2024. The Author(s).)

Phosphoserine is a ubiquitous molecule found in numerous proteins and, when combined with alpha-tricalcium phosphate (α-TCP) powder, demonstrates the ability to generate an adhesive biomaterial capable of stabilising and repairing bone fractures. Design of Experiments (DoE) approach was able to optimise the composition of phosphoserine-modified calcium phosphate cement (PM-CPC) demonstrating that the liquid:powder ratio (LPR) and quantity of phosphoserine (wt%) significantly influenced the handling, mechanical, and adhesion properties. Subsequently, the DoE optimisation process identified the optimal PM-CPC formulation, exhibiting a compressive strength of 29.2 ± 4.9 MPa and bond/shear strength of 3.6 ± 0.9 MPa after a 24 h setting reaction. Moreover, the optimal PM-CPC composition necessitated a mixing time of 20 s and displayed an initial setting time between 3 and 4 min, thus enabling homogenous mixing and precise delivery within a surgical environment. Notably, the PM-CPC demonstrated a bone-to-bone bond strength of 1.05 ± 0.3 MPa under wet conditions, coupled with a slow degradation rate during the first five days. These findings highlight the ability of PM-CPC to effectively support and stabilise bone fragments during the initial stages of natural bone healing. The developed PM-CPC formulations fulfil the clinical requirements for working and setting times, static mechanical, degradation properties, and injectability, enabling surgeons to stabilise complex bone fractures. This innovative bioinspired adhesive represents a significant advancement in the treatment of challenging bone injuries, offering precise delivery within a surgical environment and the potential to enhance patient outcomes. STATEMENT OF SIGNIFICANCE: This manuscript presents a noteworthy contribution to the field of bone fracture healing and fixation by introducing a novel phosphoserine-modified calcium phosphate cement (PM-CPC) adhesive by incorporating phosphoserine and alpha-TCP. This study demonstrates the fabrication and extensive characterisation of this adhesive biomaterial that holds great promise for stabilising and repairing complex bone fractures. Design of Experiment (DoE) software was used to investigate the correlations between process, property, and structure of the adhesive, resulting in a cost-effective formulation with desirable physical and handling properties. The PM-CPC adhesive exhibited excellent adhesion and cohesion properties in wet-field conditions. This research offers significant potential for clinical translation and contributes to the ongoing advancements in bone tissue engineering., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Diabetes is associated with excessive inflammation, which negatively impacts the fracture healing process and delays bone repair. Previously, growing evidence indicated that activation of the nod-like receptor (NLR) family, such as nod-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome induces a vicious cycle of chronic low-grade inflammatory responses in diabetic fracture. Here, we describe the synthesis of a bone adhesive hydrogel that can be locally injected into the fracture site and releases a natural inhibitor of NLRP3 (rutin) in response to pathological cue reactive oxygen species activity (ROS). The hydrogel (denoted as RPO) was facilely formed by the cross-linking of rutin-functionalized gelatin, poly(vinyl alcohol), and oxidized starch based on the dynamic schiff base and boronate ester bond. Specifically, rutin is conjugated in the RPO hydrogel via a ROS linker and is released as the linker is cleaved by active ROS. In vitro studies demonstrate that RPO hydrogel effectively mitigates oxidative stress, alleviates mitochondrial dysfunction, and limits the overactivation of NLRP3 inflammasome in bone marrow derived macrophages, thereby promoting osteogenic differentiation of bone marrow mesenchymal stem cells. In a diabetic rat fracture model, RPO hydrogel significantly accelerates bone repair by modulating the inflammatory microenvironment. Our results demonstrate that local, on-demand NLRP3 inhibition for the treatment of diabetic fracture is achievable by using an injectable bioresponsive adhesive RPO hydrogel., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Calcium phosphate cement (CPC) has attracted extensive interest from surgeons and materials scientists. However, the collapsibility of calcium phosphate cement limits its clinical application. In this work, a gel network of SA-CA formed by the reaction of citric acid (CA) and sodium alginate (SA) was introduced into the α-TCP/α-CSH composite. Furthermore, a high proportion of α-CSH provided more calcium sources for the system to combine with SA forming a gel network to improve the cohesion property of the composite, which also played a regulating role in the conversion of materials to HA. The morphology, physicochemical properties, and cell compatibility of the composites were studied with SA-CA as curing solution. The results show that SA-CA plays an important role in the compressive strength and collapse resistance of bone cement, and its properties can be regulated by changing the content of CA. When CA is 10 wt%, the mechanical strength is the highest, reaching 12.49 ± 2.03 MPa, which is 265.80% higher than water as the solidifying liquid. In addition, the cell experiments showed that the samples were not toxic to MC3T3 cells. The results of ALP showed that when SA-CA were used as curing solution, the activity of ALP was higher than that of blank sample, indicating that the composite bone cement could be conducive to the differentiation of osteoblasts. In this work, the α-CSH/α-TCP based composite regulated by gel network of SA-CA can provide a promising strategy to improve the cohesion of bone cement., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Among orthopedic surgery materials, poly (methyl methacrylate) (PMMA) is most commonly used for its excellent mechanical properties and rapid self-setting time. However, PMMA bone cement has been reported to cause thermal necrosis and to have poor bioactivity, which must be improved. In contrast, tricalcium silicate (TCS), the most significant component of Portland Cement and the most effective bone cement material, might not always meet the needs of the cement due to its poor mechanical properties and elevated pH levels during hydration. We hypothesize that the benefits of both PMMA and TCS can be harnessed by mixing them together in different proportions. This would represent a better solution for the issues faced when using them alone., Methods: We, therefore, prepared a novel organic-inorganic PMMA/TCS composite bone cement mixing PMMA and different amounts of TCS and tested its effect on the biophysical properties., Results: The addition of 30% TCS reduced the exothermic temperature and pH variation during cement setting and hydration processes. However, the mechanical and handling properties of the bioactive PMMA/TCS composite were not affected. The in vitro study also revealed that the composite materials had higher cell viability than pure PMMA and TCS. Also, the in vivo study on animals indicated that the composite materials were more capable of forming bone, which further reinforced the biocompatibility of the proposed PMMA/TCS bone cement., Conclusion: By combining the advantages of each component, it could be possible to construct a more effective composite bone cement material. This would meet the needs of implantation material for orthopedic surgeries or a possible bone filler., Competing Interests: Conflicts of interest The authors have declared that no conflicts of interest exists., (Copyright © 2022 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Bone grafting is commonly used as a treatment to repair bone defects. However, its use is challenged by the presence of medical conditions that weaken the bone, like osteoporosis. Calcium phosphate cement (CPC) is used to restore bone defects, and it is commonly available as a bioabsorbable cement paste. However, its use in clinical settings is limited by inadequate mechanical strength, inferior anti-washout characteristics, and poor osteogenic activity. There have been attempts to overcome these shortcomings by adding various natural or synthetic materials as enhancers to CPC. This review summarises the current evidence on the physical, mechanical, and biological properties of CPC after doping with synthetic materials. The incorporation of CPC with polymers, biomimetic materials, chemical elements/compounds, and combination with two or more synthetic materials showed improvement in biocompatibility, bioactivity, anti-washout properties, and mechanical strength. However, the mechanical property of CPC doped with trimethyl chitosan or strontium was decreased. In conclusion, doping of synthetic materials enhances the osteogenic features of pure CPC. The positive findings from in vitro and in vivo studies await further validation on the efficacy of these reinforced CPC composites in clinical settings.

