Effects of time delays in a mathematical bone model

In this paper we propose a mathematical model of bone remodeling with time delays of both osteoclast-derived paracrine signaling of tumor and tumor-derived paracrine signaling of osteoclast. The effects of time delays on the growth of tumor cells and bone system are studied in multiple myeloma-induced bone disease. In the case of small osteoclast-derived paracrine signaling, it is found that the growth of tumor cells slows down, the oscillation period of the ratio of osteoclasts to osteoblasts is extended with increasing time delay, and there is a competition between the delay and osteoclast-derived paracrine signaling. In the ease of large tumor-derived paraerine signaling, the tumor-derived paracrine signaling can induce a more significant decline in tumor growth for long time delay, and thus slowing down the progression of bone disease. There is an optimal coupling between the tumor-derived paracrine signaling of osteoclasts and time delay during the progressions of bone diseases, which suppresses the tumor growth and the regression of bone disease.

Geometric Bone Modeling:From Macro to Micro Structures

There is major interest within the bio-engineering community in developing accurate and non-invasive means for visualizing, modeling and analyzing bone micro-structures. Bones are composed of hierarchical bio-composite materials characterized by complex multi-scale structural geometry. The process of reconstructing a volumetric bone model is usually based upon CT/MRI scanned images. Meshes generated by current commercial CAD systems cannot be used for further modeling or analysis. Moreover, recently developed methods are only capable of capturing the micro-structure for small volumes （biopsy samples）. This paper examines the problem of re-meshing a 3D computerized model of bone micro- structure. The proposed method is based on the following phases： defining sub-meshes of the original model in a grid-based structure, remeshing each sub-mesh using the neural network （NN） method, and merging the sub-meshes into a global mesh. Applying the NN method to micro-structures proved to be quite time consuming. Therefore, a parallel, grid-based approach was applied, yielding a simpler structure in each grid cell. The performance of this method is analyzed, and the method is demonstrated on real bone micro-structures. Furthermore, the method may be used as the basis for generating a multi-resolution bone geometric model.

Selective serotonin re-uptake inhibitor sertraline inhibits bone healing in a calvarial defect model

Bone wound healing is a highly dynamic and precisely controlled process through which damaged bone undergoes repair and complete regeneration. External factors can alter this process, leading to delayed or failed bone wound healing. The findings of recent studies suggest that the use of selective serotonin reuptake inhibitors(SSRIs) can reduce bone mass, precipitate osteoporotic fractures and increase the rate of dental implant failure. With 10% of Americans prescribed antidepressants, the potential of SSRIs to impair bone healing may adversely affect millions of patients’ ability to heal after sustaining trauma. Here, we investigate the effect of the SSRI sertraline on bone healing through pre-treatment with(10 mg·kg-1sertraline in drinking water, n = 26) or without(control, n = 30) SSRI followed by the creation of a 5-mm calvarial defect. Animals were randomized into three surgical groups:(a) empty/sham,(b) implanted with a DermaMatrix scaffold soak-loaded with sterile PBS or(c) DermaMatrix soak-loaded with542.5 ng BMP2. SSRI exposure continued until sacrifice in the exposed groups at 4 weeks after surgery. Sertraline exposure resulted in decreased bone healing with significant decreases in trabecular thickness, trabecular number and osteoclast dysfunction while significantly increasing mature collagen fiber formation. These findings indicate that sertraline exposure can impair bone wound healing through disruption of bone repair and regeneration while promoting or defaulting to scar formation within the defect site.

Ultrasonic backscatter characterization of cancellous bone using a general Nakagami statistical model

The goal of this study is to analyze the statistics of the backscatter signal from bovine cancellous bone using a Nakagami model and to evaluate the feasibility of Nakagami-model parameters for cancellous bone characterization. Ultrasonic backscatter measurements were performed on 24 bovine cancellous bone specimens in vitro and the backscatter signals were compensated for the frequency-dependent attenuation prior to the envelope detection. The statistics of the backscatter envelope were modeled using the Nakagami distribution. Our results reveal that the backscatter envelope mainly followed pre-Rayleigh distributions, and the deviations of the backscatter envelope from Rayleigh distribution decreased with increasing bone density. The Nakagami shape parameter(i.e., m) was significantly correlated with bone densities(R = 0.78–0.81, p < 0.001) and trabecular microstructures(|R| = 0.46–0.78, p < 0.05). The scale parameter(i.e.,?) and signal-to-noise ratio(SNR) also yielded significant correlations with bone density and structural features. Multiple linear regressions showed that bone volume fraction(BV/TV) was the main predictor of the Nakagami parameters,and microstructure produced significantly independent contribution to the prediction of Nakagami distribution parameters,explaining an additional 10.2% of the variance at most. The in vitro study showed that statistical parameters derived with Nakagami model might be useful for cancellous bone characterization, and statistical analysis has potential for ultrasonic backscatter bone evaluation.

