Beneficial effects of moderate,early loading and adverse effects of delayed or excessive loading on bone healing

Fracture healing involves the differentiation and proliferation of cells in the callus and the synthesis and degradation of connective, cartilage and bone tissue. These processes are initiated and tightly regulated by growth factors and by the mechanical environment in the callus. In this work we incorporated the effects of mechanical stimulation on cell differentiation and ossification into a previously developed temporal-spatial model of growth factor mediated fracture healing. In particular, the stimulatory and inhibitory effects of dilatational and deviatoric strains were modeled. This predictive model was then calibrated and validated using well-defined in vivo experiments from the literature. As in the experiments, the results of the model demonstrated the beneficial and adverse effects of moderate and excessive loading, respectively, as well as the negative effects of delaying mechanical stimulation of rigidly fixed calluses. In addition, the model examined loading conditions and time points beyond those used in the experiments, providing a more complete and mechanistic characterization of the effects of loading in the biological tissue response associated with fracture healing.     

A fatigue microcrack alters fluid velocities in a computational model of interstitial fluid flow in cortical bone

Targeted remodeling is activated by fatigue microcracks and plays an important role in maintaining bone integrity. It is widely believed that fluid flow-induced shear stress plays a major role in modulating the mechanotransduction process. Therefore, it is likely that fluid flow-induced shear stress plays a major role in the initiation of the repair of fatigue damage. Since no in vivo measurements of fluid flow within bone exist, computational and mathematical models must be employed to investigate the fluid flow field and the shear stress occurring within cortical bone. We developed a computational fluid dynamic model of cortical bone to examine the effect of a fatigue microcrack on the fluid flow field. Our results indicate that there are alterations in the fluid flow field as far as 150 microm away from the crack, and that at distances farther than this, the fluid flow field is similar to the fluid flow field of intact bone. Through the crack and immediately above and below it, the fluid velocity is higher, while at the lateral edges it is lower than that calculated for the intact model, with a maximum change of 29%. Our results suggest that the presence of a fatigue microcrack can alter the shear stress in regions near the crack. These alterations in shear stress have the potential to significantly alter mechanotransduction and may play a role in the initiation of the repair of fatigue microcracks.     

Poroelastic analysis of interstitial fluid flow in a single lamellar trabecula subjected to cyclic loading

Trabecula, an anatomical unit of the cancellous bone, is a porous material that consists of a lamellar bone matrix and interstitial fluid in a lacuno-canalicular porosity. The flow of interstitial fluid caused by deformation of the bone matrix is believed to initiate a mechanical response in osteocytes for bone remodeling. In order to clarify the effect of the lamellar structure of the bone matrix—i.e., variations in material properties—on the fluid flow stimuli to osteocytes embedded in trabeculae, we investigated the mechanical behavior of an individual trabecula subjected to cyclic loading based on poroelasticity. We focused on variations in the trabecular permeability and developed an analytical solution containing both transient and steady-state responses for interstitial fluid pressure in a single trabecular model represented by a multilayered two-dimensional poroelastic slab. Based on the obtained solution, we calculated the pressure and seepage velocity of the interstitial fluid in lacuno-canalicular porosity, within the single trabecula, under various permeability distributions. Poroelastic analysis showed that a heterogeneous distribution of permeability produces remarkable variations in the fluid pressure and seepage velocity in the cross section of the individual trabecula, and suggests that fluid flow stimuli to osteocytes are mostly governed by the value of permeability in the neighborhood of the trabecular surfaces if there is no difference in the average permeability in a single trabecula.     

Inter-species investigation of the mechano-regulation of bone healing: comparison of secondary bone healing in sheep and rat

Inter-species differences in regeneration exist in various levels. One aspect is the dynamics of bone regeneration and healing, e.g. small animals show a faster healing response when compared to large animals. Mechanical as well as biological factors are known to play a key role in the process. However, it remains so far unknown whether different animals follow at all comparable mechano-biological rules during tissue regeneration, and in particular during bone healing. In this study, we investigated whether differences observed in vivo in the dynamics of bone healing between rat and sheep are only due to differences in the animal size or whether these animals have a different mechano-biological response during the healing process. Histological sections from in vivo experiments were compared to in silico predictions of a mechano-biological computer model for the simulation of bone healing. Investigations showed that the healing processes in both animal models occur under significantly different levels of mechanical stimuli within the callus region, which could explain histological observations of early intramembranous ossification at the endosteal side. A species-specific adaptation of a mechano-biological model allowed a qualitative match of model predictions with histological observations. Specifically, when keeping cell activity processes at the same rate, the amount of tissue straining defining favorable mechanical conditions for the formation of bone had to be increased in the large animal model, with respect to the small animal, to achieve a qualitative agreement of model predictions with histological data. These findings illustrate that geometrical (size) differences alone cannot explain the distinctions seen in the histological appearance of secondary bone healing in sheep and rat. It can be stated that significant differences in the mechano-biological regulation of the healing process exist between these species. Future investigations should aim towards understanding whether these differences are due to differences in cell behavior, material properties of the newly formed tissues within the callus and/or differences in response to the mechanical environment.     

