Bone Healing Process Research Articles

Effect of Remifentanil on the Osteogenic Activity of Biodegradable Polyhydroxybutyrate Bone Cement in Orthopedic Surgery Model

The objective of this research was to investigate the impacts of Remifentanil on osteogenic activity of biodegradable polyhydroxybutyrate (PHB) bone cement (BPC) in an orthopedic surgery model (OSM). PHB was prepared and characterized. Remifentanil with various concentrations were determined: 0.5, 1.5, 10, 100, and 200 μmol groups, with untreated cells serving as the control (Ctrl) group. Osteoblasts were obtained from bone tissue, and cell proliferation (CP) inhibition was assessed using the MTT assay. Alkaline phosphatase (ALP) activity and insulin-like growth factor-1 (IGF-I) activity were detected using the enzyme-linked immunosorbent assay (ELISA). Expressions of bone-related genes (Runx2, osterix, Bglap, and IBSP) were quantified using fluorescence quantification, and the reactive oxygen species (ROS) levels were measured using a fluorescence microplate reader. The results revealed that different molecular weights (MWs) increased initially and then decreased with increasing radiation time, while diverse temperatures at appropriate reactions yielded higher MWs. Microwave radiation synthesis produced the highest MW of 21.2 × 104 g/mol after a 35-minute reaction. The IGF-I activity in the cell supernatant differed greatly among different groups, with the 100 and 200 μmol groups exhibiting obvious differences with P < 0.05 to the Ctrl group. Marked differences were observed among the 100 and 200 μmol groups and the 0.5, 1.5, and 10 μmol groups, showing P < 0.05. Runx2, osterix, Bglap, and IBSP in the 10, 100, and 200 μmol groups were differed obviously to those in the Ctrl group (P < 0.05). The 10, 100, and 200 μmol groups exhibited remarkable differences based on the Ctrl group (P < 0.05). Remifentanil may negatively impact the osteogenic activity of BPC by inhibiting the activity of bone cells and interfering with the synthesis of extracellular matrix. In conclusion, Remifentanil negatively impacted the osteogenic activity of BPC in the orthopedic surgery model (OSM). Remifentanil may interfere with the bone healing process and further weaken its osteogenic capability.

Intramedullary implant stability affects patterns of fracture healing in mice with morphologically different bone phenotypes

Almost all prior mouse fracture healing models have used needles or K-wires for fixation, unwittingly providing inadequate mechanical stability during the healing process. Our contention is that the reported outcomes have predominantly reflected this instability, rather than the impact of diverse biological conditions, pharmacologic interventions, exogenous growth factors, or genetic considerations. This important issue becomes obvious upon a critical review of the literature. Therefore, the primary aim of this study was to demonstrate the significance of mouse-specific implants designed to provide both axial and torsional stability (Screw and IM Nail) compared to conventional pins (Needle and K-wires), even when used in mice with differently sized marrow canals and diverse genetic backgrounds. B6 (large medullary canal), DBA, and C3H (smaller medullary canals) mice were employed, all of which have different bone morphologies. Closed femoral fractures were created and stabilized with intramedullary implants that provide different mechanical conditions during the healing process. The most important finding of this study was that appropriately designed mouse-specific implants, providing both axial and torsional stability, had the greatest influence on bone healing outcomes regardless of the different bone morphologies encountered. For instance, unstable implants in the B6 strain (largest medullary canal) resulted in significantly greater callus, with a fracture region mainly comprising trabecular bone along with the presence of cartilage 28 days after surgery. The DBA and C3H strains (with smaller medullary canals) instead formed significantly less callus, and only had a small amount of intracortical trabeculation remaining. Moreover, with more stable fracture fixation a higher BV/TV was observed and cortices were largely restored to their original dimensions and structure, indicating an accelerated healing and remodeling process. These observations reveal that the diaphyseal cortical thickness, influenced by the genetic background of each strain, played a pivotal role in determining the amount of bone formation in response to the fracture. These findings are highly important, indicating the rate and type of tissue formed is a direct result of mechanical instability, and this most likely would mask the true contribution of the tested genes, genetic backgrounds, or various therapeutic agents administered during the bone healing process.

