RESUMEN

Skeletal growth and fracture healing rely on the mineralization of cartilage in a process called endochondral ossification. Chondrocytes firstly synthesize and then modify cartilage by the release of a wide range of particles into their extracellular space. Extracellular vesicles (EVs) are one type of such particles, but their roles in endochondral ossification are yet to be fully understood. It remains a challenge to obtain representative populations of chondrocyte-derived EVs, owing to difficulties both in preserving the function of primary chondrocytes in culture and in applying the serum-free conditions required for EV production. Here, we used the ATDC5 cell-line to recover chondrocyte-derived EVs from early- and late-differentiation stages, representing chondrocytes before and during cartilage mineralization. After screening different culture conditions, our data indicate that a serum-free Opti-MEM-based culture medium preserves chondrocyte identity and function, matrix mineralization and cell viability. We subsequently scaled-up production and isolated EVs from conditioned medium by size-exclusion chromatography. The obtained chondrocyte-derived EVs had typical ultrastructure and expression of classical EV markers, at quantities suitable for downstream experiments. Importantly, chondrocyte-derived EVs from late-differentiation stages had elevated levels of alkaline phosphatase activity. Hence, we established a method to obtain functional chondrocyte-derived EVs before and during cartilage mineralization that may aid the further understanding of their roles in endochondral bone growth and fracture healing.

RESUMEN

This study proposes a computational framework to investigate the multi-stage process of fracture healing in hard tissues, e.g., long bone, based on the mathematical Bailon-Plaza and Van der Meulen formulation. The goal is to explore the influence of critical biological factors by employing the finite element method for more realistic configurations. The model integrates a set of variables, including cell densities, growth factors, and extracellular matrix contents, managed by a coupled system of partial differential equations. A weak finite element formulation is introduced to enhance the numerical robustness for coarser mesh grids, complex geometries, and more accurate boundary conditions. This formulation is less sensitive to mesh quality and converges smoothly with mesh refinement, exhibiting superior numerical stability compared to previously available strong-form solutions. The model accurately reproduces various stages of healing, including soft cartilage callus formation, endochondral and intramembranous ossification, and hard bony callus development for various sizes of fracture gap. Model predictions align with the existing research and are logically coherent with the available experimental data. The developed multiphysics simulation clarifies the coordination of cellular dynamics, extracellular matrix alterations, and signaling growth factors during fracture healing.

Asunto(s)

RESUMEN

The goal of this study was to develop an image analysis algorithm for quantifying the effects of remodeling on cortical bone during early fracture healing. An adaptive thresholding technique with boundary curvature and tortuosity control was developed to automatically identify the endocortical and pericortical boundaries in the presence of high-gradient bone mineral density (BMD) near the healing zone. The algorithm successfully segmented more than 47,000 microCT images from 12 healing ovine osteotomies and intact contralateral tibiae. Resampling techniques were used to achieve data dimensionality reduction on the segmented images, allowing characterization of radial and axial distributions of cortical BMD. Local (transverse slice) and total (whole bone) remodeling scores were produced. These surrogate measures of cortical remodeling derived from BMD revealed that cortical changes were detectable throughout the region covered by callus and that the localized loss of cortical BMD was highest near the osteotomy. Total remodeling score was moderately and significantly correlated with callus volume and mineral composition (r > 0.64, p < 0.05), suggesting that the cortex may be a source of mineral needed to build callus.

RESUMEN

Delayed bone-healing of senile osteoporotic fractures remains a clinical challenge due to the alterations caused by aging in bone and immune systems. The novel biomaterials that address the deficiencies in both skeletal cells and immune systems are required to effectively treat the bone injuries of older patients. Zinc (Zn) has shown promise as a biodegradable material for use in orthopedic implants. To address the bone-healing deficiencies in elderly patients with bone injuries, we developed a biodegradable Zn-based alloy (Zn-2Cu-0.5Zr) with enhanced mechanical properties, including a yield strength of 198.7 MPa and ultimate tensile strength of 217.6 MPa, surpassing those of pure Zn and Zn-2Cu alloys. Cytotoxicity tests conducted on bone marrow mesenchymal stem cells (BMSCs) and MC3T3-E1 cells demonstrated that the extracts from Zn-2Cu-0.5Zr alloy exhibited no observable cytotoxic effects. Furthermore, the extracts of Zn-2Cu-0.5Zr alloy exhibited significant anti-inflammatory effects through regulation of inflammation-related cytokine production and modulation of macrophage polarization. The improved immune-osteo microenvironment subsequently contributed to osteogenic differentiation of BMSCs. The potential therapeutic application of Zn-2Cu-0.5Zr in senile osteoporotic fracture was tested using a rat model of age-related osteoporosis. The Zn-2Cu-0.5Zr alloy met the requirements for load-bearing applications and accelerated the healing process in a tibial fracture in aged rats. The imaging and histological analyses showed that it could accelerate the bone-repair process and promote the fracture healing in senile osteoporotic rats. These findings suggest that the novel Zn-2Cu-0.5Zr alloy holds potential for influencing the immunomodulatory function of macrophages and facilitating bone repair in elderly individuals with osteoporosis.