Development and design of a novel loading device for the investigation of bone adaptation around immediately loaded dental implants using the reindeer antler as implant bed

The assessment of the behavior of immediately loaded dental implants using biomechanical methods is of particular importance. The primary goal of this investigation is to optimize the function of the implants to serve for immediate loading. Animal experiments on reindeer antlers as a novel animal model will serve for investigation of the bone remodeling processes in the implant bed. The main interest is directed towards the time and loading-dependant behavior of the antler tissue around the implants. The aim and scope of this work was to design an autonomous loading device that has the ability to load an inserted implant in the antler with predefined occlusal forces for predetermined time protocols. The mechanical part of the device can be attached to the antler and is capable of cyclically loading the implant with forces of up to 100 N. For the calibration and testing of the loading device a biomechanical measuring system has been used. The calibration curve shows a logarithmic relationship between force and motor current and is used to control the force on the implant. A first test on a cast reindeer antler was performed successfully.     

On shear properties of trabecular bone under torsional loading: effects of bone marrow and strain rate

To further improve our understanding of trabecular bone mechanical behavior in torsion, our objective was to determine the effects of strain rate, apparent density, and presence of bone marrow on trabecular bone shear material properties. Torsion tests of cylindrical trabecular bone specimens from sheep lumbar vertebrae with and without bone marrow were conducted. The bones with marrow were divided into two groups and tested at shear strain rates of 0.002 and 0.05s(-1) measured at the specimen perimeter. The bones without marrow were divided into three groups and tested at shear strain rates of 0.002, 0.015, and 0.05s(-1). Comparing the results of bones with and without marrow tested at low (0.002s(-1)) and high (0.05s(-1)) strain rates, presence of bone marrow did not have any significant effect on trabecular bone shear modulus and strength. In specimens without marrow, power relationships were used to define shear strength and modulus as dependent variables in terms of strain rate and apparent density as independent variables. The shear strength was proportional to the apparent density raised to the 1.02 power and to the strain rate raised to the 0.13 power. The shear modulus was proportional to the apparent density raised to the 1.08 power and to the strain rate raised to the 0.07 power. This study provides further insight into the mechanism of bone failure in trauma as well as failure at the interface between bone and implants as it relates to prediction of trabecular bone shear properties.     

Mechanical response of bone under short-term loading of a dental implant with an internal layer simulating the nonlinear behaviour of the periodontal ligament

We consider a non-standard design for a fixed dental implant, incorporating a soft layer which simulates the presence of the periodontal ligament (PDL). Instead of being aimed at causing an a priori defined stress/strain field within the surrounding bone, upon loading, such a design simply tries to better reproduce the natural tooth-PDL configuration. To do this, the mechanical properties of the internal layer match those of the PDL, determined experimentally to be strongly nonlinear. Three-dimensional finite element analyses show that the presence of such a layer produces (i) a prosthesis mobility very similar to that of a healthy tooth, for several loading conditions, and (ii) a stress/strain distribution substantially different from that arising, upon loading, around a conventional implant. The lack of knowledge of the real mechanical fields existing, under loading, in the bone around a healthy tooth makes it very difficult to state that the stress distribution produced by the modified implant is "better" than that produced by the standard one. Nevertheless, the comparison of the results obtained here, with those of previous refined analyses of the tooth-PDL-bone system, indicates that the modified implant tends to produce a stress distribution in the bone, upon loading, closer to "natural" than that given by the standard one, within the limits imposed by the presence of threads coupling the implant with the bone.     

A three-dimensional finite element study on the biomechanical behavior of an FGBM dental implant in surrounding bone

Dental implants made of functionally graded biomaterials (FGBM) have been receiving increasing attention due to their unique advantage of being able to simultaneously satisfy biocompatibility, strength, corrosion resistance, etc., which a single composition with a uniform structure cannot satisfy. This paper investigates the biomechanical behavior of a threaded FGBM dental implant/surrounding bone system under static and harmonic occlusal forces by using a three-dimensional finite element method. The implant is a mixture of a bioceramic and a biometal with a smooth gradient in both the material composition and properties in the longitudinal direction. The interaction of the implant and the supporting bone tissues is considered. Three contact conditions at the implant-bone interface are used to model different osseointegration stages. A comprehensive parametric study is conducted to highlight the influence of the material properties, the volume fraction index, the occlusal force orientation, and the osseointegration quality on the maximum von-Mises stress, deformation distribution, natural frequencies, and harmonic response.     