The pinhole SPECT for animal model of bone metastasis with SPC-A-1BM human pulmonary adenocarcinoma bone metastasis cell line

The study was to investigate the role of pinhole single photon emission computed tomography (SPECT), the human pulmonary adenocarcinoma bone-seeking metastasis cell line SPC-A-1BM was used.These cells form typical osteolytic bone metastases when inoculated into the arterial circulation of NIH-Beige-Nude-XD (BNX) mice via the left ventricle.In order to evaluate the irradiation impact of ^(99m)Tc-MDP versus X-ray on cells growth,we used six groups of SPC-A-1BM cells in our imaging scheme and irradiated by various doses of ^(99m)Tc-MDP (37,74,111, 370,740 MBq) and X-ray(40 kV,2 mA,6 s) respectively.The cell's number of each group was well recorded in different exposure time(4,8,12,24,48,72,96 hours).After that,SPC-A-1BM cells(1×106) were inoculated into the mice via left ventricle.We compared the results obtained with those different doses of ^(99m)Tc-MDP using pinhole SPECT and conventional X-ray skeletal surveys.The data show that the cell-survival number of 111 MBq group has insignificant difference with that of X-ray and the dose is adequate to have an ideal image.Besides,it is important that the chromosome of the cells in the group of 111 MBq showed no irradiation-related damages in our test.These results implied that ^(99m)Tc-MDP pinhole SPECT may provide another way other than conventional X-ray skeletal surveys in detecting bone metastasis of pulmonary adenocarcinoma in BNX mice.

Administration of soluble activin receptor 2B increases bone and muscle mass in a mouse model of osteogenesis imperfecta

Osteogenesis imperfecta（OI） comprises a group of heritable connective tissue disorders generally defined by recurrent fractures, low bone mass, short stature and skeletal fragility. Beyond the skeletal complications of OI,many patients also report intolerance to physical activity, fatigue and muscle weakness. Indeed, recent studies have demonstrated that skeletal muscle is also negatively affected by OI, both directly and indirectly. Given the well-established interdependence of bone and skeletal muscle in both physiology and pathophysiology and the observations of skeletal muscle pathology in patients with OI, we investigated the therapeutic potential of simultaneous anabolic targeting of both bone and skeletal muscle using a soluble activin receptor 2B（ACVR2B） in a mouse model of type Ⅲ OI（oim）. Treatment of 12-week-old oim mice with ACVR2 B for 4 weeks resulted in significant increases in both bone and muscle that were similar to those observed in healthy,wild-type littermates. This proof of concept study provides encouraging evidence for a holistic approach to treating the deleterious consequences of OI in the musculoskeletal system.

New simulation model for bone formation markers in osteoporosis patients treated with once-weekly teriparatide

Daily 20-mg and once-weekly 56.5-mg teriparatide（parathyroid hormone 1–34） treatment regimens increase bone mineral density（BMD） and prevent fractures, but changes in bone turnover markers differ between the two regimens. The aim of the present study was to explain changes in bone turnover markers using once-weekly teriparatide with a simulation model. Temporary increases in bone formation markers and subsequent decreases were observed during once-weekly teriparatide treatment for 72 weeks. These observations support the hypothesis that repeated weekly teriparatide administration stimulates bone remodeling, replacing old bone with new bone and leading to a reduction in the active remodeling surface. A simulation model was developed based on the iterative remodeling cycle that occurs on residual old bone. An increase in bone formation and a subsequent decrease were observed in the preliminary simulation. For each fitted time point, the predicted value was compared to the absolute values of the bone formation and resorption markers and lumbar BMD. The simulation model strongly matched actual changes in bone turnover markers and BMD. This simulation model indicates increased bone formation marker levels in the early stage and a subsequent decrease. It is therefore concluded that remodeling-based bone formation persisted during the entire treatment period with once-weekly teriparatide.