Present surgical situations require a bone adhesive which has not yet been developed for use in clinical applications. Recently, phosphoserine modified cements (PMC) based on mixtures of o-phosphoserine (OPLS) and calcium phosphates, such as tetracalcium phosphate (TTCP) or α-tricalcium phosphate (α-TCP) as well as chelate setting magnesium phosphate cements have gained increasing popularity for their use as mineral bone adhesives. Here, we investigated new mineral-organic bone cements based on phosphoserine and magnesium phosphates or oxides, which possess excellent adhesive properties. These were analyzed by X-ray diffraction, Fourier infrared spectroscopy and electron microscopy and subjected to mechanical tests to determine the bond strength to bone after ageing at physiological conditions. The novel biomineral adhesives demonstrate excellent bond strength to bone with approximately 6.6-7.3 MPa under shear load. The adhesives are also promising due to their cohesive failure pattern and ductile character. In this context, the new adhesive cements are superior to currently prevailing bone adhesives. Future efforts on bone adhesives made from phosphoserine and Mg 2+ appear to be very worthwhile., (© 2023. The Author(s).)

Calcium phosphate cement (CPC) has been widely studied, but its lack of osteoinductivity and inadequate mechanical properties limit its application, while strontium is able to promote bone formation and inhibit bone resorption. In this study, different proportions of tristrontium silicate were introduced to create a novel strontium-modified calcium phosphate cement (SMPC). The physicochemical properties of SMPC and CPC were compared, and the microstructures of the bone cements were characterized with scanning electron microscopy assays. Then, the effect of SMPC on cell proliferation and differentiation was examined. Furthermore, local inflammatory response and osteogenesis after SMPC implantation were also confirmed in the study. Finally, a rat model of isolated vertebral defects was used to test the biomechanical properties of the cements. The results showed that SMPC has better injectability and a shorter setting time than CPC. Meanwhile, the addition of tristrontium silicate promoted the mechanical strength of calcium phosphate cement, and the compressive strength of 5% SMPC increased to 6.00 ± 0.74 MPa. However, this promotion effect gradually diminished with an increase in tristrontium silicate, which was also found in the rat model of isolated vertebral defects. Furthermore, SMPC showed a more preferential role in promoting cell proliferation and differentiation compared to CPC. Neither SMPC nor CPC showed significant inflammatory responses in vivo. Histological staining suggested that SMPCs were significantly better than CPC in promoting new bone regeneration. Importantly, this osteogenesis effect of SMPC was positively correlated with the ratio of tristrontium silicate. In conclusion, 5% SMPC is a promising substitute material for bone repair with excellent physicochemical properties and biological activity.