On the effects of cyclic transversal forces on osseointegrated dental implants: experimental and finite element shakedown analyses

This paper is concerned with the mechanical strength of fixed osseointegrated dental implants subjected to cyclic external loads, applied mainly in a direction orthogonal to their axis. Such a loading condition, seen as a basic design action for the implant, has been given little attention so far. Experimental results and numerical simulations, performed on two- and three-dimensional Finite Element models, are discussed. The shakedown theory is used to show that a common implant design (threaded fixture-abutment-connection screw) is susceptible of low-cycle fatigue failure under loading conditions well within the working range, even if the same design is able to withstand loading of the same type, but applied monotonically, much in excess of the working values. The shakedown analyses give an indication of several possible failure modalities: the low-cycle fatigue either of the implant or of the connection screw, or the loosening of the connection screw itself. Experimental and numerical results are in good qualitative agreement, and both suggest that the issue of transversal cyclic loading on fixed dental implants should be carefully reconsidered in the design phase.     

Influence of fracture gap size on the pattern of long bone healing: a computational study

Following fractures, bones restore their original structural integrity through a complex process in which several cellular events are involved. Among other factors, this process is highly influenced by the mechanical environment of the fracture site. In this study, we present a mathematical model to simulate the effect of mechanical stimuli on most of the cellular processes that occur during fracture healing, namely proliferation, migration and differentiation. On the basis of these three processes, the model then simulates the evolution of geometry, distributions of cell types and elastic properties inside a healing fracture. The three processes were implemented in a Finite Element code as a combination of three coupled analysis stages: a biphasic, a diffusion and a thermoelastic step. We tested the mechano-biological regulatory model thus created by simulating the healing patterns of fractures with different gap sizes and different mechanical stimuli. The callus geometry, tissue differentiation patterns and fracture stiffness predicted by the model were similar to experimental observations for every analysed situation.     

以牙种植体为中心的骨壁测厚方法及其评价

目的:研究一种以牙种植体为中心来测量其周围骨壁厚度的方法,并对由此方法制作完成的改良游标卡尺进行精确性评价.方法:使用Solid Edge软件设计制作一种以ITI种植体为中心来测量其周围骨壁厚度的改良游标卡尺;将种植体植入透明复合树脂块中;使用改良游标卡尺测量种植体周围树脂壁厚度,然后将树脂块连同种植体沿其长轴纵切开;拍照并用Digimizer软件对树脂块纵剖面实际壁厚进行测量;最后将两组数据通过SPSS软件进行配对t检验.结果:改良游标卡尺组测量结果为7.97-8.09mm,树脂块纵剖面组测量结果为7.98-8.12mm,标准差为0.03,t值为1.09,P值为0.28,两种测量方法差异无统计学意义.结论:以种植体为中心的改良游标卡尺满足了设计要求,精确度高且可重复性强,可用于评估种植体唇颊侧骨壁的骨吸收情况.     

Effects of mechanical loading patterns,bone graft,and proximity to periosteum on bone defect healing

The goal of this study is to elucidate whether mechanobiological factors, including mechanical loading patterns, presence of bone graft, and proximity to the periosteum, correlate to de novo tissue generation and healing in critical sized long bone defects, which are enveloped by periosteum in situ and are bridged at 16 weeks, in sheep femora. Quantitative histomorphometric measures of defect cross sections show that, along the axis least able to resist bending loads (minor centroidal axis, CA), bone laid down in the first two weeks after surgery exhibits more mineralization albeit less total area compared to bone along the axis most able to resist bending loads (major CA). Similarly, areas of the cross section along the minor CA show a higher degree of perfusion albeit less total area of perfusion compared to bone along the major CA. Furthermore, proximity to the periosteal niche, in conjunction with the presence of bone graft and predominant loading patterns, relates significantly to the radial distribution of early bone apposition and perfusion of bone at 16 weeks after surgery (linear regression with R²>0.80). In the absence of graft, early bone density is relatively evenly distributed in the defect zone, as is the intensity of perfused tissue. As measured by a steeper average slope in intensity of fluorochrome (new bone) distribution between the periosteum and the IM nail, the presence of bone graft retards initial bone formation in the defect zone and is associated with less evenly distributed tissue perfusion (steeper slope) persisting 16 weeks after surgery. Finally, although the mean area of bone resorption is not significantly different within or between groups defined by the presence of graft and/or mechanical loading patterns in the defect zone, the mean area of infilling resorption spaces is significantly higher in areas of the defect zone least able to resist bending (minor CA) but is not significantly related to the presence of bone graft. To our knowledge, the use of the major and minor centroidal axes to relate prevailing mechanical loading patterns to area and density of early bone generation in bone defects has not been reported prior to this study and may provide a new means to assess structure–function relationships in de novo bone generation and healing of bone defects.     