Postnatal ex vivo rat model for longitudinal bone growth investigations

Background: Chondrocytes in the growth plate(GP) undergo increases in volume during different cascades of cell differentiation during longitudinal bone growth. The volume increase is reported to be the most significant variable in understanding the mechanism of long bone growth.Methods: Forty-five postnatal Sprague-Dawley rat pups, 7-15 days old were divided into nine age groups(P7-P15). Five pups were allocated to each group. The rats were sacrificed and tibia and metatarsal bones were harvested. Bone lengths were measured after 0, 24, 48, and 72 hours of ex vivo incubation. Histology of bones was carried out, and GP lengths and chondrocyte densities were determined.Results: There were significant differences in bone length among the age groups after 0 and 72 hours of incubation. Histological sectioning was possible in metatarsal bone from all age groups, and in tibia from 7-to 13-day-old rats. No significant differences in tibia and metatarsal GP lengths were seen among different age groups at 0 and 72 hours of incubation. Significant differences in chondrocyte densities along the epiphyseal GP of the bones between 0 and 72 hours of incubation were observed in most of the age groups.Conclusion: Ex vivo growth of tibia and metatarsal bones of rats aged 7-15 days old is possible, with percentage growth rates of 23.87 ± 0.80% and 40.38 ± 0.95%measured in tibia and metatarsal bone, respectively. Histological sectioning of bones was carried out without the need for decalcification in P7-P13 tibia and P7-P15 metatarsal bone. Increases in chondrocyte density along the GP influence overall bone elongation.

In vivo testing of a bone graft containing chitosan, calcium sulfate and osteoblasts in a paste form in a critical size defect model in rats

Bone loss associated with musculoskeletal trauma or metabolic diseases often require bone grafting. The supply of allograft and auto-graft bones is limited. Hence, development of synthetic bone grafting materials is an active area of research. Chitosan, extracted from chitin present in crawfish shells, was tested as a de-livery vehicle for osteoblasts in a 2-3 mm size defect model in rats. Twenty-seven male Lewis rats, divided into three groups with sacrifice intervals of 3, 6 &amp;amp;9 months were used. In the experimental samples, a critical size defect was filled with chitosan bone graft paste and fixed with a plate, while in the operated control group, a critical size defect was repaired only by a plate (no paste was applied). An unoperated control group was also included. Bone growth was evaluated histologically by examining undecal-cified and decalcified stained sections. The fe-murs were also examined non-destructively by micro-computed tomography (礐T). Defects filled with chitosan bone graft paste demon-strated superior healing across all time periods compared to unfilled defects as examined by histology and micro-computed tomography. Crawfish chitosan has successfully been used as a cell delivery system for osteoblasts for use as a synthetic bone graft material.

On a Constitutive Material Model to Capture Time Dependent Behavior of Cortical Bone

It is commonly known that cortical bone exhibits viscoelastic-viscoplastic behavior which affects the biomechanical response when an implant is subjected to an external load. In addition, long term effects such as creep, relaxation and remodeling affect the success of the implant over time. Constitutive material models are commonly derived from data obtained in in vitro experiments. However during function, remodeling of bone greatly affects the bone material over time. Hence it is essential to include long term in vivo effects in a constitutive model of bone. This paper proposes a constitutive material model for cortical bone incorporating viscoelasticity, viscoplasticity, creep and remodeling to predict stress-strain at various strain rates as well as the behavior of bone over time in vivo. The rheological model and its parameters explain the behavior of bone subjected to longitudinal loading. By a proper set of model parameters, for a specific cortical bone, the present model can be used for prediction of the behavior of this bone under specific loading conditions. In addition simulation with the proposed model demonstrates excellent agreement to in vitro and in vivo experimental results in the literature.

From Sméagol to Gollum: Mechanical Stress and Bone Remodelling

This imaginary transformation from Sméagol to Gollum is a dramatization of the illusive repercussions of mechanical stress affecting bone. This paper presents the main ideas of mechanical stress and bone remodelling from a novel’s perspective. The object of this study is to provide evidence for new ways to explore bone’s functional adaptation to mechanical stress made through the copious interpretation and integration of new and existing literature. It tackles the underlying biology of bone cells and how they detect and react to strain stimuli. The different types of mechanical demands in daily activities are sifted through and any misconceptions found fallible in literature are refined. A personal experience of a stress fracture is reviewed to parallel the implications that lead to the incident with the findings on the link between mechanical stress and bone remodelling. Some factors regarding age, gender and ethnicity and the interplay with mechanical stress influencing bone remodelling are considered. Brief overviews of three new medical novelties in bone healing are outlined, hoping that these interventions of proper medical techniques can be a change for the better: one from Gollum to Sméagol rather than vice versa.