Background: Antibiotics differ in their elution characteristics from bone cement. But no such data is available on piperacillin and tazobactam. Therefore, we performed an in vitro observational study to examine (1) in vitro elution characteristics of piperacillin and tazobactam from bone cement, (2) their biological activity using minimum inhibitory concentration and (3) elution characteristics and biological activity when combined with gentamicin in bone cement., Hypothesis: The null hypothesis was that piperacillin and tazobactam after elution from bone cement can achieve concentrations higher than minimum inhibitory concentration., Material and Methods: Forty milligrams bone cement was mixed with the following combination of antibiotics: without any antibiotic (sample A, control), 4g/0.50g piperacillin/tazobactam (sample B), 6g/0.75g piperacillin/tazobactam (sample C), 8g/1.0g piperacillin/tazobactam (sample D) and 4g/0.50g piperacillin/tazobactam and 400mg gentamicin (sample E). Samples were analysed on reverse-phase ultra-high-performance liquid chromatography. Antibacterial activity in the elute were tested against standard American Type Culture Collection (ATCC) strains., Results: Detectable drug elution for piperacillin and tazobactam was seen till 21days. Peak drug levels for all formulations were seen at 48hours (140.8 & 297.5μg/mL for samples B of piperacillin and tazobactam respectively). About 0.83-1.24% of piperacillin and 23.17-29.17% of tazobactam were released from the samples. Gentamicin improved elution of piperacillin and tazobactam: 140.8 vs. 919.9μg/mL (p=0.000) for samples B & E of piperacillin respectively and 297.5 & 1138.4μg/mL (p=0.001) for samples B & E of tazobactam respectively at 2days. Sample E showed complete inhibition of tested microorganisms, while B sample was microbiologically less active compared to E on day 5., Conclusions: Piperacillin and tazobactam eluted successfully from bone cement and also retained antimicrobial activity after elution. Maximum elution was seen up to day 2 after which it reduced drastically. Antimicrobial action was seen up to 7days., Level of Evidence: III; comparative study., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Injectability and self-setting properties are important factors to increase the efficiency of bone regeneration and reconstruction, thereby reducing the invasiveness of hard tissue engineering procedures. In this study, 63S bioactive glass (BG), nano-hydroxyapatite (n-HAp), alumina, titanium dioxide, and methylene bis-acrylamide (MBAM)-mediated polymeric crosslinking composites were prepared for the formulation of an efficient self-setting bone cement. According to the cytocompatibility and physicochemical analyses, all the samples qualified the standard of the bio-composite materials. They revealed high thermal stability, injectability, and self-setting ability supported by ~ 10.73% (maximum) mass loss, ~ 92-93% injectability and 24 ± 5 min of initial setting time. Moreover, a cellular adhesion and proliferation study was additionally performed with osteoblasts like MG-63 cells, which facilitate pseudopod-like cellular extensions on the BG/n-HAp composite scaffold surface. The SAM study was employed to non-invasively assess the self-setting properties of the composite bio-cement using the post injected distribution and physical properties of the phantom. These results validate the significant potential characteristics of the BG/n-HAp self-setting bio-cement (16:4:2:1) for promising minimal-invasive bone tissue engineering applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Calcium phosphate cement (CPC) is a self-setting, biocompatible and osteoconductive bone cement, however its use as a bone substitute is still limited owing to its low bioactivity (i.e. its slow in vivo resorption and slow new bone formation rate) which is a challenging issue to be addressed. Herein, we report for the first time highly bioactive bone cement microspheres formulated from a cement paste containing α-tricalcium phosphate microparticles (α-TCP) and mesoporous calcium silicate bioactive glass nanoparticles (mesoporous BGn) using a water-in-oil emulsion method. Indeed, bioactive microspheres possess high potential as bone defect fillers for bone regeneration. The α-TCP microparticles were prepared by a solid state synthesis at 1400 ºC while mesoporous BGn were synthesized by template-assissted ultrasound-mediated sol-gel method. The particle size distribution of as-prepared cement microspheres was in the range of 200 - 450 µm with a sphericity index in the range of 0.92 - 0.94. The surface morphology of α-TCP microspheres revealed α-TCP micoparticles with smooth surfaces whereas α-TCP/BGn microspheres unveiled nano-roughened α-TCP microparticles. The as-prepared α-TCP/BGn cement microspheres exhibited larger specific surface area ca 18.6 m 2 /g, sustained release of soluble silicate (SiO 4 4- ) ions (118 ppm within a week) and high protein adsorption capacity (252 mg/g). Notably, the α-TCP/BGn cement microspheres showed excellent in vitro surface bioactivity via formation of massive amounts of bone-like hydroxyapatite spherules and aggregates on their surfaces after soaking in simulated body fluid. Importantly, the in vivo implantation of as-prepared α-TCP/BGn cement microspheres in rat calvarial critical size bone defects for 6 weeks unveiled high in vivo bioactivity in terms of substantial new bone ingrowth and significant new bone formation within the bone defect as evidenced by histological analyses, X-ray radiography and micro-computed tomography evaluations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Results of several studies during past years suggested that magnesium phosphate cements (MPCs) not only show excellent biocompatibility and osteoconductivity, but they also provide improved regeneration capacity due to higher solubility compared to calcium phosphates. These findings also highlighted that chemical similarity of bone substitutes to the natural bone tissue is not a determinant factor in the success of regenerative strategies. The aim of this study was to further improve the degradation speed of MPCs for a fast bone ingrowth within a few months. We confirmed our hypothesis, that decreasing the powder-liquid ratio (PLR) of cement results in an increased content of highly soluble phases such as struvite (MgNH 4 PO 4 ⋅6H 2 O) as well as K-struvite (MgKPO 4 ⋅6H 2 O). Promising compositions with a low PLR of 1 g ml -1 were implanted in partially-loaded tibia defects in sheep. Both cements were partially degraded and replaced by bone tissue after 4 months. The degradation speed of the K-struvite cement was significantly higher compared to the struvite cement, initially resulting in the formation of a cell-rich resorption zone at the surface of some implants, as determined by histology. Overall, both MPCs investigated in this study seem to be promising as an alternative to the clinically well-established, but slowly degrading calcium phosphate cements, depending on defect size and desired degradation rate. Whereas the K-struvite cement might require further modification towards a slower resorption and reduced inflammatory response in vivo, the struvite cement appears promising for the treatment of bone defects due to its continuous degradation with simultaneous new bone formation. STATEMENT OF SIGNIFICANCE: Cold setting bone cements are used for the treatment of bone defects that exceed a critical size and cannot heal on their own. They are applied pasty into the bone defect and harden afterwards so that the shape adapts to the individual defect. Magnesium phosphates such as magnesium ammonium phosphate hexahydrate (struvite) belong to a new class of these cold setting bone cements. They degrade much faster than the clinically established calcium phosphates. In this study, a magnesium phosphate that has hardly been investigated so far was implanted into partially-loaded defects in sheeps: Potassium magnesium phosphate hexahydrate. This showed even faster resorption compared to the struvite cement: after 4 months, 63% of the cement was already degraded., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