RESUMEN

Bone fractures and critical-size bone defects are significant public health issues, and clinical treatment outcomes are closely related to the intrinsic properties of the utilized implant materials. Zinc (Zn)-based biodegradable metals (BMs) have emerged as promising bioactive materials because of their exceptional biocompatibility, appropriate mechanical properties, and controllable biodegradation. This review summarizes the state of the art in terms of Zn-based metals for bone repair and regeneration, focusing on bridging the gap between biological mechanism and required bioactivity. The molecular mechanism underlying the release of Zn ions from Zn-based BMs in the improvement of bone repair and regeneration is elucidated. By integrating clinical considerations and the specific bioactivity required for implant materials, this review summarizes the current research status of Zn-based internal fixation materials for promoting fracture healing, Zn-based scaffolds for regenerating critical-size bone defects, and Zn-based barrier membranes for reconstituting alveolar bone defects. Considering the significant progress made in the research on Zn-based BMs for potential clinical applications, the challenges and promising research directions are proposed and discussed.

RESUMEN

BACKGROUND: Osteoporosis and diabetes are two prevalent conditions among the elderly population. Each of these conditions can profoundly influence the fracture healing process by disturbing the associated inflammatory process. However, the combined effects of osteoporosis and diabetes on fracture healing remain unclear. Therefore, the purpose of the present study is to investigate the role of osteoporosis and diabetes in fracture healing and the underlying mechanisms by developing numerical models. METHOD: This study introduces a numerical model that consists of a three-dimensional model of a tibia fracture stabilized by a Locking Compression Plate (LCP), coupled with a two-dimensional axisymmetric model which illustrates the transport and reactions of cells and cytokines throughout the inflammatory phase in early fracture healing. First, the model parameters were calibrated using available experimental data. The model was then implemented to predict the healing outcomes of fractures under five varied conditions, consisting of both osteoporotic and non-osteoporotic bones, each subjected to different physiological loads. RESULTS: The instability of the fracture callus can significantly escalate in osteoporotic fractures (e.g., when a 150 N physiological load is applied, the unstable region of the osteoporotic fracture callus can reach 26 %, in contrast to 12 % in non-osteoporotic fractures). Additionally, the mesenchymal stem cells (MSCs) proliferation and differentiation can be disrupted in osteoporotic fracture compared to non-osteoporotic fractures (e.g., on the 10th day post-fracture, the decrease in the concentration of MSCs, osteoblasts, and chondrocytes in osteoporotic fractures is nearly double that in non-osteoporotic fractures under a 150 N). Finally, the healing process of fractures can suffer significant impairment when osteoporosis coexists with diabetes (e.g., the concentration of MSCs can be drastically reduced by nearly 37 % in osteoporotic fractures under diabetic conditions when subjected to a load of 200 N) CONCLUSIONS: Fracture calluses destabilized by osteoporosis can negatively affect the fracture healing process by disrupting the proliferation and differentiation of mesenchymal stem cells (MSCs). Moreover, when osteoporosis coexists with diabetes, the fracture healing process can severely impair the fracture healing outcomes.