Melatonin rescues the mitochondrial function of bone marrow-derived mesenchymal stem cells and improves the repair of osteoporotic bone defect in ovariectomized rats.

Osteoporotic bone defects, a severe complication of osteoporosis, are distinguished by a delayed bone healing process and poor repair quality. While bone marrow-derived mesenchymal stem cells (BMMSCs) are the primary origin of bone-forming osteoblasts, their mitochondrial function is impaired, leading to inadequate bone regeneration in osteoporotic patients. Melatonin is well-known for its antioxidant properties and regulation on bone metabolism. The present study postulated that melatonin has the potential to enhance the repair of osteoporotic bone defects by restoring the mitochondrial function of BMMSCs. In vitro administration of melatonin at varying concentrations (0.01, 1, and 100 μM) demonstrated a significant dose-dependent improvement in the mitochondrial function of BMMSCs obtained from ovariectomized rats (OVX-BMMSCs), as indicated by an elevation in mitochondrial membrane potential, adenosine triphosphate synthesisand expression of mitochondrial respiratory chain factors. Melatonin reduced the level of mitochondrial superoxide by activating the silent information regulator type 1 (SIRT1) and its downstream antioxidant enzymes, particularly superoxide dismutase 2 (SOD2). The protective effects of melatonin were found to be nullified upon silencing of Sirt1 or Sod2, underscoring the crucial role of the SIRT1-SOD2 axis in the melatonin-induced enhancement of mitochondrial energy metabolism in OVX-BMMSCs. To achieve a sustained and localized release of melatonin, silk fibroin scaffolds loaded with melatonin (SF@MT) were fabricated. The study involved the surgical creation of bilateral femur defects in OVX rats, followed by the implantation of SF@MT scaffolds. The results indicated that the application of melatonin partially restored the mitochondrial energy metabolism and osteogenic differentiation of OVX-BMMSCs by reinstating mitochondrial redox homeostasis. These findings suggest that the localized administration of melatonin through bone implants holds potential as a therapeutic approach for addressing osteoporotic bone defects.

Comparative Clinical Effects and Risk Factors Associated With Vitamin D in Foot and Ankle Fracture and Arthrodesis Healing

Vitamin D deficiency in relation to bone metabolism and healing has been controversial and not well studied. However, hypovitaminosis has been widely identified within the orthopedic patient population. The current best evidence suggests a lack of data on this important topic. The ability to assess patients for optimum bone healing and metabolism is still in question due to lack of a suitable reliable biomarker and multiple other unknown variables affecting bone metabolism. To compound this effect, popular dermatological precautions in the last 20 to 30 years of avoiding sunlight also have the effect of further reducing serum vitamin D production in the skin. As a proof of concept, we performed a preliminary comparative observational retrospective review of orthopedic patients undergoing fracture and arthrodesis osseous healing to determine how serum vitamin D levels are associated with bone healing along with their confounding comorbidities. Based on our review, the current accepted vitamin D levels (≥20 ng/mL) are low and insufficient for fractures and for arthrodesis osseous healing due to observed high rates (>35%) of delayed unions, and an increased (>90%) in the number of multiple confounding comorbidities affecting bone healing process that are often not mentioned or captured in this type of study in previous literature. Obesity and diabetes are significant contributory risks factors, and the preliminary findings suggest that the current accepted adequate levels may not be enough for osseous healing. These low vitamin D levels appear to affect bone healing and prolong treatment, with worsening trends with diabetes and obesity comorbidities.

Interaction of Macrophages with Bone Healing Microenvironment: Mechanism and Biomaterials.

Extensive bone fractures, which can seriously impact both health and quality of life, cannot easily heal naturally, especially if the patient has an underlying medical condition or is aging. The most promising approach to addressing such fractures is bone regeneration through bone tissue engineering. Bone regeneration is a complex process that consists of three distinct phases: inflammation, repair, and remodeling. Macrophages play a bridging role between the various cells involved in each stage of bone regeneration, interacting with different microenvironments and advancing the bone healing process. Although the origin and function of macrophages have been extensively studied, the mechanisms underlying their interaction with the bone healing microenvironment remain unexplored, including the association of microenvironmental changes with macrophage reprogramming and the role of macrophages in cells in the microenvironment. This review summarizes the bone regeneration process and recent advances in research on interactions between macrophages and the bone healing microenvironment and discusses novel biological strategies to promote bone regeneration by modulating macrophages for the treatment of bone injury and loss.