To treat critical-size bone defects, composite materials and tissue-engineered bone grafts play important roles in bone repair materials. The purpose of this study was to investigate the bone regenerative potential of hybrid scaffolds consisting of macroporous calcium phosphate cement (CPC) and microporous mineralized collagen matrix (MCM). Hybrid scaffolds were synthetized by 3D plotting CPC and then filling with MCM (MCM-CPC group) and implanted into a 5 mm critical size femoral defect in rats. Defects left empty (control group) as well as defects treated with scaffolds made of CPC only (CPC group) and MCM only (MCM group) served as controls. Eight weeks after surgery, micro-computed tomography scans and histological analysis were performed to analyze the newly formed bone, the degree of defect healing and the activity of osteoclasts. Mechanical stability was tested by 3-point-bending of the explanted femora. Compared with the other groups, more newly formed bone was found within MCM-CPC scaffolds. The new bone tissue had a clamp-like structure which was fully connected to the hybrid scaffolds and thereby enhanced the biomechanical strength. Together, the biomimetic hybrid MCM-CPC scaffolds enhanced bone defect healing by improved osseointegration and their differentiated degradation provides spatial effects in the process of critical-bone defect healing.

The IEELEEELEAER peptide (PIE) identified from the protein hydrolysate of Mytilus edulis is reported to enhance osteoblast growth and differentiation, which also possesses a superior bone formation ability both in vitro and in vivo. Moreover, PIE bound to calcium spontaneously at the stoichiometry of 1:1, and there were amino nitrogen and carboxyl oxygen atoms in 2 glutamic acid residues at the calcium-binding sites in the PIE. The PIE-calcium complex facilitated calcium uptake through the Caco-2 cell monolayers. Incorporation of PIE into calcium phosphate cements enhanced calcium ion uptake and proliferation of osteoblasts and inhibit bacteria. This study suggest that calcium phosphate cements supplemented with PIE can serve as a potentially efficient material for bone graft used during spinal surgery., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The mixture of polymethylmethacrylate (PMMA) and β-tricalciumphospate (β-TCP) is the most widely used bone graft. Common features of bone cement are the biocompatibility, bioactivity, mechanical stability and ability to fuse with the host's bone tissue. However, there are still few studies that have evaluated these characteristics in vivo. Our study aims to acquire these parameters, using an animal model with functional characteristics similar to those of humans. The analyzed cement is Calcemex®, evaluated both in compact and fluid formulation. The chosen animal models were 5 pigs, treated with femoral and tibial implants of Calcemex® samples. After one year, the pigs were sacrificed and the specimens explanted for morphological, histological, ultrastructural and mechanical evaluations. For both formulations, the investigation highlighted the absence of foreign body reactions in the host, the histological integration with the surrounding tissues and the preservation of mechanical compression resistance.