Asunto(s)

RESUMEN

Objective To determine the effect of isopsoralen(ISO)on the healing of tibia fracture in mice and explore its underlying mechanism.Methods Fifty male C57BL/6 mice(2 month old,20±2 g)were randomly divided into model group and ISO treatment group,with 25 animals in each group.From the 3rd day after modeling,the mice from the ISO group were given an intragastric gavage of 40 mg/kg ISO,once per day for 28 consecutive days,while those of the model group was given same volume of normal saline in same way.On the 7th,14th,21st,and 28th day after gavage,the tibia on the surgical side was taken,and the fracture area was quantified by bone volume/total volume(BV/TV)after micro-CT scanning.The healing and shaping of the fracture end were observed through HE staining.ELISA was used to detect the serum contents of bone alkaline phosphatase(BALP)and procollagen type I N-terminal peptide(PINP)on the 14th day of gavage.Western blotting was employed to determine the expression levels of Collagen Ⅰ,Runx2,BMP2,OSX,and VEGF in the tibial callus tissue in 7 and 14 d after gavage.Vascular perfusion was applied to observe the callus microvessels in 28 d to quantitatively analyze the vascular volume fraction and vessel diameter.Immunohistochemical staining was conducted to observe the expression of VEGF in the callus in 14 d after gavage.Results HE staining displayed that the ISO group had faster healing process than the model group.Micro-CT quantification results showed that the ISO group had higher BV/TV ratio in 7 d after gavage though no statistical difference,significantly higher ratio in 14 d(P＜0.05),but obviously lower ratio in 21 and 28 d after gavage(both P＜0.05)when compared with the model group.The serum contents of BALP and PINP were also remarkably higher in the ISO group than the model group(P＜0.05).Western blotting results indicated that the expression levels of Collagen Ⅰ,Runx2,BMP2,OSX and VEGF in the ISO group were higher than those in the model group(P＜0.05).The results of angiography revealed that the vascular volume fraction and vessel diameter were notably increased in the ISO group than the model group(both P＜0.05).Immunohistochemical assay showed that the expression of VEGF was higher in the ISO group than the model group(P＜0.05).Conclusion ISO can improve the activity of osteoblasts,increase the expression of osteogenesis-related proteins,and accelerate the angiogenesis to promote fracture healing.

RESUMEN

Bone fracture healing is a well-orchestrated but complex process that involves numerous regulations at different scales. This complexity becomes particularly evident during the inflammatory stage, as immune cells invade the healing region and trigger a cascade of signals to promote a favorable regenerative environment. Thus, the emergence of criticalities during this stage might hinder the rest of the process. Therefore, the investigation of the many interactions that regulate the inflammation has a primary importance on the exploration of the overall healing progression. In this context, an in silico model named COMMBINI (COmputational Model of Macrophage dynamics in the Bone INjury Immunoresponse) has been developed to investigate the mechano-biological interactions during the early inflammatory stage at the tissue, cellular and molecular levels. An agent-based model is employed to simulate the behavior of immune cells, inflammatory cytokines and fracture debris as well as their reciprocal multiscale biological interactions during the development of the early inflammation (up to 5 days post-injury). The strength of the computational approach is the capacity of the in silico model to simulate the overall healing process by taking into account the numerous hidden events that contribute to its success. To calibrate the model, we present an in silico immunofluorescence method that enables a direct comparison at the cellular level between the model output and experimental immunofluorescent images. The combination of sensitivity analysis and a Genetic Algorithm allows dynamic cooperation between these techniques, enabling faster identification of the most accurate parameter values, reducing the disparity between computer simulation and histological data. The sensitivity analysis showed a higher sensibility of the computer model to the macrophage recruitment ratio during the early inflammation and to proliferation in the late stage. Furthermore, the Genetic Algorithm highlighted an underestimation of macrophage proliferation by in vitro experiments. Further experiments were conducted using another externally fixated murine model, providing an independent validation dataset. The validated COMMBINI platform serves as a novel tool to deepen the understanding of the intricacies of the early bone regeneration phases. COMMBINI aims to contribute to designing novel treatment strategies in both the biological and mechanical domains.

Asunto(s)