Microstructure-based Finite Element Modelling and Characterisation of Bovine Trabecular Bone

The mechanical behaviour of trabecular bone is dependent on both the properties of individual trabeculae as well as their three-dimensional arrangement in space. In this study, nanoindentation was used to determine trabecular stiffness of bovine bone, both dehydrated and rehydrated. Values of 18.3 GPa and 14.3 GPa were obtained for dehydrated and rehydrated trabeculae respectively. These values were then used for finite element analysis where the mesh was generated directly from an X-ray microtomography dataset. The relationship between intrinsic tissue properties and apparent stiffness was explored. Moreover, the important role of collagen in bone micromechanics was demonstrated by complementing the study with Raman spectroscopy.

Computational Simulations of Bone Remodeling under Natural Mechanical Loading or Muscle Malfunction Using Evolutionary Structural Optimization Method

Live bone inherently responds to applied mechanical stimulus by altering its internal tissue composition and ultimately biomechanical properties, structure and function. The final formation may structurally appear inferior by design but complete by function. To understand the loading response, this paper numerically investigated structural remodeling of mature sheep femur using evolutionary structural optimization method (ESO). Femur images from Computed Tomography scanner were used to determine the elastic modulus variation and subsequently construct finite element model of the femur with stiffest elasticity measured. Major muscle forces on dominant phases of healthy sheep gait were imposed on the femur under static mode. ESO was applied to progressively alter the remodeling of numerically simulated femur from its initial to final design by iteratively removing elements with low strain energy density (SED). The computations were repeated with two different mesh sizes to test the convergence. The elements within the medullary canal had low SEDs and therefore were removed during the optimization. The SEDs in the remaining elements varied with angle around the circumference of the shaft. Those elements with low SED were inefficient in supporting the load and thus fundamentally explained how bone remodels itself with less stiff inferior tissue to meet load demand. This was in line with the Wolff’s law of transformation of bone. Tissue growth and remodeling process was found to shape the sheep femur to a mechanically optimized structure and this was initiated by SED in macro-scale according to traditional principle of Wolff’s law.

Anti-Interference Study on Radiographic Bone Age Estimation Based on Artificial Intelligence Model

In this paper, the interferences of X-ray image noise on a bone age model, Xception model, were studied. We conduct a comparative experiment test according to the output performance of the neural network model using both the original image training and noise-added (Gaussian noise plus salt-pepper noise) training, and analyze the anti-interference ability of the Xception model, hoping to improve it through noise enhancement training and generalize the application ability of the model. The results show that the model trained with noise-added (Gaussian noise plussalt-pepper noise) images can make predictions that are more robust and less affected by the image disturbances, such as image noise.

斑马鱼模型在中医药防治骨质疏松应用的研究进展

随着骨质疏松(osteoporosis,OP)动物模型的不断发展,斑马鱼逐渐成为中医药防治OP的常用动物模型之一。文章整理了近五年来以斑马鱼作为动物模型在OP防治方面的运用,系统综述了不同种类斑马鱼OP模型的建立以及通过斑马鱼对单体中药、中药复方以及中成药对OP防治的药理、毒理的研究进展。以期对OP发病机制以及抗OP药物筛选、研究的动物模型选择提供新的思路与方法。