Objective: To investigate the biomechanical and elution properties of meropenem-loaded bone cement., Methods: Bone cement (Palacos LV) with 5% (2 g/4 0g), 10% (4 g/40 g), and 15% (6 g/40 g) meropenem; 5% (2 g/40 g) and 10% (4 g/40 g) vancomycin; and blank bone cement were prepared in a total of six groups named A2, A4, A6, B2, B4, and A0 (antibiotic-free). 36 cylinder specimens (6-mm diameter and 12-mm height) of all six groups were molded for a compression test. After the compression test, because of mechanical properties below the ISO standard requirements, groups B2, B4 were not subjected to a bending test. So a total of 24 rectangular strip specimens (10-mm width, 75-mm length, and 3.3-mm thickness) for groups A2, A4, A6 and A0 were molded for the bending test. Between-group differences of compressive strength, bending strength and bending modulus were analyzed. The meropenem standard was prepared as a series of standard solutions to calculate the standard curve. At a constant temperature of 37 °C, separately, meropenem-loaded bone cement cylinder specimens (12 mm in diameter and 17 mm in length) of A2, A4 and A6 were serially immersed in saline solution without stirring. The eluent drug concentration at 24, 48, 72 h and 6, 12, 24 days was measured and the drug concentration-time curve of meropenem was constructed., Results: With the exception of groups B2 and B4, all cements compressive strength values were well above the minimum requirement of the ISO 5833 standard (70 MPa). The compressive strength and bending strength values of group A4 were higher than those of group A0 (P < 0.05), but no difference was found between the A0, A2 and A6 groups (P > 0.05). There were no intergroup differences of bending modulus between the A0, A2, A4 and A6 groups (P > 0.05). A standard curve of meropenem was obtained and a regression equation was constructed: Y = 15.0265 X + 13.5218, r = 1.00. At 37 °C, the release of meropenem was rapid during the first 48 h for all A2, A4, A6 samples, and subsequent release continued to decrease., Conclusion: When adding up to 15% (6 g/40 g) meropenem to the bone cement, the biomechanical properties were not reduced, and bone cement with 10% (4 g/40 g) meropenem had the best performance. At a constant temperature of 37°C, meropenem can be released from bone cement for up to 24 days., (© 2021 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Chronic osteomyelitis is a challenging disease due to its serious rates of mortality and morbidity while the currently available treatment strategies are suboptimal. In contrast to the adopted systemic treatment approaches after surgical debridement in chronic osteomyelitis, local drug delivery systems are receiving great attention in the recent decades. Local drug delivery systems using special carriers have the pros of enhancing the feasibility of penetration of antimicrobial agents to bone tissues, providing sustained release and localized concentrations of the antimicrobial agents in the infected area while avoiding the systemic side effects and toxicity. Most important, the incorporation of osteoinductive and osteoconductive materials in these systems assists bones proliferation and differentiation, hence the generation of new bone materials is enhanced. Some of these systems can also provide mechanical support for the long bones during the healing process. Most important, if the local systems are designed to be injectable to the affected site and biodegradable, they will reduce the level of invasion required for implantation and can win the patients' compliance and reduce the healing period. They will also allow multiple injections during the course of therapy to guard against the side effect of the long-term systemic therapy. The current review presents different available approaches for delivering antimicrobial agents for the treatment of osteomyelitis focusing on the recent advances in researches for local delivery of antibiotics.HIGHLIGHTSChronic osteomyelitis is a challenging disease due to its serious mortality and morbidity rates and limited effective treatment options.Local drug delivery systems are receiving great attention in the recent decades.Osteoinductive and osteoconductive materials in the local systems assists bones proliferation and differentiationLocal systems can be designed to provide mechanical support for the long bones during the healing process.Designing the local system to be injectable to the affected site and biodegradable will reduces the level of invasion and win the patients' compliance.