RESUMEN

Zn and its alloys are increasingly under consideration for biodegradable bone fracture fixation implants owing to their attractive biodegradability and mechanical properties. However, their clinical application is a challenge for osteoporotic bone fracture healing, due to their uneven degradation mode, burst release of zinc ions, and insufficient osteo-promotion and osteo-resorption regulating properties. In this study, a type of Zn2+ coordinated zoledronic acid (ZA) and 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP) metal-organic hybrid nanostick was synthesized, which was further mixed into zinc phosphate (ZnP) solution to mediate the deposition and growth of ZnP to form a well-integrated micro-patterned metal-organic/inorganic hybrid coating on Zn. The coating protected noticeably the Zn substrate from corrosion, in particular reducing its localized occurrence as well as suppressing its Zn2+ release. Moreover, the modified Zn was osteo-compatible and osteo-promotive and, more important, performed osteogenesis in vitro and in vivo of well-balanced pro-osteoblast and anti-osteoclast responses. Such favorable functionalities are related to the nature of its bioactive components, especially the bio-functional ZA and the Zn ions it contains, as well as its unique micro- and nano-scale structure. This strategy provides not only a new avenue for surface modification of biodegradable metals but also sheds light on advanced biomaterials for osteoporotic fracture and other applications. STATEMENT OF SIGNIFICANCE: Developing appropriate biodegradable metallic materials is of clinical relevance for osteoporosis fracture healing, whereas current strategies are short of good balance between the bone formation and resorption. Here, we designed a micropatterned metal-organic nanostick mediated zinc phosphate hybrid coating modified Zn biodegradable metal to fulfill such a balanced osteogenicity. The in vitro assays verified the coated Zn demonstrated outstanding pro-osteoblasts and anti-osteoclasts properties and the coated intramedullary nail promoted fracture healing well in an osteoporotic femur fracture rat model. Our strategy may offer not only a new avenue for surface modification of biodegradable metals but also shed light on better understanding of new advanced biomaterials for orthopedic application among others.

Asunto(s)

RESUMEN

Low-level laser therapy (LLLT) is a treatment that is increasingly used in orthopedics practices. In vivo and in vitro studies have shown that low-level laser therapy (LLLT) promotes angiogenesis, fracture healing and osteogenic differentiation of stem cells. However, the underlying mechanisms during bone formation remain largely unknown. Factors such as wavelength, energy density, irradiation and frequency of LLLT can influence the cellular mechanisms. Moreover, the effects of LLLT are different according to cell types treated. This review aims to summarize the current knowledge of the molecular pathways activated by LLLT and its effects on the bone healing process. A better understanding of the cellular mechanisms activated by LLLT can improve its clinical application.

Asunto(s)

RESUMEN

Background: The rigidity in osteosynthesis causes primary healing, and it takes longer to heal. The flexibility provided to the fixation allows micromotion between fragments which accelerates secondary healing. Methods: In this study, the healing outcomes of nailing and plating in different fixation stabilities were investigated and compared by using a finite element tool. The clinical observational study was also performed to verify the results of the finite element analysis. The nonlinear contact analysis was performed on 5 different fixation configurations capturing nail and plate in immediate post-surgery. Results: The finite element analysis results showed that flexibility instead of rigidity in interlock nail implantation increases the axial and shear micromotion near the fracture site by 47.4% (P < 0.05) and 12.4% (P < 0.05), respectively. For LCDCP implantation, the flexible fixation increases the axial and shear micromotion near fracture site by 75.7% (P < 0.05) and 25.3% (P < 0.05), respectively. Conclusion: Our findings suggest that flexible fixations of interlock nail and LCDCP provide a preferred mechanical environment for healing, and hence, the LCDCP in flexible mode can be an effective alternative to interlock nail for the femur diaphyseal fracture. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-022-00795-1.

RESUMEN

BACKGROUND: Bone fracture healing is a time-consuming and high-priority orthopedic problem worldwide. OBJECTIVE: Discovering the potential mechanism of bone healing at a time course and transcriptional level may better help manage bone fracture. METHODS: In this study, we analyze a time-course bone fracture healing transcriptional dataset in a rat model (GSE592, GSE594, and GSE1371) of Gene Expression Omnibus (GEO). RNA was obtained from female Sprague-Dawley rats with a femoral fracture at the initial time (day 3) as well as early (week 1), middle (week 2), and late (week 4) time periods, with nonfracture rats used as control. Gene Ontology (GO) functional analysis and pathway examinations were performed for further measurements of GSEA and hub genes. RESULTS: Results indicated that the four stages of bone fracture healing at the initial, early, middle, and late time periods represent the phases of hematoma formation, callus formation, callus molding, and mature lamellar bone formation, respectively. Extracellular organization was positively employed throughout the four stages. At the hematoma formation phase, the muscle contraction process was downregulated. Antibacterial peptide pathway was downregulated at all phases. The upregulation of Fn1 (initial, early, middle, and late time periods), Col3a1 (initial, early, and middle time periods), Col11a1 (initial and early time periods), Mmp9 (middle and late time periods), Mmp13 (early, middle, and late time periods) and the downregulation of RatNP-3b (initial, early, middle, and late time periods) were possible symbols for bone fracture healing and may be used as therapeutic targets. CONCLUSION: These findings suggest some new potential pathways and genes in the process of bone fracture healing and further provide insights that can be used in targeted molecular therapy for bone fracture healing.