诱导膜技术在临界尺寸骨缺损修复中的应用:优势与未来发展

背景:诱导膜技术(Masquelet技术)是一种两阶段手术重建大段骨缺损的新技术,在临床中应用越来越广泛。然而,该技术修复骨缺损的机制尚不十分明确。目的:就诱导膜技术的产生背景、修复机制和优势、诱导膜的特征、膜-植骨通讯、动物模型的选择、骨水泥的种类、形貌、所载抗生素对诱导膜的影响、固定方式的选择和骨组织工程材料方面进行综述,以期为未来临界尺寸骨缺损的治疗和诱导膜技术的改进提供新思路。方法:检索PubMed、Web of Science数据库和中国知网(CNKI)中1986-2024年出版的文献,共检索到890篇参考文献。按与诱导膜技术基础研究相关的入选标准进行人工筛选和分析,排除与主题相关性差和重复的文献,纳入研究的文献包括实验类研究原著、综述、荟萃分析等,最终纳入72篇文献进行归纳和分析。结果与结论:①诱导膜技术修复骨缺损的机制尚不明确,但膜和植骨两者缺一不可;②诱导膜是一种富含多种骨形成相关细胞、生长因子和血管的分层较明显组织,其血管化和生长因子的分泌随时间而动态变化;③对于动物模型选择,从解剖结构、负重模式和骨重塑的相似度来讲,羊更为接近;从饲养成本和难度、造模周期来讲,大鼠更合适;④聚甲基丙烯酸甲酯(PMMA)骨水泥不是唯一可以用做诱导生物膜的材料,可能有更加合适的材料可以诱导出更高质量的生物膜;骨水泥负载抗生素的剂量(主要是万古霉素)为每40 g的聚甲基丙烯酸甲酯负载1-4 g抗生素;⑤对于动物(特别是大鼠)固定方式而言,钢板使用更为广泛,固定方式更加可靠,可重复性更高;⑥未来可能会有新的材料替代自体骨促进Masquelet技术的骨修复能力。

成纤维细胞生长因子受体1 抑制剂对胶原诱导关节炎模型大鼠骨破坏的影响

背景:课题组前期的研究表明靶向成纤维细胞生长因子受体1(fibroblast growth factor receptor 1,FGFR1)可能是治疗类风湿性关节炎的有效靶点。目的:探讨FGFR1抑制剂(PD173074)对胶原诱导关节炎模型大鼠骨破坏的影响。方法:将25只雌性SD大鼠随机分为5组,正常对照组、模型组、甲氨蝶呤组、PD173074低剂量组、PD173074高剂量组。除正常对照组外,其余各组大鼠建立Ⅱ型胶原诱导关节炎模型。造模成功后正常组及模型组大鼠腹腔注射无菌PBS,甲氨蝶呤组药物注射剂量为1.04 mg/kg,PD173074低剂量组和高剂量组药物注射剂量分别为5,20 mg/kg,1次/周。给药4周后取材,观察大鼠临床症状以及关节肿胀情况,踝关节Micro-CT三维重建及分析,观察踝关节病理变化,检测关节周围血管生成情况及核因子κB受体活化因子配体的表达,检测关节滑膜中p-FGFR1、血管内皮生长因子A、抗酒石酸酸性磷酸酶的表达,观察肝、脾、肾病理变化并计算肝、脾、肾指数。结果与结论:①PD173074能够减轻模型大鼠踝关节临床症状及关节肿胀,延缓骨质丢失,改善骨结构,减轻关节滑膜侵袭以及软骨骨侵蚀,降低关节周围破骨细胞数量,抑制关节滑膜组织中的血管生成,降低核因子κB受体活化因子配体的表达,抑制FGFR1磷酸化蛋白、抗酒石酸酸性磷酸酶和血管内皮生长因子A的蛋白表达。②大鼠肝、脾、肾病理观察表明经过PD173074治疗后无明显的毒副作用。③研究证明了FGFR1抑制剂能够延缓Ⅱ型胶原诱导关节炎模型大鼠关节炎症及骨破坏的进展,并抑制血管的生成。初步验证了PD173074在Ⅱ型胶原诱导关节炎模型中的治疗作用,其可能是通过抑制FGFR1磷酸化发挥作用,为寻找类风湿性关节炎新的治疗靶点提供了方向。

Design of Implant Prosthesis for Bone Injury Repair Considering Stress Shielding Effect

The failure of bone injury repair surgery is mostly due to the stress shielding effect caused by the difference of elastic modulus between the implant prosthesis and human bone,result-ing in a great damage to patients.To solve this problem,in this study,the influencing factors of the elastic modulus of implant prosthesis were investigated,the relationship between the elastic modulus of the implanted prosthesis and the influencing factors was analyzed,and then a design method of the implant prosthesis to reduce the stress shielding effect by adjusting the unit module to control the elastic modulus was established.This method was used for the biomechanical simula-tion to simulate the displacement and stress distribution between the implant prosthesis and the surrounding bone tissue,and then the reliability of the method was verified.The implant prosthe-sis with an elastic modulus consistent with that of the experimental dog bone was made by this method,and used for the animal experiments.The effects of implant prosthesis with different mod-ulus on the growth of surrounding bone tissue were observed,and at the same time,the reliability of the implant design method and the results of biomechanical simulation were verified.It is con-firmed that this method can effectively reduce the stress concentration of implant prosthesis by more than 15.4%and increase the growth of bone tissue by more than 21%.