Vascularization is an important early indicator of osteogenesis involving biomaterials. Bone repair and new bone formation are associated with extensive neovascularization. Silicon-based biomaterials have attracted widespread attention due to their rapid vascularization. Although calcium phosphate cement (CPC) is a mature substitute for bone, the application of CPC is limited by its slow degradation and insufficient promotion of neovascularization. Calcium silicate (CS) has been shown to stimulate vascular endothelial proliferation. Thus, CS may be added to CPC (CPC-CS) to improve the biocompatibility and neovascularization of CPC. In the early phase of bone repair (the inflammatory phase), macrophages accumulate around the biomaterial and exert both anti- and pro-inflammatory effects. However, the effect of CPC-CS on macrophage polarization is not known, and it is not clear whether the effect on neovascularization is mediated through macrophage polarization. In the present study, we explored whether silicon-mediated macrophage polarization contributes to vascularization by evaluating the CPC-CS-mediated changes in the immuno-environment under different silicate ion contents both in vivo and in vitro. We found that the silicon released from CPC-CS can promote macrophage polarization into the M2 phenotype and rapid endothelial neovascularization during bone repair. Dramatic neovascularization and osteogenesis were observed in mouse calvarial bone defects implanted with CPC-CS containing 60% CS. These findings suggest that CPC-CS is a novel biomaterial that can modulate immune response, promote endothelial proliferation, and facilitate neovascularization and osteogenesis. Thus, CPC-CS shows potential as a bone substitute material., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To specify the concentration of the liquid antibiotics to be added to polymethylmethacrylate (PMMA) and its impact on the quality of the spacer is the purpose of this study with liquid clindamycin added to different cements., Methods: In the present study, eight different cement mixtures were prepared and investigated. In the following, number 1 indicates the references, 2 all cements after liquid clindamycin was added to the liquid cement compound, 3 all cements after liquid clindamycin was added to the cement powder, and 4 all cements after liquid clindamycin was added to the cement dough. After curing, cements were filled into metal moulds and a pressure of 3 bar was maintained for 30 min. Mechanical investigations were carried out according to ISO 5833 (2002) and DIN 53435 (2007). For microbiological tests, standardized cylindrical mouldings (diameter: 25 mm, height: 10 mm) were produced and incubated in 10 ml buffer solution at room temperature for 24 h. All eluates were generated by spreading previously established suspensions of Staphylococcus aureus, Staphylococcus epidermidis, Cutibacterium acnes and methicillin-resistant Staphylococcus aureus (MRSA) with a 0.5 McFarland turbidity standard., Results: Apparently, we found that in all investigated cases, the admixture of liquid antibiotic negatively affected the mechanical characteristics of the cement mould. Among the various test groups, the influence on the ISO compression strength and ISO flexural modulus of the investigated test groups was only minimal when liquid clindamycin was added to cement liquid. Compared to admixing of liquid clindamycin into cement powder or dough ISO compression strength and ISO flexural modulus and flexural strength showed the maximum reduction. The efficacy against chosen germs was reduced as well when liquid antibiotic was admixed instead of powder. This admixture of liquid anti-infective agents resulted in a 234% enhanced elution after 10 days 29 a negative effect on the inhibition zones were detected during the previous period., Conclusion: The admixture of powdery antibiotic is preferable to liquid antibiotics. If no powdery antibiotic is available, we can recommend the admixture of liquid antibiotic to liquid cement prior to dough production in case powdery antibiotics cannot be used. However, we discourage the admixture of liquid antibiotic to cement powder or cement dough during early low viscose phase., (© 2021 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Prosthetic joint infections (PJI) are still an extremely concerning eventuality after joint replacement surgery; growing antibiotic resistance is also limiting the prophylactic and treatment options. Chlorhexidine (a widely used topical non-antibiotic antimicrobial compound) coatings on silica nanoparticles capable of prolonged drug release have been successfully developed and characterised. Such nanocarriers were incorporated into commercial formulation PMMA bone cement (Cemex), without adversely affecting the mechanical performance. Moreover, the bone cement containing the developed nanocarriers showed superior antimicrobial activity against different bacterial species encountered in PJI, including clinical isolates already resistant to gentamicin. Cytocompatibility tests also showed non inferior performance of the bone cements containing chlorhexidine releasing silica nanocarriers to the equivalent commercial formulation., Competing Interests: The authors have declared that no competing interests exist.

This study was aimed at fabricating and evaluating the physical and bioproperties of nanofast cement (NFC) as a replacement of the MTA. The cement particles were decreased in nanoscale, and zirconium oxide was used as a radiopacifier. The setting time and radiopacity were investigated according to ISO recommendations. Analysis of color, bioactivity, and cytotoxicity was performed using spectroscopy, simulated body fluid (SBF), and MTT assay. The setting time of cement pastes significantly dropped from 65 to 15 min when the particle sizes decreased from 2723 nm to 322 nm. Nanoparticles provide large surface areas and nucleation sites and thereby a higher hydration rate, so they reduced the setting time. Based on the resulting spectroscopy, the specimens did not exhibit clinically noticeable discoloration. Resistance to discoloration may be due to the resistance of zirconium oxide to decomposition. Scanning electron microscopy (SEM), X-ray diffraction (XRD), and infrared spectroscopy (FTIR) examinations of the immersed SBF samples showed apatite formation that was a reason for its suitable bioactivity. The results of cell culture revealed that NFC is nontoxic. This study showed that NFC was more beneficial than MTA in dental restorations., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Kh. Yousefi et al.)