Asunto(s)

RESUMEN

BACKGROUND AND OBJECTIVE: Mechanical stability plays an important role in fracture healing process. Excessive interfragmentary movement will continuously damage the tissue and newly formed capillaries at the fracture site, which leads to overproduction of platelet-derived growth factor (PDGF) that attracts more macrophages into fracture callus, ultimately persistent and enhanced inflammatory response happens. For diabetic condition, the impact of mechanical instability of fracture site on inflammatory response could be further compliciated and the relevant research in this field is relatively limited. METHODS: Building on previous experimental studies, this study presents a numerical model consisting of a system of reactive-transport equations representing the transport as well as interactions of different cells and cytokines within the fracture callus. The model is initially validated by available experimental data, and then implemented to investigate the role of mechanical stability of fracture site in inflammatory response during early stage of healing. It is assumed that there is an increased release of PDGF due to the rupture of blood vessels resulting from mechanical instability, which leads to increased production of inflammatory cytokines (i.e., TNF-α). The bone healing process under three different conditions were investigated, i.e., mechanically stable condition with normal inflammatory response (Control, Case 1), mechanically unstable condition with normal inflammatory response (Case 2) and mechanically unstable condition with diabetes (Case 3). RESULTS: Mechanical instability can promote the macrophage infiltration and thus induce an enhanced and prolonged inflammatory response, which could impede the MSCs proliferation during the early fracture healing stage (e.g., compared with the control condition, the MSCs concentration in unstable fracture with normal inflammatory response can be reduced by 3.2% and 5.2% on day 2 and day 10 post-fracture, respectively). Under diabetic condition, the mechanical instability of fracture site could lead to a significant increase of TNF-α concentration in fracture callus (Case 3) in comparison to control (Case 1) (e.g., three-fold increase in TNF-α concentration compared to control). In addition, the results show that the mechanical instability affects the cell differentiation and proliferation in fracture callus in a spatially dependent manner, e.g., for diabetic fracture patients, the mechanical instability could potentially decrease the concentration of MSCs, osteoblasts and chondrocytes by around 39%, 30% and 29% in cortical callus, respectively, in comparison to control. CONCLUSION: The mechanical instability together with diabetic condition can significantly affect the natural resolution of inflammation during early stage of healing by turning acute inflammation into chronic inflammation which is characterized by a continuously upregulated TNF-α pathway.

Asunto(s)

RESUMEN

This study investigated the protective characteristics of caffeic acid phenethyl ester (CAPE) and thymoquinone (TMQ) against the effects of cigarette smoke in recovery from bone fractures. Sixty Wistar albino rats were divided into six groups (n = 10). The rats' femur bones were fractured and then fixed with microplates and microscrews. In the CAPE group, CAPE was given by intraperitoneal injection for 30 days at a dose of 10 µmol/kg once a day. In the TMQ group, TMQ was given orogastrically for 30 days at a dose of 10 mg/kg once a day. In the cigarette groups, CAPE was given by intraperitoneal injection for 30 days at a dose of 10 µmol/kg once a day (CAPE-CG), TMQ was given orogastrically for 30 days at a dose of 10 mg/kg once a day (TMQ-CG), and controls were exposed to cigarette smoke three times a day for 8 min each time for 30 days. The controls received no postoperative treatment. The rats were sacrificed on the 30th day following surgery. According to the histopathological and immunohistochemical results, cigarette smoke had a negative impact on bone healing. TMQ and CAPE increased bone formation and reduced bone destruction. Therefore, TMQ and CAPE were found to be partially protective against the adverse effects of smoking on bone tissue.