Analysis of Cellular Crosstalk and Molecular Signal between Periosteum-Derived Precursor Cells and Peripheral Cells During Bone Healing Process Using a Paper-Based Osteogenesis-On-A-Chip Platform.

Periosteum-derived progenitor cells (PDPCs) are highly promising cell sources that are indispensable in the bone healing process. Adipose-derived stem cells (ADSCs) are physiologically close to periosteum tissue and release multiple growth factors to promote the bone healing process. Co-culturing PDPCs and ADSCs can construct periosteum-bone tissue microenvironments for the study of cellular crosstalk and molecular signal in the bone healing process. In the current work, a paper-based osteogenesis-on-a-chip platform was successfully developed to provide an in vitro three-dimensional coculture model. The platform was a paper substrate sandwiched between PDPC-hydrogel and ADSC-hydrogel suspensions. Cell secretion could be transferred through the paper substrate from one side to another side. Growth factors including BMP2, TGF-β, POSTN, Wnt proteins, PDGFA, and VEGFA were directly analyzed by a paper-based immunoassay. Cellular crosstalk was studied by protein expression on the paper substrate. Moreover, osteogenesis of PDPCs was investigated by examining the mRNA expressions of PDPCs after culture. Neutralizing and competitive assays were conducted to understand the correlation between growth factors secreted from ADSCs and the osteogenesis of PDPCs. In vitro periosteum-bone tissue microenvironment was established by the paper-based osteogenesis-on-a-chip platform. The proposed approach provides a promising assay of cellular crosstalk and molecular signal in 3D coculture microenvironment that may potentially lead to the development of effective bone regeneration therapy.

Morphology-Dependent Immunomodulatory Coating of Hydroxyapatite/PEO for Magnesium-Based Bone Implants.

One of the most critical issues concerning orthopedic implants is the risk of chronic inflammation, which poses a threat to the bone healing process. Osteo-immunomodulation plays a pivotal role in implant technology by influencing proinflammatory and anti-inflammatory responses, ultimately promoting bone healing. This study aims to investigate the morphology-dependent osteo-immunomodulatory properties of a hydroxyapatite (HA)/plasma electrolytic oxidation (PEO)-coated WE43 alloy. In this context, following the PEO process with various operational parameters (duty cycles of 50-40, 50-20, 70-40%, and frequencies of 0.5, 0.8, and 1 kHz), a layer of HA was applied as the top coating using a straightforward hot-dip process. The results revealed the formation of the PEO layer with distinct morphologies and pore sizes, depending on the operational parameters. Specifically, a uniform PEO coating with small pore sizes (5.2-5.3 μm) led to the creation of plate-like HA particles, while a random-like HA structure formed on nonuniform surfaces with large pores (7.0-11.1 μm) of PEO. Moreover, it was observed that the plate-like HA coating exhibited higher adhesion strength than the random one (classified as class 2 vs class 3 based on cross-cut standards). Furthermore, electrochemical impedance spectroscopy (EIS) and polarization studies confirmed a substantial increase in the polarization resistance (680 kΩ) and total impedance (48 559.6 Ω) for the plate-like HA/PEO as compared to the substrate (an increase of 1511-fold and 311-fold, respectively) and the random HA/PEO samples (an increase of 85-fold and 18-fold, respectively). In addition, compared to random HA coatings, there was a significant enhancement in the viability (150% control vs 96% control), proliferation, and differentiation of MG63 cells when exposed to plate-like HA coatings. Moreover, surface morphology and chemistry pronouncedly impacted macrophages' viability, morphology, and phenotype. Notably, plate-like HA coatings resulted in a higher upregulation of BMP-2 and TGF-β than proinflammatory cytokines (IL-6 and M-CSF), indicating a polarization of macrophage type 1 (M1) toward type 2 (M2). In summary, the bilayer HA/PEO coating exhibited remarkable osteo-immunomodulatory activity, making it highly appealing for use in bone implant applications.