Aims: Osteosarcoma represents the second most common cause of death in children and young adults. No biomaterial allowing local drug delivery has been specifically developed. However, a biocompatible bioactive implantable material could prevent some amputations, and the local release of an antitumor agent could limit risks of relapse and metastasis. Methods: We propose a proof of concept of a self-setting paste combining amorphous calcium phosphate and doxorubicin-loaded particles of bone-like carbonated nanocrystalline apatite, as a means of local release. Results: The cement formulation and doping, first with folic acid and then with doxorubicin, was successful. Its physicochemistry was scrutinized. Preliminary in vivo data on an invasive osteosarcoma rat model suggest a limiting effect on metastatic events in the lungs without signs of toxicity.

Deep infection is a serious complication in endoprosthetic surgery. In correlation to the patient local or systemic compromising factors conservative and surgical proceedings has to be evaluated. Systemic antibiotic therapy is the gold standard in infection management. Implanted silver-coated or silver-containing medical devices have been proven to their antimicrobial effectiveness since the 1990s by several investigators. The outcomes showed that long time implantation could cause damaging of the surrounding tissues, especially of adjacent nerves. The aim of our study was to evaluate the release of silver (I) ions from bone cement mixed with either nanosilver particles (AgNPs), different concentrations of silver sulfate (Ag2SO4) or from pure metallic silver strips. Therefore, we choose two methods: the first, called "static model", was chosen to evaluate the maximal accumulative concentration of silver (I) ions, with the second, called "dynamic model", we simulated a continuous reduction of the ions. In an additional test design, the different materials were evaluated for their antimicrobial activity using an agar gel diffusion assay. The outcome showed that neither the addition of 1% (w/w) nanosilver nor 0.1% silver sulfate (w/w) to polymethylmethacrylat bone cement has the ability to release silver (I) ions in a bactericidal/antifungal concentration. However, the results also showed that the addition of 0.5% (w/w) and 1% (w/w) silver sulfate (Ag2SO4) to bone cement is an effective amount of silver for use as a temporary spacer., (© 2021. The Author(s).)

This study investigated whether mixing low viscosity alginic acid with calcium phosphate cement (CPC) causes interconnected porosity in the CPC and enhances bone replacement by improving the biological interactions. Furthermore, we hypothesized that low viscosity alginic acid would shorten the setting time of CPC and improve its strength. CPC samples were prepared with 0, 5, 10, and 20% low viscosity alginic acid. After immersion in acetate buffer, possible porosification in CPC was monitored in vitro using scanning electron microscopy (SEM), and the setting times and compressive strengths were measured. In vivo study was conducted by placing CPC in a hole created on the femur of New Zealand white rabbit. Microcomputed tomography and histological examination were performed 6 weeks after implantation. SEM images confirmed that alginic acid enhanced the porosity of CPC compared to the control, and the setting time and compressive strength also improved. When incorporating a maximum amount of alginic acid, the new bone mass was significantly higher than the control group (P = 0.0153). These biological responses are promising for the translation of these biomaterials and their commercialization for clinic applications.

Calcium phosphate cements have the advantage that they can be prepared as a paste that sets in a few minutes and can be easily adapted to the shape of the bone defect, which facilitates its clinical application. In this research, six formulations of brushite (dicalcium phosphate dihydrated) cement were obtained and the effect of the addition of sodium alginate was analyzed, such as its capacity as a tetracycline release system. The samples that contain sodium alginate set in 4 or 5 min and showed a high percentage of injectability (93%). The cements exhibit compression resistance values between 1.6 and 2.6 MPa. The drug was released in a range between 12.6 and 13.2% after 7 days. The antimicrobial activity of all the cements containing antibiotics was proven. All samples reached values of cell viability above 70 percent. We also observed that the addition of the sodium alginate and tetracycline improved the cell viability.

The use of drug delivery systems is a good technique to leave the right quantity of medicine in the patient's body in a suitable dose, because the drug application is delivered directly to the affected region. The current techniques such as HPLC and UV-Vis for the drug delivery calculation has some disadvantages, as the accuracy and the loss of the sample after characterization. With the aim of reducing the amount of material used during the characterization and have a non-destructive test with instantaneous results, the present paper shows the possibility of using electrochemical impedance spectroscopy (EIS) to have a drug delivery measurement during the release phenomena for a calcium phosphate cement (CFC) delivery system with gentamicin sulfate (GS) and lidocaine hydrochloride (LH), at a ratio of 1% and 2%, respectively. The equivalent circuit and the chemical mechanism involved during the measurements have been proposed as a tool to determine the drug delivery profile. The method has been compared with the UV-Vis technique. XRD was realized to verify conditions, before and after release. It was possible to verify the potential for using EIS as an instant technique to quantify drug delivery.