RESUMEN

The implementation of novel coaxial dipole antennas has been shown to be a satisfactory diagnostic platform for the prediction of orthopaedic bone fracture healing outcomes. These techniques require mechanical deflection of implanted metallic hardware (i.e., rods and plates), which, when loaded, produce measurable changes in the resonant frequency of the adjacent antenna. Despite promising initial results, the coiled coaxial antenna design is limited by large antenna sizes and nonlinearity in the resonant frequency data. The purpose of this study was to develop two Vivaldi antennas (a.k.a., "standard" and "miniaturized") to address these challenges. Antenna behaviors were first computationally modeled prior to prototype fabrication. In subsequent benchtop tests, metallic plate segments were displaced from the prototype antennas via precision linear actuator while measuring resultant change in resonant frequency. Close agreement was observed between computational and benchtop results, where antennas were highly sensitive to small displacements of the metallic hardware, with sensitivity decreasing nonlinearly with increasing distance. Greater sensitivity was observed for the miniaturized design for both stainless steel and titanium implants. Additionally, these data demonstrated that by taking resonant frequency data during implant displacement and then again during antenna displacement from the same sample, via linear actuators, that "antenna calibration procedures" could be used to enable a clinically relevant quantification of fracture stiffness from the raw resonant frequency data. These improvements mitigate diagnostic challenges associated with nonlinear resonant frequency response seen in previous antenna designs.

RESUMEN

AIMS: Alcoholism is a well-known detrimental factor in fracture healing. However, the underlying mechanism of alcohol-inhibited fracture healing remains poorly understood. METHODS: MicroRNA (miR) sequencing was performed on bone mesenchymal stem cells (BMSCs). The effects of alcohol and miR-19a-3p on vascularization and osteogenic differentiation were analyzed in vitro using BMSCs and human umbilical vein endothelial cells (HUVECs). An in vivo alcohol-fed mouse model of femur fracture healing was also established, and radiological and histomorphometric analyses were used to evaluate the role of miR-19a-3p. The binding of miR-19a-3p to forkhead box F2 (FOXF2) was analyzed using a luciferase reporter assay. RESULTS: miR-19a-3p was identified as one of the key regulators in the osteogenic differentiation of BMSCs, and was found to be downregulated in the alcohol-fed mouse model of fracture healing. In vitro, miR-19a-3p expression was downregulated after ethanol administration in both BMSCs and HUVECs. Vascularization and osteogenic differentiation were independently suppressed by ethanol and reversed by miR-19a-3p. In addition, the luciferase reporter assay showed that FOXF2 is the direct binding target of miR-19a-3p. In vivo, miR-19a-3p agomir stimulated callus transformation and improved the alcohol-impaired fracture healing. CONCLUSION: This study is the first to demonstrate that the miR-19a-3p/FOXF2 axis has a pivotal role in alcohol-impaired fracture healing, and may be a potential therapeutic target. Cite this article: Bone Joint Res 2022;11(6):386-397.

RESUMEN

INTRODUCTION: In the early stage of fracture fixation, the aim of a unilateral external fixator (UEF) to stimulate healing and maintain stability may be suppressed by using inadequate number of pins. Cortical thinning due to age or osteoporosis endangers a successful fracture fixation. MATERIALS AND METHODS: This study evaluates the initial strength and stability of the fracture fixation and tissue differentiation under the influences of variable cortical thickness (5 mm to 1 mm) and variable number of pins (1 to 4 in each bone fragment). A finite element program was utilised to develop 20 three-dimensional models of simplified diaphyseal tibia with fracture callus fixed with UEF. A mechano-regulation code based on the deviatoric strain theory was written and applied to simulate tissue differentiation. The values of von Mises stress, interfragmentary strain (IFS), and fibrocartilage index (FCI) were evaluated. RESULTS: Cortical thinning from 5 mm to 1 mm increased IFS and FCI by an average of 30.3% and 18.7%, respectively, and resulted in higher stresses in the UEF and bone. Using 1 pin in each bone fragment produced excessive IFS in the models with 1 mm, 2 mm and 3 mm cortical thickness. Inserting the second pin into the bone fragment could considerably reduce the IFS and fibrocartilaginous tissue formation in the fracture site and improve load transmission to the fixator. Whereas inserting the fourth pin could minimally affect the mechano-biological environment of healing. CONCLUSIONS: This study suggests that initial instability due to cortical thinning can be efficiently alleviated by adding the number of pins up to 3 in a UEF; additionally, it may improve the knowledge about applying UEFs adequately stable, whilst promoting inclination toward endochondral ossification, simultaneously.