Psychostimulants prescribed to children for ADHD following distal radius fractures significantly reduce bone density as a function of duration.

Methylphenidate and mixed amphetamine salts (MAS) are psychostimulant medications widely prescribed for various psychiatric disorders. Although these medications are known to adversely impact bone mineral content and density, as well as biomechanical integrity during skeletal development in rats, their effect on bone density in children remains largely unknown. The primary aim of this work was to investigate the effects of methylphenidate and MAS on bone density following distal radius fractures in pediatric populations, and secondarily assess any impact on healing. The retrospective case-control study was designed to assess fracture healing in patients treated with stimulant drugs and matched controls. For the primary outcome, X-rays ( n = 188) were evaluated using an optical density image analysis technique to compare bone density throughout the bone healing process. Results showed that methylphenidate and MAS significantly reduced bone healing by approximately 20% following distal radius fractures in these children. The data also suggested that duration of psychostimulant use played a role in bone healing; the longer the treatment (1-5 years), the lower the bone density was observed (by approximately 52%) as compared to controls (no medication). However, subjects taking these drugs for longer than 5 years did not show a significant difference. Our results suggested that children taking psychostimulants for up to 5 years had slower bone healing following distal radius fractures. Orthopedic surgeons planning elective surgeries should be cognizant of this as a potential issue in recovery after any elective bone procedures and preoperatively optimize bone health as well as counsel patients and their families.

Chitosan Nanoparticle/Simvastatin for Experimental Maxillary Bony Defect Healing: A Histological and Histomorphometrical Study.

Biomaterials such as chitosan and simvastatin (Sim) have been introduced to accelerate the extensive and multicellular biological process of bone healing. The aim of this study was to evaluate the bone healing potential of chitosan and Sim, alone or combined. Forty-two male New Zealand rabbits were divided into three groups: chitosan nanoparticles (ChN), Sim and chitosan simvastatin nanoparticles (ChSimN). Two bony defects were created in the maxillary bone. The hole on the right side received one of the experimental materials, while the other side was assigned as the control and left to heal without any intervention. Bone specimens were collected at 2 and 4 weeks and then taken for histological and histomorphometrical analyses. The histological findings revealed that ChN possessed the highest number of osteoblasts and osteoclasts at weeks 2 and osteocytes after 4 weeks. There was a significant difference between the two healing periods regarding all bone parameters across all groups. ChN stood out as the only group that had a significant difference in the count of all bone cells between the two periods, thus having the best potential in promoting bone healing.

Oral fibroblasts rescue osteogenic differentiation of mesenchymal stem cells after exposure to Zoledronic acid in a paracrine effect.

Background: Medication-related osteonecrosis of the jaw is a serious complication that develops in oncologic patients treated with Zoledronic acid. Although used for over 30years, the influence of Zoledronic acid on bone has been thoroughly investigated, mainly on osteoclasts. While decreasing osteoclast differentiation and function, for many years it was thought that Zoledronic acid increased osteoblast differentiation, thus increasing bone volume. Moreover, despite the influence of soft tissue on the bone healing process, the impact of zoledronic acid on the interaction between soft tissue and bone was not investigated. Aim: Our goal was to investigate the influence of Zoledronic Acid and soft tissue cells on osteogenic differentiation of mesenchymal stem cells (MSCs). Materials and methods: Osteogenic differentiation of MSCs was examined after exposure to Zoledronic Acid. To determine the influence of soft tissue cells on MSCs' osteogenic differentiation, conditioned media from keratinocytes and oral fibroblasts were added to osteogenic medium supplemented with Zoledronic Acid. Proteomic composition of keratinocytes' and fibroblasts' conditioned media were analyzed. Results: Zoledronic Acid decreased osteogenic differentiation of MSCs by seven-fold. The osteogenic differentiation of MSCs was restored by the supplementation of fibroblasts' conditioned medium to osteogenic medium, despite Zoledronic acid treatment. Five osteogenic proteins involved in the TGFβ pathway were exclusively identified in fibroblasts' conditioned medium, suggesting their role in the rescue effect. Conclusion: Oral fibroblasts secrete proteins that enable osteogenic differentiation of MSCs in the presence of Zoledronic Acid.