Background: This study aimed to prepare the polymethylmethacrylate (PMMA) bone cement release system with different concentrations of enoxaparin sodium (ES) and to investigate the release characteristics of ES after loading into the PMMA bone cement., Methods: In the experimental group, 40 g Palacos®R PMMA bone cement was loaded with various amount of ES 4000, 8000, 12,000, 16,000, 20,000, and 24,000 AXaIU, respectively. The control group was not loaded with ES. Scanning electron microscopy (SEM) was used to observe the surface microstructure of the bone cement in the two groups. In the experiment group, the mold was extracted continuously with pH7.4 Tris-HCL buffer for 10 days. The extract solution was collected every day and the anti-FXa potency was measured. The experiment design and statistical analysis were conducted using a quantitative response parallel line method., Results: Under the SEM, it was observed that ES was filled in the pores of PMMA bone cement polymer structure and released from the pores after extraction. There was a burst effect of the release. The release amount of ES on the first day was 0.415, 0.858, 1.110, 1.564, 1.952, and 2.513, respectively, from the six groups with various ES loading amount of 4000, 8000, 12,000, 16,000, 20,000, and 24,000 AXaIU, all reaching the peak of release on the first day. The release decreased rapidly on the next day and entered the plateau phase on the fourth day., Conclusion: The prepared ES-PMMA bone cement has high application potential in orthopedic surgery. ES-PMMA bone cement shows good drug release characteristics. The released enoxaparin sodium has a local anti-coagulant effect within 24 h after application, but it will not be released for a long time, which is complementary to postoperative anti-coagulation therapy.

Cleft alveolar bone defects can be treated potentially with tissue engineered bone grafts. Herein, we developed novel biphasic bone constructs consisting of two clinically certified materials, a calcium phosphate cement (CPC) and a fibrin gel that were biofabricated using 3D plotting. The fibrin gel was loaded with mesenchymal stromal cells (MSC) derived from bone marrow. Firstly, the degradation of fibrin as well as the behavior of cells in the biphasic system were evaluated in vitro. Fibrin degraded quickly in presence of MSC. Our results showed that the plotted CPC structure acted slightly stabilizing for the fibrin gel. However, with passing time and fibrin degradation, MSC migrated to the CPC surface. Thus, the fibrin gel could be identified as cell delivery system. A pilot study in vivo was conducted in artificial craniofacial defects in Lewis rats. Ongoing bone formation could be evidenced over 12 weeks but the biphasic constructs were not completely osseous integrated. Nevertheless, our results show that the combination of 3D plotted CPC constructs and fibrin as suitable cell delivery system enables the fabrication of novel regenerative implants for the treatment of alveolar bone defects.

This paper reports the creation of hydroxyapatite/polyester nanografts by "graft-from" polymerization of d,l-lactide with [Ca 5 (OH)(PO 4 ) 3 ] 2 as the initiator and tin(II)-2-ethylhexanoate as the catalyst. Model polymerizations were performed with cyclooctanol as initiator to confirm the grafting on the surface of the hydroxyapatite nanocrystals. Polymers with the highest molecular mass (M n ) between 4250 Da (cyclooctanol) and 6100 Da (hydroxyapatite) were produced. In both cases the molecular mass distributions of the polymers formed were monomodal. The materials obtained were characterized by size-exclusion chromatography, NMR and FT-IR spectroscopy, and thermal methods. Their suitability as additives for commercial bone cement (Simplex P Speedset, Stryker Orthopaedics) has been confirmed by thermal analysis techniques and mechanical testing. The results obtained show that addition of the hydroxyapatite/ polyester nanografts improved both thermal and mechanical properties of the bone cement.

Acrylic bone cements (ABC) are widely used in orthopedics for joint fixation, antibiotic release, and bone defect filling, among others. However, most commercially available ABCs exhibit a lack of bioactivity and are susceptible to infection after implantation. These disadvantages generate long-term loosening of the prosthesis, high morbidity, and prolonged and expensive treatments. Due to the great importance of acrylic bone cements in orthopedics, the scientific community has advanced several efforts to develop bioactive ABCs with antibacterial activity through several strategies, including the use of biodegradable materials such as chitosan (CS) and nanostructures such as graphene oxide (GO), with promising results. This paper reviews several studies reporting advantages in bioactivity and antibacterial properties after incorporating CS and GO in bone cements. Detailed information on the possible mechanisms by which these fillers confer bioactive and antibacterial properties to cements, resulting in formulations with great potential for use in orthopedics, are also a focus in the manuscript. To the best of our knowledge, this is the first systematic review that presents the improvement in biological properties with CS and GO addition in cements that we believe will contribute to the biomedical field.