Asunto(s)

RESUMEN

In response to mechanical forces and the aging process, bone in the adult skeleton is continuously remodeled by a process in which old and damaged bone is removed by bone-resorbing osteoclasts and subsequently is replaced by new bone by bone-forming cells, osteoblasts. During this essential process of bone remodeling, osteoclastic resorption is tightly coupled to osteoblastic bone formation. Bone-resorbing cells, multinuclear giant osteoclasts, derive from the monocyte/macrophage hematopoietic lineage and their differentiation is driven by distinct signaling molecules and transcription factors. Critical factors for this process are Macrophage Colony Stimulating Factor (M-CSF) and Receptor Activator Nuclear Factor-κB Ligand (RANKL). Besides their resorption activity, osteoclasts secrete coupling factors which promote recruitment of osteoblast precursors to the bone surface, regulating thus the whole process of bone remodeling. Bone morphogenetic proteins (BMPs), a family of multi-functional growth factors involved in numerous molecular and signaling pathways, have significant role in osteoblast-osteoclast communication and significantly impact bone remodeling. It is well known that BMPs help to maintain healthy bone by stimulating osteoblast mineralization, differentiation and survival. Recently, increasing evidence indicates that BMPs not only help in the anabolic part of bone remodeling process but also significantly influence bone catabolism. The deletion of the BMP receptor type 1A (BMPRIA) in osteoclasts increased osteoblastic bone formation, suggesting that BMPR1A signaling in osteoclasts regulates coupling to osteoblasts by reducing bone-formation activity during bone remodeling. The dual effect of BMPs on bone mineralization and resorption highlights the essential role of BMP signaling in bone homeostasis and they also appear to be involved in pathological processes in inflammatory disorders affecting bones and joints. Certain BMPs (BMP2 and -7) were approved for clinical use; however, increased bone resorption rather than formation were observed in clinical applications, suggesting the role BMPs have in osteoclast activation and subsequent osteolysis. Here, we summarize the current knowledge of BMP signaling in osteoclasts, its role in osteoclast resorption, bone remodeling, and osteoblast-osteoclast coupling. Furthermore, discussion of clinical application of recombinant BMP therapy is based on recent preclinical and clinical studies.

Asunto(s)

RESUMEN

Due to their superior mechanical and chemical properties, titanium (Ti) and its alloys have been widely used as orthopedic implantable devices. However, their bioinertness represents a limitation, which can be overcome by employing various surface modifications, such as TiO2 nanotube (TNT) fabrication via electrochemical anodization. Anodic TNTs present tunable dimensions and unique structures, turning them into feasible drug delivery platforms. In the present work, TNTs were loaded with icariin (Ica) through an adhesive intermediate layer of polydopamine (DP), and their in vitro and in vivo biological performance was evaluated. The successful fabrication of the modified surfaces was verified by scanning electron microscopy (SEM), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), and contact angle measurements (CA), while the in vitro release of Ica was evaluated via UV-VIS spectrophotometry. In terms of in vitro behaviour, comparative studies on RAW 264.7 macrophages demonstrated that the TNT substrates, especially TNT-DP-Ica, elicited a lower inflammatory response compared to the Ti support. Moreover, the in vivo implantation studies evinced generation of a reduced fibrotic capsule around this implant and increased thickness of the newly formed bone tissue at 1 month and 3 months post-implantation, respectively. Overall, our results indicate that the controlled release of Ica from TNT surfaces could result in an improved osseointegration process.

RESUMEN

In this study, a coupled computational modelling framework for bone fracture repair is presented that enables predictions of both healing and remodelling phases of the fracture region and is used to investigate the role of an internal fixation plate on the long-term healing performance of a fracture tibia under a range of different conditions. It was found that introduction of a titanium plate allowed the tibia to undergo successful healing at higher loading conditions and fracture gaps, compared with the non-plated versions. While these plated cases showed faster rates of repair in the healing phase, their performance was substantially different once they entered the remodelling phase, with substantial regions of stress shielding predicted. This framework is one of the few implementations of both fracture healing and remodelling phases of bone repair and includes several innovative approaches to smoothing, time-averaging and time incrementation in its implementation, thereby avoiding any unwanted abrupt changes between tissue phenotypes. This provides a better representation of tissue development in the fracture site when compared with fracture healing models alone and provides a suitable platform to investigate the long-term performance of orthopaedic fixation devices. This would enable the more effective design of permanent fixation devices and optimisation of the spatial and temporal performance of bioabsorbable implants.

Asunto(s)