Nanomechanical Characterization of Bone Quality Depending on Tissue Age via Bimodal Atomic Force Microscopy

Characterization of bone quality during the healing process is crucial for successful implantation procedures and patient comfort. In this study, a bone implant specimen that underwent a 4-week healing period was investigated. Bimodal atomic force microscopy (AFM) was employed to simultaneously obtain the morphology and elastic modulus maps of the newly formed and pre-existing bone regions within the sample. Results indicate that the new bone matrix possessed lower mineralization levels and presented larger, uneven mineral grains, exhibiting the attributes of a woven bone. On the other hand, the old bone matrix exhibited a more uniform and mineralized structure, which is characteristic of lamellar bones. The new bone had a lower overall elastic modulus than the old bone. Bimodal AFM further confirmed that the new bone displayed three regions comprising unmineralized, partially mineralized, and fully matured sections, which indicate a turbulent change in its composition. Meanwhile, the old bone exhibited two sections comprising partially mineralized and matured bone parts, which denote the final phase of mineralization. This study provides valuable insights into the morphological and nanomechanical differences between the old and new bone matrixes and presents a novel approach to investigate bone quality at different phases of the bone-healing process.

Recent Advances in Bioengineering Bone Revascularization Based on Composite Materials Comprising Hydroxyapatite.

The natural healing process of bone is impaired in the presence of tumors, trauma, or inflammation, necessitating external assistance for bone regeneration. The limitations of autologous/allogeneic bone grafting are still being discovered as research progresses. Bone tissue engineering (BTE) is now a crucial component of treating bone injuries and actively works to promote vascularization, a crucial stage in bone repair. A biomaterial with hydroxyapatite (HA), which resembles the mineral makeup of invertebrate bones and teeth, has demonstrated high osteoconductivity, bioactivity, and biocompatibility. However, due to its brittleness and porosity, which restrict its application, scientists have been prompted to explore ways to improve its properties by mixing it with other materials, modifying its structural composition, improving fabrication techniques and growth factor loading, and co-cultivating bone regrowth cells to stimulate vascularization. This review scrutinizes the latest five-year research on HA composite studies aimed at amplifying vascularization in bone regeneration.

Substrate Stiffness of Bone Microenvironment Controls Functions of Pre-Osteoblasts and Fibroblasts In Vitro.

The formation of bone in a bone defect is accomplished by osteoblasts, while the over activation of fibroblasts promotes fibrosis. However, it is not clear how the extracellular matrix stiffness of the bone-regeneration microenvironment affects the function of osteoblasts and fibroblasts. This study aim to investigate the effect of bone-regeneration microenvironment stiffness on cell adhesion, cell proliferation, cell differentiation, synthesizing matrix ability and its potential mechanisms in mechanotransduction, in pre-osteoblasts and fibroblasts. Polyacrylamide substrates mimicking the matrix stiffness of different stages of the bone-healing process (15 kPa, mimic granulation tissue; 35 kPa, mimic osteoid; 150 kPa, mimic calcified bone matrix) were prepared. Mouse pre-osteoblasts MC3T3-E1 and mouse fibroblasts NIH3T3 were plated on three types of substrates, respectively. There were significant differences in the adhesion of pre-osteoblasts and fibroblasts on different polyacrylamide substrates. Runx2 expression increased with increasing substrate stiffness in pre-osteoblasts, while no statistical differences were found in the Acta2 expression in fibroblasts on three substrates. OPN expression in pre-osteoblasts, as well as Fn1 and Col1a1 expression in fibroblasts, decreased with increasing stiffness. The difference between the cell traction force generated by pre-osteoblasts and fibroblasts on substrates was also found. Our results indicated that substrate stiffness is a potent regulator of pre-osteoblasts and fibroblasts with the ability of promoting osteogenic differentiation of pre-osteoblasts, while having no effect on myofibroblast differentiation of fibroblasts.

Biocompatibility Assessment of Zinc Alloys as a New Potential Material for Bioabsorbable Implants for Osteosynthesis.