Experimental and computational analysis of micromotions of an uncemented femoral knee implant using elastic and plastic bone material models

It is essential to calculate micromotions at the bone-implant interface of an uncemented femoral total knee replacement (TKR) using a reliable computational model. In the current study, experimental measurements of micromotions were compared with predicted micromotions by Finite Element Analysis (FEA) using two bone material models: linear elastic and post-yield material behavior, while an actual range of interference fit was simulated. The primary aim was to investigate whether a plasticity model is essential in order to calculate realistic micromotions. Additionally, experimental bone damage at the interface was compared with the FEA simulated range.TKR surgical cuts were applied to five cadaveric femora and micro- and clinical CT- scans of these un-implanted specimens were made to extract geometrical and material properties, respectively. Micromotions at the interface were measured using digital image correlation. Cadaver-specific FEA models were created based on the experimental set-up. The average experimental micromotion of all specimens was 53.1 ± 42.3 µm (mean ± standard deviation (SD)), which was significantly higher than the micromotions predicted by both models, using either the plastic or elastic material model (26.5 ± 23.9 µm and 10.1 ± 10.1 µm, respectively; p-value < 0.001 for both material models). The difference between the two material models was also significant (p-value < 0.001). The predicted damage had a magnitude and distribution which was comparable to the experimental bone damage. We conclude that, although the plastic model could not fully predict the micro motions, it is more suitable for pre-clinical assessment of a press-fit TKR implant than using an elastic bone model.     

Nalpha-trinitrophenyl glucagon: an inhibitor of glucagon-stimulated cyclic AMP production and its effects on glycogenolysis.

Nalpha-Trinitrophenyl glucagon was prepared by reaction with trinitrobenzene sulfonic acid and purified by ion-exchange chromatography. This derivative has essentially no ability to activate adenylate cyclase from rat liver nor to increase the levels of cyclic AMP in isolated hepatocytes nor to stimulate protein kinase activity. This derivative also can act as a glucagon antagonist with regard to cyclic AMP production and can decrease the degree of stimulation of adenylate cyclase caused by glucagon, as well as lowering the glucagon-stimulated elevation of cyclic AMP levels in intact hepatocytes. Nevertheless, this derivative is capable of activating glycogenolysis in isolated hepatocytes and in augmenting the effect of glucagon on glycogenolysis. This metabolic effect of the glucagon derivative thus appears to occur independent of changes in cyclic AMP levels. These results suggest that glucagon can also activate glycogenolysis by a cyclic AM-independent process.     

Effect of cyclic loading on the nanoscale deformation of hydroxyapatite and collagen fibrils in bovine bone

Cyclic compressive loading tests were carried out on bovine femoral bones at body temperature $(37\,^{\circ }\hbox {C})$ , with varying mean stresses ( $-55$ to $-80$  MPa) and loading frequencies (0.5–5 Hz). At various times, the cyclic loading was interrupted to carry out high-energy X-ray scattering measurements of the internal strains developing in the hydroxyapatite (HAP) platelets and the collagen fibrils. The residual strains upon unloading were always tensile in the HAP and compressive in the fibrils, and each increases in magnitude with loading cycles, which can be explained from damage at the HAP–collagen interface and accumulation of plastic deformation within the collagen phase. The samples tested at a higher mean stress and stress amplitude, and at lower loading frequencies exhibit greater plastic deformation and damage accumulation, which is attributed to greater contribution of creep. Synchrotron microcomputed tomography of some of the specimens showed that cracks are produced during cyclic loading and that they mostly occur concentric with Haversian canals.     

Electrokinetic effects on luminal and transmural fluid flow in capillaries

The influence on fluid flow of the fixed charge on the surface of capillaries is calculated using the linearised Poisson-Boltzmann equations. The results depend strongly upon the ratio of the capillary radius to the Debye length. At physiological ionic strength, the Debye length is less than 1 nm and electrostatic effects are negligible. In particular, they can not explain the Copley-Scott Blair phenomenon in artificial capillaries. Electrostatic effects can be significant in smaller channels and it is calculated that in intercellular clefts in the capillary endothelium the apparent viscosity of the fluid may increase more than 50%. These effects can also be important in the flow in the narrow gap between a red cell and the blood capillary wall. Using the Fitzgerald-Lighthill model of this flow and parameters typical of the human microcirculation, the theory predicts that the apparent viscosity in the gap will be increased by about 5%.