In the last several years, zinc and its alloys have come into focus as bioabsorbable materials by qualifying themselves with an excellent corrosion rate, mechanical properties, anti-bacterial effects. and considerable biocompatibility. In this study, the biocompatibility of zinc-silver alloys containing 3.3 wt% silver (ZnAg3) was assessed by evaluating their cell viability, the proliferation rate, and the cell toxicity. Two alloys were investigated in which one was phosphated and the other was non-phosphated. The alloys were tested on human osteoblasts (hOb), which are, to a large extent, responsible for bone formation and healing processes. The performance of the phosphated alloy did not differ significantly from the non-phosphated alloy. The results showed a promising biocompatibility with hOb for both alloys equally in all conducted assays, qualifying ZnAg3 for further investigations such as in vivo studies.

An Empirical Model Linking Physico-Chemical Biomaterial Characteristics to Intra-Oral Bone Formation.

Facial trauma, bone resection due to cancer, periodontal diseases, and bone atrophy following tooth extraction often leads to alveolar bone defects that require bone regeneration in order to restore dental function. Guided bone regeneration using synthetic biomaterials has been suggested as an alternative approach to autologous bone grafts. The efficiency of bone substitute materials seems to be influenced by their physico-chemical characteristics; however, the debate is still ongoing on what constitutes optimal biomaterial characteristics. The purpose of this study was to develop an empirical model allowing the assessment of the bone regeneration potential of new biomaterials on the basis of their physico-chemical characteristics, potentially giving directions for the design of a new generation of dental biomaterials. A quantitative data set was built composed of physico-chemical characteristics of seven commercially available intra-oral bone biomaterials and their in vivo response. This empirical model allowed the identification of the construct parameters driving optimized bone formation. The presented model provides a better understanding of the influence of driving biomaterial properties in the bone healing process and can be used as a tool to design bone biomaterials with a more controlled and custom-made composition and structure, thereby facilitating and improving the clinical translation.

Evolution from Bioinert to Bioresorbable: In Vivo Comparative Study of Additively Manufactured Metal Bone Scaffolds.

Additively manufactured scaffolds offer significant potential for treating bone defects, owing to their porous, customizable architecture and functionalization capabilities. Although various biomaterials have been investigated, metals - the most successful orthopedic material - have yet to yield satisfactory results. Conventional bio-inert metals, such as titanium (Ti) and its alloys, are widely used for fixation devices and reconstructive implants, but their non-bioresorbable nature and the mechanical property mismatch with human bones limit their application as porous scaffolds for bone regeneration. Advancements in additive manufacturing have facilitated the use of bioresorbable metals, including magnesium (Mg), zinc (Zn), and their alloys, as porous scaffolds via Laser Powder Bed Fusion (L-PBF) technology. This in vivo study presents a comprehensive, side-by-side comparative analysis of the interactions between bone regeneration and additively manufactured bio-inert/bioresorbable metal scaffolds, as well as their therapeutic outcomes. The research offers an in-depth understanding of the metal scaffold-assisted bone healing process, illustrating that Mg and Zn scaffolds contribute to the bone healing process in distinct ways, but ultimately deliver superior therapeutic outcomes compared to Ti scaffolds. These findings suggest that bioresorbable metal scaffolds hold considerable promise for the clinical treatment of bone defects in the near future.

Traumatic brain injury stimulates sympathetic tone-mediated bone marrow myelopoiesis to favor fracture healing

Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system (CNS) plays a pivotal role in regulating immune system and skeletal homeostasis. However, the impact of CNS injury on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells (HSCs) and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of β3- or β2-adrenergic receptor (AR) eliminate TBI-mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells. Importantly, flow cytometry confirmed that deletion of β2-AR inhibits M2 polarization of macrophages at 7th day and 14th day; and TBI-induced HSCs proliferation was impaired in β3-AR knockout mice. Moreover, β3- and β2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process. Thus, we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow. These results implicate that the adrenergic signals could serve as potential targets for fracture management.

Graphene oxide/gallium nanoderivative as a multifunctional modulator of osteoblastogenesis and osteoclastogenesis for the synergistic therapy of implant-related bone infection.

Currently, implant-associated bacterial infections account for most hospital-acquired infections in patients suffering from bone fractures or defects. Poor osseointegration and aggravated osteolysis remain great challenges for the success of implants in infectious scenarios. Consequently, developing an effective surface modification strategy for implants is urgently needed. Here, a novel nanoplatform (GO/Ga) consisting of graphene oxide (GO) and gallium nanoparticles (GaNPs) was reported, followed by investigations of its in vitro antibacterial activity and potential bacterium inactivation mechanisms, cytocompatibility and regulatory actions on osteoblastogenesis and osteoclastogenesis. In addition, the possible molecular mechanisms underlying the regulatory effects of GO/Ga nanocomposites on osteoblast differentiation and osteoclast formation were clarified. Moreover, an in vivo infectious microenvironment was established in a rat model of implant-related femoral osteomyelitis to determine the therapeutic efficacy and biosafety of GO/Ga nanocomposites. Our results indicate that GO/Ga nanocomposites with excellent antibacterial potency have evident osteogenic potential and inhibitory effects on osteoclast differentiation by modulating the BMP/Smad, MAPK and NF-κB signaling pathways. The in vivo experiments revealed that the administration of GO/Ga nanocomposites significantly inhibited bone infections, reduced osteolysis, promoted osseointegration located in implant-bone interfaces, and resulted in satisfactory biocompatibility. In summary, this synergistic therapeutic system could accelerate the bone healing process in implant-associated infections and can significantly guide the future surface modification of implants used in bacteria-infected environments.

Construction of Multifunctional Zinc Ion Sustained-Release Biocoating on the Surface of Carbon Fiber Reinforced Polyetheretherketone with Enhanced Anti-inflammatory Activity, Angiogenesis, and Osteogenesis.

Current treatments of carbon fiber-reinforced polyetheretherketone (CFRPEEK) as orthopedic implants remain unsatisfactory due to the bioinert surface. The multifunctionalization of CFRPEEK, which endows it with regulating the immune inflammatory response, promoting angiogenesis, and accelerating osseointegration, is critical to the intricate bone healing process. Herein, a multifunctional zinc ion sustained-release biocoating, consisting of a carboxylated graphene oxide, zinc ion, and chitosan layer, covalently grafts on the surface of amino CFRPEEK (CP/GC@Zn/CS) to coordinate with the osseointegration process. The release behavior of zinc ions theoretically conforms to the different demands in the three stages of osseointegration, including the burst release of zinc ions in the early stage (7.27 μM, immunomodulation), continuous release in the middle stage (11.02 μM, angiogenesis), and slow release in the late stage (13.82 μM, osseointegration). In vitro assessments indicate that the multifunctional zinc ion sustained-release biocoating can remarkably regulate the immune inflammatory response, decrease the oxidative stress level, and promote angiogenesis and osteogenic differentiation. The rabbit tibial bone defect model further confirms that, compared to the unmodified group, the bone trabecular thickness of the CP/GC@Zn/CS group increases 1.32-fold, and the maximum push-out force improves 2.05-fold. In this study, a multifunctional zinc ion sustained-release biocoating constructed on the surface of CFRPEEK that conforms to the requirements of different osseointegration stages can be an attractive strategy for the clinical application of inert implants.

Advances of Blood Coagulation Factor XIII in Bone Healing.

The biologic process of bone healing is complicated, involving a variety of cells, cytokines, and growth factors. As a result of bone damage, the activation of a clotting cascade leads to hematoma with a high osteogenic potential in the initial stages of healing. A major factor involved in this course of events is clotting factor XIII (FXIII), which can regulate bone defect repair in different ways during various stages of healing. Autografts and allografts often have defects in clinical practice, making the development of advanced materials that support bone regeneration a critical requirement. Few studies, however, have examined the promotion of bone healing by FXIII in combination with biomaterials, in particular, its effect on blood coagulation and osteogenesis. Therefore, we mainly summarized the role of FXIII in promoting bone regeneration by regulating the extracellular matrix and type I collagen, bone-related cells, angiogenesis, and platelets, and described the research progress of FXIII = related biomaterials on osteogenesis. This review provides a reference for investigators to explore the mechanism by which FXIII promotes bone healing and the combination of FXIII with biomaterials to achieve targeted bone tissue repair.